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Impact of body composition on very-low-density lipoprotein-triglycerides kinetics - PubMed This site needs JavaScript to work properly. Please enable it to take advantage of the complete set of features! Clipboard, Search History, and several other advanced features are temporarily unavailable. Skip to main page content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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Log in Show account info Close Account Logged in as: username Dashboard Publications Account settings Log out Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation Search: Search Advanced Clipboard User Guide Save Email Send to Clipboard My Bibliography Collections Citation manager Display options Display options Format Abstract PubMed PMID Save citation to file Format: Summary (text) PubMed PMID Abstract (text) CSV Create file Cancel Email citation Subject: 1 selected item: 18984851 - PubMed To: From: Format: Summary Summary (text) Abstract Abstract (text) MeSH and other data Send email Cancel Add to Collections Create a new collection Add to an existing collection Name your collection: Name must be less than 100 characters Choose a collection: Unable to load your collection due to an error Please try again Add Cancel Add to My Bibliography My Bibliography Unable to load your delegates due to an error Please try again Add Cancel Your saved search Name of saved search: Search terms: Test search terms Would you like email updates of new search results? Saved Search Alert Radio Buttons Yes No Email: ( change ) Frequency: Monthly Weekly Daily Which day? The first Sunday The first Monday The first Tuesday The first Wednesday The first Thursday The first Friday The first Saturday The first day The first weekday Which day? Sunday Monday Tuesday Wednesday Thursday Friday Saturday Report format: Summary Summary (text) Abstract Abstract (text) PubMed Send at most: 1 item 5 items 10 items 20 items 50 items 100 items 200 items Send even when there aren't any new results Optional text in email: Save Cancel Create a file for external citation management software Create file Cancel Your RSS Feed Name of RSS Feed: Number of items displayed: 5 10 15 20 50 100 Create RSS Cancel RSS Link Copy Full text links Atypon Full text links Actions Cite Collections Add to Collections Create a new collection Add to an existing collection Name your collection: Name must be less than 100 characters Choose a collection: Unable to load your collection due to an error Please try again Add Cancel Display options Display options Format Abstract PubMed PMID Share Permalink Copy Page navigation Title & authors Abstract Similar articles Cited by Publication types MeSH terms Substances Related information LinkOut - more resources Title & authors Abstract Similar articles Cited by Publication types MeSH terms Substances Related information LinkOut - more resources Am J Physiol Endocrinol Metab Actions Search in PubMed Search in NLM Catalog Add to Search . 2009 Jan;296(1):E165-73. doi: 10.1152/ajpendo.90675.2008. Epub 2008 Nov 4. Impact of body composition on very-low-density lipoprotein-triglycerides kinetics Lars C Gormsen 1 , Birgitte Nellemann , Lars P Sørensen , Michael D Jensen , Jens S Christiansen , Søren Nielsen Affiliations Expand Affiliation 1 Dept. of Nuclear Medicine, Aarhus Univ. Hospital, DK-8000 Aarhus C, Denmark. [email protected] PMID: 18984851 DOI: 10.1152/ajpendo.90675.2008 Free article Item in Clipboard Impact of body composition on very-low-density lipoprotein-triglycerides kinetics Lars C Gormsen et al. Am J Physiol Endocrinol Metab . 2009 Jan . Free article Show details Display options Display options Format Abstract PubMed PMID Am J Physiol Endocrinol Metab Actions Search in PubMed Search in NLM Catalog Add to Search . 2009 Jan;296(1):E165-73. doi: 10.1152/ajpendo.90675.2008. Epub 2008 Nov 4. Authors Lars C Gormsen 1 , Birgitte Nellemann , Lars P Sørensen , Michael D Jensen , Jens S Christiansen , Søren Nielsen Affiliation 1 Dept. of Nuclear Medicine, Aarhus Univ. Hospital, DK-8000 Aarhus C, Denmark. [email protected] PMID: 18984851 DOI: 10.1152/ajpendo.90675.2008 Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID Abstract Upper body obese (UBO) subjects have greater cardiovascular disease risk than lower body obese (LBO) or lean subjects. Obesity is also associated with hypertriglyceridemia that may involve greater production and impaired removal of very-low-density lipoprotein (VLDL)-triglycerides (TG). In these studies, we assessed the impact of body composition on basal VLDL-TG production, VLDL-TG oxidation, and VLDL-TG storage. VLDL-TG kinetics were assessed in 10 UBO, 10 LBO, and 10 lean women using a bolus injection of [1-(14)C]VLDL-TG. VLDL-TG oxidation was measured by (14)CO(2) production (hyamine trapping) and VLDL-TG adipose tissue storage by fat biopsies. Insulin sensititvity was assessed by the hyperinsulinemic-euglycemic clamp technique and body composition by dual X-ray absorptiometry in combination with computed tomography. Hepatic VLDL-TG production was significantly greater in UBO than in lean women [(mumol/min) UBO: 64.8 (SD 40.0) vs. LBO: 42.5 (SD 25.6) vs. lean: 31.8 (SD 13.3), P = 0.04], whereas VLDL-TG oxidation was similar in the three groups and averaged 20% of resting energy expenditure [(mumol/min) UBO: 38.3 (SD 26.5) vs. LBO: 23.5 (SD 13.5) vs. lean: 21.1 (SD 9.7), P = 0.09]. In UBO women, more VLDL-TG was deposited in upper body subcutaneous fat [VLDL-TG redeposition in abdominal adipose tissue (mumol/min): UBO: 5.0 (SD 2.9) vs. LBO: 4.0 (SD 3.2) vs. lean: 1.3 (SD 1.0), ANOVA P = 0.01]; in LBO women, more VLDL-TG was deposited in femoral fat [VLDL-TG redeposition in femoral adipose tissue (mumol/min): UBO: 5.1 (SD 3.1) vs. LBO: 5.8 (SD 4.3) vs. lean: 2.3 (SD 1.5), ANOVA P = 0.04]. Only a small proportion of VLDL-TG (8-16%) was partitioned into redeposition in either group. We found that elevated VLDL-TG production without concomitant increased clearance via oxidation and adipose tissue redeposition contributes to hypertriglyceridemia in UBO women. PubMed Disclaimer Similar articles Impaired insulin-mediated antilipolysis and lactate release in adipose tissue of upper-body obese women. Nellemann B, Gormsen LC, Sørensen LP, Christiansen JS, Nielsen S. Nellemann B, et al. Obesity (Silver Spring). 2012 Jan;20(1):57-64. doi: 10.1038/oby.2011.290. Epub 2011 Sep 29. Obesity (Silver Spring). 2012. PMID: 21959346 Body composition determines direct FFA storage pattern in overweight women. Søndergaard E, Gormsen LC, Nellemann B, Jensen MD, Nielsen S. Søndergaard E, et al. Am J Physiol Endocrinol Metab. 2012 Jun 15;302(12):E1599-604. doi: 10.1152/ajpendo.00015.2012. Epub 2012 Apr 17. Am J Physiol Endocrinol Metab. 2012. PMID: 22510710 VLDL-triglyceride kinetics during hyperglycemia-hyperinsulinemia: effects of sex and obesity. Mittendorfer B, Patterson BW, Klein S, Sidossis LS. Mittendorfer B, et al. Am J Physiol Endocrinol Metab. 2003 Apr;284(4):E708-15. doi: 10.1152/ajpendo.00411.2002. Epub 2002 Dec 10. Am J Physiol Endocrinol Metab. 2003. PMID: 12475756 Determinants of VLDL-triglycerides production. Nielsen S, Karpe F. Nielsen S, et al. Curr Opin Lipidol. 2012 Aug;23(4):321-6. doi: 10.1097/MOL.0b013e3283544956. Curr Opin Lipidol. 2012. PMID: 22617755 Review. Removal of triacylglycerols from chylomicrons and VLDL by capillary beds: the basis of lipoprotein remnant formation. Karpe F, Bickerton AS, Hodson L, Fielding BA, Tan GD, Frayn KN. Karpe F, et al. Biochem Soc Trans. 2007 Jun;35(Pt 3):472-6. doi: 10.1042/BST0350472. Biochem Soc Trans. 2007. PMID: 17511631 Review. See all similar articles Cited by TG/HDL Ratio Is an Independent Predictor for Estimating Resting Energy Expenditure in Adults with Normal Weight, Overweight, and Obesity. Widmer A, Mercante MG, Silver HJ. Widmer A, et al. Nutrients. 2022 Dec 1;14(23):5106. doi: 10.3390/nu14235106. Nutrients. 2022. PMID: 36501139 Free PMC article. Emerging Evidence of Pathological Roles of Very-Low-Density Lipoprotein (VLDL). Huang JK, Lee HC. Huang JK, et al. Int J Mol Sci. 2022 Apr 13;23(8):4300. doi: 10.3390/ijms23084300. Int J Mol Sci. 2022. PMID: 35457118 Free PMC article. Review. Adipocyte Proteins and Storage of Endogenous Fatty Acids in Visceral and Subcutaneous Adipose Tissue in Severe Obesity. Lytle KA, Bush NC, Triay JM, Kellogg TA, Kendrick ML, Swain JM, Gathaiya NW, Hames KC, Jensen MD. Lytle KA, et al. Obesity (Silver Spring). 2021 Jun;29(6):1014-1021. doi: 10.1002/oby.23149. Epub 2021 Apr 24. Obesity (Silver Spring). 2021. PMID: 33893721 Free PMC article. Clinical Trial. Metabolic communication during exercise. Murphy RM, Watt MJ, Febbraio MA. Murphy RM, et al. Nat Metab. 2020 Sep;2(9):805-816. doi: 10.1038/s42255-020-0258-x. Epub 2020 Aug 3. Nat Metab. 2020. PMID: 32747791 Review. Visceral fat does not contribute to metabolic disease in lipodystrophy. Malandrino N, Reynolds JC, Brychta RJ, Chen KY, Auh S, Gharib AM, Startzell M, Cochran EK, Brown RJ. Malandrino N, et al. Obes Sci Pract. 2019 Jan 24;5(1):75-82. doi: 10.1002/osp4.319. eCollection 2019 Feb. Obes Sci Pract. 2019. PMID: 30847226 Free PMC article. See all "Cited by" articles Publication types Research Support, Non-U.S. Gov't Actions Search in PubMed Search in MeSH Add to Search MeSH terms Absorptiometry, Photon Actions Search in PubMed Search in MeSH Add to Search Adipose Tissue / metabolism* Actions Search in PubMed Search in MeSH Add to Search Adult Actions Search in PubMed Search in MeSH Add to Search Blood Glucose / metabolism Actions Search in PubMed Search in MeSH Add to Search Body Composition / physiology* Actions Search in PubMed Search in MeSH Add to Search Calorimetry, Indirect Actions Search in PubMed Search in MeSH Add to Search Female Actions Search in PubMed Search in MeSH Add to Search Humans Actions Search in PubMed Search in MeSH Add to Search Insulin / blood Actions Search in PubMed Search in MeSH Add to Search Insulin / metabolism Actions Search in PubMed Search in MeSH Add to Search Kinetics Actions Search in PubMed Search in MeSH Add to Search Lipoproteins, VLDL / metabolism* Actions Search in PubMed Search in MeSH Add to Search Middle Aged Actions Search in PubMed Search in MeSH Add to Search Obesity / metabolism* Actions Search in PubMed Search in MeSH Add to Search Triglycerides / metabolism* Actions Search in PubMed Search in MeSH Add to Search Young Adult Actions Search in PubMed Search in MeSH Add to Search Substances Blood Glucose Actions Search in PubMed Search in MeSH Add to Search Insulin Actions Search in PubMed Search in MeSH Add to Search Lipoproteins, VLDL Actions Search in PubMed Search in MeSH Add to Search Triglycerides Actions Search in PubMed Search in MeSH Add to Search very low density lipoprotein triglyceride Actions Search in PubMed Search in MeSH Add to Search Related information MedGen PubChem Compound PubChem Compound (MeSH Keyword) PubChem Substance LinkOut - more resources Full Text Sources Atypon Medical MedlinePlus Health Information Miscellaneous NCI CPTAC Assay Portal Full text links [x] Atypon [x] Cite Copy Download .nbib .nbib Format: AMA APA MLA NLM Send To Clipboard Email Save My Bibliography Collections Citation Manager [x] NCBI Literature Resources MeSH PMC Bookshelf Disclaimer The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited. Follow NCBI Twitter Facebook LinkedIn GitHub Connect with NLM Twitter SM-Facebook SM-Youtube National Library of Medicine 8600 Rockville Pike Bethesda, MD 20894 Web Policies FOIA HHS Vulnerability Disclosure Help Accessibility Careers NLM NIH HHS USA.gov
Bilirubin; a diagnostic marker for appendicitis - PubMed This site needs JavaScript to work properly. Please enable it to take advantage of the complete set of features! Clipboard, Search History, and several other advanced features are temporarily unavailable. Skip to main page content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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Log in Show account info Close Account Logged in as: username Dashboard Publications Account settings Log out Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation Search: Search Advanced Clipboard User Guide Save Email Send to Clipboard My Bibliography Collections Citation manager Display options Display options Format Abstract PubMed PMID Save citation to file Format: Summary (text) PubMed PMID Abstract (text) CSV Create file Cancel Email citation Subject: 1 selected item: 24080115 - PubMed To: From: Format: Summary Summary (text) Abstract Abstract (text) MeSH and other data Send email Cancel Add to Collections Create a new collection Add to an existing collection Name your collection: Name must be less than 100 characters Choose a collection: Unable to load your collection due to an error Please try again Add Cancel Add to My Bibliography My Bibliography Unable to load your delegates due to an error Please try again Add Cancel Your saved search Name of saved search: Search terms: Test search terms Would you like email updates of new search results? Saved Search Alert Radio Buttons Yes No Email: ( change ) Frequency: Monthly Weekly Daily Which day? The first Sunday The first Monday The first Tuesday The first Wednesday The first Thursday The first Friday The first Saturday The first day The first weekday Which day? Sunday Monday Tuesday Wednesday Thursday Friday Saturday Report format: Summary Summary (text) Abstract Abstract (text) PubMed Send at most: 1 item 5 items 10 items 20 items 50 items 100 items 200 items Send even when there aren't any new results Optional text in email: Save Cancel Create a file for external citation management software Create file Cancel Your RSS Feed Name of RSS Feed: Number of items displayed: 5 10 15 20 50 100 Create RSS Cancel RSS Link Copy Full text links Elsevier Science Full text links Actions Cite Collections Add to Collections Create a new collection Add to an existing collection Name your collection: Name must be less than 100 characters Choose a collection: Unable to load your collection due to an error Please try again Add Cancel Display options Display options Format Abstract PubMed PMID Share Permalink Copy Page navigation Title & authors Abstract Comment in Similar articles Cited by Publication types MeSH terms Substances Related information LinkOut - more resources Title & authors Abstract Comment in Similar articles Cited by Publication types MeSH terms Substances Related information LinkOut - more resources Observational Study Int J Surg Actions Search in PubMed Search in NLM Catalog Add to Search . 2013;11(10):1114-7. doi: 10.1016/j.ijsu.2013.09.006. Epub 2013 Sep 27. Bilirubin; a diagnostic marker for appendicitis N D'Souza 1 , D Karim , R Sunthareswaran Affiliations Expand Affiliation 1 Poole Hospital, UK. Electronic address: [email protected]. PMID: 24080115 DOI: 10.1016/j.ijsu.2013.09.006 Free article Item in Clipboard Observational Study Bilirubin; a diagnostic marker for appendicitis N D'Souza et al. Int J Surg . 2013 . Free article Show details Display options Display options Format Abstract PubMed PMID Int J Surg Actions Search in PubMed Search in NLM Catalog Add to Search . 2013;11(10):1114-7. doi: 10.1016/j.ijsu.2013.09.006. Epub 2013 Sep 27. Authors N D'Souza 1 , D Karim , R Sunthareswaran Affiliation 1 Poole Hospital, UK. Electronic address: [email protected]. PMID: 24080115 DOI: 10.1016/j.ijsu.2013.09.006 Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID Abstract Introduction: Every investigation that can contribute towards a diagnosis of appendicitis is valuable to the emergency general surgeon. Previous research has suggested that hyperbilirubinaemia is a more specific marker for both simple and perforated appendicitis than WBC (white blood count) and CRP (C-reactive protein), but this investigation is not commonly used to help diagnose appendicitis. Aims: This study investigated whether there is an association between hyperbilirubinaemia and appendicitis. We also reviewed the diagnostic value of bilirubin in perforated vs simple appendicitis, and compared it with the serum C-reactive protein (CRP) and white blood cell count (WBC). Methods: This single centre, prospective observational study included all patients admitted with right iliac fossa (RIF) pain who had liver function tests performed. Statistical analysis was performed using Fisher's exact test to compare bilirubin, WBC and CRP levels for normal appendices, simple appendicitis, and perforated appendicitis. Results: 242 patients were included in this study, of whom 143 were managed operatively for RIF pain. Hyperbilirubinaemia was significantly associated with appendicitis vs RIF pain of other aetiologies (p < 0.0001). Bilirubin had a higher specificity (0.96), than WBC (0.71) and CRP (0.62), but a lower sensitivity (0.27 vs 0.68 and 0.82 respectively). Hyperbilirubinaemia was associated with perforated appendicitis vs simple appendicitis with statistical significance (p < 0.0001). Bilirubin had a higher specificity (0.82) than both WBC (0.34) and CRP (0.21), but a lower sensitivity (0.70 vs 0.80 and 0.95 respectively). Conclusion: Our findings confirm that hyperbilirubinaemia has a high specificity for distinguishing acute appendicitis, especially when perforated, from other causes of RIF pain, particularly those not requiring surgery. Keywords: Appendicitis; Diagnostic techniques and procedures; Hyperbilirubinaemia; Sensitivity and specificity. Copyright © 2013 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved. PubMed Disclaimer Comment in Correspondence to: Bilirubin; a diagnostic marker for appendicitis. Dholakia S, Khalid U. Dholakia S, et al. Int J Surg. 2014;12(2):188. doi: 10.1016/j.ijsu.2013.11.015. Epub 2013 Dec 1. Int J Surg. 2014. PMID: 24296156 No abstract available. Similar articles The value of biochemical markers in predicting a perforation in acute appendicitis. McGowan DR, Sims HM, Zia K, Uheba M, Shaikh IA. McGowan DR, et al. ANZ J Surg. 2013 Jan;83(1-2):79-83. doi: 10.1111/ans.12032. Epub 2012 Dec 12. ANZ J Surg. 2013. PMID: 23231057 Hyperbilirubinaemia: its utility in non-perforated appendicitis. Sandstrom A, Grieve DA. Sandstrom A, et al. ANZ J Surg. 2017 Jul;87(7-8):587-590. doi: 10.1111/ans.13373. Epub 2015 Nov 17. ANZ J Surg. 2017. PMID: 26573997 Hyperbilirubinaemia in appendicitis: the diagnostic value for prediction of appendicitis and appendiceal perforation. Adams HL, Jaunoo SS. Adams HL, et al. Eur J Trauma Emerg Surg. 2016 Apr;42(2):249-52. doi: 10.1007/s00068-015-0540-x. Epub 2015 May 22. Eur J Trauma Emerg Surg. 2016. PMID: 26038057 Elevated serum bilirubin in assessing the likelihood of perforation in acute appendicitis: a diagnostic meta-analysis. Giordano S, Pääkkönen M, Salminen P, Grönroos JM. Giordano S, et al. Int J Surg. 2013;11(9):795-800. doi: 10.1016/j.ijsu.2013.05.029. Epub 2013 May 31. Int J Surg. 2013. PMID: 23732757 Review. Hyperbilirubinemia as a predictor for appendiceal perforation: a systematic review. Burcharth J, Pommergaard HC, Rosenberg J, Gögenur I. Burcharth J, et al. Scand J Surg. 2013;102(2):55-60. doi: 10.1177/1457496913482248. Scand J Surg. 2013. PMID: 23820677 Review. See all similar articles Cited by Elevated total and direct bilirubin are associated with acute complicated appendicitis: a single-center based study in Saudi Arabia. Alfehaid MS, Babiker AM, Alkharraz AH, Alsaeed HY, Alzunaydi AA, Aldubaiyan AA, Sinyan HA, Alkhalaf BK, Alshuwaykan R, Khalil R, Al-Wutayd O. Alfehaid MS, et al. BMC Surg. 2023 Nov 10;23(1):342. doi: 10.1186/s12893-023-02258-2. BMC Surg. 2023. PMID: 37950198 Free PMC article. The Diagnostic Accuracy of Hyperbilirubinemia in Predicting Appendicitis and Appendiceal Perforation. Khalid SY, Elamin A. Khalid SY, et al. Cureus. 2023 Nov 3;15(11):e48203. doi: 10.7759/cureus.48203. eCollection 2023 Nov. Cureus. 2023. PMID: 37929270 Free PMC article. Bilirubin as a Predictor of Complicated Appendicitis in a District General Hospital: A Retrospective Analysis. Halaseh SA, Kostalas M, Kopec C, Nimer A. Halaseh SA, et al. Cureus. 2022 Sep 11;14(9):e29036. doi: 10.7759/cureus.29036. eCollection 2022 Sep. Cureus. 2022. PMID: 36237793 Free PMC article. The predictive value of ischemia-modified albumin in the diagnosis of acute appendicitis: A prospective case-control study. Ünsal A, Turhan VB, Öztürk D, Buluş H, Türkeş GF, Erel Ö. Ünsal A, et al. Ulus Travma Acil Cerrahi Derg. 2022 Apr;28(4):523-528. doi: 10.14744/tjtes.2020.58675. Ulus Travma Acil Cerrahi Derg. 2022. PMID: 35485513 Free PMC article. Magnetic resonance imaging (MRI) for diagnosis of acute appendicitis. D'Souza N, Hicks G, Beable R, Higginson A, Rud B. D'Souza N, et al. Cochrane Database Syst Rev. 2021 Dec 14;12(12):CD012028. doi: 10.1002/14651858.CD012028.pub2. Cochrane Database Syst Rev. 2021. PMID: 34905621 Free PMC article. Review. See all "Cited by" articles Publication types Observational Study Actions Search in PubMed Search in MeSH Add to Search MeSH terms Abdominal Pain / blood Actions Search in PubMed Search in MeSH Add to Search Abdominal Pain / etiology Actions Search in PubMed Search in MeSH Add to Search Adolescent Actions Search in PubMed Search in MeSH Add to Search Adult Actions Search in PubMed Search in MeSH Add to Search Aged Actions Search in PubMed Search in MeSH Add to Search Aged, 80 and over Actions Search in PubMed Search in MeSH Add to Search Appendicitis / blood* Actions Search in PubMed Search in MeSH Add to Search Appendicitis / diagnosis Actions Search in PubMed Search in MeSH Add to Search Bilirubin / blood* Actions Search in PubMed Search in MeSH Add to Search Biomarkers / blood Actions Search in PubMed Search in MeSH Add to Search Child Actions Search in PubMed Search in MeSH Add to Search Child, Preschool Actions Search in PubMed Search in MeSH Add to Search Humans Actions Search in PubMed Search in MeSH Add to Search Hyperbilirubinemia / blood Actions Search in PubMed Search in MeSH Add to Search Male Actions Search in PubMed Search in MeSH Add to Search Middle Aged Actions Search in PubMed Search in MeSH Add to Search Prospective Studies Actions Search in PubMed Search in MeSH Add to Search Young Adult Actions Search in PubMed Search in MeSH Add to Search Substances Biomarkers Actions Search in PubMed Search in MeSH Add to Search Bilirubin Actions Search in PubMed Search in MeSH Add to Search Related information Cited in Books MedGen PubChem Compound (MeSH Keyword) LinkOut - more resources Full Text Sources Elsevier Science Ovid Technologies, Inc. Other Literature Sources The Lens - Patent Citations scite Smart Citations Medical MedlinePlus Health Information Research Materials NCI CPTC Antibody Characterization Program Miscellaneous NCI CPTAC Assay Portal Full text links [x] Elsevier Science [x] Cite Copy Download .nbib .nbib Format: AMA APA MLA NLM Send To Clipboard Email Save My Bibliography Collections Citation Manager [x] NCBI Literature Resources MeSH PMC Bookshelf Disclaimer The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited. Follow NCBI Twitter Facebook LinkedIn GitHub Connect with NLM Twitter SM-Facebook SM-Youtube National Library of Medicine 8600 Rockville Pike Bethesda, MD 20894 Web Policies FOIA HHS Vulnerability Disclosure Help Accessibility Careers NLM NIH HHS USA.gov
Coffee for Cardioprotection and Longevity - PubMed This site needs JavaScript to work properly. Please enable it to take advantage of the complete set of features! Clipboard, Search History, and several other advanced features are temporarily unavailable. Skip to main page content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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official website and that any information you provide is encrypted
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Log in Show account info Close Account Logged in as: username Dashboard Publications Account settings Log out Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation Search: Search Advanced Clipboard User Guide Save Email Send to Clipboard My Bibliography Collections Citation manager Display options Display options Format Abstract PubMed PMID Save citation to file Format: Summary (text) PubMed PMID Abstract (text) CSV Create file Cancel Email citation Subject: 1 selected item: 29474816 - PubMed To: From: Format: Summary Summary (text) Abstract Abstract (text) MeSH and other data Send email Cancel Add to Collections Create a new collection Add to an existing collection Name your collection: Name must be less than 100 characters Choose a collection: Unable to load your collection due to an error Please try again Add Cancel Add to My Bibliography My Bibliography Unable to load your delegates due to an error Please try again Add Cancel Your saved search Name of saved search: Search terms: Test search terms Would you like email updates of new search results? Saved Search Alert Radio Buttons Yes No Email: ( change ) Frequency: Monthly Weekly Daily Which day? The first Sunday The first Monday The first Tuesday The first Wednesday The first Thursday The first Friday The first Saturday The first day The first weekday Which day? Sunday Monday Tuesday Wednesday Thursday Friday Saturday Report format: Summary Summary (text) Abstract Abstract (text) PubMed Send at most: 1 item 5 items 10 items 20 items 50 items 100 items 200 items Send even when there aren't any new results Optional text in email: Save Cancel Create a file for external citation management software Create file Cancel Your RSS Feed Name of RSS Feed: Number of items displayed: 5 10 15 20 50 100 Create RSS Cancel RSS Link Copy Full text links Elsevier Science Full text links Actions Cite Collections Add to Collections Create a new collection Add to an existing collection Name your collection: Name must be less than 100 characters Choose a collection: Unable to load your collection due to an error Please try again Add Cancel Display options Display options Format Abstract PubMed PMID Share Permalink Copy Page navigation Title & authors Abstract Similar articles Cited by Publication types MeSH terms Substances Related information LinkOut - more resources Title & authors Abstract Similar articles Cited by Publication types MeSH terms Substances Related information LinkOut - more resources Review Prog Cardiovasc Dis Actions Search in PubMed Search in NLM Catalog Add to Search . 2018 May-Jun;61(1):38-42. doi: 10.1016/j.pcad.2018.02.002. Epub 2018 Feb 21. Coffee for Cardioprotection and Longevity James H O'Keefe 1 , James J DiNicolantonio 2 , Carl J Lavie 3 Affiliations Expand Affiliations 1 Saint Luke's Mid America Heart Institute, Kansas City, MO, United States. Electronic address: [email protected]. 2 Saint Luke's Mid America Heart Institute, Kansas City, MO, United States. 3 Department of Cardiovascular Diseases, John Ochsner Heart and Vascular Institute, Ochsner Clinical School, The University of Queensland School of Medicine, New Orleans, LA, United States. PMID: 29474816 DOI: 10.1016/j.pcad.2018.02.002 Item in Clipboard Review Coffee for Cardioprotection and Longevity James H O'Keefe et al. Prog Cardiovasc Dis . 2018 May-Jun . Show details Display options Display options Format Abstract PubMed PMID Prog Cardiovasc Dis Actions Search in PubMed Search in NLM Catalog Add to Search . 2018 May-Jun;61(1):38-42. doi: 10.1016/j.pcad.2018.02.002. Epub 2018 Feb 21. Authors James H O'Keefe 1 , James J DiNicolantonio 2 , Carl J Lavie 3 Affiliations 1 Saint Luke's Mid America Heart Institute, Kansas City, MO, United States. Electronic address: [email protected]. 2 Saint Luke's Mid America Heart Institute, Kansas City, MO, United States. 3 Department of Cardiovascular Diseases, John Ochsner Heart and Vascular Institute, Ochsner Clinical School, The University of Queensland School of Medicine, New Orleans, LA, United States. PMID: 29474816 DOI: 10.1016/j.pcad.2018.02.002 Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID Abstract Coffee, a complex brew containing hundreds of biologically active compounds, exerts potent effects on long-term human health. Recently, a plethora of studies have been published focusing on health outcomes associated with coffee intake. An inverse association between coffee consumption and all-cause mortality has been seen consistently in large prospective studies. Habitual coffee consumption is also associated with lower risks for cardiovascular (CV) death and a variety of adverse CV outcomes, including coronary heart disease (CHD), congestive heart failure (HF), and stroke; coffee's effects on arrhythmias and hypertension are neutral. Coffee consumption is associated with improvements in some CV risk factors, including type 2 diabetes (T2D), depression, and obesity. Chronic coffee consumption also appears to protect against some neurodegenerative diseases, and is associated with improved asthma control, and lower risks for liver disease and cancer. Habitual intake of 3 to 4 cups of coffee appears to be safe and is associated with the most robust beneficial effects. However, most of the studies regarding coffee's health effects are based on observational data, with very few randomized controlled trials. Furthermore, the possible benefits of coffee drinking must be weighed against potential risks, which are generally due to its high caffeine content, including anxiety, insomnia, headaches, tremulousness, and palpitations. Coffee may also increase risk of fracture in women, and when consumed in pregnancy coffee increases risk for low birth weight and preterm labor. Keywords: Cancer; Cardiovascular disease; Coffee; Coronary heart disease; Diabetes; Heart failure; Stroke. Copyright © 2018. Published by Elsevier Inc. PubMed Disclaimer Similar articles Effects of habitual coffee consumption on cardiometabolic disease, cardiovascular health, and all-cause mortality. O'Keefe JH, Bhatti SK, Patil HR, DiNicolantonio JJ, Lucan SC, Lavie CJ. O'Keefe JH, et al. J Am Coll Cardiol. 2013 Sep 17;62(12):1043-1051. doi: 10.1016/j.jacc.2013.06.035. Epub 2013 Jul 17. J Am Coll Cardiol. 2013. PMID: 23871889 Review. Coffee and tea: perks for health and longevity? Bhatti SK, O'Keefe JH, Lavie CJ. Bhatti SK, et al. Curr Opin Clin Nutr Metab Care. 2013 Nov;16(6):688-97. doi: 10.1097/MCO.0b013e328365b9a0. Curr Opin Clin Nutr Metab Care. 2013. PMID: 24071782 Review. Coffee consumption and health: umbrella review of meta-analyses of multiple health outcomes. Poole R, Kennedy OJ, Roderick P, Fallowfield JA, Hayes PC, Parkes J. Poole R, et al. BMJ. 2017 Nov 22;359:j5024. doi: 10.1136/bmj.j5024. BMJ. 2017. PMID: 29167102 Free PMC article. Review. Coffee: A Selected Overview of Beneficial or Harmful Effects on the Cardiovascular System? Whayne TF Jr. Whayne TF Jr. Curr Vasc Pharmacol. 2015;13(5):637-48. Curr Vasc Pharmacol. 2015. PMID: 25277696 Review. Coffee consumption and cardiovascular diseases and mortality in patients with type 2 diabetes: A systematic review and dose-response meta-analysis of cohort studies. Shahinfar H, Jayedi A, Khan TA, Shab-Bidar S. Shahinfar H, et al. Nutr Metab Cardiovasc Dis. 2021 Aug 26;31(9):2526-2538. doi: 10.1016/j.numecd.2021.05.014. Epub 2021 May 24. Nutr Metab Cardiovasc Dis. 2021. PMID: 34112583 See all similar articles Cited by Association of daily sitting time and coffee consumption with the risk of all-cause and cardiovascular disease mortality among US adults. Zhou H, Nie J, Cao Y, Diao L, Zhang X, Li J, Chen S, Zhang X, Chen G, Zhang Z, Li B. Zhou H, et al. BMC Public Health. 2024 Apr 17;24(1):1069. doi: 10.1186/s12889-024-18515-9. BMC Public Health. 2024. PMID: 38632571 Free PMC article. Acute Effects of Coffee Consumption on Blood Pressure and Endothelial Function in Individuals with Hypertension on Antihypertensive Drug Treatment: A Randomized Crossover Trial. Lima de Castro FBA, Castro FG, da Cunha MR, Pacheco S, Freitas-Silva O, Neves MF, Klein MRST. Lima de Castro FBA, et al. High Blood Press Cardiovasc Prev. 2024 Jan;31(1):65-76. doi: 10.1007/s40292-024-00622-8. Epub 2024 Feb 3. High Blood Press Cardiovasc Prev. 2024. PMID: 38308805 Clinical Trial. Exploring the connection between caffeine intake and constipation: a cross-sectional study using national health and nutrition examination survey data. Kang Y, Yan J. Kang Y, et al. BMC Public Health. 2024 Jan 2;24(1):3. doi: 10.1186/s12889-023-17502-w. BMC Public Health. 2024. PMID: 38167025 Free PMC article. Plants of the Rubiaceae Family with Effect on Metabolic Syndrome: Constituents, Pharmacology, and Molecular Targets. González-Castelazo F, Soria-Jasso LE, Torre-Villalvazo I, Cariño-Cortés R, Muñoz-Pérez VM, Ortiz MI, Fernández-Martínez E. González-Castelazo F, et al. Plants (Basel). 2023 Oct 15;12(20):3583. doi: 10.3390/plants12203583. Plants (Basel). 2023. PMID: 37896046 Free PMC article. Review. Caffeine causes cell cycle arrest at G0/G1 and increases of ubiquitinated proteins, ATP and mitochondrial membrane potential in renal cells. Kanlaya R, Subkod C, Nanthawuttiphan S, Thongboonkerd V. Kanlaya R, et al. Comput Struct Biotechnol J. 2023 Sep 21;21:4552-4566. doi: 10.1016/j.csbj.2023.09.023. eCollection 2023. Comput Struct Biotechnol J. 2023. PMID: 37799542 Free PMC article. 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Familial hypercholesterolemia: A review - PMC Back to Top Skip to main content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer \| PMC Copyright Notice Ann Pediatr Cardiol. 2014 May-Aug; 7(2): 107–117. doi: 10.4103/0974-2069.132478 PMCID: PMC4070199 PMID: 24987256 Familial hypercholesterolemia: A review Mithun J Varghese Mithun J Varghese Department of Cardiology, Christian Medical College, Vellore, Tamil Nadu, India Find articles by Mithun J Varghese Author information Copyright and License information PMC Disclaimer Department of Cardiology, Christian Medical College, Vellore, Tamil Nadu, India Address for correspondence: Dr. Mithun J Varghese, Department of Cardiology, Christian Medical College, Vellore - 632 004, Tamil Nadu, India. E-mail: moc.liamg@vjnuhtimrd Copyright : © Annals of Pediatric Cardiology This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Familial hypercholesterolemia (FH) is a genetic disorder of lipoprotein metabolism resulting in elevated serum low-density lipoprotein (LDL) cholesterol levels leading to increased risk for premature cardiovascular diseases (CVDs). The diagnosis of this condition is based on clinical features, family history, and elevated LDL-cholesterol levels aided more recently by genetic testing. As the atherosclerotic burden is dependent on the degree and duration of exposure to raised LDL-cholesterol levels, early diagnosis and initiation of treatment is paramount. Statins are presently the mainstay in the management of these patients, although newer drugs, LDL apheresis, and other investigational therapies may play a role in certain subsets of FH, which are challenging to treat. Together these novel treatments have notably improved the prognosis of FH, especially that of the heterozygous patients. Despite these achievements, a majority of children fail to attain targeted lipid goals owing to persistent shortcomings in diagnosis, monitoring, and treatment. This review aims to highlight the screening, diagnosis, goals of therapy, and management options in patients with FH. Keywords: Familial hypercholesterolemia, heterozygous familial hypercholesterolemia, homozygous familial hypercholesterolemia, low-density lipoprotein receptor mutation INTRODUCTION Familial hypercholesterolemia (FH) is a genetic disorder of lipoprotein metabolism characterized by highly elevated plasma total-cholesterol levels with detrimental cardiovascular consequences that commence in childhood. Although atherosclerosis due to FH manifests primarily in adulthood, it has a precocious inception as early as the 1 st decade of life.[ 1 ] That early treatment of risk factors can reverse the atherosclerotic changes in the arterial system[ 2 ] underscores the need for prompt detection and treatment of children with this condition. Fagge identified this disorder more than a century ago as a skin ailment,[ 3 ] but its correlation with atherosclerosis was first recognized in 1939 by Norwegian physician Carl Muller.[ 4 ] The past decade saw a flurry of research in this disease with respect to its genetic basis and therapy. However, FH remains underdiagnosed till late due to the lack of awareness among pediatricians and the general public and the diagnosis is often arrived at only after the irreversible consequences of atherosclerosis have been established. This review describes the current status of the diagnosis, screening, and management of this malady. GENETICS OF FH ’Familial hypercholesterolemia’ represents the phenotypic manifestation of abnormal lipoprotein metabolism caused by a variety of genetic abnormalities. After the seminal discovery by Brown and Goldstein that mutations in the low-density lipoprotein receptor (LDLR) was the cause of monogenetic FH, over 1,500 mutations of this gene have been detected[ 5 , 6 ] and these account for more than 80% of cases of monogenetic FH.[ 7 ] Heterozygous FH (HeFH) is not an uncommon disorder in children, with an estimated prevalence of 1 in 500 in the western world.[ 8 ] Homozygous FH (HoFH), although uncommon (prevalence is less than one per million in the general population), is a critical condition which commences in the first few years of life.[ 9 ] It is principally noted in countries such as Lebanon, Canada, and South Africa possibly because of the founder mutations and isolation of population.[ 10 ] In addition to the LDLR defect, two other sets of autosomal dominant mutations play a central role in the pathogenesis of FH; one, a defective apo-B100 component of LDL, known as familial defective apoB-100 (clinically indistinguishable from heterozygous LDLR mutations).[ 11 , 12 , 13 ] Secondly, a gain of function mutation affecting proprotein convertase subtilisin/kexin 9 (PCSK9) encoded by chromosome 1 has also been shown to trigger FH by negatively modulating LDL receptor expression.[ 14 ] Although the rare autosomal recessive form of FH called autosomal recessive hypercholesterolemia has been described in a few families,[ 15 , 16 ] in clinical practice, monogenetic hypercholesterolemia is primarily an autosomal dominant disorder with greater than 90% penetrance. Though single gene disorders play a crucial role in the etiology of FH, linkage studies have exposed that the majority of cases of FH are caused by numerous unexceptional genetic variations.[ 11 ] An interplay of these polygenic variations together with environmental factors remains the leading cause for hypercholesterolemia in the general population.[ 17 , 18 ] However, a monogenetic etiology is usually the reason for more severe forms of LDL elevation and also for phenotypic expression of FH in the 1 st decade of life. SCREENING FOR FH The ideal strategy to screen for FH is currently a controversial issue. Former lipid guidelines advocated ‘targeted screening’, which comprised a fasting lipid profile test in children with risk factors for FH such as a family history of premature cardiovascular diseases (CVDs), dyslipidemia, or obesity.[ 19 ] However, despite its cost effectiveness, this approach entailed the risk of missing 30-60% of affected patients.[ 20 ] An alternative approach to screening is termed ‘cascade screening’,[ 21 , 22 ] wherein health workers actively screen for disease among the first and second degree relatives of patients diagnosed by targeted screening. Although this method is associated with improved detection rates, there remains a considerable risk of missing affected individuals. This shortcoming has prompted some of the recent guidelines to recommend a strategy of universal lipid screening.[ 23 , 24 ] However, the cost effectiveness or utility of universal screening as well as the psychological impact on the children and the parents are not well-studied. Furthermore, a minority of patients of FH (7%) may have a normal lipid profile at the time of screening,[ 25 ] thus, facing the risk of missing the diagnosis in some despite screening of the entire population. An equally important question is what to screen — lipids or genes? Genetic screening strategy involves searching for the common genes causing FH among suspected children and their close relatives. Recent National Institute for Health and Care Excellence (NICE) guidelines recommend a DNA testing on all patients diagnosed with FH and a subsequent genetic screening among their close relatives in order to augment case detection rates.[ 26 ] Although intuitively attractive, a significant number of patients clinically diagnosed with FH are negative for mutations conventionally tested for by genetic screening, probably due to polygenic inheritance.[ 27 ] In such patients, genetic cascade testing is expected to have a very low yield and is unlikely to be cost effective.[ 17 ] Hence, genetic cascade screening is likely to benefit only probands where a definite mutation is identified; in others, a strategy of lipid profile-based cascade screening is preferable. The ideal age of lipid screening among children is also a keenly debated issue. The normal cord blood levels of LDL-cholesterol ranges from 35 to 70 mg/dl.[ 28 ] Although cord blood LDL levels for screening for FH is an appealing concept, studies have shown significant overlap in these levels between neonates with and without HeFH,[ 29 ] thus precluding this as a screening strategy. The Lipid Research Clinics prevalence studies demonstrated that by the age of 2 years, the serum lipid level reached that of young adults,[ 30 ] while the National Health and Nutrition Examination Surveys (NHANESs)[ 31 ], reported that the peak lipid levels are reached by the age of 9-11 years. Therefore, universal screening is best performed between 9 and 11 years of age, whereas a screening at any time after the age of 2 years is preferred in those who are candidates of targeted screening.[ 11 , 32 , 33 ] Table 1 summarizes national lipid association guidelines for screening children for FH. Table 1 National lipid association key screening recommendations for FH Open in a separate window Clinical features and diagnosis Patients with HeFH are, by and large, asymptomatic in childhood and adolescence and typically diagnosed by screening methods. Their total and LDL-cholesterol levels are characteristically over the 95 th centile of the recommended levels and a strong family history corroborates the diagnosis. Some involved persons may bear peripheral markers of fat deposition such as tendon xanthoma or arcus lipoides. Homozygous or compound HeFH, on the other hand, presents in the 1 st decade of life with a distinctive and severe clinical phenotype. The age at presentation depends on the degree of LDL receptor activity,[ 16 ] those with the null phenotype (<2% LDL receptor activity) tend to present earlier, resulting even in intrauterine death. These patients have primarily dermatological and ocular manifestations — tendon xanthomas and interdigital xanthomas are pathognomic of HoFH [ Figure 1 ]. Tendon xanthomas are frequently missed on visual inspection alone and necessitate careful palpation in the Achilles, biceps and triceps tendons for early detection. Although tuberous xanthomas, xanthelasma, and corneal arcus appear in conditions other than FH,[ 34 ] their occurrence at a younger age should prompt evaluation for FH. Severe atherosclerosis involving multiple vascular beds, including coronary, cerebral, and peripheral vascular system, manifest in a myriad ways. Though coronary atherosclerosis is frequently the cause of premature death, calcific aortic valve stenosis and aortic root disease, including supravalvular aortic stenosis due to cholesterol and inflammatory cell infiltration, may result in significant morbidity in these patients, often requiring aortic valve and root replacement.[ 35 ] Open in a separate window Figure 1 Dermatological manifestations: (a) Eruptive xanthoma, (b) tendon xanthoma, and (c) tuberous xanthoma in a 12-year-old girl with homozygous familial hypercholesterolemia (FH). (d) Her father who was diagnosed to have heterozygous FH with coronary artery disease had xanthelasma When FH is suspected based on elevated lipid levels and clinical features, secondary dyslipidemias such as diabetes, endocrine disorders including hypothyroidism, renal disorders, obesity, and incriminating drugs must be ruled out before arriving at the diagnosis. A detailed family history should be taken not only to assess the mode of transmission but also to identify other affected individuals for early commencement of treatment. A comprehensive CVD risk assessment is required in all diagnosed patients and correction of modifiable risk factors must be pursued. The value of CVD risk assessment tools used in adults such as Framingham Risk Score have not been validated in the pediatric and adolescent populations with FH and are liable to underestimate the risk.[ 11 ] Ancillary investigations such as carotid intima medial thickness and ankle brachial index, which are usually used in research settings, may be helpful in monitoring the progression of disease in selected cases. The diagnosis of FH is typically based on elevation of total-, LDL-, and non-HDL-cholesterol above the 95 th centile recommended for the age and sex of the patient together with positive family history or identification of a causative mutation. The MEDPED criteria from the United States,[ 36 ] the Dutch Lipid Clinic criteria,[ 37 ] and the British Simon Broome Registry criteria[ 38 ] [ Table 2 ] are validated diagnostic systems in this regard. The first relies solely on the age and the blood lipid levels of the patient, while the latter two require family history and clinical findings as well. These criteria are credited with simplicity and ease of use; however, they may be relatively ineffective at diagnosing index cases. Moreover, these criteria may not be clinically sensitive when applied to mild phenotypes and children in whom phenotypic expression is not yet completed. Table 2 Criteria for diagnosis of familial hypercholesterolemia Open in a separate window Management Lipid targets Recommendations differ with respect to target lipid levels in pediatric and adolescent patients. National Lipid Association guidelines recommend a target LDL level of <130 mg/dl or >50% reduction from baseline values.[ 24 ] More rigorous targets are proposed in patients with additional risk factors such as diabetes, obesity, and a family history of CVD. Belgian multisocietal guidelines, on the other hand, recommend age-specific targets.[ 33 ] In children aged 10-14 years, an LDL level of <160 mg/dl or >30% reduction from baseline levels is targeted. A rigorous target lipid level of <130 mg/dl is recommended in children between the ages of 14 and 18 years. In patients older than 18 years, a lipid target of <100 mg/dl is deemed appropriate. It should be noted that, a recent cross-sectional study in the Netherlands showed that no more than 21% of HeFH patients realized their lipid goals despite the recent advances in therapy.[ 39 ] Among patients who failed to achieve LDL-cholesterol goal, only 21% were on maximal dose of approved drugs, suggesting shortcomings in adequate monitoring and implementation of therapy.[ 39 ] Lifestyle changes Therapeutic lifestyle adjustments forman important part in the management of FH. This encompasses specific dietary manipulations, physical activity, limitation of alcohol intake, and total avoidance of tobacco products. Recent guidelines recommend a low calorie diet with a total fat intake of ≤3% of the total dietary intake including <8% of saturated fat and <75 mg/1,000 kcal cholesterol for these patients.[ 33 ] However, dietary restrictions are noted to have a modest effect in lowering lipid levels,[ 40 ] with unproven long-term clinical benefits.[ 41 ] Consequently, a concurrent drug therapy is indicated in patients with severe hypercholesterolemia. Dietary supplementation of phytosterol esters and stanol esters is controversial: Although a few recent studies have demonstrated a reduction of LDL levels in children with FH,[ 42 ] there are concerns regarding their accumulation in atheromas[ 43 ] and lowering of serum levels of lipid soluble vitamins.[ 44 ] Similarly, dietary supplementation of soy proteins and polyunsaturated fatty acids in this population is not substantiated by clinical evidence and is, hence, not currently recommended.[ 33 ] Drug therapy-when to start? The former guidelines issued by National Heart, Lung, and Blood Institute (NHLBI) advised treatment with bile acid sequestrants, the lowest age recommended for initiation being 10 years.[ 19 ] This was based on the excellent long-term safety profile of this group of drugs owing to lack of their systemic absorption. However, modest efficacy[ 45 ] and poor tolerability of these drugs resulted in alterations in the recent expert opinions and consensus papers.[ 23 , 24 , 33 ] In a recent statement by the American Heart Association,[ 46 ] later endorsed by the American Academy of Pediatrics,[ 20 ] statins were proposed as first-line drugs and the age of initiation of therapy was lowered to 8 years. Bile acid Sequestrants Formerly, this class of drugs was deemed the first-line of therapy of FH in children owing to their lack of systemic uptake. They bind to bile acids in the intestine, thereby, preventing their systemic absorption; this results in a greater conversion of cholesterol to bile acids and an enhanced production of LDL receptors by the liver. Cholestyramine and colestipol were the most frequently used drugs in this class; however, they fell out of favor due to their modest efficacy (10-20% LDL reduction) and gastrointestinal intolerance. Of late, a novel drug in this class, colesevelam hydrochloride, has been studied in HeFH patients. A short-term, randomized trial showed good tolerability and efficacy of colesevelam alone and in combination with statins leading to a renewed interest in this class of drugs.[ 47 ] Statins Statins (3-hydroxy-3methyl-glutaryl-CoA reductase inhibitors) are currently the first line of drugs in the treatment of FH in children and adolescents. They inhibit the rate-limiting step in cholesterol synthesis, thus, increasing the expression of LDL receptors, resulting in the rapid clearance of LDL from the blood. However, they have a restricted role in patients of HoFH with null phenotype in view of the need for receptor production for their action. Among the various generic statins available, the Food and Drug Administration (FDA) has approved of pravastatin in children over 8 years of age and lovastatin, atorvastatin, and simvastatin above the age of 10 years.[ 48 ] The prepubertal commencement of statin therapy remains controversial,[ 49 ] as this can potentially hamper the production of steroid hormones in the body. Moreover, their effects on muscles and the liver are still an issue of grave concern. A recent Cochrane review[ 50 ] and two meta-analysis[ 51 , 52 ] of placebo-controlled trials on statins in children and adolescents with FH showed no major side effects with regard to growth, sexual development, muscle, and liver toxicity. Concurrently, they showed excellent efficacy in lipid lowering with a 26.5% mean relative reduction in LDL-cholesterol levels. The apprehension regarding growth disruption by statins at puberty was allayed, in part, by the paradoxical finding of increased growth in the children treated with the drug.[ 51 , 52 ] However, it is noteworthy that all the trials included in these meta-analyses studied only short-term outcomes; the long-term safety of statins in this population is unknown. The longest follow-up data on the effects of statin therapy in pediatric population is a retrospective study over a 7-year period in 185 children with FH treated with pravastatin, which revealed minor side effects in 13% of patients and myopathy in four patients.[ 53 ] Modern trends of drug usage among children indicate that the utilization of statins in the pediatric population is in the upswing,[ 54 ] despite the aforementioned concerns in relation to long-term safety. There are specific recommendations on the subject of monitoring of patients commencing statin therapy. Creatine phosphokinase (CK) to assess muscle toxicity and aspartate amino transferase (AST), and alanine amino transferase (ALT) to monitor liver toxicity are mandatory prior to initiation of statins. Follow-up measurements must be done 1-3 months after starting the drug and yearly thereafter. Drug therapy should be interrupted when CK levels reach five times and AST and ALT three times over the upper limit of normal; the same drug at a lower dose or a different statin may be introduced after a drug-free interval of 3 months. Other drugs may be tried if the patient does not tolerate statins despite these measures.[ 33 ] Ezetimibe Ezetimibe is a new class of cholesterol absorption inhibitors that acts on the brush border of the small intestinal epithelium. The specific site of its action is believed to be the epithelial cell Niemann — Pick C1-like protein.[ 55 ] As their mechanism of action is not based on the expression of LDL receptors, they are especially beneficial in the management of HoFH. Clinical trials have displayed their efficacy in reducing LDL levels when used alone[ 56 ] or in combination with statins.[ 57 , 58 ] However, the initial fervor over their use was dampened by the largest prospective trial (ENHANCE trial) on cholesterol absorption inhibitors until this time, which demonstrated that ezetimibe added to high dose simvastatin failed to lessen carotid intima medial thickness in spite of a significant diminution in LDL levels.[ 59 ] Lastly, the discovery of a small but significant rise in the incidence of cancer in patients treated with ezetimibe patients in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial[ 60 ] is a cause for concern in view of the need for lifelong therapy required in patients with FH. Therefore, additional data is required on clinically significant outcomes as well as safety endpoints before their widespread adoption in pediatric practice. Although US Food and Drug Administration (FDA) has approved of ezetemibe therapy in children over the age of 10years, current guidelines recommend drug initiation before 18 years of age only in patients intolerant to statins and in patients who fail to realize lipid goals with statin monotherapy.[ 11 , 33 ] Therapeutic options in patients who failed to attain lipid targets despite maximal medical therapy Newer drugs Mipomirsen, an antisense oligonucleotide that targets apoB-100 mRNA in the liver, is presently under investigation in the therapy of FH. This drug significantly lowered LDL and lipoprotein (a) levels in adults with heterozygous[ 61 ] and homozygous[ 62 ] hypercholesterolemia in recent phase 3 trials. Although the mean LDL reduction with 200 mg of subcutaneous mipomirsen administered weekly was significant in patients with HoFH (-24.7% in treatment group and -3.3% in the placebo group, P = 0.0003), the response to therapy was inconsistent and compounded by a significant number of nonresponders.[ 62 ] The most frequent side effects of mipomirsen include reactions at the site of injection and flu-like symptoms, but apprehension regarding their hepatic toxicity, especially steatosis, still remains. Moreover, as they have not been studied in the pediatric population in a prospective clinical trial, their safety profile in this group of patients is not defined. Serum PCSK9 are proteins which bind to LDL receptors and promote their degradation, thus, raising LDL levels in the blood. A variety of molecular techniques based on terminating the effect of PCSK9 in order to lower LDL-cholesterol levels is under investigation, including the development of monoclonal antibodies that bind to PCSK9,[ 63 ] antisense nucleotide-based therapy,[ 64 ] and small interfering RNAs.[ 65 ] In a randomized control trial experimenting on monoclonal antibodies in adults with various forms of hypercholesterolemia, the combination of this drug with 10 and 80 mg of atorvastatin was more efficacious than80mg of atorvastatin alone in reducing LDL levels.[ 66 ] However, as this antibody requires some residual LDL receptor function to fulfill its function, it is useful only in patients with HeFH and non-null phenotype HoFH. Lomitapide is a new lipid-lowering agent with a novel method of action: It inhibits the microsomal triglyceride transfer protein(MTP). The role of MTP in the production of LDL involves assisting inthe transfer of triglycerides to apolipoprotein B.[ 67 ] The US FDA has approved of its use as an orphan drug in the treatment of HoFH.[ 68 ] In a recently published phase 3 dose escalation trial, lomitapide reduced LDL-cholesterol by 50% in HoFH patients with poorly controlled LDL levels.[ 69 ] Although this small study showed a satisfactory safety profile of the drug, there are still lingering doubts regarding the hepatic side effects like steatosis and transaminitis owing to their distinctive mechanism of action. In addition to the aforementioned drugs, other classes of drugs like thyroid mimetics (e.g., eprotirome and sobetirome),[ 70 ] HDL-bound enzyme cholesterol ester transfer protein (CETP) inhibitors (e.g., torcetrapib, anacetrapib, and evacetrapib) and reconstituted high-density lipoprotein (rHDL)[ 71 ] are currently under research in the treatment of elevated LDL-cholesterol and shows variable efficacy and safety. All the ongoing trials on modern drug therapy of dyslipidemia focuses on adult patients and excludes the pediatric population. Given that a majority of these novel therapies are yet unproven with regard to clinical efficacy and safety endpoints, their role is presently confined to that of a lipid apheresis-sparing therapy in patients with HoFH who have fallen short of their lipid goals. Additional studies in the pediatric population are required prior to their clinical adoption in the treatment of heterozygous patients. LDL apheresis Patients with homozygous and compound HeFH frequently have elevated lipid levels in spite of optimal medical therapy. These are fitting candidates for LDL apheresis, which has proved to be a very beneficial treatment option to reducing LDL levels. Numerous studies have affirmed its capability to lower LDL-cholesterol levels by 55-75%.[ 72 ] Commonly used techniques of LDL apheresis include heparin-induced extracorporeal LDL-cholesterol precipitation (HELP), dextran sulfate cellulose adsorption (DSA), double filtration plasmapheresis (DFPP), polyacrylate full blood adsorption (PFBA also known as DALI), and immune adsorption. Details on the techniques are beyond the scope of this update and interested readers may consult excellent reviews available on the subject.[ 73 , 74 , 75 ] The decline in LDL-cholesterol levels by apheresis is a transitory event and is associated with a rebound escalation of lipid levels after the procedure. This rebound is expeditious in patients without FH, slower in those with HeFH and delayed in patients in HoFH.[ 76 ] Weekly to fortnightly sessions are advocated for patients with HoFH, as such episodic sittings have been shown to reduce the degree of rebound and retard the progression of atherosclerosis.[ 77 , 78 ] Regular apheresis therapy along with medications in patients of HoFH has improved the average life expectancy to over 50 years of age compared to the formerly bleak prognosis of death in the2 nd or 3 rd decade.[ 79 ] Despite its established efficacy, lipid apheresis has not yet been widely embraced in clinical practice due to lack of accessibility for the majority of patients, the prohibitive cost involved, the invasive nature of the procedure, and the lack of motivation among patients. Gene therapy HoFH was among the first disorders wherein gene therapy was experimented. Contrary to other treatment alternatives, the possibility of a definitive cure by a one-time procedure for a disease that lasts a lifetime renders this an appealing choice. However, due to the problems related to appropriate gene vector, lack of persistent gene expression as well as due to safety concerns,[ 80 ] this modality failed to demonstrate substantial clinical efficacy in preliminary trials. Upcoming research should focus on improving gene vectors and transfer techniques, while concurrently reducing their oncogenic dangers before it can be relevant to clinical practice.[ 81 ] Surgical options In addition to the therapies enumerated prior, surgical options including ileal bypass and portocaval shunt have been tried earlier in refractory cases. Owing to the significant comorbidities involved and the need for treatment before the onset of clinical effects of atherosclerosis, these never became a popular choice of treatment. Recent case reports of successful pediatric liver transplant done for the treatment of HoFH suggest excellent efficacy and good safety profile of this option.[ 82 , 83 ] However, in view of the scarcity of donor liver available and complexities of the transplant and post-transplant management, such a decision should be taken only after carefully assessing the risk benefit ratio. Natural and modified natural history of FH The natural history of FH depends primarily on the degree of functional LDL receptor activity present, and in turn, on LDL-cholesterol levels, resulting in widely varying prognosis even among homozygous individuals.[ 84 ] Symptom onset is age-dependent and typically occurs in the 2 nd decade in homozygous patients. The extent of atherosclerosis is primarily determined by the degree of LDL elevation and its duration, calculated by the cholesterol year score.[ 85 ] Precocious onset of clinically significant atherosclerotic changes are very common and involve multiple vascular beds including coronary, cerebral, and peripheral systems.[ 85 ] Studies in the pre-statin era indicated poor outcomes in the majority of patients with HoFH, cardiovascular events being the chief cause of morbidity and mortality.[ 86 ] Aortic root disease was reported to be the commonest cardiac manifestation followed by coronary artery disease.[ 86 ] While some studies in this interval purported a mean survival of 18 years among patients with HoFH,[ 87 ] others observed an average survival of 40 years;[ 86 ] this variation may be ascribed to the differences in the proportion of receptor-negative patients included in these studies. It was conventionally believed that modern day drug therapy for HoFH does not alter prognosis owing to the lack of significant reduction in LDL. However, this assumption was challenged by a recent retrospective analysis by Raal et al ., involving 149 patients, wherein patients treated with statins had hazard ratios for mortality and cardiovascular events of 0.34 and 0.49, respectively when compared with patients in the pre-statin era, despite achieving only a modest 26% reduction in LDL levels. 87 Although this result may be partly influenced by the beneficial effects of cardiovascular preventive drugs such as antiplatelet agents and beta blockers, this study underscores the benefit of statin therapy even in FH homozygous individuals. Among patients with untreated HeFH, coronary artery disease (CAD) develops in about 50% of males by the age of 50 years and 30% of females by 60 years. Although CAD appears 10years later in females compared to males, an accelerated development of CAD is observed after menopause.[ 88 , 89 ] Simon Broome registry data from England in the pre-statin era showed that mortality associated with CAD was increased a 100-fold in the age group of 20-40 years and four-fold in the 40-59 year age group.[ 38 ] Among those surviving to the age of 60 years, however, the risk seems akin to that in the general population.[ 38 ] The benefits of present day therapeutic advances in this population is confirmed by a large prospective study from the UK, which reveals a 37% relative reduction in standardized mortality rate from 3.4 in the pre-statin era to 2.1 after widespread use of statins.[ 90 ] Despite strong association of FH with coronary and peripheral vascular disease, its relation with stroke risk is more controversial. A large prospective registry data from United Kingdom showed that ischemic stroke mortality among treated HeFH patients not to be different from general population.[ 91 ] The reason for this difference is presently unknown. CONCLUSION FH is a grave ailment with its genesis in early childhood resulting in damaging consequences in later life. Although the need for a screening strategy to detect this disease early is widely accepted, there is no consensus regarding whom and when to screen. Early initiation of lipid-lowering therapy and lifestyle measures might improve the clinical outcome. While such treatment initiatives have notably improved the prognosis of HeFH, the outcomes of familial homozygous hypercholesterolemia remain disappointing. Although most cases may be treated with a combination of statins and cholesterol absorption inhibitors, some will have need of more invasive therapies such as LDL apheresis. 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Epub 2010 Jan 20. Long-term walnut supplementation without dietary advice induces favorable serum lipid changes in free-living individuals S Torabian 1 , E Haddad , Z Cordero-MacIntyre , J Tanzman , M L Fernandez , J Sabate Affiliations Expand Affiliation 1 Department of Nutrition, School of Public Health, Loma Linda University, Loma Linda, CA, USA. [email protected] PMID: 20087377 DOI: 10.1038/ejcn.2009.152 Item in Clipboard Randomized Controlled Trial Long-term walnut supplementation without dietary advice induces favorable serum lipid changes in free-living individuals S Torabian et al. Eur J Clin Nutr . 2010 Mar . Show details Display options Display options Format Abstract PubMed PMID Eur J Clin Nutr Actions Search in PubMed Search in NLM Catalog Add to Search . 2010 Mar;64(3):274-9. doi: 10.1038/ejcn.2009.152. Epub 2010 Jan 20. Authors S Torabian 1 , E Haddad , Z Cordero-MacIntyre , J Tanzman , M L Fernandez , J Sabate Affiliation 1 Department of Nutrition, School of Public Health, Loma Linda University, Loma Linda, CA, USA. [email protected] PMID: 20087377 DOI: 10.1038/ejcn.2009.152 Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID Abstract Background/objectives: Walnuts have been shown to reduce serum lipids in short-term well-controlled feeding trials. Little information exists on the effect and sustainability of walnut consumption for longer duration in a free-living situation. Subjects/methods: A randomized crossover design in which 87 subjects with normal to moderate high plasma total cholesterol were initially assigned to a walnut-supplemented diet or habitual (control) diet for a 6-month period, then switched to the alternate dietary intervention for a second 6-month period. Each subject attended seven clinics 2 months apart. At each clinic, body weight was measured, and in five clinics (months 0, 4, 6, 10 and 12), a blood sample was collected. Results: Our study showed that supplementing a habitual diet with walnuts (12% of total daily energy intake equivalent) improves the plasma lipid profile. This beneficial effect was more significant in subjects with high plasma total cholesterol at baseline. Significant changes in serum concentrations of total cholesterol (P=0.02) and triglycerides (P=0.03) were seen and nearly significant changes in low-density lipoprotein cholesterol (LDL-C) (P=0.06) were found. No significant change was detected in either high-density lipoprotein (HDL) cholesterol LDL to HDL ratio. Conclusions: Including walnuts as part of a habitual diet favorably altered the plasma lipid profile. The lipid-lowering effects of walnuts were more evident among subjects with higher lipid baseline values, precisely those people with greater need of reducing plasma total and LDL-C. PubMed Disclaimer Comment in Long-term walnut supplementation without dietary advice induces favorable serum lipid changes in free-living individuals. Um CY, He K. Um CY, et al. Eur J Clin Nutr. 2011 Mar;65(3):421; author reply 422. doi: 10.1038/ejcn.2010.246. Epub 2010 Nov 10. Eur J Clin Nutr. 2011. PMID: 21063430 No abstract available. Similar articles Long-term walnut supplementation without dietary advice induces favorable serum lipid changes in free-living individuals. Um CY, He K. Um CY, et al. Eur J Clin Nutr. 2011 Mar;65(3):421; author reply 422. doi: 10.1038/ejcn.2010.246. Epub 2010 Nov 10. Eur J Clin Nutr. 2011. PMID: 21063430 No abstract available. Influence of body mass index and serum lipids on the cholesterol-lowering effects of almonds in free-living individuals. Jaceldo-Siegl K, Sabaté J, Batech M, Fraser GE. Jaceldo-Siegl K, et al. Nutr Metab Cardiovasc Dis. 2011 Jun;21 Suppl 1:S7-13. doi: 10.1016/j.numecd.2011.03.007. Epub 2011 May 12. Nutr Metab Cardiovasc Dis. 2011. PMID: 21570268 Serum lipid profiles in Japanese women and men during consumption of walnuts. Iwamoto M, Imaizumi K, Sato M, Hirooka Y, Sakai K, Takeshita A, Kono M. Iwamoto M, et al. Eur J Clin Nutr. 2002 Jul;56(7):629-37. doi: 10.1038/sj.ejcn.1601400. Eur J Clin Nutr. 2002. PMID: 12080402 Clinical Trial. Almonds have a neutral effect on serum lipid profiles: a meta-analysis of randomized trials. Phung OJ, Makanji SS, White CM, Coleman CI. Phung OJ, et al. J Am Diet Assoc. 2009 May;109(5):865-73. doi: 10.1016/j.jada.2009.02.014. J Am Diet Assoc. 2009. PMID: 19394473 Review. Walnuts decrease risk of cardiovascular disease: a summary of efficacy and biologic mechanisms. Kris-Etherton PM. Kris-Etherton PM. J Nutr. 2014 Apr;144(4 Suppl):547S-554S. doi: 10.3945/jn.113.182907. Epub 2014 Feb 5. J Nutr. 2014. PMID: 24500935 Review. See all similar articles Cited by In Vitro Assessment of the Bioaccessibility of Zn, Ca, Mg, and Se from Various Types of Nuts. Moskwa J, Naliwajko SK, Puścion-Jakubik A, Soroczyńska J, Socha K, Koch W, Markiewicz-Żukowska R. Moskwa J, et al. Foods. 2023 Dec 12;12(24):4453. doi: 10.3390/foods12244453. Foods. 2023. PMID: 38137257 Free PMC article. Tree Nut and Peanut Consumption and Risk of Cardiovascular Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Houston L, Probst YC, Chandra Singh M, Neale EP. Houston L, et al. Adv Nutr. 2023 Sep;14(5):1029-1049. doi: 10.1016/j.advnut.2023.05.004. Epub 2023 May 5. Adv Nutr. 2023. PMID: 37149262 Free PMC article. Review. Nuts and seeds consumption and risk of cardiovascular disease, type 2 diabetes and their risk factors: a systematic review and meta-analysis. Arnesen EK, Thorisdottir B, Bärebring L, Söderlund F, Nwaru BI, Spielau U, Dierkes J, Ramel A, Lamberg-Allardt C, Åkesson A. Arnesen EK, et al. Food Nutr Res. 2023 Feb 14;67. doi: 10.29219/fnr.v67.8961. eCollection 2023. Food Nutr Res. 2023. PMID: 36816545 Free PMC article. Review. The Effect of Walnut Intake on Lipids: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Alshahrani SM, Mashat RM, Almutairi D, Mathkour A, Alqahtani SS, Alasmari A, Alzahrani AH, Ayed R, Asiri MY, Elsherif A, Alsabaani A. Alshahrani SM, et al. Nutrients. 2022 Oct 23;14(21):4460. doi: 10.3390/nu14214460. Nutrients. 2022. PMID: 36364723 Free PMC article. Review. Association of nut consumption with CVD risk factors in young to middle-aged adults: The Coronary Artery Risk Development in Young Adults (CARDIA) study. Yi SY, Steffen LM, Zhou X, Shikany JM, Jacobs DR Jr. Yi SY, et al. Nutr Metab Cardiovasc Dis. 2022 Oct;32(10):2321-2329. doi: 10.1016/j.numecd.2022.07.013. Epub 2022 Jul 31. Nutr Metab Cardiovasc Dis. 2022. PMID: 35970686 Free PMC article. 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Walnut consumption in a weight reduction intervention: effects on body weight, biological measures, blood pressure and satiety - PMC Back to Top Skip to main content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer \| PMC Copyright Notice Nutr J. 2017; 16: 76. Published online 2017 Dec 4. doi: 10.1186/s12937-017-0304-z PMCID: PMC5715655 PMID: 29202751 Walnut consumption in a weight reduction intervention: effects on body weight, biological measures, blood pressure and satiety Cheryl L. Rock , Shirley W. Flatt , Hava-Shoshana Barkai , Bilge Pakiz , and Dennis D. Heath Cheryl L. Rock Department of Family Medicine and Public Health, School of Medicine, University of California, 3855 Health Sciences Drive, Room 3077, La Jolla, CA 92093-0901 USA Find articles by Cheryl L. Rock Shirley W. Flatt Department of Family Medicine and Public Health, School of Medicine, University of California, 3855 Health Sciences Drive, Room 3077, La Jolla, CA 92093-0901 USA Find articles by Shirley W. Flatt Hava-Shoshana Barkai Department of Family Medicine and Public Health, School of Medicine, University of California, 3855 Health Sciences Drive, Room 3077, La Jolla, CA 92093-0901 USA Find articles by Hava-Shoshana Barkai Bilge Pakiz Department of Family Medicine and Public Health, School of Medicine, University of California, 3855 Health Sciences Drive, Room 3077, La Jolla, CA 92093-0901 USA Find articles by Bilge Pakiz Dennis D. Heath Department of Family Medicine and Public Health, School of Medicine, University of California, 3855 Health Sciences Drive, Room 3077, La Jolla, CA 92093-0901 USA Find articles by Dennis D. Heath Author information Article notes Copyright and License information PMC Disclaimer Department of Family Medicine and Public Health, School of Medicine, University of California, 3855 Health Sciences Drive, Room 3077, La Jolla, CA 92093-0901 USA Cheryl L. Rock, Phone: 858-822-1126, Email: ude.dscu@kcorlc . Corresponding author. Received 2017 Sep 21; Accepted 2017 Nov 27. Copyright © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/ ), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated. Associated Data Data Availability Statement The datasets generated and/or analyzed during the current study are not publicly available due to the private (and not public) sponsorship but are available from the corresponding author on reasonable request. Abstract Background Dietary strategies that help patients adhere to a weight reduction diet may increase the likelihood of weight loss maintenance and improved long-term health outcomes. Regular nut consumption has been associated with better weight management and less adiposity. The objective of this study was to compare the effects of a walnut-enriched reduced-energy diet to a standard reduced-energy-density diet on weight, cardiovascular disease risk factors, and satiety. Methods Overweight and obese men and women ( n = 100) were randomly assigned to a standard reduced-energy-density diet or a walnut-enriched (15% of energy) reduced-energy diet in the context of a behavioral weight loss intervention. Measurements were obtained at baseline and 3- and 6-month clinic visits. Participants rated hunger, fullness and anticipated prospective consumption at 3 time points during the intervention. Body measurements, blood pressure, physical activity, lipids, tocopherols and fatty acids were analyzed using repeated measures mixed models. Results Both study groups reduced body weight, body mass index and waist circumference (time effect p < 0.001 for each). Change in weight was −9.4 (0.9)% vs. -8.9 (0.7)% (mean [SE]), for the standard vs. walnut-enriched diet groups, respectively. Systolic blood pressure decreased in both groups at 3 months, but only the walnut-enriched diet group maintained a lower systolic blood pressure at 6 months. The walnut-enriched diet group, but not the standard reduced-energy-density diet group, reduced total cholesterol and low-density lipoprotein cholesterol (LDL-C) at 6 months, from 203 to 194 mg/dL and 121 to 112 mg/dL, respectively ( p < 0.05). Self-reported satiety was similar in the groups. Conclusions These findings provide further evidence that a walnut-enriched reduced-energy diet can promote weight loss that is comparable to a standard reduced-energy-density diet in the context of a behavioral weight loss intervention. Although weight loss in response to both dietary strategies was associated with improvements in cardiovascular disease risk factors, the walnut-enriched diet promoted more favorable effects on LDL-C and systolic blood pressure. Trial registration The trial is registered at ( {"type":"clinical-trial","attrs":{"text":"NCT02501889","term_id":"NCT02501889"}} NCT02501889 ). Keywords: Weight loss, Nuts, Satiety, Cardiovascular disease risk factors, Blood pressure Introduction Current guidelines for the management of overweight and obesity recommend prescribing a reduced-energy diet as a primary treatment intervention to promote weight loss, as part of a comprehensive lifestyle intervention, and conclude that a variety of dietary approaches can produce weight loss [ 1 ]. However, dietary patterns, specific foods, and macronutrient composition may differentially affect metabolic factors, satiety, and the postprandial gastrointestinal peptide response that could affect hunger and appetite [ 2 , 3 ]. Dietary strategies that help patients reduce energy intake and adhere to a reduced-energy diet may increase the likelihood of improved long-term health outcomes and reduced risk for obesity-related conditions and diseases. In several large cohorts and a few clinical trials, a dietary pattern that includes regular nut consumption has been associated with less weight gain in adulthood and a lower degree of adiposity [ 4 – 11 ]. In a few previous studies, the effects of consuming almonds, pistachios, walnuts and peanuts on weight change and cardiovascular disease risk factors in the context of a weight loss intervention have been examined, with mixed results [ 12 – 18 ]. A proposed mechanism for the favorable effect of nuts on weight control is that they promote increased satiety, resulting in a compensatory reduction in total energy intake [ 4 , 5 ]. Feelings of satiety, fullness, and hunger following walnut consumption has been examined in only a few previous studies. In those studies, acute postprandial peptide response and early phase satiety was observed to be similar following a meal with or without walnuts, although increased satiety and fullness were found on days 3 and 4 following a walnut-containing meal [ 19 , 20 ]. Measuring responses over the long-term would better model the observational studies that have linked regular nut consumption with lower adiposity and better weight control. In the present study, we compared the effects of a walnut-enriched reduced-energy diet to a reduced-energy-density diet, which has been suggested to be a useful dietary strategy to promote reduced energy intake without compromising meal satiety [ 21 ]. The primary objective of this study was to compare the effects of a walnut-enriched reduced-energy diet to a standard reduced-energy-density diet on body weight and cardiovascular disease risk factors in a sample of overweight and obese adults in an intensive 6-month weight loss intervention. A secondary objective was to examine whether there is a differential response in satiety- and appetite-related ratings scales in association with a walnut-enriched reduced-energy diet and a reduced-energy-density diet among the participants in this weight-loss study. Methods Subjects One hundred non-diabetic overweight and obese men and women were randomized from a screened sample of 647 (Fig. 1 ). To be included in the study, participants had to meet the following criteria: Aged 21 years and older, body mass index (BMI) between 27 and 40 kg/m 2 ; willing and able to participate in clinic visits, group sessions, and telephone and internet communications; able to provide data through questionnaires and telephone; willing to maintain contact with investigators for 6 months; willing to allow blood collections; no known allergy to tree nuts; and capable of performing a simple test for assessing cardiopulmonary fitness. Exclusion criteria were any of the following: Inability to participate in physical activity due to severe disability; history or presence of a comorbid diseases where diet modification and increased physical activity may be contraindicated; self-reported pregnancy or breastfeeding or planning a pregnancy within the next year; currently involved in another diet intervention study or weight loss program; and having a history or presence of a significant psychiatric disorder or any condition that would interfere with participation in the trial. The University of California, San Diego (UCSD), institutional review board approved the study protocol, and all participants provided written informed consent. Open in a separate window Fig. 1 Flow chart for study participants Prior to enrollment, potential participants were screened for diabetes and considered ineligible with a fasting blood glucose ≥125 mg/dL. At screening and recruitment, the ability to participate in moderate intensity physical activity was assessed by questionnaire, a standard procedure for screening participants for community-based weight loss programs of this nature. Participants were additionally asked to report all prescription medications and were asked if they had ever been told by a doctor that they had high blood cholesterol. Once enrolled, participants were randomly assigned to one of the two study arms using a sequence stratified by age (≤52 vs. >52 years) and BMI (≤33 vs. >33 kg/m 2 ). Intervention All participants were provided a detailed diet prescription in an individual counseling session with a dietitian, in which a caloric deficit was set based on the participant’s goals, and a sample meal plan was developed according to study arm and participant food preferences. The overall goal of the dietary guidance was to promote a reduction in energy intake, aiming for a 500- to 1000-kcal/day deficit relative to expenditure. All participants had follow-up contact with the dietitian by telephone or email a minimum of every 1–2 weeks for additional support and to reinforce adherence throughout the intervention. Participants assigned to the standard reduced-energy-density diet arm were provided diet plans that emphasized lower energy density food choices such as vegetables, fruit and whole grains, as well as lean protein sources and reduced-fat dairy foods, with macronutrient composition within current guidelines ( https://www.choosemyplate.gov/MyPlate ). Participants assigned to this study group were asked to refrain from eating any nuts (and products containing them) for the duration of the study. Participants assigned to the walnut-enriched reduced-energy study group were instructed to consume an average of 42 g (1.5 oz) of walnuts/day for diet prescriptions that were ≥1500 kcal/day, or 28 g (1 oz) of walnuts/ for diet prescriptions <1500 kcal/day, all within their energy-reduced diet plan (thus, walnuts provided approximately 15% of total energy intake). Participants were provided meal and snack suggestions and recipes to facilitate adherence, and the nuts were distributed to participants assigned to that group on a weekly basis for 12 weeks and then biweekly for the remainder of the study. Also, participants were queried about walnut consumption for the previous week when the walnuts were distributed, and adherence was recorded. Use of a Web-based planning and tracking program that enabled tracking kilocalories was encouraged. All participants were provided a scale and were asked to weigh themselves daily and to record their progress. An activity tracker was provided and participants were asked to gradually build up to a minimum of 10,000 steps per day within the first month and then to maintain or increase that level of lifestyle activity. An additional daily exercise goal was an average of at least 60 min/day of purposeful aerobic activity at a moderate level of intensity. Strength training 2–3 times/week also was encouraged. Tools such as measuring cups, small exercise equipment, and videos were provided to encourage adherence. In addition to individualized diet prescription and counseling, all participants were assigned to a series of closed group sessions (weekly for 12 weeks, then biweekly), based on a semi-structured cognitive-behavioral weight loss intervention. Briefly, strategies discussed included: Planning and tracking meals and exercise; environmental control; realistic goal-setting; triggers to eating and ways to deal with them; problem-solving; dealing with negative thoughts; promoting self-efficacy through goal accomplishments and other strategies; self-nurturing; dealing with lapses; and addressing body image concerns. Measurements Study data were collected and managed using a Research Electronic Data Capture (REDcap) database hosted at UCSD [ 22 ]. At baseline and 3- and 6-month follow-up data collection clinic visits, weight, height (baseline only), waist circumference, and blood pressure were measured, and a fasting (≥6 h) blood sample and questionnaires were collected. Systolic and diastolic blood pressure was averaged from two sitting blood pressure measurements. The 3-min step test, which measures heart rate during the first 30 s of recovery from stepping, was used to assess cardiopulmonary fitness. This test has high reliability and is sensitive to change [ 23 ]. Physical activity was estimated using the Godin Leisure-Time Exercise Questionnaire, a validated self-report measure of physical activity that has been widely used in previous research [ 24 ]. This questionnaire assesses weekly hours of moderate and strenuous physical activity. These data were compared with current recommendations for physical activity in adults, which are 150 min weekly of moderate physical activity, or 75 min weekly of strenuous physical activity, or a combination of these [ 25 ]. Participants were asked to rate general (rather than meal-specific) satiation by using a visual analog scale (VAS), an approach which has been shown to have validity, reliability, and reproducibility [ 26 ]. Similar to other studies in which satiety and satiation over time (rather than meal-specific) have been assessed [ 19 ], participants were asked to complete these scales before lunch and dinner meals at three time points during the 6 months of active participation (weeks 1, 6, and 13). Specifically, subjects were asked to rate their satiety by answering three questions. Each of the questions was completed by the participant and transferred by staff (blinded to study arm assignment) to a REDCap (Vanderbilt University, Nashville, TN, USA) file database, with a 100 mm horizontal line anchored at either end, so that answers can be quantified on a continuous scale. The questions are: “How hungry do you feel?” with anchor values ranging from “I have never been more hungry” (scored as 0) to “I am not hungry at all” (scored as 100); “How full do you feel?”, with anchor values ranging from “Not at all full” (scored as 0) to “Totally full” (scored as 100); and “How much do you think you could eat now?” with anchor values ranging from “Nothing at all” (scored as 0) to “A lot” (scored as 100). Laboratory measures Laboratory measurements were conducted with plasma samples that had been frozen at -80 ο C after blood collection and processing. Total cholesterol, triglycerides, and high-density lipoprotein cholesterol (HDL-C) were measured by Arup Laboratories (Salt Lake City, UT, USA) using enzymatic methods. The coefficient of variation (CV) for human serum for cholesterol at 76.2 mg/dL and 276 mg/dL is 1.6% and 1.4%, respectively; for triglycerides at 104 mg/dL and 261 mg/dL is 1.9% and 1.8%, respectively; and for HDL-C at 46.4 mg/dL and 80.4 mg/dL is 0.6% and 0.7%, respectively. Low-density lipoprotein cholesterol (LDL-C) values were calculated by the Friedewald equation [ 27 ]. Tocopherols and fatty acids were measured as dietary biomarkers because we anticipated that the walnut-enriched diet group could have different circulating concentrations compared to participants in the standard diet arm, reflecting differential intake of these dietary constituents due to regular walnut consumption. The detection and quantification of plasma tocopherols was accomplished by high performance liquid chromatography, using fluorescent detection at a wavelength of 295 nm excitation and 325 nm emission. Tocopherols were quantified by peak height using a standard curve prepared in bovine serum matrix from pure external compounds. Additionally, pooled in-house quality control samples were analyzed concurrently with batches of study samples, together with other commercially available reference samples, to monitor accuracy and precision. Also, the laboratory participates in the National Institute of Standards and Technology quality assurance program. Red blood cell (RBC) fatty acids were measured by OmegaQuant Laboratories (Sioux Falls, SD, USA) by gas chromatography (GC) with flame ionization detection. GC was carried out using a GC2010 Gas Chromatograph (Shimadzu Corporation, Columbia, MD, USA) equipped with a SP2560, 100-m fused silica capillary column (0.25 mm internal diameter, 0.2 um film thickness; Supelco, Bellefonte, PA, USA). Fatty acids were identified by comparison with a standard mixture of fatty acids characteristic of RBCs (GLC OQ-A, NuCheck Prep, Elysian, MN, USA) which was also used to determine individual fatty acid calibration curves. Fatty acid composition was expressed as a percent of total identified fatty acids. Statistical analysis Demographic characteristics were compared at baseline between groups using chi-square tests for categorical variables and t-tests for continuous variables. Body measurements (weight, BMI, waist circumference), blood pressure, physical activity, lipids, tocopherols and fatty acids were analyzed using repeated measures mixed models assuming unstructured covariance. Change in an indicator of adiposity between groups (weight change as a percentage of initial weight) was also analyzed. Study time, diet group, and the group by time interaction were modeled as fixed effects in each model. Variables that were skewed were log transformed in analysis. Lipid concentrations were examined by sex to assess significant differences at baseline. We tested to see which of the lipids changed between baseline and 6 months, and if a significant change was observed, we performed multivariate analysis to identify predictors of such a lipid change. Power analysis for our sample size was based on published literature for nut consumption in a weight loss intervention [ 15 – 17 ]. Significance was set at alpha = 0.05. All statistical analysis was performed using the SAS software version 9.4 for Windows (SAS Institute Inc., Cary, North Carolina, USA). Results During the course of the study, 3 participants dropped out (one in the standard diet group and 2 in the walnut-enriched diet group). Overall compliance with prescribed walnut consumption in that study arm was 98%; review of monitoring records indicated that of the 47 participants, 43 reported consuming 97–100%, 2 reported consuming 92–96%, and 2 reported consuming 67–69% of the walnuts prescribed during the study. As shown in Table 1 , the randomized study groups did not differ by sex, age, education, or race/ethnicity. Both groups demonstrated a reduction in body weight, BMI, and waist circumference (time effect p < 0.001 for each) during the course of the study, and the two diet groups did not differ in degree of weight lost, with no significant group by time interactions, as shown in Table 2 . Both groups decreased their systolic blood pressure at 3 months, but only those in the walnut-enriched diet group maintained a lower systolic blood pressure at 6 months compared to baseline (Table 3 ). Participants in both study groups also decreased their diastolic blood pressure at 3 and 6 months, and increased their physical activity ( p < 0.001 for each). There was no significant group by time interaction observed in the blood pressure or physical activity models (Table 3 ). Cardiopulmonary fitness, as indicated by the step test recovery heart rate, improved in both study groups. Table 1 Characteristics of study participants in the weight reduction intervention Standard reduced-energy-density diet ( n = 51) Walnut-enriched reduced-energy diet ( n = 49) p (between groups) * Sex (N [%]) 0.53 Female 27 (53%) 31 (63%) Male 24 (47%) 18 (37%) Age (years), mean (SE) 52.2 (1.6) 53.3 (1.4) 0.63 Education (years), mean (SE) 16.1 (0.3) 16.2 (0.3) 0.88 Race/ethnicity (%) 0.84 Non-Hispanic white 73 73 Hispanic/Latino 14 18 African-American 6 2 Asian-American 2 2 Mixed/other 6 4 Open in a separate window p values are from chi-square tests (categorical variables), or t-tests (continuous variables) Table 2 Body measurements of study participants in the weight reduction intervention Standard reduced- energy-density diet Walnut-enriched reduced-energy diet p (between groups) n Mean (SE) n Mean (SE) Body weight, kg a Baseline 51 90.9 (1.8) 49 91.1 (2.3) 0.96 3 Months 51 84.7 (1.8) 48 85.9 (2.3) 0.70 6 Months 50 82.1 (2.0) 47 82.4 (2.2) 0.92 Body mass index, kg/m 2 a Baseline 51 32.4 (0.4) 49 32.4 (0.5) 0.96 3 Months 51 30.3 (0.5) 48 30.6 (0.5) 0.63 6 Months 50 29.4 (0.6) 47 29.6 (0.5) 0.77 Weight change, kg 3 Months 51 −6.0 (0.6) 48 −5.5 (0.5) 0.51 6 Months 50 −8.5 (0.9) 47 −7.9 (0.6) 0.58 % Weight change 3 Months 51 −6.6 (0.6) 48 −6.1 (0.6) 0.53 6 Months 50 −9.4 (0.9) 47 −8.9 (0.7) 0.63 Waist circumference, cm a Baseline 51 109.9 (1.2) 49 111.5 (1.6) 0.42 3 Months 51 101.7 (1.3) 48 104.6 (1.6) 0.16 6 Months 50 98.9 (1.4) 47 100.7 (1.5) 0.39 Open in a separate window a Body weight, body mass index, and waist circumference showed a significant time effect compared with baseline, p < 0.001 for each variable, in both study groups at each follow-up point Table 3 Blood pressure and physical activity variables for study participants in the weight reduction intervention Standard reduced-energy-density diet Walnut-enriched reduced-energy diet p (between groups) n Mean(SE) n Mean(SE) Systolic blood pressure, mm Hg Baseline 51 123 (2) 49 124 (3) 0.77 3 Months 49 117 (2) 48 116 (2) * 0.73 6 Months 49 119 (2) 46 118 (2) * 0.68 Diastolic blood pressure, mm Hg Baseline 51 82 (1) 49 82 (2) 0.72 3 Months 49 77 (1) * 48 76 (1) * 0.57 6 Months 49 78 (2) * 46 77 (1) * 0.70 Moderate/strenuous physical activity, minutes/week Baseline 51 120 (22) 49 133 (18) 0.53 3 Months 51 328 (31) * 48 337 (33) * 0.84 6 Months 49 351 (31) * 47 321 (29) * 0.48 % Meeting physical activity recommendations Baseline 51 25 49 45 0.04 3 Months 51 78 48 79 0.93 6 Months 47 85 47 81 0.58 Step test, heart rate/30s Baseline 51 57 (2) 49 60 (2) 0.14 3 Months 47 47 (1) * 47 49 (1) * 0.33 6 Months 47 45 (1)* 45 47 (1) * 0.18 Open in a separate window * Different from baseline within group, p < 0.01 for each Participants assigned to the walnut-enriched diet group, but not the standard reduced-energy-density diet group, had a reduction in total cholesterol concentration at 6 months, from 203 to 194 mg/dL ( p = 0.04), as shown in Table 4 . Triglycerides decreased in the standard diet group at 3 months and in both groups at 6 months, which decreased an average of 22 mg/dL from 128 to 106 ( p < 0.01 in log-transformed analysis). HDL-C did not change significantly between baseline and 6 months in either of the diet groups. In a subgroup analysis among the 21 men in the study, those assigned to the walnut-rich diet group had lower HDL-C levels (42 [ 10 ] vs. 50 [ 7 ] mg/dL [mean (SD)]) than those assigned to the standard reduced-energy-density diet at baseline ( p = 0.05) and at 3 months, 41(9) vs 54 (13) mg/dL ( p = 0.02) (data not shown). By 6 months, the men assigned to the walnut-enriched diet group had increased their HDL-C to 49 (18) mg/dL, and those in the standard reduced-energy-density diet group had also increased HDL-C to 59 (13) mg/dL (data not shown). Although 27% of the cohort reported having been told by a doctor that they had high cholesterol, only 10% of the cohort reported taking prescription medications to lower lipids. Table 4 Biological measures of study participants in the weight reduction intervention Standard reduced-energy-density diet Walnut-enriched reduced-energy diet p (between groups) p (group x time interaction) Mean(SE) Mean(SE) Cholesterol, mg/dL 0.84 Baseline 200 (5) 203 (6) 0.76 3 Months 199 (5) 198 (5) 0.95 6 Months 194 (6) 194 (6) a 0.91 Triglycerides, mg/dL 0.50 Baseline 130 (10) 123 (7) 0.55 3 Months 110 (8) a 115 (9) 0.66 6 Months 109 (9) a 103 (6) a 0.61 HDL cholesterol, mg/dL 0.08 Baseline 58 (2) 59 (2) 0.70 3 Months 60 (2) 58 (2) 0.37 6 Months 60 (2) 61 (2) 0.94 LDL Cholesterol, mg/dL 0.60 Baseline 116 (4) 121 (5) 0.42 3 Months 116 (5) 116 (4) 0.80 6 Months 112 (5) 112 (5) a 0.96 Alpha-tocopherol, μmol/L 0.96 Baseline 30.5 (1.3) 30.8 (1.0) 0.83 3 Months 30.0 (1.1) 30.3 (1.2) 0.72 6 Months 31.6 (1.2) 32.2 (1.3) 0.84 Beta-tocopherol, μmol/L 0.70 Baseline 0.33 (0.02) 0.33 (0.01) 0.38 3 Months 0.38 (0.01) a 0.27 (0.01) a 0.38 6 Months 0.28 (0.01) a 0.26 (0.01) a 0.99 Gamma-tocopherol, μmol/L 0.48 Baseline 4.23 (0.29) 3.99 (0.27) 0.55 3 Months 4.04 (0.31) 4.13 (0.20) 0.82 6 Months 4.08 (0.33) 4.30 (0.29) 0.74 Delta-tocopherol, μmol/L 0.98 Baseline 0.11 (0.01) 0.11 (0.01) 0.82 3 Months 0.10 (0.01) 0.10 (0.01) 0.88 6 Months 0.09 (0.01) a 0.08 (0.01) a 0.76 Linoleic acid, % <0.001 Baseline 0.111 (0.002) 0.110 (0.002) 0.77 3 Months 0.104 (0.002) a 0.111 (0.002) 0.004 6 Months 0.107 (0.002) a 0.112 (0.001) a 0.01 Alpha-linolenic acid, % <0.001 Baseline 0.00122 (0.00006) 0.00118 (0.00004) 0.57 3 Months 0.00105 (0.00006) a 0.00147 (0.00005) a <0.001 6 Months 0.00118 (0.00005) 0.00158 (0.00007) a <0.001 Open in a separate window a Different from baseline within group, p < 0.05 The overall change (in both groups combined) in total cholesterol at 6 months was −7 mg/dL and for triglycerides was −20 mg/dL. A multivariate model for change in triglycerides did not show that diet group assignment, weight loss, age, sex, or level of physical activity were significantly associated; however, a model for change in total cholesterol showed that weight change and age were significantly associated. In the multivariate model for change in cholesterol at 6 months, R-squared was 0.17 and the two factors significantly associated were age ( p = 0.002) and weight change ( p = 0.02). Diet, baseline BMI, baseline physical activity, and change in physical activity were not significantly related to cholesterol change. Participants >50 years of age decreased their cholesterol by 2 mg/dL compared with a decrease of 19 mg/dL for subjects younger than 50 years of age. Those who lost ≥5% of initial weight decreased their cholesterol by an average of 13 mg/dL compared with an increase in cholesterol of 18 mg/dL in subjects who did not lose at least 5% of initial body weight. As shown in Table 4 , we did not observe changes in alpha- or gamma-tocopherol, which are the major tocopherols in the plasma, and only minor changes in beta- and delta-tocopherol concentrations. Also, we observed increased concentrations of alpha-linolenic acid and linoleic acid in the walnut-enriched diet group over the study period, but not in the standard reduced-energy-density diet group (Table 4 ). Self-reported satiety was similar across the study in the diet groups (Table 5 ). Feelings of hunger decreased and fullness was greater at week 12 than week 1 in the standard reduced-energy-density diet group ( p < 0.05). Fullness was lower in the walnut-rich diet arm at week 12 ( p = 0.04). Table 5 Self-reported satiety (on a 100-point visual analog scale where Hunger is scored 0 = very hungry, 100 = not hungry at all; Fullness is scored 0 = not full, 100 = full; Quantity is scored 0 = nothing, 100 = a lot) in the weight reduction intervention Standard reduced-energy-density diet, mean(SEM) Walnut-enriched reduced-energy diet, mean(SEM) Lunch Dinner Lunch Dinner Hunger Week 1 43 (3) 40 (4) 49 (3) 40 (3) Week 6 50 (4) 43 (4) 42 (4) 45 (4) Week 12 53 (5) a 49 (4) a 44 (4) 44 (4) Fullness Week 1 44(4) 48 (5) 51(4) 51(5) Week 6 53 (5) 53 (42) 58 (4) 52 (5) Week 12 52 (6) a 61 (5) a 48 (4) b 49 (4) b Quantity Week 1 44(4) 50 (4) 49 (3) 55(4) Week 6 49 (4) 53 (4) 48 (4) 47 (4) Week 12 41 (4) 38 (5) 44 (3) 49 (4) Open in a separate window a Both hunger and fullness were greater at week 12 than week 1 in the standard reduced-energy-density diet group ( p < 0.05) b At week 12, fullness was lower in the walnut-rich diet arm than in the standard reduced-energy-density diet group ( p = 0.04) Discussion Findings from this study provide further evidence that a walnut-enriched reduced-energy diet can promote weight loss that is comparable to a standard reduced-energy-density diet in the context of a behavioral weight loss intervention. Although weight loss in response to both dietary strategies was associated with improvements in lipids and blood pressure, the walnut-enriched diet promoted more favorable effects on some cardiovascular disease risk factors, such as LDL-C and systolic blood pressure. Previous studies that have examined the effect of prescribing regular nut consumption on weight change in a weight loss intervention have had mixed results. Two studies found more weight loss in association with almond consumption (at doses of 50–84 g/day for 3 months) compared with controls [ 12 , 16 ], while a study examining the effect of a similar amount of almonds over a longer time frame (18 months) did not observe more weight loss compared to controls [ 15 ]. In a study that examined the effects of prescribing peanuts (16% of energy), weight loss was similar to controls, although the peanut-containing study arm had more favorable effects on cardiovascular disease risk factors [ 13 ]. Providing a daily snack of pistachios (53 g/day) vs. pretzels promoted a greater reduction of BMI and plasma triglyceride concentration but only a trend for a difference in body weight change in another study [ 14 ]. In a 12-month intervention study aimed to promote weight loss and healthy lifestyle, prescribing 30 g/day walnuts was associated with greater weight loss and improved diet quality compared to providing general dietary advice during the 3-month intensive phase of the intervention, although these differences were not evident at study end [ 17 ]. We recently examined the effects of a walnut-rich or higher-monounsaturated fat diet vs. a lower-fat diet prescription on weight loss and selected lipids and biomarkers in the context of a 12-month behavioral weight loss program [ 18 , 28 ]. Participants were stratified by insulin resistance status to allow examination of whether insulin resistance might be associated with differential response to diet composition. Similar to the present study, we observed that prescribing walnuts was associated with weight loss that was comparable to a standard lower fat diet, but better than a higher fat, lower carbohydrate diet without walnuts with regard to biomarker response [ 18 ]. In addition to promoting a similar degree of weight loss, we observed similar self-reported satiety in response to a walnut-enriched reduced-energy diet and a reduced-energy-density diet, that has been proposed to promote reduced energy intake without compromising meal satiety [ 21 ]. Notably, walnuts are very high in energy density, but when consumed as a component of a reduced-energy diet, this strategy may help to promote adherence to restricted total energy intake. The effects of tree nuts on blood lipids and several other cardiovascular disease risk factors were recently examined in a systematic review and meta-analysis [ 29 ], as well as in an earlier pooled analysis [ 30 ], and our observations of lower cholesterol and LDL-C in response to walnut consumption are in agreement with their conclusions. Across the 61 trials that met the eligibility criteria for the meta-analysis, that study found an average reduction of −4.7 and −4.8 mg/dL for total cholesterol and LDL-C, respectively, per one ounce/day serving of tree nuts in interventions ranging from 3 to 26 weeks [ 29 ]. Results of the present study, in which we observed this walnut-specific effect to be even greater in the context of a weight loss intervention, add to the evidence base. We also observed the effect to be modulated by age and degree of weight loss, with a greater reduction in cholesterol in younger individuals (<50 years) and those with greater weight loss (≥5% of initial weight). Previous meta-analyses of the effects of nut consumption on blood pressure are not in agreement, with one of them concluding that there are no significant effects [ 29 ] and another showing a reduction in systolic blood pressure in participants without type 2 diabetes [ 31 ] as observed in the present study. Walnuts are rich in gamma-tocopherol and polyunsaturated fatty acids, particularly alpha-linolenic and linoleic fatty acids [ 32 ]. In previous studies, an increase in gamma-tocopherol concentration has been observed in participants who were prescribed daily walnut consumption [ 33 , 34 ]. In our previous trial that prescribed walnuts in a weight loss intervention [ 18 , 35 ], we observed that walnut prescription minimized the reduction in plasma gamma-tocopherol that occurs in association with reduced energy intake and weight loss, as was observed in the present study. The increase in RBC alpha-linolenic and linoleic fatty acid concentrations in those assigned to the walnut-enriched reduced-energy study arm, and the differences across diet groups, is consistent with previous walnut feeding and walnut-rich diet interventions [ 18 , 33 , 36 ]. These changes in dietary biomarkers also provide strong support for the self-reported high level of adherence in participants instructed to consume walnuts daily in the present study. Notably, replacing saturated fats with polyunsaturated fats has been consistently associated with reduced risk for cardiovascular disease [ 37 , 38 ]. This study has some strengths and limitations. A strength is the heterogeneity of the study sample, which included both men and women and participants across racial/ethnic groups. Also, the retention rate was very high, which is not typical of weight loss intervention studies, and this reduces ambiguity in drawing inferences from this study. A limitation of the study is the lack of detailed information about dietary intake. We encouraged study participants to self-monitor dietary intake as a component of the behavioral strategies to promote weight control, but we did not collect detailed dietary data in an effort to minimize subject burden. Because this was a sample of free-living individuals, some variability in adherence to the prescribed diet is likely. However, the weight loss demonstrated by study participants suggests that most were consuming a reduced-energy diet, and the RBC fatty acid biomarker is indicative of good compliance by participants in the walnut-enriched diet group. Conclusions In conclusion, findings from this study provide further evidence that a walnut-enriched reduced-energy diet can promote weight loss that is comparable to a standard reduced-energy-density diet in the context of a behavioral weight loss intervention. Weight loss in response to both of these dietary strategies was associated with improvements in lipids and blood pressure, although the walnut-enriched diet promoted more favorable effects on LDL-C and systolic blood pressure. Acknowledgements We thank David Wang, Sam Sobrevinas, Jamie Fletcher, Daniel Wang, Jessica Hawks, and Pey-Lih Littler for their valuable assistance with the conduct of this study. We also thank Lita Hinton for her assistance with manuscript preparation and submission. Funding This study was funded by the American Institute for Cancer Research (AICR) and the California Walnut Commission through the AICR Matching Grant Program. The funding agencies had no role in the design of study, data collection and analysis, or presentation of the results. The California Walnut Commission provided the walnuts that were distributed to the participants in that study group. Availability of data and materials The datasets generated and/or analyzed during the current study are not publicly available due to the private (and not public) sponsorship but are available from the corresponding author on reasonable request. Abbreviations BMI Body mass index CV Coefficient of variation GC Gas chromatography HDL-C High-density lipoprotein cholesterol LDL-C Low-density lipoprotein RBC Red blood cell REDcap Research Electronic Data Capture SE Standard error UCSD University of California, San Diego VAS Visual analog scale Authors’ contributions CLR designed and led the study throughout all phases, including the interpretation of the results and the development of the manuscript. SWF was responsible for data management, statistical analysis and interpretation, and presentation of the findings and results. HSB coordinated and operationalized the study, including screening, recruitment and enrollment, data collection and management, and conducted the intervention and dietary counseling of participants. BP contributed to the study design and analysis, and was responsible for all necessary intramural study activities, including institutional review board approval and monitoring. DDH conducted the laboratory analysis and contributed to interpretation of those data. All authors contributed to the writing of the manuscript, and all authors read and approved the final manuscript. Notes Ethics approval and consent to participate The UCSD institutional review board approved the study protocol (#151015), and all participants provided written informed consent. Prior to recruitment and operationalizing the study, the trial was registered at http://www.clinicaltrials.gov ( {"type":"clinical-trial","attrs":{"text":"NCT02501889","term_id":"NCT02501889"}} NCT02501889 ). Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References 1. Jensen MD, Ryan DH, Apovian CM, et al. Guidelines (2013) for managing overweight and obesity in adults. Obesity. 2014; 22 :i–xvi. doi: 10.1002/oby.20778. [ PubMed ] [ CrossRef ] [ Google Scholar ] 2. Fleming JA, Kris-Etherton PM. Macronutrient content of the diet: what do we know about energy balance and weight maintenance? Curr Obes Rep. 2016; 5 :208–213. doi: 10.1007/s13679-016-0209-8. [ PubMed ] [ CrossRef ] [ Google Scholar ] 3. Delzenne N, Blundell J, Brouns F, et al. 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2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease - American College of Cardiology Guidelines JACC ACC.24 Members About Join Create Free Account or Log in to MyACC Menu Home Clinical Topics Acute Coronary Syndromes Anticoagulation Management Arrhythmias and Clinical EP Cardiac Surgery Cardio-Oncology Cardiovascular Care Team Congenital Heart Disease and Pediatric Cardiology COVID-19 Hub Diabetes and Cardiometabolic Disease Dyslipidemia Geriatric Cardiology Heart Failure and Cardiomyopathies Invasive Cardiovascular Angiography and Intervention Noninvasive Imaging Pericardial Disease Prevention Pulmonary Hypertension and Venous Thromboembolism Sports and Exercise Cardiology Stable Ischemic Heart Disease Valvular Heart Disease Vascular Medicine Latest In Cardiology Clinical Updates & Discoveries Advocacy & Policy Perspectives & Analysis Meeting Coverage ACC Member Publications ACC Podcasts View All Cardiology Updates Education and Meetings Online Learning Catalog Earn Credit View the Education Catalog Products ACC Anywhere: The Cardiology Video Library ACCSAP ACCEL CardioSource Plus for Institutions and Practices CathSAP ECG Drill and Practice EchoSAP EP SAP HF SAP Heart Songs Nuclear Cardiology Online Courses Collaborative Maintenance Pathway (CMP) Resources Understanding MOC Image and Slide Gallery Meetings Annual Scientific Session and Related Events Chapter Meetings Live Meetings Live Meetings - International Webinars - Live Webinars - OnDemand Certificates and Certifications Tools and Practice Support ACC Accreditation Services ACC Quality Improvement for Institutions Program CardioSmart National Cardiovascular Data Registry (NCDR) MedAxiom Advocacy at the ACC Cardiology as a Career Path Cardiology Careers Cardiovascular Buyers Guide Clinical Solutions Clinician Well-Being Portal Diversity and Inclusion Infographics Innovation Program Mobile and Web Apps < Back to Listings 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease Mar 17, 2019

\| Melvyn Rubenfire, MD, FACC Print Font Size A A A Authors: Arnett DK, Blumenthal RS, Albert MA, et al. Citation: 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;March 17:[Epub ahead of print]. The following are key perspectives from the 2019 American College of Cardiology/American Heart Association (ACC/AHA) Guideline on the Primary Prevention of Cardiovascular Disease (CVD): Scope of Guideline The guideline is a compilation of the most important studies and guidelines for atherosclerotic CVD (ASCVD) outcomes related to nine topic areas. The focus is primary prevention in adults to reduce the risk of ASCVD (acute coronary syndromes, myocardial infarction, stable or unstable angina, arterial revascularization, stroke/transient ischemic attack, peripheral arterial disease), as well as heart failure and atrial fibrillation. The guideline emphasizes patient-physician shared decisions with a multidisciplinary team-based approach to the implementation of recommended preventive strategies with sensitivities to the social determinants of health that may include specific barriers to care, limited health literacy, financial distress, cultural influences, education level, and other socioeconomic risk factors related to short- and long-term health goals. Assessment of ASCVD Risk Assessment of ASCVD risk is the foundation of primary prevention. For those aged 20-39 years, it is reasonable to measure traditional risk factors every 4-6 years to identify major factors (e.g., tobacco, dyslipidemia, family history of premature ASCVD, chronic inflammatory diseases, hypertension, or type 2 diabetes mellitus [T2DM]) that provide rationale for optimizing lifestyle and tracking risk factor progression and need for treatment. For adults aged 20-39 years and those aged 40-59 years who are not already at elevated (≥7.5%) 10-year risk, estimating a lifetime or 30-year risk for ASCVD may be considered ( ASCVD Risk Estimator Plus ). For those aged 20-59 years not at high short-term risk, the 30-year and lifetime risk would be reasons for a communication strategy for reinforcing adherence to lifestyle recommendations and for some drug therapy (e.g., familial hypercholesterolemia, hypertension, prediabetes, family history of premature ASCVD with dyslipidemia or elevated lipoprotein [a] Lp[a]). Estimating Risk of ASCVD Electronic and paper chart risk estimators are available that utilize population-based and clinical trial outcomes with the goal of matching need and intensity of preventive therapies to absolute risk (generally 10 years) for ASCVD events. The guideline suggests the race- and sex-specific Pooled Cohort Equation (PCE) ( ASCVD Risk Estimator Plus ) to estimate 10-year ASCVD risk for asymptomatic adults aged 40-79 years. Adults should be categorized into low (<5%), borderline (5 to <7.5%), intermediate (≥7.5 to <20%), or high (≥20%) 10-year risk. The PCEs are best validated among non-Hispanic whites and non-Hispanic blacks living in the United States. In other race/ethnic groups and some non-US populations, the PCE may over- or under-estimate risk (e.g., HIV infection, chronic inflammatory or autoimmune disease, and low socioeconomic levels). Consideration should be given to use of other risk prediction tools if validated in a population with similar characteristics. Examples include the general Framingham CVD risk score, Reynolds risk score, SCORE, and QRISK/JBS3 tools. Among borderline and intermediate-risk adults, one may consider additional individual "risk-enhancing" clinical factors that can be used to revise the 10-year ASCVD risk estimate. For initiating or intensifying statin therapy, include: family history of premature ASCVD (men <55 years, women <65 years); low-density lipoprotein cholesterol (LDL-C) ≥160 mg/dl or non-high-density lipoprotein cholesterol (non-HDL-C) ≥190 mg/dl; chronic kidney disease (estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m 2 ); metabolic syndrome; pre-eclampsia and premature menopause (<40 years); inflammatory diseases including rheumatoid arthritis, lupus, psoriasis, HIV; South Asian ancestry; biomarkers including fasting triglycerides ≥175 mg/dl, Lp(a) ≥50 mg/dl, high-sensitivity C-reactive protein ≥2 mg/L, apolipoprotein B >130 mg/dl, and ankle-brachial index (ABI) <0.9. After considering these clinically available risk-enhancing factors, if there is still uncertainty about the reliability of the risk estimate for individuals in the borderline or intermediate-risk categories, further testing to document subclinical coronary atherosclerosis with computed tomography-derived coronary artery calcium score (CACs) is reasonable to more accurately reclassify the risk estimate upward or downward. For persons at intermediate predicted risk (≥7.5 to <20%) by the PCE or borderline (5 to <7.5%) predicted risk, CACs helps refine risk assessment. CACs can re-classify risk upward (particularly when score is ≥100 or ≥75th age/sex/race percentile) or downward (if CACs = 0), which is not uncommon, particularly in men <50 and women <60 years. In MESA (Multi-Ethnic Study of Atherosclerosis), the CACs was strongly associated with 10-year ASCVD risk in a graded fashion across age, sex, and race/ethnic groups, and independent of traditional risk factors. CAC may refine ASCVD risk estimates among lower-risk women (<7.5% 10-year risk), younger adults (<45 years), and older adults (≥75 years), but more data are needed to support its use in these subgroups. A CACs = 0 identifies individuals at lower risk of ASCVD events and mortality over a ≥10-year period, who appear to derive little or no benefit from statins and for which drug interventions can be delayed. The absence of CAC does not rule out noncalcified plaque, and clinical judgment about risk should prevail. CAC might also be considered in refining risk for selected low-risk adults (<5% 10-year risk) such as those with a strong family history of premature coronary heart disease (CHD). There are Internet-available risk estimation tools (MESA and ASTROCHARM), which incorporate both risk factors and CAC for estimating 10-year CHD or ASCVD risk, respectively. CAC measurement is not intended as a "screening" test for all, but rather is a decision aid in select adults to facilitate the clinician-patient risk discussion. Nutrition Dietary patterns associated with CVD mortality include—sugar, low-calorie sweeteners, high-carbohydrate diets, low-carbohydrate diets, refined grains, trans fat, saturated fat, sodium, red meat, and processed red meat (such as bacon, salami, ham, hot dogs, and sausage). All adults should consume a healthy plant-based or Mediterranean-like diet high in vegetables, fruits, nuts, whole grains, lean vegetable or animal protein (preferably fish), and vegetable fiber, which has been shown to lower the risk of all-cause mortality compared to control or standard diet. Longstanding dietary patterns that focus on low intake of carbohydrates and a high intake of animal fat and protein as well as high carbohydrate diets are associated with increased cardiac and noncardiac mortality. The increased availability of affordable, palatable, and high-calorie foods along with decreased physical demands of many jobs have fueled the epidemic of obesity and the consequent increases in hypertension and T2DM. Obesity Adults diagnosed as obese (body mass index [BMI] ≥30 kg/m 2 ) or overweight (BMI 25-29.9 kg/m 2 ) are at increased risk of ASCVD, heart failure, and atrial fibrillation compared with those of a normal weight. Obese and overweight adults are advised to participate in comprehensive lifestyle programs for 6 months that assist participants in adhering to a low-calorie diet (decrease by 500 kcal or 800-1500 kcal/day) and high levels of physical activity (200-300 minutes/week). Clinically meaningful weight loss (≥5% initial weight) is associated with improvement in blood pressure (BP), LDL-C, triglycerides, and glucose levels among obese or overweight individuals, and delays the development of T2DM. In addition to diet and exercise, FDA-approved pharmacologic therapies and bariatric surgery may have a role for weight loss in select patients. Physical Activity Despite the public health emphasis for regular exercise based on extensive observational data that aerobic physical activity lowers ASCVD, approximately 50% of adults in the United States do not meet minimum recommendations. There is a strong inverse dose-response relationship between the amount of moderate-to-vigorous physical activity and incident ASCVD events and mortality. Adults should engage in at least 150 minutes/week of moderate-intensity or 75 minutes/week of vigorous-intensity physical activity including resistance exercise. Diabetes T2DM, defined as a hemoglobin A1c (HbA1c) >6.5%, is a metabolic disorder characterized by insulin resistance leading to hyperglycemia. The development and progression are heavily influenced by dietary pattern, physical activity, and body weight. All with T2DM should undergo dietary counseling for a heart-healthy diet that in T2DM lowers CVD events and CVD mortality. Among options include the Mediterranean, DASH, and vegetarian/vegan diets that achieve weight loss and improve glycemic control. At least 150 minutes/week of moderate to vigorous physical activity (aerobic and resistance) in T2DM lowers HbA1c about 0.7% with an additional similar decrease by weight loss. Other risk factors should be identified and treated aggressively. For younger individuals, or those with a mildly elevated HbA1c at the time of diagnosis of T2DM, clinicians can consider a trial of lifestyle therapies for 3-6 months before drug therapy. First-line therapy to improve glycemic control and reduce CVD risk is metformin. Compared to lifestyle modifications, metformin resulted in a 32% reduction in micro- and macrovascular diabetes-related outcomes, a 39% reduction in myocardial infarction, and a 36% reduction in all-cause mortality. The goal is a HbA1c 6.5-7%. Several classes of medications have been shown to effectively lower blood glucose but may not affect ASCVD risk including the often-used sulfonylureas. Two classes of glucose-lowering medications have recently demonstrated a reduction in ASCVD events in adults with T2DM and ASCVD. Sodium-glucose cotransporter 2 (SGLT-2) inhibitors act in the proximal tubule to increase urinary excretion of glucose and sodium, leading to a reduction in HbA1c, weight, and BP and in randomized clinical trials, significant reduction in ASCVD events and heart failure. The majority of patients studied had established CVD at baseline, although limited data suggest this class of medications may be beneficial for primary prevention. The glucagon-like peptide-1 receptor (GLP-1R) agonists increase insulin and glucagon production in the liver, increase glucose uptake in muscle and adipose tissue, and decrease hepatic glucose production. GLP-1R agonists have been found to significantly reduce the risk of ASCVD events in adults with T2DM at high ASCVD risk. In patients with T2DM and additional risk factors for CVD, it may be reasonable to initiate these two classes of medications for primary prevention of CVD. Lipids Primary ASCVD prevention requires assessing risk factors beginning in childhood. For those <19 years of age with familial hypercholesterolemia, a statin is indicated. For young adults (ages 20-39 years), priority should be given to estimating lifetime risk and promoting a healthy lifestyle. Statin should be considered in those with a family history of premature ASCVD and LDL-C ≥160 mg/dl. ASCVD risk-enhancing factors, (see risk estimate section), should be considered in all patients. Statin Treatment Recommendations The following are guideline recommendations for statin treatment: Patients ages 20-75 years and LDL-C ≥190 mg/dl, use high-intensity statin without risk assessment. T2DM and age 40-75 years, use moderate-intensity statin and risk estimate to consider high-intensity statins. Risk-enhancers in diabetics include ≥10 years for T2DM and 20 years for type 1 DM, ≥30 mcg albumin/mg creatinine, eGFR <60 ml/min/1.73 m 2 , retinopathy, neuropathy, ABI <0.9. In those with multiple ASCVD risk factors, consider high-intensity statin with aim of lowering LDL-C by 50% or more. Age >75 years, clinical assessment and risk discussion. Age 40-75 years and LDL-C ≥70 mg/dl and <190 mg/dl without diabetes, use the risk estimator that best fits the patient and risk-enhancing factors to decide intensity of statin. Risk 5% to <7.5% (borderline risk). Risk discussion: if risk-enhancing factors are present, discuss moderate-intensity statin and consider coronary CACs in select cases. Risk ≥7.5-20% (intermediate risk). Risk discussion: use moderate-intensity statins and increase to high-intensity with risk enhancers. Option of CACs to risk stratify if there is uncertainty about risk. If CAC = 0, can avoid statins and repeat CAC in the future (5-10 years), the exceptions being high-risk conditions such as diabetes, family history of premature CHD, and smoking. If CACs 1-100, it is reasonable to initiate moderate-intensity statin for persons ≥55 years. If CAC >100 or 75th percentile or higher, use statin at any age. Risk ≥20% (high risk). Risk discussion to initiate high-intensity statin to reduce LDL-C by ≥50%. Both moderate- and high-intensity statin therapy reduce ASCVD risk, but a greater reduction in LDL-C is associated with a greater reduction in ASCVD outcomes. The dose response and tolerance should be assessed in about 6-8 weeks. If LDL-C reduction is adequate (≥30% reduction with intermediate- and 50% with high-intensity statins), regular interval monitoring of risk factors and compliance with statin therapy are necessary to determine adherence and adequacy of effect (about 1 year). For patients aged >75 years, assessment of risk status and a clinician-patient risk discussion are needed to decide whether to continue or initiate statin treatment. The CACs may help refine ASCVD risk estimates among lower-risk women (<7.5%) and younger adults (<45 years), particularly in the setting of risk enhancers. Hypertension In the United States, hypertension accounts for more ASCVD deaths than any other modifiable risk factor. The prevalence of stage I hypertension defined as systolic BP (SBP) ≥130 or diastolic BP (DBP) ≥80 mm Hg among US adults is 46%, higher in blacks, Asians, and Hispanic Americans, and increases dramatically with increasing age. A meta-analysis of 61 prospective studies observed a log-linear association between SBP levels <115 to >180 mm Hg and DBP levels <75 to 105 mm Hg and risk of ASCVD. In that analysis, 20 mm Hg higher SBP and 10 mm Hg higher DBP were each associated with a doubling in the risk of death from stroke, heart disease, or other vascular disease. An increased risk of ASCVD is associated with higher SBP and SBP has been reported across a broad age spectrum, from 30 to >80 years of age. In adults with elevated or borderline hypertension (BP 120-129/<80 mm Hg) or hypertension, the initial recommendations include weight loss, heart-healthy diet (DASH or DASH Mediterranean), sodium restriction of 1000 mg reduction and optimal <1500 mg/d), diet rich in potassium with supplements as necessary, exercise as described including aerobic, isometric resistance (hand-grip), dynamic resistance (weights), and limited alcohol (men <3 and women <2 per day). In adults with stage I hypertension (BP 130-139/80-89 mm Hg) and estimated 10-year ASCVD risk of <10%, nonpharmacologic therapy is recommended. In those with a 10% or higher 10-year ASCVD risk, use of BP-lowering medication is recommended with a BP target of <130/80 mm Hg including persons with chronic kidney disease and diabetes. A target of <130/80 mm Hg is also recommended for Stage 2 hypertension, defined as BP ≥140/90 mm Hg with nonpharmacological and BP-lowering medication. Tobacco Tobacco use is the leading preventable cause of disease, disability, and death in the United States. Smoking and smokeless tobacco (e.g., chewing tobacco) increases the risk for all-cause mortality and causal for ASCVD. Secondhand smoke is a cause of ASCVD and stroke, and almost one third of CHD deaths are attributable to smoking and exposure to secondhand smoke. Even low levels of smoking increase risks of acute myocardial infarction; thus, reducing the number of cigarettes per day does not totally eliminate risk. Electronic Nicotine Delivery Systems (ENDS), known as e-cigarettes and vaping, are a new class of tobacco products that emit aerosol containing fine and ultrafine particulates, nicotine, and toxic gases that may increase risk for CV and pulmonary diseases. Arrhythmias and hypertension with e-cigarette use have been reported. Chronic use is associated with persistent increases in oxidative stress and sympathetic stimulation in the healthy young. All adults should be assessed at every visit for tobacco use, and those who use tobacco should be assisted and strongly advised to quit on every visit. Referral to specialists is helpful for both behavioral modification, nicotine replacement, and drug treatments. Amongst the treatments include varieties of nicotine replacement, the nicotine receptor blocker varenicline, and bupropion, an antidepressant. Aspirin For decades, low-dose aspirin (75-100 mg with US 81 mg/day) has been widely administered for ASCVD prevention. By irreversibly inhibiting platelet function, aspirin reduces risk of atherothrombosis but at the risk of bleeding, particularly in the gastrointestinal (GI) tract. Aspirin is well established for secondary prevention of ASCVD and is widely recommended for this indication, but recent studies have shown that in the modern era, aspirin should not be used in the routine primary prevention of ASCVD due to lack of net benefit. Most important is to avoid aspirin in persons with increased risk of bleeding including a history of GI bleeding or peptic ulcer disease, bleeding from other sites, age >70 years, thrombocytopenia, coagulopathy, chronic kidney disease, and concurrent use of nonsteroidal anti-inflammatory drugs, steroids, and anticoagulants. The following are recommendations based on meta-analysis and three recent trials: Low-dose aspirin might be considered for primary prevention of ASCVD in select higher ASCVD adults aged 40-70 years who are not at increased bleeding risk. Low-dose aspirin should not be administered on a routine basis for primary prevention of ASCVD among adults >70 years. Low-dose aspirin should not be administered for primary prevention among adults at any age who are at increased bleeding risk. Clinical Topics: Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Atrial Fibrillation/Supraventricular Arrhythmias, Homozygous Familial Hypercholesterolemia, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Acute Heart Failure, Diet, Exercise, Hypertension, Smoking Keywords: ACC Annual Scientific Session, ACC19, Aspirin, Atherosclerosis, Atrial Fibrillation, Bariatric Surgery, Blood Pressure, Cholesterol, LDL, Coronary Disease, Diabetes Mellitus, Type 2, Diet, Dyslipidemias, Exercise, Heart Failure, HIV, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Hyperglycemia, Hypertension, Inflammation, Kidney Failure, Chronic, Lipids, Lipoproteins, Metabolic Syndrome, Metformin, Myocardial Infarction, Obesity, Plaque, Atherosclerotic, Pre-Eclampsia, Primary Prevention, Risk Factors, Smoking, Stroke, Tobacco, Triglycerides, Weight Loss < Back to Listings x You must be logged in to save to your library. 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Meditative Movements for Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis - PMC Back to Top Skip to main content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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Published online 2020 Feb 1. doi: 10.1155/2020/5745013 PMCID: PMC7016481 PMID: 32089725 Meditative Movements for Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis Tingwei Xia , 1 Yue Yang , 2 Weihong Li , 1 Zhaohui- Tang , 1 Qingsong Huang , 1 Zongrun Li , 1 and Yongsong Guo 1 Tingwei Xia 1 Chengdu University of TCM, Chengdu, Sichuan Province, China Find articles by Tingwei Xia Yue Yang 2 Department of TCM, Qingyang District People's Hospital, Chengdu, Sichuan Province, China Find articles by Yue Yang Weihong Li 1 Chengdu University of TCM, Chengdu, Sichuan Province, China Find articles by Weihong Li Zhaohui- Tang 1 Chengdu University of TCM, Chengdu, Sichuan Province, China Find articles by Zhaohui- Tang Qingsong Huang 1 Chengdu University of TCM, Chengdu, Sichuan Province, China Find articles by Qingsong Huang Zongrun Li 1 Chengdu University of TCM, Chengdu, Sichuan Province, China Find articles by Zongrun Li Yongsong Guo 1 Chengdu University of TCM, Chengdu, Sichuan Province, China Find articles by Yongsong Guo Author information Article notes Copyright and License information PMC Disclaimer 1 Chengdu University of TCM, Chengdu, Sichuan Province, China 2 Department of TCM, Qingyang District People's Hospital, Chengdu, Sichuan Province, China Weihong Li: nc.ude.mctudc@hwl Academic Editor: Martin Offenbaecher Received 2019 Aug 20; Accepted 2019 Dec 28. Copyright © 2020 Tingwei Xia et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Objective Physical activity plays a specific role in the fundamental aspect of diabetes care. It is necessary to develop exercise programs for these patients. The aim of this systematic review is to summarize current evidence regarding the effectiveness of meditative movement in patients with type 2 diabetes. Methods The following databases were searched: PubMed, CENTRAL, Web of Science, Ovid LWW, and EMBASE. Two independent investigators searched and screened the studies by finding duplications, excluding irrelevant titles and abstracts, and then selecting eligible studies by reviewing full texts. 21 studies fulfilled the inclusion criteria. Meta-analyses were performed on glycated hemoglobin (HbA1c), fasting blood glucose (FBG) and postprandial blood glucose (PPBG), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and body mass index (BMI). Results Meta-analyses showed that meditative movements significantly improved FBG, HbA1c, PPBG, TC, LDL-C, and HDL-C. No improvement was found in BMI. Conclusions The results demonstrated a favorable effect or tendency of meditative movements to improve blood glucose and blood lipid levels in patients with type 2 diabetes mellitus. The special effects of meditative movements in type 2 diabetes mellitus patients need further research. 1. Background Physical activity is an important part of the diabetes lifestyle management and negatively associated with the risk of type 2 diabetes mellitus (T2DM). It plays a specific role in the fundamental aspect of diabetes care [ 1 – 3 ]. Type 2 diabetes is one of the most common diseases in older adults. However, the incidence of children, adolescents, or young people is on the rise, due to the rising level of obesity, lack of physical activity, and poor diet [ 2 ]. As the International Diabetes Federation reported, there are approximately 451 million people (ages 18–99 years) with diabetes in the world [ 3 ]. And approximately 90–95% of all cases are type 2 diabetes [ 2 ]. By 2017, nearly 5 million people between the ages of 20 and 99 had died of diabetes and its complications [ 4 ]. At the same time, there are 374 million people with impaired glucose tolerance who are at high risk of developing diabetes [ 4 ]. Diabetic complications affect hundreds of millions of patients with type 2 diabetes [ 5 ]. T2DM patients have a high risk of liver fibrosis and liver steatosis [ 6 , 7 ]. Due to the presentation and progression of these complications, patients may lose their vision, kidney, and nerve function. Their activity and cognitive ability may be impaired, and their quality of life may deteriorate. This leads to limited employment and productivity and increased costs for the patient and society [ 8 – 11 ]. Meditative movements, combining breath control, relaxation, musculoskeletal stretching, and a meditative state of mind, have been shown to be effective for treating type 2 diabetes [ 12 ]. Meditative movements, including Tai Chi, Yoga, and Qigong, reported by the National Health Interview Survey, are popular among American adults in workplace [ 13 ]. Yoga and Tai Chi, especially, are recommended by the American Diabetes Association for older adults with type 2 diabetes to increase flexibility, muscular strength, and balance [ 1 ]. Plenty of clinical researches have focused on the effectiveness of meditative movements on type 2 diabetes. Present systematic reviews or meta-analyses about meditative movements have shown that it is beneficial to chronic obstructive pulmonary disease, sleep quality, cancer, and major depressive disorder [ 14 – 17 ]. However, the systematic review and meta-analysis of meditative movements on type 2 diabetes have not been conducted. Therefore, we performed a systematic review and meta-analysis to evaluate the effectiveness of meditative movements as a complementary therapy for patients with type 2 diabetes. 2. Data and Methods This review was performed according to our previous protocol [ 18 ]. Our protocol of this systematic review and meta-analysis on PROSPERO was registered in advance (no. CRD42019128495 , https://www.crd.york.ac.uk/PROSPERO ). 2.1. Data Sources and Search Strategies The following databases were searched using the developed search strategy [ 18 ] from inception to December 2018: PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, Ovid LWW, and EMBASE. 2.2. Inclusion and Exclusion Criteria We identified studies using the following inclusion criteria as in our protocol [ 18 ]: participants (with a clear diagnosis of type 2 diabetes), intervention (Tai Chi or Qigong or Yoga), control (any type of control group), primary outcomes (HbA1c, FBG, and PPBG), secondary outcomes (TC, TG, HDL-C, LDL-C, and BMI), and study type (randomized controlled trials (RCTs)). 2.3. Trials Inclusion and Data Extraction Two investigators independently searched and screened the studies. The process of study selection was performed using the methods according to the PRISMA guidelines [ 19 ]. Data extraction was performed by two investigators independently. Data extraction contained, in addition to outcomes, information regarding country of origin, number of randomized participants, number of participants included in type of intervention, frequency of intervention, and duration of intervention. Finally, all differences were resolved by consensus. 2.4. Trials Quality Assessment Definitions in the assessment of bias risk of a trial were conducted according to the Cochrane Handbook criteria for judging the ROB with the “risk of bias” assessment tool [ 20 ]. The following domains should be evaluated: random sequence generation, allocation concealment, blinding of participants and investigators, the blindness of outcome assessments, incomplete outcome data, selective outcome reporting, and other biases. The quality of studies was divided into three categories: low, unclear, or high bias. 2.5. Statistical Analysis We used the RevMan 5.3.0 provided by Cochrane Collaboration to analyze the results of the studies. This meta-analysis only included continuous data, so we expressed them as the mean ± standard deviation and then calculated the standardized mean difference (SMD) and obtained the two-sided P value and 95% confidence interval (CI). The complete case data was used as the analysis data. The degree of heterogeneity was quantified using the χ 2 test and I 2 value. We performed subgroup analysis according to total sample size (>60 versus ≤ 60), duration (>3 months versus ≤ 3 months), control type (nonexercise versus other active exercises), type of meditative movement (Tai Chi/Qigong versus Yoga), and region (Asia versus non-Asia), as well as a sensitivity analysis if necessary. A test for the interaction between the treatment and subgroups was performed to examine whether treatment effects differed among subgroups. An interaction of P value ≥0.05 was considered to indicate that the effect of treatment did not differ significantly among subgroups. Publication bias was assessed by visual inspection of a funnel plot. 3. Results 3.1. Literature Screening We retrieved 818 original papers from the electronic bibliographic databases. The full text of 127 articles was assessed according to the predetermined inclusion criteria. Finally, 21 studies fulfilled the inclusion criteria and were further analyzed [ 21 – 44 ]. The detailed process of the studies evaluation and the reasons for exclusion are shown in Figure 1 . Open in a separate window Figure 1 Flow chart of selection process. 3.2. Characteristics of Included Studies The characteristics of these included trials are described in Table 1 . Among them, the data of three studies were reported by six different articles [ 24 – 27 , 37 , 38 ]. Patients included in these studies were from China [ 23 , 39 ], Taiwan (China) [ 29 ], India [ 22 , 24 – 27 , 31 – 35 ], Iran [ 41 ], Japan [ 42 ], Thailand [ 30 ], Australia [ 40 , 43 , 44 ], Cuba [ 37 , 38 ], and USA [ 21 , 28 , 36 ]. Six studies offered Tai Chi [ 23 , 29 , 30 , 39 , 40 , 44 ], three studies offered Qigong [ 28 , 42 , 43 ], and twelve studies offered Yoga [ 21 , 22 , 24 – 27 , 31 – 38 , 41 ]. The sample sizes of the included studies ranged from 10 to 277. The treatment duration lasted from 45 days to 36 weeks. The frequency ranged from 2 to 7 times weekly, and exercise time lasted 10–120 min per session. Controls were divided into nonexercise groups and other active exercise groups. The exercise forms of other active exercise groups include seated calisthenics, stretching, aerobic exercise plus home-based exercise, progressive resistance training, and physical activity. In three studies, two control groups were set up in each, including nonexercise and other active exercises [ 28 , 31 , 37 , 38 ]. Table 1 Characteristics of included studies. Authors, year Location Participants Number Experimental group Control group Follow-up Outcome measures Types of treatment Duration (min) Frequency Zhang Y., 2008 China Women with T2DM E: 10; C: 10 Tai Chi 60 min Five times weekly Nonexercise 14 weeks (1)FBG (2)TC, HDL-C, LDL-C, TG Chen S. C., 2010 Taiwan (China) Patients with T2DM E: 56; C: 48 Tai Chi 60 min Three times weekly Other active exercises (aerobic exercise plus home-based exercise) 12 weeks (1)HbA1c, FBG Lam P., 2008 Australia Adults with T2DM E: 28; C: 25 Tai Chi 60 min Two classes weekly Nonexercise 24 weeks (1)HbA1c (2)TC, TG Youngwanichsetha S., 2013 Thailand Women with T2DM E:32; CG:32 Tai Chi 50 min Three times weekly Nonexercise 12 weeks (1)HbA1c, FBG (2) BMI ORR R., 2006 Australia Older adults with T2DM E: 17; C: 18 Tai Chi 60 min Twice weekly Other active exercises (sham exercise, e.g., seated calisthenics and stretching) 16 weeks (1) FBG Xiao C. M., 2015 China Older adults with DM E: 16; C: 16 Tai Chi 1 to 2 hours Three sessions per week Nonexercise 12 weeks (1)HbA1c Sreedevi A., 2017 India Women with diabetes E:41; C1:42; C2:41 Yoga 60 min Twice weekly C1: other active exercises (physical activity); C2: nonexercise 12 weeks (1)HbA1c, FBG (2) TC, BMI Hegde S. V., 2011 India People with type 2 diabetes E:60; C:63 Yoga n.r. Three times weekly Nonexercise 12 weeks (1)HbA1c, FBG, PPBG (2) BMI Keerthi G. S., 2017 India People with type 2 diabetes E:62; C:62 Yoga 45 min Three times weekly Nonexercise 12 weeks (1) FBG Gordon L. A., 2008 and Gordon L.,2008 Cuba People with type 2 diabetes E:77; C1:77; C2:77 Yoga 60 min 3–4 times per week C1: other active exercises (conventional physical training); C2: Nonexercise 24 weeks (1)HbA1c, FBG (2)TG, TC, HDL-C, LDL-C, BMI Singh S., 2008 and Kyizom T., 2010 India People with type 2 diabetes E:30; C:30 Yoga 45 min 5 days per week Nonexercise 45 days (1)FBG, PPBG (2)TG, TC, HDL-C, LDL-C, BMI Mullur R. S., 2016 USA People with type 2 diabetes E:5; C:5 Yoga 10 min n.r. Nonexercise 12 weeks (1)HbA1c, FBG (2)BMI Yang K., 2009 USA People with type 2 diabetes E:13; C:10 Yoga 60 min Twice per week Nonexercise 12 weeks (1)FBG (2)TG, TC, HDL-C, LDL-C Jyotsna V. P., 2013 India People with type 2 diabetes E:36; C:28 Yoga n.r. 7 days per week Other active exercises (brisk walking) 24 weeks (1)HbA1c, FBG, PPBG Nagarathna R., 2012 India People with type 2 diabetes E:141; C:136 Yoga 60 min 5–7 days per week Other active exercises (physical exercises) 36 weeks (1)HbA1c, FBG, PPBG (2)TG, TC, HDL-C, LDL-C Habibi N., 2013 Iran Women with T2DM E:16; C:10 Yoga 75 min Three times weekly n.r. 12 weeks (1)FBG (2)BMI Shantakumari N., 2012 and Shantakumari N., 2013 India People with type 2 diabetes E:50; C:50 Yoga 60 min 7 days per week Nonexercise 12 weeks (1)FBG, PPBG (2)TG, TC, HDL-C, LDL-C, BMI Vaishali K., 2012 India People with type 2 diabetes E:27; C:30 Yoga 45–60 min 6 days per week Nonexercise 12 weeks (1)HbA1c, FBG (2)TC, TG, HDL-C, LDL-C Liu X., 2011 Australia People with type 2 diabetes E:20; C:21 Qigong 1–1.5 hour Three times weekly Nonexercise 12 weeks (1)HbA1c, FBG, PPBG (2)HDL-C, TG Sun G. C., 2010 USA Adults with type 2 diabetes E:11; C1:10; C2:11 Qigong 30–60 min Three times weekly C1: nonexercise; C2: Other active exercises (the progressive resistance training) 12 weeks (1)HbA1c, FBG; Tsujiuchi T., 2002 Japan Adults with type 2 diabetes E:16; C:10 Qigong 2 h n.r. Nonexercise 16 weeks (1)HbA1c Open in a separate window E: experimental; C: control; FBG: fasting blood glucose; HbA1c: glycated hemoglobin; TC: total cholesterol; TG: triglycerides; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; BMI: body mass index; n.r.: not reported. 3.3. Risk of Bias of Studies The bias condition of selected studies was shown in Figures Figures2 2 and and3. 3 . We assessed the risk of bias in all included articles. Eleven studies used the generation of the allocation sequence. Allocation concealment was used in 6 studies. None of the studies blinded their participants. However, nine studies were blinding of outcome assessors to the treatment allocation, whereas the risk of selective reporting bias was not reported in most studies. Open in a separate window Figure 2 Risk of bias graph. Open in a separate window Figure 3 Risk of bias summary. 4. Outcome 4.1. Glycemic Control Sixteen RCTs, with three studies setting up two control groups in each, reported FBG as a primary outcome. We split the study with two control groups into two sets of data for summary analysis. A total of 19 sets of data were included. The combined result was statistically significant (SMD = 0.81, 95% CI (0.38, 1.24), P =0.0002) compared to the control group, with high heterogeneity ( I 2 = 93%, P < 0.00001) ( Figure 4 ). We carried out sensitivity analyses to explore potential sources of heterogeneity, and the results did not change substantively. The heterogeneity ranged from 67% to 93%. So, we conducted subgroup analyses and interaction tests according to the total sample size, duration, control type, intervention type, and region. Test for interaction showed significant results between subgroups of the nonexercise and other active exercises ( P -interaction = 0.002). The result indicated that the difference of the control types was partly the reason why there was severe heterogeneity in the overall analysis. The detailed results are shown in Table 2 . Open in a separate window Figure 4 Forest plot of the comparison between meditation movements and the control group for the outcome FBG. Table 2 Subgroup analyses based on various exclusion criteria for FBG. Subgroup n SMDs, mmol/L (95% CI) I 2 (%) Heterogeneity, P value P interaction Total sample size 0.87 >60 10 0.84 (0.22, 1.47) 96 <0.00001 ≤60 9 0.91 (0.38, 1.44) 76 <0.0001 Duration 0.11 >3 months 5 1.79 (0.30, 3.28) 98 <0.00001 ≤3 months 14 0.55 (0.29, 0.80) 65 0.0004 Control type 0.002 Nonexercise 12 1.42 (0.71, 2.13) 93 0.64 Other active exercises 6 0.27 (0.15, 0.38) 0 <0.00001 Intervention type 0.71 Tai Chi/Qigong 5 0.74 (0.16, 1.32) 72 0.007 Yoga 14 0.89 (0.35, 1.44) 95 <0.00001 Region 0.28 Asia 13 1.50 (-0.25, 3.25) 78 <0.00001 Non-Asia 6 0.53 (0.25, 0.80) 97 <0.00001 Open in a separate window CIs, confidence intervals; n, number of trials; SMDs, standardized mean differences. Thirteen studies reported HbA1c. Sixteen sets of data were included. The heterogeneity was high ( P < 0.00001, I 2 = 92%). We carried out sensitivity analyses to investigate the potential sources of heterogeneity. After removing one set of data, the results changed obviously. The heterogeneity was calculated as P =0.64, I 2 = 0%. The combined result was statistically significant (SMD = 0.36, 95% CI (0.24, 0.48), and P < 0.00001) ( Figure 5 ). It showed that one study was the potential source of heterogeneity. However, when we looked up the study again, we did not find differences in methodology and other aspects. The study showed that meditation movements had more significant effects on HbA1c than other studies. Five studies reported the PPBG. It showed a favorable effect of meditation movements on reducing PPBG (SMD = 0.30, 95% CI (0.14, 0.46), and P =0.0002), with low heterogeneity ( P =0.29, I 2 = 19%) ( Figure 6 ). Open in a separate window Figure 5 Forest plot of the comparison between meditation movements and the control group for the outcome HbA1c. Open in a separate window Figure 6 Forest plot of the comparison between meditation movements and the control group for the outcome PPBG. 4.2. Lipid Profile The aggregated results suggested that the meditation movements had significant effects on TC (SMD = 0.64, 95% CI (0.02, 1.26), and P =0.04; P for heterogeneity < 0.00001, I 2 = 95%) ( Figure 7 ), LDL-C (SMD = 0.61, 95% CI (0.16, 1.06), and P =0.008; P for heterogeneity < 0.00001, I 2 = 88%) ( Figure 8 ), triglycerides (SMD = 0.19, 95% CI (0.06, 0.31), and P =0.004; P for heterogeneity = 0.14, I 2 = 33%) ( Figure 9 ), and HDL-C (SMD = −0.53, 95% CI (−0.90, −0.15), and P =0.006; P for heterogeneity < 0.00001, I 2 = 85%) ( Figure 10 ). Open in a separate window Figure 7 Forest plot of the comparison between meditation movements and the control group for the outcome TC. Open in a separate window Figure 8 Forest plot of the comparison between meditation movements and the control group for the outcome LDL. Open in a separate window Figure 9 Forest plot of the comparison between meditation movements and the control group for the outcome TG. Open in a separate window Figure 10 Forest plot of the comparison between meditation movements and the control group for the outcome HDL. It showed no effects of meditation movements on reducing BMI (SMD = 0.42, 95% CI (−0.20, 1.03), and P =0.18) with low heterogeneity ( P < 0.00001, I 2 = 95%) ( Figure 11 ). Open in a separate window Figure 11 Forest plot of the comparison between meditation movements and the control group for the outcome BMI. 4.3. Publication Bias The FBG included in the study was selected as an indicator. It can be seen that the graph is not obviously asymmetrical ( Figure 12 ). There might have been no publication bias in the comparison of meditation movements and the control group. Open in a separate window Figure 12 Evaluation of publication bias for FBG. 5. Discussion Meditative movements (specifically Tai Chi, Qigong, and Yoga), including a focus of the mind on the body and breathing for deep relaxation, are special forms of exercise. More and more studies have been conducted on the effectiveness of these practices in health and healing [ 14 ]. As the first systematic review and meta-analysis synthesize the evidence of the effects of meditative movements on type 2 diabetes, we found that meditative movements may have positive effects on the treatment of type 2 diabetes. This evidence suggests that there is a possibility for using these exercises as an augmentation approach to control blood glucose for type 2 diabetes. 5.1. Summary of Main Results The present results showed that the meditative movements significantly improved FBG, HbA1c, PPBG, TC, LDL-C, and HDL-C in patients with type 2 diabetes mellitus. No improvement was found in BMI. As for the primary outcomes, significant heterogeneity was noted during our analyses of FBG and HbA1c. Sensitivity analyses were carried out to explore the potential sources of heterogeneity for FBG. We found that the heterogeneity or the synthesized results of studies on FBG did not change substantively. Therefore, subgroup analyses and interaction tests were carried out to investigate the impact of various exclusion criteria according to the total sample size, duration, control type, intervention type, and region. No evidence of heterogeneity was observed within the total sample size, duration, intervention type, and region. However, the overall combined effects of the trials showed significant results between subgroups of the nonexercise and other active exercises. It indicated that the reason for heterogeneity might be caused by the difference of the control types. Although the results showed a significant difference in reducing FBG between meditative movements and other active exercises, it was more significant compared to the nonexercise group. There is no doubt that other active exercises had a better effect on lowering blood sugar than nonexercise. Sensitivity subgroup analyses were also conducted to explore the potential sources of heterogeneity for HbA1c. We found only one study was the potential source of heterogeneity where no differences were found in methodology and other aspects. It showed more significant effects of meditation movements on HbA1c than other studies. Psychological stress has been proven to play a role in the etiology of type 2 diabetes [ 45 ]. It is regarded both as a predictor of new-onset type 2 diabetes and as a prognostic factor in people with existing type 2 diabetes. The disturbances across multiple biological systems reflecting chronic allostatic load might exist [ 46 ]. Numerous studies have shown that it is a common independent risk factor for disease occurrence [ 47 – 50 ]. Meditative movements could be regarded as a combination of mindfulness intervention and physical activity [ 51 ]. This characteristic determines that its intervention in type 2 diabetes is multifaceted. Diaphragmatic breathing practice might be beneficial to reduce negative subjective and physiological consequences of stress in healthy adults [ 52 ]. This might partly explain why meditative movements have a more positive influence on type 2 diabetes, comparing to other active exercises and nonexercises. Yoga and Tai Chi are mainly recommended to increase flexibility, muscle strength, and balance, which shows that the particularity of meditative movements is not yet well-known. Plenty of studies have shown that meditative movements are effective for glucose control in patients with type 2 diabetes [ 53 – 56 ]. It is necessary to develop exercise programs because the optimal form of exercise and appropriate parameters of exercise in type 2 diabetes patients are not yet clear. 5.2. Limitations Several limitations have to be mentioned. Heterogeneity among the studies was significant. We conducted sensitivity analyses and subgroup analyses. The control types, other active exercises and nonexercises, might be the main source of heterogeneity. To some extent, they could explain the source of heterogeneity. But the risk of bias and heterogeneity could also be caused by study quality or the exercise intensity. Because participants cannot be blinded to the meditative movements, performance bias could not be ruled out. The distribution of the included studies is also a great concern. Most trials were conducted in Asia or America. No studies were from the European countries. Due to the limited number of included studies in Qigong, more comprehensive subgroups could not be made. This may have influenced the explanatory effect and the soundness of the pooled effects. Since we only performed a search for English studies, it is possible that articles may have been published in other languages. 5.3. Implications for Research There are a few points that should be considered in the future. The methodological quality of these studies was poor in random sequence generation, allocation concealment, and blinding of outcome assessment. More studies with rigorous design and normative description are needed in this field. We first summarized the current condition of meditative movements for type 2 diabetes. The particularity of meditative movements, which differs from purely physical activity, should be valued in future studies. In summary, based on the evidence, meditative movements have significant effects on controlling blood glucose and blood lipid levels in patients with type 2 diabetes mellitus. These results support the idea that meditative movements are a possible alternative exercise for type 2 diabetes mellitus management. Due to the aforementioned limitations and potential bias, more high-quality randomized controlled studies should be conducted. In addition to increasing flexibility, muscle strength, and balance, the special effects of meditative movements in type 2 diabetes mellitus patients still need further research. Acknowledgments The authors would like to thank Mr. Tao Yin for data collection. This work was funded by the National Key Research and Development Program of China (no. 2017YFC1703304), International Science and Technology Cooperation Project of the Department of Science and Technology of Sichuan Province (no. 18GJHZ0235), and the National Natural Science Foundation of China (no. 81873204). Ethical Approval This study was based on previously published studies; therefore, ethical approval and patient consent are not relevant. Disclosure This paper was not commissioned and was externally peer-reviewed. TWX and YY are co-first authors. Conflicts of Interest The authors declare that they have no conflicts of interest. Authors' Contributions TWX and YY contributed equally to this work. References 1. 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Effects of tree nuts on blood lipids, apolipoproteins, and blood pressure: systematic review, meta-analysis, and dose-response of 61 controlled intervention trials - PMC Back to Top Skip to main content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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Published online 2015 Nov 11. doi: 10.3945/ajcn.115.110965 PMCID: PMC4658458 PMID: 26561616 Effects of tree nuts on blood lipids, apolipoproteins, and blood pressure: systematic review, meta-analysis, and dose-response of 61 controlled intervention trials 1, 2, 3 Liana C Del Gobbo , 4, * Michael C Falk , 5 Robin Feldman , 5 Kara Lewis , 5 and Dariush Mozaffarian 4 Liana C Del Gobbo 4 Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA; and Find articles by Liana C Del Gobbo Michael C Falk 5 Life Sciences Research Organization, Bethesda, MD Find articles by Michael C Falk Robin Feldman 5 Life Sciences Research Organization, Bethesda, MD Find articles by Robin Feldman Kara Lewis 5 Life Sciences Research Organization, Bethesda, MD Find articles by Kara Lewis Dariush Mozaffarian 4 Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA; and Find articles by Dariush Mozaffarian Author information Article notes Copyright and License information PMC Disclaimer 4 Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA; and 5 Life Sciences Research Organization, Bethesda, MD * To whom correspondence should be addressed. E-mail: ude.drofnats@obbogled . 1 Supported by National Heart, Lung, and Blood Institute grant R01-HL085710-07. 2 The International Tree Nut Council (ITNC) had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. 3 Supplemental Tables 1–4, Supplemental Figures 1–10, and Supplemental Material are available from the “Online Supporting Material” link in the online posting of the article and from the same link in the online table of contents at http://ajcn.nutrition.org . Received 2015 Mar 11; Accepted 2015 Sep 23. Copyright © 2015 American Society for Nutrition Abstract Background: The effects of nuts on major cardiovascular disease (CVD) risk factors, including dose-responses and potential heterogeneity by nut type or phytosterol content, are not well established. Objectives: We examined the effects of tree nuts (walnuts, pistachios, macadamia nuts, pecans, cashews, almonds, hazelnuts, and Brazil nuts) on blood lipids [total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein, and triglycerides], lipoproteins [apolipoprotein A1, apolipoprotein B (ApoB), and apolipoprotein B100], blood pressure, and inflammation (C-reactive protein) in adults aged ≥18 y without prevalent CVD. Design: We conducted a systematic review and meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Two investigators screened 1301 potentially eligible PubMed articles in duplicate. We calculated mean differences between nut intervention and control arms, dose-standardized to one 1-oz (28.4 g) serving/d, by using inverse-variance fixed-effects meta-analysis. Dose-response for nut intake was examined by using linear regression and fractional polynomial modeling. Heterogeneity by age, sex, background diet, baseline risk factors, nut type, disease condition, duration, and quality score was assessed with meta-regression. Publication bias was evaluated by using funnel plots and Egger’s and Begg’s tests. Results: Sixty-one trials met eligibility criteria ( n = 2582). Interventions ranged from 3 to 26 wk. Nut intake (per serving/d) lowered total cholesterol (−4.7 mg/dL; 95% CI: −5.3, −4.0 mg/dL), LDL cholesterol (−4.8 mg/dL; 95% CI: −5.5, −4.2 mg/dL), ApoB (−3.7 mg/dL; 95% CI: −5.2, −2.3 mg/dL), and triglycerides (−2.2 mg/dL; 95% CI: −3.8, −0.5 mg/dL) with no statistically significant effects on other outcomes. The dose-response between nut intake and total cholesterol and LDL cholesterol was nonlinear ( P -nonlinearity < 0.001 each); stronger effects were observed for ≥60 g nuts/d. Significant heterogeneity was not observed by nut type or other factors. For ApoB, stronger effects were observed in populations with type 2 diabetes (−11.5 mg/dL; 95% CI: −16.2, −6.8 mg/dL) than in healthy populations (−2.5 mg/dL; 95% CI: −4.7, −0.3 mg/dL) ( P -heterogeneity = 0.015). Little evidence of publication bias was found. Conclusions: Tree nut intake lowers total cholesterol, LDL cholesterol, ApoB, and triglycerides. The major determinant of cholesterol lowering appears to be nut dose rather than nut type. Our findings also highlight the need for investigation of possible stronger effects at high nut doses and among diabetic populations. Keywords: nuts, cholesterol, lipids, apolipoprotein, cardiovascular INTRODUCTION Accumulating evidence from prospective observational studies and a large clinical trial suggests that nut intake lowers the risk of cardiovascular disease (CVD) 6 ( 1 , 2 ). Tree nuts are rich in unsaturated fats, soluble fiber, antioxidants, and phytosterols ( 3 ), which separately or together may produce beneficial effects on serum lipids, blood pressure, and inflammation ( 4 , 5 ). Prior meta-analyses of controlled trials have shown that tree nut intake lowers total and LDL cholesterol ( 6 – 8 ). However, effects of nut consumption on other key CVD risk factors, including specific lipoproteins, blood pressure, and inflammation, are not established. In addition, 2 of these prior meta-analyses evaluated only one type of nuts—almonds ( 6 ) ( n = 5 trials) and walnuts ( 7 ) ( n = 13 trials)—and potential effects of other tree nuts remain unclear. Furthermore, previous analyses ( 6 – 9 ) have not standardized pooled effects to a common dose or tested for nonlinearity of dose-responses, preventing conclusions about the magnitude of effects for a given intake of nuts or potential for nonlinear effects. Therefore, key questions remain on the major cardiovascular mechanisms influenced by tree nuts, on whether some types of nuts are preferential for improving risk, and on dose-response relations of these effects. To address these knowledge gaps, we performed a systematic review and meta-analysis of controlled interventional trials to examine the effects of tree nuts (walnuts, pistachios, macadamia nuts, pecans, cashews, almonds, hazelnuts, pine nuts, and Brazil nuts) on major CVD risk factors, including blood lipids (total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides), lipoproteins [apolipoprotein A1, apolipoprotein (ApoB), and apolipoprotein B100], blood pressure (systolic and diastolic), and inflammation (C-reactive protein, CRP) in adults aged ≥18 y without prevalent CVD. We hypothesized that tree nuts would lower concentrations of LDL cholesterol and its primary lipoprotein, ApoB. As a secondary hypothesis, we evaluated potential differences in effects by nut type. METHODS We followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines ( 10 ) during all stages of implementation, analysis, and reporting of this meta-analysis. A review protocol has not been published. Eligibility criteria We searched for all published controlled trials that reported the effect of tree nut consumption on blood lipids (total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides), lipoproteins (apolipoprotein A1, ApoB, and apolipoprotein B100), blood pressure (systolic and diastolic), or inflammation (CRP). We did not include body weight or adiposity as outcomes because a meta-analysis of nut intake and body weight was recently reported ( 11 ). Trials had to be controlled but could be randomized or nonrandomized (with plans to evaluate only randomized trials and all trials combined) and provided mean levels of the outcome in each group with an accompanying measure of statistical uncertainty (e.g., 95% CI, SE) or other data to calculate variance. We excluded trials testing nonnut parts of the plant, nut oils, nuts other than tree nuts (e.g., areca, betel), or legumes (e.g., peanuts) and trials testing mixed dietary interventions for which the specific effect of nuts could not be evaluated. We also excluded trials among children (aged <18 y), participants with known CVD (myocardial infarction, angina, stroke, severe heart failure, coronary revascularization, or peripheral vascular disease), and participants receiving medication treatment of diabetes, obesity, metabolic syndrome, hypertension, or hyperlipidemia. For crossover trials without a washout period, we excluded trials with an intervention period <3 wk to minimize carryover effects ( 12 ). Trials with ≥20% dropout rates or having imbalanced dropout between intervention and control groups were also excluded. Articles presenting only observational data, editorials/commentaries, letters, and reviews were not eligible. Search and selection of articles Potentially eligible articles were identified by means of a systematic search in PubMed from the earliest available online indexing year to March 2013, without language restrictions. Query terms were as follows: ( Apolipoproteins B [MeSH]) OR Apolipoprotein A-1 [MeSH]) OR ( Cholesterol, HDL [MeSH] OR Cholesterol, LDL [MeSH])) OR Triglycerides [MeSH]) OR Lipoprotein(a) [MeSH]) OR C-Reactive Protein [MeSH] OR Factor VIII [MeSH]) OR Fibrinogen [MeSH] OR von Willebrand Factor [MeSH]) OR Carotid Intima-Media Thickness [MeSH]) OR Blood Pressure [MeSH]) OR Heart Rate [MeSH] OR ( diabetes or cardiovascular ) AND ( Nuts [MeSH] or Tree nuts or almonds or pecans or brazil nuts or hazelnuts or macadamia or pine nuts or pistachios or walnuts ). Two investigators (MF, KL) screened the titles and abstracts of all potentially eligible articles in duplicate, as well as the full text of all articles identified for further review. In addition, citation lists and the first 20 “related citations” on PubMed of all final included articles were hand-searched for additional eligible trials. Data extraction Data were screened and extracted independently and in duplicate by 2 investigators (MF, KL) by using a standardized electronic form, including information on study randomization (yes, no), design (parallel, crossover), nut type, age (mean), sex (percent male), baseline disease condition, treatment duration, dose (g/d), and description of the placebo or control condition. Differences in data extraction between investigators were infrequent and were resolved by consensus. For each outcome, we extracted its mean value (concentration/amount), variance measure, and the number of participants in the treatment and control arms for all reported periods (e.g., baseline, end treatment). Study quality was assessed by using the Academy of Nutrition and Dietetics (formerly American Dietetic Association) Evidence Analysis Process ( 13 ), which evaluates relevance and validity by using a 14-question quality control checklist, including questions on comparability of control and intervention groups, handling of dropouts, blinding, appropriateness of statistical methods, and potential biases (see “Assessment” on last page of Supplemental Material ). Studies meeting criteria for ≥6 of the 10 validity questions, including questions 2, 3, 6, and 7, were given a positive quality rating; studies meeting ≥6 of the 10 validity questions, but not questions 2, 3, 6, and 7, were given a quality rating of neutral; and studies not meeting at least 6 of 10 validity questions were considered of lower quality ( 13 ). Statistical analysis For parallel trials, the primary effect measure was the mean difference in change from baseline to follow-up in the intervention vs. control group ( 14 ). For crossover trials, the primary effect measure was the mean difference at follow-up in the intervention vs. control periods. The SE of the difference measure was extracted (when directly reported), calculated by using a related statistical measure of uncertainty, or estimated by using the IQR of the difference measure provided in studies. To address within-individual correlation in crossover trials, the median reported correlation across all crossover trials ( r = 0.60) was used in calculating the SE of the difference when the study-specific correlation coefficient was not otherwise provided. In trials with repeated measures, we included the estimate closest to the median duration of follow-up across trials (4 wk). For trials with more than one comparison group, we included estimates from the control diet most like the intervention diet other than the inclusion of nuts. For each trial, the effect size and corresponding variance were standardized to one 1-oz daily serving (28.4 g) of nuts. Meta-analyses were performed by using fixed-effects inverse-variance weighting, evaluating randomized trials, nonrandomized trials, and all trials combined. Heterogeneity was quantified by using the I 2 statistic ( 15 ), with >30% considered at least moderate heterogeneity. Heterogeneity was evaluated by prespecified sources, including randomized vs. nonrandomized trials, age, sex, background diet, baseline risk factor level, nut type, comorbidity, intervention duration, and quality score by using meta-regression. For categorical sources of heterogeneity with ≥3 subgroups, P -heterogeneity from meta-regression was obtained for each indicator category relative to the primary reference category ( 16 ). To test dose-response relations, we plotted the relation between absolute nut intake (g/d) and the absolute mean difference in each outcome, with nonlinearity evaluated by using the F test of linear lack of fit. Fractional polynomial models were used to evaluate nonlinear dose-response relations, with the best-fitting model considered the one with the lowest deviance. Publication bias was evaluated by visual inspection of funnel plots and by Egger’s ( 17 ) and Begg’s ( 18 ) tests. All analyses were performed with STATA 12 (StataCorp LP), with 2-tailed α = 0.05. RESULTS Study characteristics Of 1301 articles, 61 trials met eligibility criteria ( 19 – 80 ) ( Figure 1 ), totaling 2582 unique participants in 42 randomized and 18 nonrandomized trials ( Table 1 ). Trials directly provided nuts to the intervention group, rather than relying only on dietary advice to consume nuts. Compliance was most often assessed by using self-reported dietary recalls or direct supervision of nut consumption. Median participant age was 45 y, and two-thirds of trials (41/61) included both men and women (see Supplemental Table 1 for individual study details). Open in a separate window FIGURE 1 Screening and selection of randomized ( n = 42) and nonrandomized controlled trials ( n = 19) on tree nut intake and lipids/apolipoproteins, blood pressure, and C-reactive protein ( 19 – 80 ). TABLE 1 Summary of 61 trials included in meta-analysis of the effect of tree nut intake on lipids/apolipoproteins, blood pressure, and C-reactive protein, stratified by randomization status and tree nut type 1 Study type/nut type Trials, n Participants (maximum), n Median age, y Male, % Cardiovascular (CVD) comorbidities 2 Median duration, wk Median nut dose, 3 g/d Quality score, n trials 4 Randomized controlled trials Walnut 17 939 54 47 5 trials ( n = 1 with diabetes) 5 49 10(+), 5(Ø), 2(−) Pistachio 6 229 48 50 2 trials ( n = 1 with prostate disease) 4 60 4(+), 2(Ø) Macadamia 2 68 48 70 1 trial (overweight/obese) 4.5 59 2(Ø) Pecan 2 65 41 45 2 trials (high cholesterol, MetS) 6 70 1(+), 1(Ø) Cashew 2 54 64 83 2 trials ( n = 1 with diabetes) 8 85.5 1(+), 1(Ø) Almond 9 429 50 56 3 trials (obese, high cholesterol, diabetes) 4 60 6(+), 3(Ø) Hazelnut 2 201 46 68 2 trials (high cholesterol) 8 36 2(Ø) Mixed nuts 2 106 51 51 2 trials (obese, MetS) 9 30 1(+), 1(Ø) Overall 42 2101 53 53 19/42 trials (45%) with CVD comorbidities 5.5 59.5 23(+), 17(Ø), 2(−) Nonrandomized trials Walnut 4 78 60 43 0 trials 6 45 3(Ø), 1(−) Pistachio 1 17 48 100 0 trials 3 100 1(Ø) Macadamia 2 41 37 50 0 trials 3.5 43 2(−) Almond 7 199 46 45 2 trials (obese, high cholesterol) 4 84 2(+), 5(Ø) Hazelnut 4 109 45 64 1 trials (high cholesterol) 4 54 1(+), 3(Ø) Brazil 1 37 35 0 0 trials 8 5 1(−) Overall 19 481 45 50 3/19 trials (16%) with CVD comorbidities 4 49.5 3(+), 12(Ø), 4(−) All trials Overall 61 2582 45 50 22/61 trials (36%) with CVD comorbidities 4 56 26(+), 29(Ø), 6(−) Open in a separate window 1 Total cholesterol and LDL cholesterol were measured as outcomes in 61 trials; HDL cholesterol in 60 trials; triglycerides in 59 trials; apolipoprotein A1 and apolipoprotein B in 23 and 20 trials, respectively; blood pressure in 21 trials; C-reactive protein in 12 trials; and apolipoprotein B100 in 5 trials ( 19 – 80 ). Descriptive information for individual studies is given in Supplemental Table 1. For a summary of the number of studies and effect sizes by outcome, see Table 2 . Outcomes included total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, apolipoprotein A1, apolipoprotein B, apolipoprotein B100, systolic blood pressure, diastolic blood pressure, and C-reactive protein. CVD, cardiovascular disease; MetS, metabolic syndrome. 2 CVD comorbidities refers to trials of patients with diabetes or those that enrolled at least some participants with high cholesterol, metabolic syndrome, or overweight/obesity. Other conditions are specified. Participants were either not receiving medication for CVD comorbidities, or medication use was not specified in the trial. 3 For meta-analysis, nut dose (g/d) was standardized to 1 serving (28.4 g) of nuts/d. 4 A quality control checklist comprising 14 questions on relevance and validity was used to award studies a positive (+), neutral (Ø), or negative score (−). Further details on the questions and scoring system are given in the Supplemental Appendix . Most trials examined walnuts ( n = 21) or almonds ( n = 16); others examined pistachios ( n = 7), hazelnuts ( n = 6), macadamia nuts ( n = 4), pecans ( n = 2), cashews ( n = 2), mixed tree nuts ( n = 2), and Brazil nuts ( n = 1). The dose of nuts varied from 5 to 100 g/d (median: 56 g/d), and the duration of intervention was from 3 to 26 wk (median: 4 wk). Participants had existing disease conditions in 45% (19/42) of randomized trials and 16% (3/19) of nonrandomized trials; these were most commonly hypertension, hyperlipidemia, and metabolic syndrome ( Table 1 ). In 14 trials, participants received detailed advice to maintain total energy constant between intervention arms; in the remaining 47 trials, participants were provided nuts on top of a common background diet. The most common background diet (i.e., recommended to both intervention and control arms) was habitual diet ( n = 30 trials); other background diets included American Heart Association, low-fat, high-fat, and Mediterranean-type diets. Most trials obtained a positive ( n = 26) or neutral ( n = 29) quality score; 6 trials had a negative score. Main outcomes Compared with control, consumption of tree nuts significantly lowered concentrations (mg/dL) of total cholesterol (weighted mean difference per 28 g serving/d: −4.7; 95% CI: −5.3, −4.0), LDL cholesterol (−4.8; 95% CI: −5.5, −4.2), ApoB (−3.7; 95% CI: −5.2, −2.3), and triglycerides (−2.2; 95% CI: −3.8, −0.5) ( Table 2 ). Reductions in total cholesterol were seen in both randomized trials (−3.6; 95% CI: −4.4, −2.9) and nonrandomized trials (−6.7; 95% CI: −7.8, −5.6); effects in the latter were significantly larger ( P -interaction < 0.001) ( Supplemental Figure 1 ). Similar findings were seen for LDL cholesterol: randomized trials, −4.2 (95% CI: −5.0, −3.4); nonrandomized trials, −6.0 (95% CI: −7.1, −4.9); P -interaction = 0.01 ( Figure 2 ). For ApoB, no significant differences in effects were observed in randomized trials (−4.2; 95% CI: −5.7, −2.6) vs. nonrandomized trials (−1.1; 95% CI: −5.1, 3.0) ( P -interaction = 0.17) ( Supplemental Figure 2 ). Effects on triglycerides were also not statistically significant in nonrandomized trials (−4.6; 95% CI: −8.4, −0.8) vs. randomized trials (−1.6; 95% CI: −3.5, 0.24) ( P -interaction = 0.16) ( Supplemental Figure 3 ). TABLE 2 WMDs in lipids/apolipoproteins, blood pressure, and CRP per 1 serving of tree nuts/d (28.4 g/d) in randomized and nonrandomized controlled trials ( 19 – 80 ) 1 Randomized controlled trials Nonrandomized trials All trials Outcome Trials, n WMD (95% CI) I 2 Trials, n WMD (95% CI) I 2 Trials, n WMD (95% CI) P value 2 Total cholesterol 38 −3.6 (−4.4, −2.9) 53.8 23 −6.7 (−7.8, −5.6) 76.8 61 −4.7 (−5.3, −4.0) 0.001 LDL cholesterol 38 −4.2 (−5.0, −3.4) 38.2 23 −6.0 (−7.1, −4.9) 62.9 61 −4.8 (−5.5, −4.2) 0.01 HDL cholesterol 38 −0.04 (−0.8, 0.7) 0 22 −0.7 (−1.7, 0.4) 35.9 60 −0.3 (−0.9, 0.4) 0.33 TG 37 −1.6 (−3.5, 0.24) 0 22 −4.6 (−8.4, −0.8) 0 59 −2.2 (−3.8, −0.5) 0.16 ApoA1 15 −0.8 (−2.1, 0.6) 12.8 8 1.0 (−2.7, 4.7) 0 23 −0.6 (−1.9, 0.7) 0.38 ApoB 13 −4.2 (−5.7, −2.6) 20.3 7 −1.1 (−5.1, 3.0) 0 20 −3.7 (−5.2, −2.3) 0.17 ApoB100 3 −1.5 (−5.8, 2.8) 0 2 −5.2 (11.0, 0.6) 0 5 −2.8 (−6.2, 0.7) 0.31 SBP 17 1.3 (−0.03, 2.6) 0 4 −3.3 (−5.7, 0.9) 0 21 0.3 (−0.8, 1.4) 0.001 DBP 17 0.6 (−0.7, 1.8) 0 3 −1.6 (−5.8, 2.5) 0 20 0.4 (−0.8, 1.6) 0.32 CRP 8 0.2 (−1.7, 2.0) 0 4 −0.4 (−5.7, 4.8) 0 12 0.1 (−1.6, 1.8) 0.84 Open in a separate window 1 Values for lipids/apolipoproteins and CRP are presented in mg/dL; blood pressure is presented in mmHg. The WMD represents the amount by which the tree nut intervention changed the outcome on average compared with the control group or period. Estimates were pooled by using fixed-effects, inverse-variance meta-analysis. Outcomes included total cholesterol, LDL cholesterol, HDL cholesterol, TG, ApoA1, ApoB, ApoB100, SBP, DBP, and CRP. The I 2 index indicates the percentage of total variability in the effect sizes due to between-study heterogeneity, with I 2 > 30% considered at least moderate heterogeneity. ApoA1, apolipoprotein A1; ApoB, apolipoprotein B; ApoB100, apolipoprotein B100; CRP, C-reactive protein; DBP, diastolic blood pressure; SBP, systolic blood pressure; TG, triglycerides; WMD, weighted mean difference. 2 P -heterogeneity between WMD of randomized controlled trials and nonrandomized trials is shown. Open in a separate window FIGURE 2 WMD in LDL cholesterol (mg/dL) per 1 serving of nuts/d (28.4 g/d) in randomized and nonrandomized controlled trials, pooled by using fixed-effects meta-analysis ( 19 – 80 ). To convert mg/dL to mmol/L, multiply by 0.0259. WMD, weighted mean difference. No significant effects of tree nut consumption were identified for HDL cholesterol, apolipoprotein A1, apolipoprotein B100, systolic or diastolic blood pressure, or CRP ( Supplemental Figures 4–9 ). These findings were similar when randomized and nonrandomized trials were separately evaluated. Dose-responses between nut intake and outcomes When we evaluated dose-responses, tree nut intake lowered total cholesterol and LDL cholesterol in a nonlinear fashion ( P -nonlinearity < 0.001); stronger effects were observed in trials providing doses of ≥60 g nuts/d ( Figure 3 ). In contrast, there was little evidence for nonlinear dose-response relations between nut intake and ApoB or triglycerides ( P -nonlinearity > 0.05 each). Open in a separate window FIGURE 3 Dose-response relations between tree nut intake (g/d) and absolute (unstandardized) mean difference (mg/dL) in total cholesterol ( n = 61 trials) (A), LDL cholesterol ( n = 61 trials) (B), apolipoprotein B ( n = 19 trials) (C), and triglycerides ( n = 59 trials) (D) ( 19 – 80 ). Nut intake lowers total cholesterol and LDL cholesterol in a nonlinear fashion ( P -nonlinearity = 0.001 for both), with stronger effects observed above a nut dose of ∼60 g nuts/d. Linear dose-response relations were observed between nut intake and apolipoprotein B ( r = −0.12) and triglycerides ( r = −0.16). The 95% CI is depicted in the shaded regions. Heterogeneity Heterogeneity was at least moderate ( I 2 > 30%) among trials of total cholesterol and LDL cholesterol and nonrandomized trials of triglycerides and HDL cholesterol, as well as low ( I 2 < 30%) among trials of apolipoproteins, blood pressure, and CRP ( Table 2 ). No significant differences in effects by nut type were observed ( Supplemental Table 2 ), although relatively few trials were available for certain nut types. Heterogeneity by quality score, with greater effect sizes found in lower quality trials, was observed for total cholesterol and LDL cholesterol ( P -heterogeneity = 0.09 and 0.005, respectively); however, these differences were no longer statistically significant in analyses including only randomized controlled trials ( Supplemental Table 3 ). Visual inspection of funnel plots suggested that nonrandomized trials more frequently reported larger effect sizes for total cholesterol and LDL cholesterol ( Supplemental Figure 10 ). For ApoB, significant heterogeneity by comorbidity was found, with stronger effects observed in studies including participants with type 2 diabetes (weighted mean difference: −11.5; 95% CI: −16.2, −6.8) than among healthy populations (−2.5; 95% CI: −4.7, −0.3) ( P -heterogeneity = 0.015) (Supplemental Tables 2 and 3). No significant heterogeneity by other disease conditions, age, sex, background diet, baseline outcome level, or intervention duration was observed. Evaluation of publication bias Visual inspection of funnel plots did not suggest publication bias. Statistical evidence of publication bias was also not detected by using Egger’s or Begg’s tests ( Supplemental Table 4 ). DISCUSSION In this systematic review and meta-analysis of controlled trials including 2582 participants, nut consumption lowered total cholesterol, LDL cholesterol, and its primary apolipoprotein, ApoB. Effects on total cholesterol and LDL cholesterol were generally larger in nonrandomized vs. randomized trials but statistically evident in each. For ApoB, stronger effects were also observed in populations with type 2 diabetes. These benefits were not significantly different across diverse types of tree nuts or when added to a variety of background diets. Nut consumption also lowered triglyceride concentrations, although effects were small in magnitude and only statistically significant in nonrandomized trials. Significant effects of nut consumption on HDL cholesterol, ApoA, blood pressure, or CRP were not identified. This meta-analysis provides the most comprehensive estimates to date of the effects of tree nut intake on major cardiovascular disease risk factors, including dose-response relations and presentation of effects by different nut types. Accumulating evidence indicates that nut intake lowers risk of CVD events, including consistent findings from prospective observational studies ( 1 , 81 ) and the Prevención con Dieta Mediterránea trial ( 2 ). Our findings showing that nut intake significantly improves the lipid profile, lowering LDL cholesterol, ApoB, and triglycerides, provide critical mechanistic evidence to support a causal link between nut intake and lowered CVD risk. In dose-response analyses, the relations between tree nut intake and total cholesterol and LDL cholesterol were nonlinear, with stronger effects at consumption amounts at ≥60 g (about 2 oz, or 2 servings) per day. Trials providing 100 g nuts/d lowered concentrations of LDL cholesterol by up to 35 mg/dL, an effect size comparable to some statin regimens ( 82 ). As a point of caution, only 5 trials (4 nonrandomized, 1 randomized) provided nuts in this quantity, however, and additional trials comparing the effects of multiple nut doses on LDL cholesterol within the same study, particularly at high amounts (e.g., 100 g nuts/d) are needed. In comparison, effects of nuts on ApoB appeared more linear, which could relate to differential effects of tree nuts on LDL cholesterol particle size vs. particle number at different doses, a smaller number of studies of high-dose nut consumption and ApoB, or chance. Further randomized studies of high-dose nut consumption will help clarify whether benefits on blood lipids and apolipoproteins are nonlinear. We did not observe significant heterogeneity in outcomes across different types of tree nuts. In addition, our meta-regression demonstrated that the major determinant of cholesterol lowering appears to be the total dose of tree nut consumption rather than nut type. Significant heterogeneity in effects was also not observed for most other factors, including age, sex, background diet, baseline outcome level, and intervention duration; an exception was that tree nut intake lowered ApoB to a 3- to 4-fold greater degree in trials of diabetic populations in comparison to trials including only nondiabetic participants. In diabetic patients, ApoB provides more accurate information about atherogenic particles than LDL cholesterol concentrations ( 83 ). These findings suggest that nut consumption may be particularly important for lowering CVD risk in patients with diabetes. On the basis of the magnitude of effects of nut intake on lowering LDL cholesterol and ApoB observed in this meta-analysis, together with the established relation between LDL cholesterol and ApoB and CVD events ( 84 ), we calculated the predicted changes in risk of CVD events if one daily serving of nuts was incorporated into the diet. For an LDL cholesterol reduction of 4.2 mg/dL and an ApoB reduction of 4.1 mg/dL per daily serving of nuts observed in randomized trials of this meta-analysis, a 4% (HR: 0.96; 95% CI: 0.93, 0.99) and a 6% lower risk of coronary events are predicted, respectively. These calculated effects are smaller than associations between nut intake and CVD events observed in both prospective cohorts ( 81 , 85 ) and the Prevención con Dieta Mediterránea trial ( 2 ). For instance, in prospective observational studies ( 85 ), a daily serving (28.4 g) of nuts was associated with 29% lower risk of CVD (HR: 0.71; 95% CI: 0.59, 0.85), whereas in the Prevención con Dieta Mediterránea trial, a Mediterranean diet supplemented with one daily serving (30 g) of mixed nuts reduced CVD events by 28% (HR: 0.72; 95% CI: 0.54, 0.96) over 4.8 y of follow-up ( 2 ). These consistent effect sizes in prospective studies and controlled clinical trials suggest that tree nuts have additional cardiovascular benefits beyond LDL cholesterol and ApoB lowering, for example, improving blood glucose and endothelial function ( 59 ). Similarly, specific constituents in tree nuts, such as polyunsaturated fats, are thought to influence CVD risk through both lipid and nonlipid mechanisms ( 86 – 88 ). Our study has several strengths. Our systematic search makes it unlikely that large reports were missed, and error and bias were minimized by independent, duplicate decisions on study inclusion and data extraction. Effect sizes were standardized to a common dose, avoiding combining of heterogeneous comparisons (e.g., “high vs. low” intake) and, importantly, allowing quantitative assessment of dose-response relations. The duration of trials was adequate to achieve changes and stabilization of lipid values ( 12 ). We evaluated multiple cardiovascular disease risk factors, including apolipoproteins; separately evaluated different types of tree nuts; and assessed several sources of heterogeneity. The identified trial populations were relatively diverse, including differences in age, sex, disease status, and background diet, increasing generalizability of our findings. Potential limitations should be considered. Compliance was often assessed by self-report, and low compliance would cause underestimation of effects. Greater effect sizes were observed in lower quality, nonrandomized trials, yet significant effects on total cholesterol, LDL cholesterol, and ApoB were still seen in high-quality, randomized trials. The relatively few trials in some subgroups examined in heterogeneity analyses limited statistical power to detect potential interaction; for example, few estimates ( n ≤ 2) were available for some nut types, such as Brazil nuts, cashews, and pecans. Although larger effects on lowering LDL cholesterol were observed at higher nut doses in our study, we did not examine the effects of nuts on weight change. A recent meta-analysis of controlled trials on this topic ( 11 ) found that nut intake had nonsignificant, inverse effects on adiposity, but doses in most included trials were modest (<56 g/d, or 2 servings, of nuts). Furthermore, nut intake was associated with less weight gain over time in US cohorts of male and female health professionals ( 89 , 90 ). Taken together, the inverse associations with weight gain observed in both controlled trials and free-living populations suggest that nut intake might augment satiety and displace other, less healthful foods in the diet, potentially resulting in less weight gain over time. In conclusion, this systematic review and meta-analysis of controlled trials demonstrates that tree nut consumption lowers total cholesterol, LDL cholesterol, ApoB, and triglycerides. Our findings also highlight the need for additional investigation of potentially stronger effects at high doses of nuts and among diabetic populations. Acknowledgments The authors’ responsibilities were as follows—LCDG, MCF, RF, and KL: conducted research; LCDG: analyzed data and performed statistical analysis; LCDG and DM: wrote the manuscript; LCDG: had primary responsibility for final content; and all authors: designed research and read and approved the final manuscript. DM reports ad hoc honoraria from Bunge, Pollock Institute, and Quaker Oats; ad hoc consulting for Foodminds, Nutrition Impact, Amarin, Astra Zeneca, Winston, and Strawn LLP; membership, Unilever North America Scientific Advisory Board; and chapter royalties from UpToDate. LCDG and DM received modest ad hoc consulting fees from the Life Sciences Research Organization (LSRO) in Bethesda, MD, to support this study. 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Relaxation Techniques - StatPearls - NCBI Bookshelf Warning: The NCBI web site requires JavaScript to function. more... An official website of the United States government Here's how you know The .gov means it's official. Federal government websites often end in .gov or .mil. Before
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Norelli ; Ashley Long ; Jeffrey M. Krepps . Author Information and Affiliations Authors Samantha K. Norelli 1 ; Ashley Long 2 ; Jeffrey M. Krepps 3 . Affiliations 1 Campbell University School of OM 2 Nova Southeastern University KPCOM 3 Campbell University, School of OM Last Update: August 28, 2023 . Continuing Education Activity Relaxation techniques are therapeutic exercises designed to assist individuals by decreasing tension and anxiety. Relaxation therapy has been a part of psychotherapy for ages; however, these techniques can be expanded to include diverse environments as complementary therapies to treat stress, anxiety, depression, and pain. In addition to its psychological impact, stress can cause physiological responses such as increased heart rate, palpitations, diaphoresis, shortness of breath, and muscle tension. Relaxation techniques can aid in the reduction of these unpleasant responses. Many variations of relaxation strategies exist and can be facilitated by a variety of health professionals or learned via self-help modalities. This activity describes the benefits of relaxation techniques in individuals undergoing stress and highlights the role of the interprofessional team in encouraging these practices to improve the lives of their patients. Objectives: Identify the indications for relaxation techniques. Describe the types of relaxation techniques. Outline the clinical benefits of relaxation. Summarize interprofessional team strategies for enhancing care coordination and communication to advance the utilization of relaxation techniques to improve outcomes. Access free multiple choice questions on this topic. Introduction Relaxation techniques are therapeutic exercises designed to assist individuals with decreasing tension and anxiety, physically and psychologically. Strategies to assist patients with relaxation have long been a hallmark component of psychotherapy; however, they can be utilized throughout healthcare environments as complementary therapies to treat patients experiencing various types of distress, including but not limited to anxiety, depression, pain, and stress [1] . Relaxation techniques encompass an array of strategies to increase feelings of calm and decrease feelings of stress. Feelings of stress can include physiological responses such as increased heart rate, shortness of breath, and muscle tension, along with the subjective emotional experience; and relaxation techniques can aid in the reduction of these symptoms [2] . Many variations of relaxation strategies exist and can be facilitated by a variety of health professionals and learned via self-help. Indications Relaxation techniques are therapeutic exercises indicated to assist patients in decreasing physical and psychological tension and anxiety. Preparation The following are step-by-step examples of relaxation techniques that can be relayed to patients by health professionals. It is helpful to know a variety of relaxation techniques to offer to patients as different strategies work for different patients. Relaxation techniques have been shown to reduce cortisol levels in patients, leading to a decrease in somatic and subjective experiences of stress [3] . Like all beneficial, healthy activities, each relaxation technique should be practiced over time and implemented regularly for optimal stress reduction. Technique or Treatment Box Breathing While there are many different forms of deep breathing exercises, box breathing can be particularly helpful with relaxation. Box breathing is a breathing exercise to assist patients with stress management and can be implemented before, during, and/or after stressful experiences. Box breathing uses four simple steps. Its title is intended to help the patient visualize a box with four equal sides as they perform the exercise. This exercise can be implemented in a variety of circumstances and does not require a calm environment to be effective. Step One: Breathe in through the nose for a count of 4. Step Two: Hold breath for a count of 4. Step Three: Breath out for a count of 4. Step Four: Hold breath for a count of 4. Repeat Note: The length of the steps can be adjusted to accommodate the individual (e.g., 2 seconds instead of 4 seconds for each step). Guided Imagery Guided imagery is a relaxation exercise intended to assist patients with visualizing a calming environment. Visualization of tranquil settings assists patients with managing stress via distraction from intrusive thoughts. Cognitive behavioral theory suggests that emotions are derived from thoughts, therefore, if intrusive thoughts can be managed, the emotional consequence is more manageable. Imagery employs all five senses to create a deeper sense of relaxation. Guided imagery can be practiced individually or with the support of a narrator. Step One: Sit or lie down comfortably. Ideally, the space will have minimal distractions. Step Two: Visualize a relaxing environment by either recalling one from memory or created one through imagination (e.g., a day at the beach). Elicit elements of the environment using each of the five senses using the following prompts: What do you see? (e.g., deep, blue color of the water) What do you hear? (e.g., waves crashing along the shore) What do you smell? (e.g., fruity aromas from sunscreen) What do you taste? (e.g., salty sea air) What do you feel? (e.g., warmth of the sun) Step Three: Sustain the visualization as long as needed or able, focusing on taking slow, deep breaths throughout the exercise. Focus on the feelings of calm associated with being in a relaxing environment. Progressive Muscle Relaxation Progressive Muscle Relaxation (PMR) is a relaxation technique targeting the symptom of tension associated with anxiety. The exercise involves tensing and releasing muscles, progressing throughout the body, with the focus on the release of the muscle as the relaxation phase. Progressive muscle relaxation can be practiced individually or with the support of a narrator. Step One: Sit or lie down comfortably. Ideally, the space will have minimal distractions. Step Two: Starting at the feet, curl the toes under and tense the muscles in the foot. Hold for 5 seconds, then slowly release for 10 seconds. During the release, focus attention on the alleviation of tension and the experience of relaxation. Step Three: Tense the muscles in the lower legs. Hold for 5 seconds, then slowly release for 10 seconds. During the release, focus attention on the alleviation of tension and the experience of relaxation. Step Four: Tense the muscles in the hips and buttocks. Hold for 5 seconds, then slowly release for 10 seconds. During the release, focus attention on the alleviation of tension and the experience of relaxation. Step Five: Tense the muscles in the stomach and chest. Hold for 5 seconds, then slowly release for 10 seconds. During the release, focus attention on the alleviation of tension and the experience of relaxation. Step Six: Tense the muscles in the shoulders. Hold for 5 seconds, then slowly release for 10 seconds. During the release, focus attention on the alleviation of tension and the experience of relaxation. Step Seven: Tense the muscles in the face (e.g., squeezing eyes shut). Hold for 5 seconds, then slowly release for 10 seconds. During the release, focus attention on the alleviation of tension and the experience of relaxation. Step Eight: Tense the muscles in the hand, creating a fist. Hold for 5 seconds, then slowly release for 10 seconds. During the release, focus attention on the alleviation of tension and the experience of relaxation. Note: Be careful not to tense to the point of physical pain, and be mindful to take slow, deep breaths throughout the exercise. Clinical Significance Relaxation strategies are used as therapeutic interventions for patients experiencing stress. It is widely accepted that high stress, particularly sustained rates of high stress, have negative effects on physical and mental health. Chronic stress in childhood and adulthood can lead to increased blood pressure and mental health issues among other health concerns [4] . Additionally, chronic stress has been shown to affect brain development, specifically the amygdala which is essential for emotion regulation and the pre-frontal cortex which is necessary for executive functioning and decision-making; therefore, it is useful to have relaxation strategies as coping tools to share with patients to decrease stress. [5] [6] [7] [8] Enhancing Healthcare Team Outcomes The healthcare profession is stressful for physicians, nurses, pharmacists and other related professionals. Burnout from stress is common. Thus, many types of relaxation techniques have been developed to help ease the tension and relieve the stress. There is literature to show that stress free individuals are more efficient and effective compared to stressed individuals. [9] Review Questions Access free multiple choice questions on this topic. Comment on this article. References 1. Parás-Bravo P, Alonso-Blanco C, Paz-Zulueta M, Palacios-Ceña D, Sarabia-Cobo CM, Herrero-Montes M, Boixadera-Planas E, Fernández-de-Las-Peñas C. Does Jacobson's relaxation technique reduce consumption of psychotropic and analgesic drugs in cancer patients? A multicenter pre-post intervention study. BMC Complement Altern Med. 2018 May 02; 18 (1):139. [ PMC free article : PMC5930442 ] [ PubMed : 29720148 ] 2. Volpato E, Banfi P, Nicolini A, Pagnini F. A quick relaxation exercise for people with chronic obstructive pulmonary disease: explorative randomized controlled trial. Multidiscip Respir Med. 2018; 13 :13. [ PMC free article : PMC5932751 ] [ PubMed : 29744054 ] 3. Dawson MA, Hamson-Utley JJ, Hansen R, Olpin M. Examining the effectiveness of psychological strategies on physiologic markers: evidence-based suggestions for holistic care of the athlete. J Athl Train. 2014 May-Jun; 49 (3):331-7. [ PMC free article : PMC4080595 ] [ PubMed : 24490842 ] 4. Brenhouse HC, Danese A, Grassi-Oliveira R. Neuroimmune Impacts of Early-Life Stress on Development and Psychopathology. Curr Top Behav Neurosci. 2019; 43 :423-447. [ PubMed : 30003509 ] 5. Kuloor A, Kumari S, Metri K. Impact of yoga on psychopathologies and quality of life in persons with HIV: A randomized controlled study. J Bodyw Mov Ther. 2019 Apr; 23 (2):278-283. [ PubMed : 31103108 ] 6. Garland SN, Xie SX, DuHamel K, Bao T, Li Q, Barg FK, Song S, Kantoff P, Gehrman P, Mao JJ. Acupuncture Versus Cognitive Behavioral Therapy for Insomnia in Cancer Survivors: A Randomized Clinical Trial. J Natl Cancer Inst. 2019 Dec 01; 111 (12):1323-1331. [ PMC free article : PMC6910189 ] [ PubMed : 31081899 ] 7. Huang AJ, Grady D, Mendes WB, Hernandez C, Schembri M, Subak LL. A Randomized Controlled Trial of Device Guided, Slow-Paced Respiration in Women with Overactive Bladder Syndrome. J Urol. 2019 Oct; 202 (4):787-794. [ PMC free article : PMC6842393 ] [ PubMed : 31075059 ] 8. Lopez-Lopez L, Valenza MC, Rodriguez-Torres J, Torres-Sanchez I, Granados-Santiago M, Valenza-Demet G. Results on health-related quality of life and functionality of a patient-centered self-management program in hospitalized COPD: a randomized control trial. Disabil Rehabil. 2020 Dec; 42 (25):3687-3695. [ PubMed : 31074660 ] 9. Anderson KGC, Langley J, O'Brien K, Paul S, Graves K. Examining the artist-patient relationship in palliative care. A thematic analysis of artist reflections on encounters with palliative patients. Arts Health. 2019 Feb; 11 (1):67-78. [ PMC free article : PMC6494112 ] [ PubMed : 31038040 ] Disclosure: Samantha Norelli declares no relevant financial relationships with ineligible companies. Disclosure: Ashley Long declares no relevant financial relationships with ineligible companies. Disclosure: Jeffrey Krepps declares no relevant financial relationships with ineligible companies. Copyright © 2024, StatPearls Publishing LLC. This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal. Bookshelf ID: NBK513238 PMID: 30020610 Share Views PubReader Print View Cite this Page Norelli SK, Long A, Krepps JM. Relaxation Techniques. [Updated 2023 Aug 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. In this Page Continuing Education Activity Introduction Indications Preparation Technique or Treatment Clinical Significance Enhancing Healthcare Team Outcomes Review Questions References Bulk Download Bulk download StatPearls data from FTP Related information PMC PubMed Central citations PubMed Links to PubMed Similar articles in PubMed Behavioural modification interventions for medically unexplained symptoms in primary care: systematic reviews and economic evaluation. [Health Technol Assess. 2020] Behavioural modification interventions for medically unexplained symptoms in primary care: systematic reviews and economic evaluation. Leaviss J, Davis S, Ren S, Hamilton J, Scope A, Booth A, Sutton A, Parry G, Buszewicz M, Moss-Morris R, et al. Health Technol Assess. 2020 Sep; 24(46):1-490. Florida Domestic Violence. [StatPearls. 2024] Florida Domestic Violence. Houseman B, Semien G. StatPearls. 2024 Jan Evaluating telehealth lifestyle therapy versus telehealth psychotherapy for reducing depression in adults with COVID-19 related distress: the curbing anxiety and depression using lifestyle medicine (CALM) randomised non-inferiority trial protocol. [BMC Psychiatry. 2022] Evaluating telehealth lifestyle therapy versus telehealth psychotherapy for reducing depression in adults with COVID-19 related distress: the curbing anxiety and depression using lifestyle medicine (CALM) randomised non-inferiority trial protocol. Young LM, Moylan S, John T, Turner M, Opie R, Hockey M, Saunders D, Bruscella C, Jacka F, Teychenne M, et al. BMC Psychiatry. 2022 Mar 27; 22(1):219. Epub 2022 Mar 27. Review Stretch-based relaxation training. [Patient Educ Couns. 1994] Review Stretch-based relaxation training. Carlson CR, Curran SL. Patient Educ Couns. 1994 Apr; 23(1):5-12. Review Breathlessness with pulmonary metastases: a multimodal approach. [J Adv Pract Oncol. 2013] Review Breathlessness with pulmonary metastases: a multimodal approach. Brant JM. J Adv Pract Oncol. 2013 Nov; 4(6):415-22. See reviews... See all... Recent Activity Clear Turn Off Turn On Relaxation Techniques - StatPearls Relaxation Techniques - StatPearls Your browsing activity is empty. Activity recording is turned off. Turn recording back on See more... Follow NCBI Twitter Facebook LinkedIn GitHub NCBI Insights Blog Connect with NLM Twitter Facebook Youtube National Library of Medicine 8600 Rockville Pike Bethesda, MD 20894 Web Policies FOIA HHS Vulnerability Disclosure Help Accessibility Careers NLM NIH HHS USA.gov
What are the effects of psychological stress and physical work on blood lipid profiles? - PMC Back to Top Skip to main content An official website of the United States government Here's how you know The .gov means it’s official. Federal government websites often end in .gov or .mil. Before
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the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer \| PMC Copyright Notice Medicine (Baltimore). 2017 May; 96(18): e6816. Published online 2017 May 5. doi: 10.1097/MD.0000000000006816 PMCID: PMC5419930 PMID: 28471984 What are the effects of psychological stress and physical work on blood lipid profiles? Seyedeh Negar Assadi , MD ∗ Monitoring Editor: Yung-Hsiang Chen. Author information Article notes Copyright and License information PMC Disclaimer Department of Occupational Health Engineering, School of Health, Social Determinants of Health Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. ∗ Correspondence: Seyedeh Negar Assadi, Department of Occupational Health Engineering, School of Health, Social Determinants of Health Research Center, Mashhad University of Medical Sciences, Mashhad, Iran (e-mail: ri.ca.smum@nidassa ). Received 2016 Oct 6; Revised 2017 Mar 15; Accepted 2017 Apr 13. Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0 Abstract Blood lipids disorders are prevalent in the world. Some of their risk factors are modifiable such as mental and physical stress which existed in some places such as work environment. Objective of this study was to determine the effects of psychological and physical stress on the lipid profiles. It was a historical cohort study. The people who were employed as general worker were participated. The study was conducted with flexible interview for getting history, lipid profile examination, and a checklist including occupational and nonoccupational risk factors and using the health issues. According to the type of stress exposures, the study population was divided into 5 groups. Groups were followed for lipid profiles. These groups were exposed to psychological stress, physical stress or both of them; mild psychological stress (group 1), mild physical work without psychological stress (group 2), mild psychological stress and mild physical work (group 3), moderate physical work without psychological stress (group 4), and heavy physical work without psychological stress (group 5). Data were analyzed with SPSS 16. ANOVA, χ 2 , and exact test were calculated with considering P < .05 as significant level. Relative risks were calculated with confidence interval 95%. The means of lipid profiles were in normal ranges. The relative risks for triglycerides more than 200 mg/dL was 1.57 (1.02–2.42) and low density lipoprotein (LDL) more than 130 mg/dL was 14.54 (3.54–59.65) in group 1. The relative risks for high density lipoprotein (HDL) less than 45 mg/dL was 14.61 (8.31–25.68) in group 1 and 16.00 (8.30–30.83) in group 3. After multinomial logistic regression they had significant differences. Psychological stress was a risk factor for lipid disorders, and suitable physical activity was protective in this situation. Keywords: lipid disorder, physical activity, stress, work 1. Introduction Lipid disorders are prevalent in the world. [ 1 ] Some of their risk factors are modifiable such as mental and physical stresses in some situations like workplaces. The main etiology of lipid disorders is genetic factor and family history that is not changeable. In recent decade researchers have worked on risk factors for lipid disorders. [ 1 ] Hypertriglyceridemia, hypercholesterolemia, and related lipid disorders are very common, their prevalence are between 20% and 50% in different populations. [ 1 ] There are a few studies that showed the role of environmental risk factors for dyslipidemia besides nutritional conditions. [ 1 , 2 ] Psychological stress had effects on human body especially on some specific organs and parameters and physiological parameters too, lipid profile was one of them. Physical stresses caused by physical works could be affected lipid profiles too. Night shift work could be a risk factor for hyperlipidemia but the background of well-being is important in this situation. [ 2 , 3 ] Researchers reported lipid disorders; related to job stress in professional drivers. Their study showed the effects of stress on triglycerides, low density lipoprotein (LDL), and high density lipoprotein (HDL). [ 4 ] Scientists showed the relationship between job stress and dyslipidemia including total cholesterol and LDL and decreased HDL. [ 5 ] Researchers studied the association between the occupational stress and hypertension, type 2 diabetes mellitus, lipid disorders. [ 6 ] Other researcher showed the cardiovascular disease and its risk factors in law enforcement personnel. [ 7 ] Another study demonstrated the association between job stress and combined dyslipidemia among workers. [ 8 ] There are also some studies about the dyslipidemias in female law enforcement officers and railway workers, and male aircrew personnel. [ 9 – 11 ] Some studies showed lipid disorders in people with jobs that had psychological stress. [ 12 – 14 ] Researchers demonstrated the effectiveness of wellbeing, preventive methods, and treatment on lipid disorders. [ 15 – 17 ] Night shift work was reported as a risk factor for cardiovascular disorders in different jobs, [ 18 – 20 ] which are common in the society. [ 21 , 22 ] Chemicals such as carbon disulfide was also introduced as a cardiovascular risk factor. [ 23 , 24 ] All together some studies have showed the effects of work stress on health and wellbeing. [ 25 – 28 ] Objective of this study was to determine the effects of psychological and physical stress on lipid profiles. 2. Materials and methods Study design and target population; it was a historical cohort study, which was performed on people who were employed as general workers during 2005 to 2016. The main aim was to compare the effects of psychological and physical stress on participants’ lipid profiles. Data were collected with flexible interview, physical examination, and a checklist including history, measurement of lipid profile and risk factors and using the data from health issues. According to type of exposures the study population was divided into 5 groups. Groups were followed for lipid profiles. These industries had not another risk factor for lipid profile changes. They were not used carbon disulfide, they had low to moderate fat in nutrition. All of them had shift work. Simple random sampling method was used with α = 0.05, power = 90, P1 = 25%, and P2 = 50%, the calculated study population was 1000 for each group (5 groups), and 5000 in total. The inclusion criteria were people who worked in general working with at least 5 years work experience in the same work. The exclusion criteria were having the hyperlipidemia and related diseases before beginning this job and having the positive family history in lipid profile disorders and anxiety disorders. The validity and reliability of checklist were checked with specialists’ opinions and also with performing a pilot study with correlation coefficient 90%. The participants were interviewed by author using a checklist. The results of blood examinations in periodic examination were taken and body mass index (BMI) was calculated. The level of cholesterol in total and ingredients (LDL and HDL) and triglyceride were important for researcher. These values were high risk; BMI was equal and more than 30 kg/m 2 , triglycerides was equal and more than 200 mg/dL, total cholesterol was equal and more than 200 mg/dL, LDL was equal and more than 130 mg/dL, and HDL was equal and more than 45 mg/dL. 2.1. Exposure assessment Two types of physical and psychological stress were assessed in this study and 5 groups with different exposures were evaluated: mild psychological stress (group 1), mild physical work without psychological stress (group 2), mild psychological stress and mild physical work (group 3), moderate physical work without psychological stress (group 4), and heavy physical work without psychological stress (group 5). Group 1: workers with more than 1% to 25% of total grade in work environmental scale and modified standard stress scale. Group 2: workers with mild physical work without psychological stress. Group 3: workers with more than 1% to 25% of total grade in work environmental scale and modified standard stress scale and mild physical work. Group 4: workers moderate physical work without psychological stress. Group 5: workers with heavy physical work without psychological stress. Job stress was assessed with work environmental scale and modified standard stress scale; there were 10 items with 0 to 10 grades. Items were in organizational (change, coworkers, supervisor relationships), career development (achievement, improvement), role (ambiguity, conflict), task (under or over load), and environmental fields. Stress were recognized with more than 1% to 25% of total grades as mild level, and the severity of physical work was assessed with standards aerobic tests (McArdle step test) and calculated metabolic equivalent tasks or metabolic equivalent of tasks (METs) with according to VO 2 max (mL/kg/m) at the preplacement of participants; preplacement examinations results were used for physical stress determination. METs less than or equal to 3 indicates mild activity, between 3 and 6 shows moderate activity and more than 6 declares a heavy work. Other work exposures were kept in the standard levels. The researcher determined the stress level according to work environmental scale and modified standard stress scale. By using of blood examinations were done in periodic examinations the relation between the job risks and lipid profiles were showed. For statistical analysis, data were analyzed with SPSS 16. χ 2 , exact test, ANOVA, and regression were used to compare qualitative and quantitative variables, P -value less than .05 was considered for significant levels and relative risks were calculated with confidence interval 95%. 2.2. Ethical consideration This study, involving human participants, was done in accordance with the ethical standards and with the 1964 Helsinki declaration and comparable ethical standards and was implemented by getting consent that was obtained from all the participants. The researcher used from preplacement for physical tests and periodic examinations for lipid profiles in the industries. 3. Results The study participants were divided into 5 groups based on exposure to physical or psychological stresses. The age, work duration, total cholesterol, and HDL showed significant differences between study groups ( P < .05). They were male workers and had not smoking. They had rotating shift work and low to moderate fat food. Participants in group 4 (moderate physical work) had the highest age, work duration and BMI. Triglycerides, LDL were the most in group 5 (heavy physical work) and HDL was the least in this group too. Total cholesterol had the highest level in group 3 (mild psychological stress and mild physical work). The results of blood test are demonstrated in Table Table1 1 ( P < .05). Table 1 Means of risk factors amounts and comparison between 5 groups ( P < .05). Open in a separate window The highest number of persons with BMI more than 30 and total cholesterol more than 200 was in group 4. The highest number of workers with triglycerides more than 200 and HDL less than 45 was found in group 5. The most number of participants with LDL more than 130 were in groups 5. These items are demonstrated in Table Table2 2 ( P < .05). Table 2 Frequencies of risk factors and comparison between 5 groups ( P < .05). Open in a separate window After deleting the effect of BMI and age with regression, the relative risks for triglycerides more than 200 mg/dL was 1.57 (1.02–2.42) and for LDL more than 130 mg/dL was 14.54 (3.54–59.65) in group 1 (mild psychological stress). The relative risks for HDL less than 45 mg/dL were 14.61 (8.31–25.68) in group 1 and 16.00 (8.30–30.83) in group 3. In groups 2 and 4 the relative risks of LDL more than130 mg/dL and HDL less than 45 mg/dL were below one. The relative risks in group 5 was below one; 0.62 (0.387–1.00), 0.150 (0.104–0.215). Table Table3 3 shows the relative risks in different groups. Table 3 The relative risks of lipid disorders in 5 groups ( P < .05). Open in a separate window 4. Discussion According to our findings, psychological stress was a risk factor for increasing triglycerides, and LDL and for decreasing HDL. After multinomial logistic regression they had significant differences. Stressful situations are hazards for lipid profiles. These hazards include physical and psychological stress such as night shift work. [ 18 , 19 ] Psychological stress had effects on different part of human body especially some organs and physiological parameters, lipid profiles are one of these parameters. Physical stresses induced by heavy physical works could affects lipid profiles too. It seems that psychological stresses that were mentioned in many studies were more prominent in relation to dyslipidemias. In this study researcher showed that at the beginning of the study mean of triglycerides in group 5, and total cholesterol and LDL in group 3 were more than other groups. The least HDL was found in group 5. The means of lipid profiles were in the normal ranges. The highest mean related to age and BMI were observed in group 4 and 5. Other studies had demonstrated the effectiveness of wellbeing and preventive methods on lipid profiles. [ 15 , 16 ] The older workers had dyslipidemias, they were in group 4 and 5 more than other groups. Lipid disorders were more prevalent by aging. The highest numbers of people with BMI equal and more than 30 kg/m 2 were in group 4 and 5 too. Obesity was a risk factor for lipid disorders. [ 2 , 3 , 11 ] The number of people with triglycerides more 200 mg/dL was more in group 5. With regard to cholesterol concentration, the number of people with total cholesterol more 200 was highest in group 4, the highest amount of LDL were observed in group 4 and 5, and the least amount of HDL was found in group 5. The effects of lifestyle on blood lipid profiles had been demonstrated in other studies. [ 11 ] After deleting the effects of BMI and age, the risk of increased triglycerides, and LDL were observed in group 1 that had mild psychological stress. The risk of decrease in HDL was also discovered in group 1 and 3. The group 3 had mild psychological stress with mild physical work or mild physical stress. It seems that psychological stress had more prominent effects on the lipid profiles. With moderate to heavy physical work the risk of lipid disorders were reduced. The risk of dyslipidemias could be reduced with proper nutrition and wellbeing. Psychological stress must be assessed in all the situations especially in work environment. There were some studies that evaluated psychological stresses. [ 26 ] According to the results of this study, researcher believes that job analysis and determining the risk factors for different jobs specially in works with psychological stress are necessary. Researcher demonstrated the effects of Job stress on cardiovascular risk factors in male workers. [ 29 ] In other studies were worked on some specific jobs with physical and psychological risks for example shift workers and their effects on risk factors of cardiovascular disorders. [ 30 – 32 ] In this study after deleting BMI effect or obesity and age with regression, the risks of dyslipidemias were observed in group 1 and 3; the participants who had mild psychological stress and those with mild psychological stress with mild physical activity. Another scientist studied about the burnout syndrome that could be a predictor of hyperlipidemia among employees. [ 33 ] Burnout syndrome was an occupational psychological stress. Job stress could be seen in various forms which varied in different occupations. [ 34 ] Working in the environment with psychological stress without a proper physical health and normal activity could be caused some disorders specially cardiovascular disorders. [ 35 ] Author found that the psychological stress was an important risk factor for dyslipidemia especially in people who have worked. The modification of psychological stresses are not always possible but person's nutrition and physical activity could be modified to prevent dyslipidemias and cardiovascular disorders. Other studies had also showed the risk factors for dyslipidemias such as obesity. [ 36 ] Suitable physical activity help to reduce weight and BMI resulted to improving dyslipidemias. Psychological stress is a strong risk factor for dyslipidemias. Changing this situation in daily environment and work place is necessary. One study demonstrated the effect of prevention on improving dyslipidemias. [ 37 ] In other study was demonstrated the emotional effects on wellbeing of office workers. [ 38 ] In this research there were not have exact job analysis for other occupational hazards and it was a limitation for this study. The author of this article recommended to the people with psychological stress to have a regular physical activity in the daily program and modifying the psychological stress by consultation with a psychologist. Job stress or chronic stress had unsuitable effects on workers’ health and occupational medicine specialist must be had attention to this. [ 39 , 40 ] Psychological stress could be resulted from personal conflict, social and family problems, and working. Considering the importance of mental health on wellbeing, the author recommends the job modification in working situations. 5. Conclusions Psychological stress was a risk factor for lipid disorders, and proper physical activity was protective in this situation. One of the physical activities is work activity; work activity without stress could be harmless and useful. However, psychological stress could be eliminated in the workplace. Acknowledgments The author appreciated the supports of Mashhad University of Medical Sciences. 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the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer \| PMC Copyright Notice Cochrane Database Syst Rev. 2013 Jun; 2013(6): CD009934. Published online 2013 Jun 18. doi: 10.1002/14651858.CD009934.pub2 PMCID: PMC7433290 PMID: 23780706 Green and black tea for the primary prevention of cardiovascular disease Monitoring Editor: Louise Hartley , Nadine Flowers , Jennifer Holmes , Aileen Clarke , Saverio Stranges , Lee Hooper , Karen Rees , and Cochrane Heart Group Warwick Medical School, University of Warwick, Division of Health Sciences, CoventryWarwickshireUK, CV4 7AL University of Warwick, Warwick Medical School, CoventryUK University of East Anglia, Norwich Medical School, Norwich Research Park, NorwichUK, NR4 7TJ Karen Rees, Email: [email protected] , Email: ku.oc.oohay@nerak_seer . Author information Copyright and License information PMC Disclaimer Warwick Medical School, University of Warwick, Division of Health Sciences, CoventryWarwickshireUK, CV4 7AL University of Warwick, Warwick Medical School, CoventryUK University of East Anglia, Norwich Medical School, Norwich Research Park, NorwichUK, NR4 7TJ Karen Rees, Email: [email protected] , Email: ku.oc.oohay@nerak_seer . Corresponding author. Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. This article is an update of with doi: 10.1002/14651858.CD009934 . Abstract Background There is increasing evidence that both green and black tea are beneficial for cardiovascular disease (CVD) prevention. Objectives To determine the effects of green and black tea on the primary prevention of CVD. Search methods We searched the following databases on 12 October 2012 without language restrictions: CENTRAL in The Cochrane Library , MEDLINE (OVID), EMBASE (OVID) and Web of Science (Thomson Reuters). We also searched trial registers, screened reference lists and contacted authors for additional information where necessary. Selection criteria Randomised controlled trials (RCTs) lasting at least three months involving healthy adults or those at high risk of CVD. Trials investigated the intake of green tea, black tea or tea extracts. The comparison group was no intervention, placebo or minimal intervention. The outcomes of interest were CVD clinical events and major CVD risk factors. Any trials involving multifactorial lifestyle interventions or focusing on weight loss were excluded to avoid confounding. Data collection and analysis Two review authors independently selected trials for inclusion, abstracted data and assessed the risk of bias. Trials of green tea were analysed separately from trials of black tea. Main results We identified 11 RCTs with a total of 821 participants, two trials awaiting classification and one ongoing trial. Seven trials examined a green tea intervention and four examined a black tea intervention. Dosage and form of both green and black tea differed between trials. The ongoing trial is examining the effects of green tea powder capsules. No studies reported cardiovascular events. Black tea was found to produce statistically significant reductions in low‐density lipoprotein (LDL) cholesterol (mean difference (MD) ‐0.43 mmol/L, 95% confidence interval (CI) ‐0.56 to ‐0.31) and blood pressure (systolic blood pressure (SBP): MD ‐1.85 mmHg, 95% CI ‐3.21 to ‐0.48. Diastolic blood pressure (DBP): MD ‐1.27 mmHg, 95% CI ‐3.06 to 0.53) over six months, stable to sensitivity analysis, but only a small number of trials contributed to each analysis and studies were at risk of bias. Green tea was also found to produce statistically significant reductions in total cholesterol (MD ‐0.62 mmol/L, 95% CI ‐0.77 to ‐0.46), LDL cholesterol (MD ‐0.64 mmol/L, 95% CI ‐0.77 to ‐0.52) and blood pressure (SBP: MD ‐3.18 mmHg, 95% CI ‐5.25 to ‐1.11; DBP: MD ‐3.42, 95% CI ‐4.54 to ‐2.30), but only a small number of studies contributed to each analysis, and results were not stable to sensitivity analysis. When both tea types were analysed together they showed favourable effects on LDL cholesterol (MD ‐0.48 mmol/L, 95% CI ‐0.61 to ‐0.35) and blood pressure (SBP: MD ‐2.25 mmHg, 95% CI ‐3.39 to ‐1.11; DBP: MD ‐2.81 mmHg, 95% CI ‐3.77 to ‐1.86). Adverse events were measured in five trials and included a diagnosis of prostate cancer, hospitalisation for influenza, appendicitis and retinal detachment but these are unlikely to be directly attributable to the intervention. Authors' conclusions There are very few long‐term studies to date examining green or black tea for the primary prevention of CVD. The limited evidence suggests that tea has favourable effects on CVD risk factors, but due to the small number of trials contributing to each analysis the results should be treated with some caution and further high quality trials with longer‐term follow‐up are needed to confirm this. Plain language summary Green and black tea to prevent cardiovascular disease Cardiovascular disease (CVD) is a worldwide healthcare burden. However, it is thought that CVD risk can be lowered by changing a number of modifiable risk factors such as diet, and this includes the intake of tea. This review assessed the effectiveness of green tea, black tea or black/green tea extracts in healthy adults and those at high risk of CVD. We found 11 randomised controlled trials, four of which examined black tea interventions and seven examined green tea interventions. There were variations in the dosage and form (drink, tablets or capsules) of the black and green tea interventions, and the duration of the interventions ranged from three months to six months. Adverse events were reported in five of the included trials. These included a diagnosis of prostate cancer, hospitalisation for influenza, appendicitis and retinal detachment; these are unlikely to be associated with the intervention. The results showed black and green tea to have a beneficial effect on lipid levels and blood pressure, but these results were based on only a small number of trials that were at risk of bias. Analysis conducted over both tea types showed beneficial effects of tea on LDL‐cholesterol and blood pressure but again this was based on only a few trials that were at risk of bias. To date the small number of studies included suggest some benefits of green and black tea on blood pressure and lipid levels but more longer‐term trials at low risk of bias are needed to confirm this. Background Description of the condition Cardiovascular diseases (CVD) are the result of complications in the heart and blood vessels ( WHO 2011 ), and include cerebrovascular disease, coronary heart disease (CHD), and peripheral arterial disease (PAD). Around 29.6% of total global deaths can be attributed to CVD ( World Health Report 2003 ) and it is estimated that 17 million deaths per year are caused by CVD ( Mackay 2004 ). One of the main mechanisms thought to cause CVD is atherosclerosis, where the arteries become blocked by plaques or atheromas ( NHS 2010 ). Atherosclerosis can cause CVD when the arteries are completely blocked by a blood clot or when blood flow is restricted by a narrowed artery limiting the amount of blood and oxygen that can be delivered to organs or tissue ( British Heart Foundation 2012 ). While arteries may naturally become harder and narrower with age this process may be accelerated by factors such as smoking, high cholesterol, high blood pressure, obesity, a sedentary lifestyle and ethnicity ( NHS 2010 ). Ruptures of unstable plaque can also lead to CVD. Unstable plaques are thought to activate an inflammatory response in the body. This inflammatory response causes the structure of atherosclerotic plaque to weaken and rupture leading to the formation of blood clots ( Spagnoli 2007 ). A number of dietary factors have been found to be associated with CVD risk such as a low consumption of fruit and vegetables ( Begg 2007 ), a high intake of saturated fat ( Siri‐Tarino 2010 ) and a high consumption of salt ( He 2011 ). These factors are important since they can be modified in order to lower CVD risk making them a prime target for interventions aimed at primary prevention and management of CVD. Description of the intervention According to Deka ( Deka 2011 ), records show tea has been used largely due to its medicinal purposes from as far back as the 10 th century and it is now consumed worldwide. Tea leaves come from the plant Camillia sinesis and there are three main types of tea: green, black and oolong. The type of tea produced from the leaves depends on how the leaves are processed. For instance, partly fermented leaves produce oolong tea, fermented leaves produced black tea while non‐fermented leaves create green tea ( Deka 2011 ). All types of tea made from Camillia sinesis are rich in flavonoids. These are water‐soluble plant pigments that belong to the larger group of polyphenolic compounds ( Corradini 2011 ; Scalbert 2005 ). The main class of flavonoids found in tea are flavanols. These include epigallocatechin (EGC), epigallocatechin gallate (EGCG), epicatechin gallate (ECG) and epicatechin (EC) ( Kris‐Etherton 2002 ). Whilst the total flavonoid content in green and black tea is similar, their chemical structures differ. This is mainly due to the oxidation process used in the manufacture of black tea that converts flavonoids, such as catechin found in green tea, into more complex varieties, mainly thearubigins and theaflavins ( Deka 2011 ; Stangl 2006 ). In green tea catechin constitutes around 80% to 90% of total flavonoids, whereas in black tea they account for 20% to 30% of total flavonoids ( Stangl 2006 ). Green tea is also thought to have a high content of vitamins and minerals with five cups a day providing between 5% to 10% of a person’s daily requirement of riboflavin, niacin, folic acid and pantothenic acid. Furthermore, this amount of green tea a day provides 45% of the daily requirement of manganese, 25% of potassium and 5% of magnesium ( Shukla 2007 ). How the intervention might work Observational, epidemiological and experimental evidence have indicated that the consumption of green and black tea may have a beneficial effect on cardiovascular function ( Deka 2011 ; Kuriyama 2008 ; Mineharu 2010 ; Nagao 2007 ; Sesso 1999 ). In particular, observational studies suggest that a high intake of both green and black tea is related to a reduction in CVD risk ( Kuriyama 2008 ; Sesso 1999 ). For example, de Koning Gans et al ( de Koning Gans 2010 ), in a prospective cohort study of 37,514 participants in the Netherlands, found that consuming three to six cups of tea (mainly black tea) a day was associated with a reduction in the risk of CHD mortality (hazard ratio (HR) = 0.55, 95% confidence interval (CI) 0.31 to 0.97) (cup size was not stated in the article). This is supported by Mineharu et al ( Mineharu 2010 ) who reported a strong inverse relationship between the intake of more than six cups of green tea daily and CVD mortality in a cohort of 76,979 Japanese adults. These observational findings, however, must be cautiously interpreted because of the potential for confounding effects by factors commonly associated with tea drinking, such as healthier lifestyles, which might contribute to the observed inverse associations. Indeed, some studies have failed to show any relationship between the intake of tea and CVD risk ( Brown 1993 ; Hertog 1997 ). Meta‐analyses of observational studies corroborate the findings from individual studies showing an inverse relationship between tea and CVD risk ( Arab 2009 ; Peters 2001 ). Peters and colleagues examined the association between tea and CVD by analysing 10 cohort studies and seven case‐control studies ( Peters 2001 ). They found an 11% reduction in the risk of myocardial infarction when consuming three or more cups of tea a day. However, these authors suggest that their findings must be cautiously interpreted since there was evidence of publication bias of smaller positive studies. Evidence from intervention studies also show the benefit of tea consumption in reducing the risk factors for CVD ( Brown 2009 ; Nagao 2007 ). Fujita et al. ( Fujita 2008 ), for instance, conducted a randomised double‐blind placebo‐controlled study to investigate the benefits of taking black tea extract in 47 Japanese patients with borderline hypercholesterolaemia. They found that black tea extract significantly lowered patients low‐density lipoprotein (LDL) cholesterol and blood total cholesterol levels. A systematic review that searched for RCTs until 2006 and included 12 trials of green tea, and 12 of black tea compared with control (all assessed as at moderate to high risk of bias) found little effect of either type of tea on systolic or diastolic blood pressure or high‐density lipoprotein (HDL) cholesterol ( Hooper 2008 ). However, it was not stated in the primary studies of this review whether tea was caffeinated or decaffeinated. This is important since the impact of tea on CVD risk factors may be due, in part, to the acute effects of caffeine. Nonetheless, there was some evidence from moderate to poor quality trials that green tea reduced LDL cholesterol (black tea had no effect) and black tea improved flow mediated dilatation, an emerging risk factor for CVD ( Hooper 2008 ). None of the included studies assessed mortality or cardiovascular events. A more recent systematic review examined green tea consumption and its antioxidant effects in 31 controlled intervention studies published up to June 2010 ( Ellinger 2011 ). The findings indicated that there was some evidence that regular green tea consumption of at least 0.6 ‐ 1.5 L/day reduced lipid peroxidation and increased antioxidant capacity. Ellinger et al ( Ellinger 2011 ) therefore concluded that there was evidence, although limited, for the antioxidant effects of green tea which are suggested to protect against CVDs. However, many of the included studies were very short term and it is unclear whether benefits are sustained over longer periods. The reduction of CVD risk by tea may be largely due to the high levels of polyphenols, in particular flavonoids, which both green and black tea contain. However, the exact mechanisms through which increased tea consumption reduces CVD risk are unknown. Some potential mechanisms include reducing weight, improving insulin sensitivity, improving dyslipidaemia, improving endothelial function by lowering oxidative stress, platelet inhibition and anti‐inflammatory effects ( Deka 2011 ). Furthermore, tea and their flavonoids have antioxidant properties that help to reduce CVD risk ( Deka 2011 ; Gardner 2007 ). Why it is important to do this review Tea is the second most consumed beverage worldwide after water ( Kris‐Etherton 2002 ) and due to such high frequency of intake worldwide, even a small impact of tea on human health could have large implications for public health ( Peters 2001 ). However, there is still inconclusive evidence from interventional and observational studies of tea consumption on clinical cardiovascular endpoints. An up‐to‐date systematic review is needed to clarify the association between tea consumption and CVD risk, which will then provide guidance for national and international governments, local authorities, practitioners and members of the public. The current review updates and expands the most recent systematic reviews ( Ellinger 2011 ; Hooper 2008 ). We have included only randomised controlled trials of either green or black tea and examined the effects over longer time periods (at least three months) as these are most relevant for public health interventions. Objectives The primary objective was to determine the effectiveness of green and black tea consumption for the primary prevention of CVD. Methods Criteria for considering studies for this review Types of studies All randomised controlled trials (RCTs). Cross‐over trials were eligible for inclusion in this review if identified, but we would have used data only from the first half as a parallel group design. Types of participants Adults aged 18 and over from the general population and adults at high risk of CVD. This review focused on the effects of green and black tea intake on participants in primary prevention trials. We therefore excluded studies where more than 25% of participants had CVD at baseline including those who have experienced a previous myocardial infarction (MI), stroke, revascularisation procedure (coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA)), those with angina, or angiographically‐defined CHD, cerebrovascular disease (stroke) and PAD. We also excluded studies where more than 25% of the participants had type 2 diabetes. While patients with type 2 diabetes are at increased risk of CVD, interventions for diabetes are covered specifically by the Cochrane Metabolic and Endocrine Disorders review group. Types of interventions The intervention was the intake of green or black tea as a beverage or the intake of tea extracts. No limit was placed on the amount of tea consumed. Studies examining green tea and green tea extracts were examined separately from those examining black tea and black tea extracts. We intended to examine the effect of "dose" and duration of tea intake if there were sufficient studies, and the effects of caffeine intake. We focused on follow‐up periods of six months or more as these are most relevant for public health interventions, and considered trials with follow‐up periods of three months or more where longer term trials were lacking. Trials were only considered where the comparison group was no intervention, placebo or minimal intervention (e.g. leaflet to follow a dietary pattern with no person‐to‐person intervention or reinforcement). Trials using multifactorial lifestyle interventions and trials focusing on weight loss were excluded from the review to avoid confounding. Types of outcome measures Primary outcomes Cardiovascular mortality All‐cause mortality Non‐fatal endpoints such as MI, CABG, PTCA, angina, or angiographically‐defined CHD, stroke, carotid endarterectomy, or PAD Secondary outcomes Changes in blood pressure (systolic and diastolic blood pressure) and blood lipids (total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides) Occurrence of type 2 diabetes as a major CVD risk factor Health‐related quality of life Adverse effects Costs Search methods for identification of studies Electronic searches We searched the following electronic databases without language restrictions on 12 October 2012: Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 9 of 12, September 2012) in The Cochrane Library ; MEDLINE (OVID) (1946 to Week 1 October 2012); EMBASE Classic + EMBASE (OVID) (1947 to 2012 Week 40); Web of Science (Thomson Reuters) (1970 to 12 October 2012); Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment Database (HTA) and Health Economics Evaluations Database (HEED) (Issue 3 of 4, July 2012) on The Cochrane Library . Medical subject headings (MeSH) or equivalent and text word terms were used. The Cochrane sensitive‐maximising RCT filter (Lefebvre 2011) was used for MEDLINE and adaptations of it were used for EMBASE and Web of Science. Searches were tailored to individual databases. The search strategies are shown in Appendix 1 . Searching other resources We checked reference lists of reviews and retrieved articles for additional studies. We searched the metaRegister of controlled trials (mRCT) (www.controlled‐trials.com/mrct), Clinical trials.gov (www.clinicaltrials.gov), the WHO International Clinical Trials Registry platform (ICTRP) (http://apps.who.int/trialsearch/) for ongoing trials and Google Scholar for additional studies. We also searched OpenGrey to identify any relevant grey literature.The search strategies are shown in Appendix 2 . We also performed citation searches on key articles. We contacted experts in the field for unpublished and ongoing trials and authors were contacted where necessary for any additional information. Data collection and analysis Selection of studies Two review authors (Louise Hartley (LH), Nadine Flowers (NF)) reviewed the title and abstract of each paper and retrieved potentially relevant references. We then obtained the full text of potentially relevant studies and the same two authors (LH, NF) independently selected studies to be included in the review by using predetermined inclusion criteria. In all cases we resolved all disagreements about study inclusion by consensus and consulted a third review author (Karen Rees (KR)) if disagreements persisted. Data extraction and management Two review authors independently (LH, NF or Jennifer Holmes (JH)) extracted data using a proforma. We also contacted chief investigators to provide additional relevant information when necessary. Details of the study design, participant characteristics, study setting, intervention (including number of components, tea or extract, duration, flavonoid and caffeine dose), and outcome data (including details of outcome assessment, adverse effects) and methodological quality (randomisation, blinding and attrition) were extracted from each included study. We resolved any disagreements about extracted data by consensus and consulted a third author (KR) if disagreements persisted. Assessment of risk of bias in included studies We assessed risk of bias by examining the random sequence generation and allocation concealment, description of drop‐outs and withdrawals (including analysis by intention‐to‐treat), blinding (participants, personnel and outcome assessment) and selective outcome reporting ( Higgins 2011 ) in each trial. Two authors (LH, NF) independently assessed the risk of bias of included studies and rated each domain as having a low risk of bias, a high risk of bias or an unclear risk of bias. Measures of treatment effect Data were processed in accordance with the Cochrane Handbook for Systematic Reviews of Interventions ( Higgins 2011 ). For continuous outcomes net changes were compared (i.e. intervention group minus control group differences) and a mean difference (MD) and 95% confidence interval (CIs) calculated for each study. Assessment of heterogeneity For each outcome, tests of heterogeneity were conducted (using the Chi 2 test of heterogeneity and I 2 statistic). Where there was no heterogeneity a fixed‐effect meta‐analysis was performed. If substantial heterogeneity (I 2 greater than 50%) was detected the review authors looked for possible explanations for this (for example, participants and intervention). If the heterogeneity could not be explained, the review authors considered the following options: provide a narrative overview and not aggregate the studies at all or use a random‐effects model with appropriate cautious interpretation. Subgroup analysis and investigation of heterogeneity Results were stratified by i) black tea, ii) green tea. It was our intention to stratify studies by “dose” of tea intake and duration of the intervention but there were insufficient trials that met the inclusion criteria to do this. Similarly, the lack of included studies meant that we were unable to examine the effects of caffeine intake. Sensitivity analysis We carried out sensitivity analysis excluding studies with inadequate or unclear allocation concealment. There were insufficient trials to examine the effects of publication bias using funnel plots and tests of asymmetry ( Egger 1997 ). Results Description of studies Results of the search The searches generated 2319 hits and 1736 after de‐duplication. Screening the titles and abstracts identified 135 papers for formal inclusion or exclusion. Of these, 11 RCTs (12 papers) met the inclusion criteria. We identified one ongoing trial (one paper) and there are two trials (two papers) awaiting classification. Details of the flow of studies through the review are given in Figure 1 . Open in a separate window 1 Study flow diagram. Included studies Details of the methods, participants, intervention, comparison group and outcome measures for each of the studies included in the review are shown in the Characteristics of included studies table. Eleven trials with 11 trial arms were included with 821 participants randomised. None of the included studies reported on both black and green tea. Four included studies examined black tea ( Bahorun 2012 ; Fujita 2008 ; Hodgson 2012 ; Mukamal 2007 ). The health status of participants varied between studies; one of the studies recruited participants with borderline, or mild to moderate hypercholesterolaemia ( Fujita 2008 ); one study recruited participants with either diabetes or two other cardiovascular disease risk factors ( Mukamal 2007 ) and the remaining studies recruited healthy participants ( Bahorun 2012 ; Hodgson 2012 ;). All four trials examining black tea recruited both male and female participants. One trial was conducted in the USA ( Mukamal 2007 ) while the other studies were conducted in Japan ( Fujita 2008 ), Mauritius ( Bahorun 2012 ) and Australia ( Hodgson 2012 ). The duration of the intervention and follow‐up periods varied between three months ( Bahorun 2012 ; Fujita 2008 ) and six months ( Hodgson 2012 ; Mukamal 2007 ). All four studies used black tea extracts, in tablet form ( Fujita 2008 ) or as a drink ( Bahorun 2012 ; Hodgson 2012 ; Mukamal 2007 ). Again, the dosage and type of black tea extracts varied between studies; 1 g black tea extract per day ( Fujita 2008 ); 1.29 g black tea polyphenols per day ( Hodgson 2012 ); three servings of 200 mL of black tea a day ( Bahorun 2012 ) and 318 mg black tea catechins per day ( Mukamal 2007 ). Seven of the included studies examined green tea ( Bogdanski 2012 ; Janjua 2009 ; Maron 2003 ; Nantz 2009 ; Shen 2010 ; Smith 2010 ; Stendell‐Hollis 2010 ). In these studies the health status of participants varied; one of the studies recruited participants with borderline, or mild to moderate hypercholesterolaemia ( Maron 2003 ); one study recruited participants with hypertension ( Bogdanski 2012 ); one study recruited breast cancer survivors ( Stendell‐Hollis 2010 ) and one recruited postmenopausal women with osteopenia ( Shen 2010 ). The remaining three studies recruited healthy participants ( Janjua 2009 ; Nantz 2009 ; Smith 2010 ). Four trials examining green tea recruited female participants only (154 randomised) ( Janjua 2009 ; Shen 2010 ; Smith 2010 ; Stendell‐Hollis 2010 ). Five trials were conducted in the USA ( Janjua 2009 ; Nantz 2009 ; Shen 2010 ; Smith 2010 ; Stendell‐Hollis 2010 ). The remaining studies were conducted in China ( Maron 2003 ) and Poland ( Bogdanski 2012 ). The duration of the intervention and follow‐up periods varied between three months ( Bogdanski 2012 ; Maron 2003 ; Nantz 2009 ; Smith 2010 ), six months ( Shen 2010 ; Stendell‐Hollis 2010 ) and two years ( Janjua 2009 ). Five of the studies used green tea extracts, in the form of tablets or capsules. Dosage and type of green tea extracts varied between studies; 500 mg per day of green tea polyphenols ( Shen 2010 ); 375 mg green tea extract ( Bogdanski 2012 ); 250 mg twice a day of green tea polyphenols ( Janjua 2009 ); 200 mg theanine and 400 mg decaffeinated catechin green tea extract per day ( Nantz 2009 ); and 75 mg theaflavins, 150 mg green tea catechins, and 150 mg other tea polyphenols per day ( Maron 2003 ). One study provided participants with one beverage a day containing green tea extract ( Smith 2010 ) while the remaining study provided participants with green tea bags containing 58.91 mg of catechins ( Stendell‐Hollis 2010 ). One ongoing trial (one paper) was identified. Details of this trial are provided in the Characteristics of ongoing studies table. Briefly, the trial ( Mitsuhiro Yamada 2009 ) examines the effects of 10 green tea powder capsules three times a day for 12 weeks in adults prone to metabolic syndrome. The outcomes measured include blood pressure and lipid levels. No anticipated end date was provided for this trial. Excluded studies Details and reasons for exclusion for the studies that most closely missed the inclusion criteria are presented in the Characteristics of excluded studies table. Reasons for exclusion for the majority of studies was their short‐term duration (< three months). Other reasons for exclusion include the control not being a minimal intervention or no intervention/placebo, and no outcomes of interest. Short‐term studies As stated above, the reason for exclusion for the majority of studies was that they were short term (< three months follow‐up). We focused on three or more months follow‐up as we were interested in the sustained effects of tea intake which are most relevant for public health interventions. Other systematic reviews have included some of these short‐term studies ( Ellinger 2011 ) and for interest we have listed them in Table 1 . 1 Short term trials of tea intake (<3 months duration) Study Green/Black or extracts? Dose Duration Alexopoulos 2009 Black and Green tea 6 g/d 2 wks Basu 2011 Green tea and Green tea extract 4 cups/d or 2 capsules and 4 cups of water /d 8 wks Basu 2010 Green tea and Green tea extract 4 cups/d or 2 capsules and 4 cups of water /d 8 wks Batista 2009 Green tea extract 250 mg/d 8 wks Belza 2009 Green tea extract 500 mg 4 hrs Bingham 1997 Black tea 6 mugs/d 4 wks Brown 2011 Green tea extract 530 mg twice a day 6 wks Davies 2003 Black tea 5 servings a day 3 wks de Maat 2000 Black tea, Green tea and Green tea extract 6 cups (150 mL)/day or 6 x 4 capsules/day with 6 x 150 mL of control beverage 4 wks Eichenberger 2010 Green tea extract In a beverage consumed once a day 21 days Fisunoglu 2010 Black tea 5 servings (200 mL)/d 6 wks Frank 2009 Green tea extract 6 capsules/d 3 wks Freese 1999 Green tea extract 3 g a day 4 wks Grassi 2009 Black tea 0mg, 100 mg, 200 mg, 400 mg or 800 mg twice a day 1 wk Hirata 2004 Black tea 450 mL 2hrs Hodgson 2003 Black tea 1250 mL/d 4 wks Hodgson 1999 Black or Green tea 5 cups/d 7 d Hodgson 2002a Black tea 5 cups/d 4 wks Inami 2007 Green tea extract 500 mg 4 wks Ishikawa 1997 Black tea 5 cups/d (750 mL) 4 wks Kurita 2010 Black tea > 200 mL twice a day 8 wks Nagaya 2004 Green tea 400ml 2 hrs Penugonda 2009 Green tea or Green tea extract 4 cups a day or 2 capsules and 4 cups of water a day 8 wks Princen 1998 Black or Green tea 6 cups/d of Black or Green tea or 3,6g tablet of Green tea polyphenols/day 4 wks Quinlan 1997 Black tea 400 mL 60 mins Quinlan 2000 Black tea 300 mL 105 mins Rakic 1996 Black tea 5 cups per day 2 weeks Schmidschonbein 1991 Black tea 1 litre 7 hours Trautwein 2010 Black tea extract one capsule/d 11 wks Vlachopoulos 2006 Black or Green tea 6 gm 3 hrs Hodgson 2002b Black and Green tea 1000 mL/d or 250 mL/d 7 d or 4 wks Hodgson 2002c Black tea one cup 4 hrs Miller 2012 Green tea extract 1.06 g 90 mins Erba 2005 Green tea 2 cups 42 days Wu 2012 Green tea extract 400 mg or 800 mg per day 2 mths Alexopoulos 2008 Green tea 6 g 120 mins Arima 2009 Black tea 1 cup 6 hours Unno 2005 Tea 10, 224 or 674 mg of tea catechins 6 hours Yoshikawa 2012 Tea 1069 mg/day of total catechins 1 wk Steptoe 2007 Black tea 4 sachets a day 6 wks Open in a separate window d:day Risk of bias in included studies Details are provided for each of the included studies in the 'Risk of bias' tables in Characteristics of included studies and summarised in Figure 2 ; Figure 3 . Open in a separate window 2 'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies. Open in a separate window 3 'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study. Allocation Three of the trials that examined black tea clearly stated the methods of random sequence generation ( Bahorun 2012 ; Hodgson 2012 ; Mukamal 2007 ) and were judged to be of low risk of bias. The methods of allocation concealment were not stated in two of the studies that examined black tea. In the two trials where this was clear, the methods were judges to be of low risk of bias ( Hodgson 2012 ; Mukamal 2007 ). The methods of random sequence generation were unclear in four of the green tea trials ( Bogdanski 2012 ; Maron 2003 ; Shen 2010 ; Smith 2010 ). In the three trials where this was clear, the methods used were judged to be of low risk of bias ( Janjua 2009 ; Nantz 2009 ; Stendell‐Hollis 2010 ). Allocation concealment methods were not stated in five of the seven green tea trials. In the remaining two trials, the methods of allocation concealment were clear and so judged to be of low risk of bias ( Bogdanski 2012 ; Stendell‐Hollis 2010 ). Blinding Two trials examining black tea stated that they were double blind (participants and personnel were blind to treatment allocation, as were outcome assessors) and were regarded at low risk of bias ( Fujita 2008 ; Hodgson 2012 ). One trial was stated as single blind (participants were not blinded to treatment allocation, but outcome assessors were blinded to the treatment allocation) ( Mukamal 2007 ) while one trial did not state if it had used blinding ( Bahorun 2012 ). All of the trials examining green tea stated that they were double blind and placebo‐controlled and so were regarded as being at low risk of performance bias. However, in six of the trials no details were provided as to whether outcome assessors were blinded ( Bogdanski 2012 ; Janjua 2009 ; Maron 2003 ; Nantz 2009 ; Smith 2010 ; Stendell‐Hollis 2010 ) and so were regarded as being at unclear risk of detection bias. Incomplete outcome data Loss to follow‐up was reported in all four of the black tea trials. Three of the four included studies were judged as low risk of bias as they clearly reported reasons for withdrawals, exclusions and losses to follow‐up ( Fujita 2008 ; Hodgson 2012 ; Mukamal 2007 ). Two of these studies had also performed intention‐to‐treat (ITT) analyses ( Hodgson 2012 ; Mukamal 2007 ). One of the trials examining black tea was judged at high risk of bias as losses to follow‐up had not been reported by group and no ITT analysis had been performed ( Bahorun 2012 ). Four of the seven trials looking at green tea reported loss to follow‐up ( Nantz 2009 ; Janjua 2009 ; Shen 2010 ; Stendell‐Hollis 2010 ) and one trial was judged as low risk of bias as withdrawals and exclusions were clearly reported ( Nantz 2009 ). Three studies were judged at high risk of bias as either losses to follow‐up were not reported and no ITT analysis had been performed ( Maron 2003 ), or losses to follow‐up were unbalanced between groups and no ITT analysis was performed ( Janjua 2009 ; Stendell‐Hollis 2010 ). The remaining three studies were judged as unclear as in two studies no information on loss to follow‐up was provided ( Bogdanski 2012 ; Smith 2010 ) and in the third study no reasons were reported for loss to follow‐up but an ITT analysis was performed ( Shen 2010 ). Selective reporting Three of the four studies looking at black tea were judged as unclear as there was insufficient information to judge the risk of selective reporting ( Fujita 2008 ; Hodgson 2012 ; Mukamal 2007 ). The remaining study was judged as low risk as all expected outcomes were reported ( Bahorun 2012 ). One study examining green tea was judged as unclear due to there being insufficient information to judge the risk of selective reporting ( Nantz 2009 ). The remaining six trials have been judged as low risk as all expected outcomes were reported ( Bogdanski 2012 ; Janjua 2009 ; Maron 2003 ; Shen 2010 ; Smith 2010 ; Stendell‐Hollis 2010 ). Other potential sources of bias For studies of both black and green tea, there was insufficient information to judge the risk of bias from other potential sources. Effects of interventions Cardiovascular events None of the included studies provided clinical event data. Mortality None of the included studies provided mortality data. Cardiovascular risk factors Black tea Three of the four included trials examining the effects of black tea measured lipid levels ( Bahorun 2012 ; Fujita 2008 ; Mukamal 2007 ) and contribute to the meta‐analysis. For one study ( Bahorun 2012 ), the reported results for all lipid measurements were split by gender. For LDL‐cholesterol (three studies, one study reporting males and females separately, 147 participants) moderate heterogeneity was observed between the studies (I 2 = 33%) so a random‐effects meta‐analysis was performed. From the pooled analysis, black tea was found to lower LDL‐cholesterol (mean difference (MD) ‐0.43 mmol/L, 95% confidence interval (CI) ‐0.56 to ‐0.31) ( Analysis 1.1 ). Results were similar for the fixed‐effect model, the random‐effects results were reported as the effect estimate is more conservative with wider confidence intervals. Sensitivity analysis, removing studies with unclear allocation concealment, retained one study and statistical significance (MD ‐0.39 mmol/L, 95% CI ‐0.54 to ‐0.24). 1.1 Analysis Comparison 1 Black Tea, Outcome 1 LDL‐Cholesterol. A random‐effects meta‐analysis was also conducted for HDL‐cholesterol (three studies, one reporting males and females separately, 146 participants) where heterogeneity was again observed between studies (I 2 = 36%). We found no evidence of effect of black tea on HDL levels in the four trials reporting this ( Analysis 1.2 ). 1.2 Analysis Comparison 1 Black Tea, Outcome 2 HDL‐Cholesterol. For triglyceride levels, significant heterogeneity existed between the trials (three studies, one reporting males and females separately, I 2 = 64%) and a meta‐analysis was not performed ( Analysis 1.3 ). In one trial, black tea was found to significantly reduce triglyceride levels (MD ‐0.17 mmol/L. 95% CI ‐0.30 to ‐0.04) ( Fujita 2008 ) whilst for female participants in another trial, triglycerides were found to increase in those given black tea (MD 0.55 mmol/L, 95% CI ‐0.01 to 1.11) but this was not statistically significant ( Bahorun 2012 ). For their male counterparts, black tea was found to have no effect on triglyceride levels (MD ‐0.32 mmol/L, 95% CI ‐1.06 to 0.42) ( Bahorun 2012 ), a finding supported by the final study (MD 0.03 mmol/L, 95% CI ‐0.17 to 0.23) ( Mukamal 2007 ) (and the only study with low risk of bias from allocation concealment). 1.3 Analysis Comparison 1 Black Tea, Outcome 3 Triglycerides. Two trials (one reporting males and females separately) of black tea measured total cholesterol levels ( Bahorun 2012 ; Fujita 2008 ) ( Analysis 1.4 ). However, significant heterogeneity was found to exist between the trials (I 2 = 84%) and therefore a meta‐analysis was not performed. One trial showed a statistically significant reduction in total cholesterol (MD ‐0.54 mmol/L, 95% CI ‐0.63 to ‐0.45) ( Fujita 2008 ) whilst in the second trial black tea was found to have no effect on total cholesterol in females (MD 0.41 mmol/L, 95% CI ‐0.19 to 1.01) or males (MD 0.00 mmol/L, 95% CI ‐0.59 to 0.59) ( Bahorun 2012 ). 1.4 Analysis Comparison 1 Black Tea, Outcome 4 Total Cholesterol. Two included trials examined the effect of black tea on blood pressure ( Hodgson 2012 ; Mukamal 2007 ). The meta‐analysis (123 participants) showed a statistically significant reduction in systolic blood pressure (SBP) (MD ‐1.85 mmHg, 95% CI ‐3.21 to ‐0.48) ( Analysis 1.5 ). Diastolic blood pressure (DBP) (123 participants) was also reduced with the black tea intervention, however, this result did not reach statistical significance (MD ‐1.27 mmHg, 95% CI ‐3.06 to 0.53) ( Analysis 1.6 ). Sensitivity analysis removing studies at unclear risk of bias from allocation concealment did not remove either study, so results were unchanged. 1.5 Analysis Comparison 1 Black Tea, Outcome 5 Systolic blood pressure. 1.6 Analysis Comparison 1 Black Tea, Outcome 6 Diastolic blood pressure. Green tea Four of the seven included trials examined the effects of green tea on lipid levels ( Bogdanski 2012 ; Maron 2003 ; Smith 2010 ; Stendell‐Hollis 2010 ) and so contributed to the meta‐analysis. From the pooled analysis, the green tea intervention showed a statistically significant reduction in total cholesterol (327 participants) (MD ‐0.62 mmol/L, 95% CI ‐0.77 to ‐0.46) ( Analysis 2.1 ) and LDL‐cholesterol (327 participants) (MD ‐0.64 mmol/L, 95% CI ‐0.77 to ‐0.52) ( Analysis 2.2 ) compared to placebo. For triglycerides (327 participants) the pooled analysis found green tea to lower triglyceride levels (MD ‐0.08 mmol/L, 95% CI ‐0.24 to 0.07) ( Analysis 2.3 ), however, this result did not reach statistical significance. 2.1 Analysis Comparison 2 Green Tea, Outcome 1 Total Cholesterol. 2.2 Analysis Comparison 2 Green Tea, Outcome 2 LDL Cholesterol. 2.3 Analysis Comparison 2 Green Tea, Outcome 3 Triglycerides. For HDL cholesterol (four studies, 327 participants), moderate heterogeneity was found between studies (I 2 = 39%) so a random‐effects meta‐analysis was performed ( Analysis 2.4 ). From the pooled analysis, there was no evidence of effect of green tea on HDL cholesterol levels (MD 0.01 mmol/L, 95% CI ‐0.08 to 0.11). Results were similar for the fixed‐effect model; the random‐effects results were reported as the effect estimate is more conservative with wider confidence intervals. Sensitivity analysis, removing studies with unclear allocation concealment, retained one study (MD ‐0.10 mmol/L, 95% CI ‐0.27 to 0.07). 2.4 Analysis Comparison 2 Green Tea, Outcome 4 HDL‐Cholesterol. Three trials examining green tea measured blood pressure ( Bogdanski 2012 ; Nantz 2009 ; Smith 2010 ) but one did not provide any individual group data and could not be included in a meta‐analysis. The pooled analysis showed a statistically significant reduction in SBP (167 participants) (MD ‐3.18 mmHg, 95% CI ‐5.25 to ‐1.11) ( Analysis 2.5 ) and DBP (167 participants) (MD ‐3.42, 95% CI ‐4.54 to ‐2.30) ( Analysis 2.6 ) in the green tea group. The trial not included in the meta‐analysis showed no significant change in blood pressure in either the tea (SBP change 1.10%, DBP change ‐7.20%) or control group (SBP decrease 0%, DBP decrease 1.10%) ( Smith 2010 ). For all three trials allocation concealment was unclear, and sensitivity analyses removed them from the pooled analysis. 2.5 Analysis Comparison 2 Green Tea, Outcome 5 Systolic Blood Pressure. 2.6 Analysis Comparison 2 Green Tea, Outcome 6 Diastolic Blood Pressure. All tea (Green and Black) Six trials (four using green tea and two using black tea, one reporting males and females separately) measured total cholesterol levels ( Bahorun 2012 ; Bogdanski 2012 ; Fujita 2008 ; Maron 2003 ; Smith 2010 ; Stendell‐Hollis 2010 ). Significant heterogeneity (I 2 = 66%) was found between the trials and so a meta‐analysis was not performed. Two of the four trials showed tea to significantly reduce total cholesterol ( Fujita 2008 ; Maron 2003 ) while in two trials, tea was found to reduce total cholesterol but this result did not reach statistical significance ( Bogdanski 2012 ; Smith 2010 ). In the remaining two trials, tea was found to have no effect on total cholesterol levels ( Bahorun 2012 ; Stendell‐Hollis 2010 ). Seven trials (one examining males and females separately) looked at HDL‐cholesterol (473 participants), LDL‐cholesterol (474 participants) and triglyceride levels (476 participants) (three using black tea and four using green tea) and contributed to the meta‐analysis ( Bahorun 2012 ; Bogdanski 2012 ; Fujita 2008 ; Maron 2003 ; Mukamal 2007 ; Smith 2010 ; Stendell‐Hollis 2010 ). For LDL cholesterol (I 2 = 49%), HDL‐cholesterol (I 2 = 33%) and triglycerides (I 2 = 37%), moderate heterogeneity was observed between the studies so random‐effects meta‐analyses were performed. The pooled analysis showed tea to significantly reduce LDL‐cholesterol (MD ‐0.48 mmol/L, 95% CI ‐0.61 to ‐0.35) ( Analysis 3.2 ), have no effect on HDL‐cholesterol (MD 0.00 mmol/L, 95% CI ‐0.04 to 0.04) ( Analysis 3.3 ) and decrease triglycerides (MD ‐0.06 mmol/L, 95% CI ‐0.19 to 0.06) ( Analysis 3.4 ), although this did not reach statistical significance. 3.2 Analysis Comparison 3 All Tea, Outcome 2 LDL‐Cholesterol. 3.3 Analysis Comparison 3 All Tea, Outcome 3 HDL‐Cholesterol. 3.4 Analysis Comparison 3 All Tea, Outcome 4 Triglycerides. Five trials (three using green tea and two using black tea) measured blood pressure ( Bogdanski 2012 ; Hodgson 2012 ; Mukamal 2007 , Nantz 2009 : Smith 2010 ). Only four of these contributed to the meta‐analysis as one trial did not report individual group data ( Smith 2010 ). The meta‐analysis showed a statistically significant reduction in SBP (290 participants) (MD ‐2.25 mmHg, 95% CI ‐3.39 to ‐1.11) ( Analysis 3.5 ) and DBP (290 participants) (MD ‐2.81 mmHg, 95% CI ‐3.77 to ‐1.86) ( Analysis 3.6 ) with the tea intervention. 3.5 Analysis Comparison 3 All Tea, Outcome 5 Systolic Blood Pressure. 3.6 Analysis Comparison 3 All Tea, Outcome 6 Diastolic Blood Pressure. Adverse effects Adverse effects were monitored in five trials. Generally, side effects were mild and not attributable to the tea interventions as there were no significant differences in adverse events between the treatment and placebo groups ( Janjua 2009 ; Maron 2003 ; Nantz 2009 ; Shen 2010 ). However, in one study ( Mukamal 2007 ), adverse events included a new diagnosis of prostate cancer and a single hospitalisation for influenza among participants assigned to tea and in another study adverse events in the tea group included appendicitis and retinal detachment ( Janjua 2009 ) . Quality of Life Quality of life was measured in one of the trials ( Shen 2010 ). Supplementation of 500 mg green tea polyphenols (GTP) daily to postmenopausal osteopenic women for 24 weeks had no influence on quality of life (as assessed by SF‐36 questionnaires). Costs None of the included studies provided data on costs. Discussion Summary of main results Eleven trials that randomised 821 participants in studies of three or more months duration were identified from the 1735 papers screened. Four of these examined black tea interventions and seven examined green tea interventions. None of the trials measured clinical events or mortality as they were relatively short term and conducted in mainly healthy participants. The review showed that black tea produced a statistically significant reduction in LDL‐cholesterol and systolic and diastolic blood pressure (stable to sensitivity analyses). For green tea statistically significant reductions were found in total cholesterol, LDL cholesterol and systolic and diastolic blood pressure but the studies contributing to these analyses were removed in sensitivity analyses. However, only a small number of trials contributed to these analyses, and most trials were very small. Only one trial looked at the effects of tea on health‐related quality of life. Few adverse events were measured and none directly attributable to the intervention. Overall completeness and applicability of evidence This review included adult participants who were at varying levels of CVD risk and included both free‐living men and women. Most of the trials were conducted in developed countries. None of the 11 included studies examined our primary outcomes as trials were relatively short term in follow‐up and participants were predominantly healthy. We were also not able to examine the effects of “dose” or duration of the intervention, or the effects of caffeine intake due to the limited number of included trials. Furthermore, due to the varying doses of extracts/tea consumed between the included studies, we could not draw any conclusions about the number of cups of tea per day that would be required to reduce CVD risk factors. The effectiveness of green tea could not be rigorously assessed as only four trials (447 participants) ( Bogdanski 2012 ; Maron 2003 ; Nantz 2009 ; Smith 2010 ) examined cardiovascular risk factors at three months and one study at six months (39 participants) ( Stendell‐Hollis 2010 ). The remaining two trials examining green tea evaluated quality of life and adverse events over six months ( Shen 2010 ) or adverse events over two years ( Janjua 2009 ). Similarly, few trials were identified that examined the effectiveness of black tea. Four trials were found that measured cardiovascular risk factors (279 participants). Two of these had three months follow‐up ( Bahorun 2012 ; Fujita 2008 ) and two had six months follow‐up ( Hodgson 2012 ; Mukamal 2007 ). One study examining black tea stratified lipid outcomes by gender ( Bahorun 2012 ) and found differences in responses between men and women. Whilst there is well‐established literature on differences in cardio‐metabolic risk profiles between men and women ( Mosca 2011 ), we cannot make any conclusions based on only one study. However, if sufficient evidence accrues, future updates of this review will examine the influence of gender on the outcomes of interest. There was considerable variability in the interventions, participants recruited and outcomes measured in the included trials. The one ongoing trial will add to the evidence base but more trials are needed. Quality of the evidence The studies included in this review were at some risk of bias and as such, the results should be treated with caution. In five of the included trials the methods of random sequence generation were not stated or unclear while in seven trials the details of allocation concealment were not stated. Nine of the 11 included studies stated that they were double blind and in one trial, participants were not blinded to treatment allocation but outcome assessors were. Risk of bias related to incomplete outcome data was high in four studies, low in four studies and unclear in three studies. Bias due to selective outcome reporting was considered unclear in four studies and low in the remaining seven. For all studies there was insufficient information to judge the risk of other biases. In addition, small study bias is a risk in this review as most trials were very small. We were unable to examine the effects of publication bias in funnel plots due to the limited number of included studies. However, small studies are often less methodologically robust, more likely to be conducted in selected populations and have been shown to report larger beneficial effects than larger trials ( Nüesch 2010 ; Sterne 2000 ; Sterne 2001 ). The results of the review need to be interpreted with this in mind. Potential biases in the review process A comprehensive search was conducted across major databases for interventions involving black or green tea or tea extract. Systematic review reference lists were also screened and authors contacted when necessary. All screening, inclusion and exclusion and data abstraction were carried out independently by two review authors. Data entry and analysis were also conducted by two review authors. Our decision to restrict this review to interventions only investigating black or green tea avoided the potential confounding effects of other behavioural interventions on our outcomes e.g. those involving exercise, different dietary interventions or interventions that focused on weight loss. However, this limited the number of trials eligible for inclusion. In addition, the small number of trials on which this review is based, limitations in reporting methodological quality, an unclear risk of bias in most trials and little or no data for primary or secondary outcomes mean that caution should be used when interpreting the results of this review. Agreements and disagreements with other studies or reviews To our knowledge, no other systematic review including only randomised controlled trials has been carried out solely to examine the effects of black and green tea in adults for the primary prevention of CVD. Other systematic reviews have looked at flavonoid consumption on cardiovascular risk, which include tea, but also other flavonoid‐rich foods ( Hooper 2008 ). As in our review, the review by Hooper et al (2008) ( Hooper 2008 ) found no studies examining tea that assessed mortality or cardiovascular events. Other systematic reviews have solely concentrated on the antioxidant effects of green tea consumption ( Ellinger 2011 ) with findings providing some evidence that regular intake of green tea (at least 0.6 to 1.5L/day) reduced lipid peroxidation and increased antioxidant capacity. However, we cannot directly compare the effects on CVD risk factors between the two reviews as Ellinger et al (2011) did not examine CVD risk factors and included very short‐term studies which did not meet our inclusion criteria. Authors' conclusions Implications for practice Few trials met the inclusion criteria for our review and none reported our primary outcomes. Small beneficial effects were seen in the four trials of black tea and in three trials of green tea on cardiovascular risk factors, which is promising. This is because small reductions in CVD risk factors, such as blood pressure and lipid levels, throughout a whole population may lead to large reductions in CVD incidence ( Emberson 2004 ). However, studies included in this review were at some risk of bias and as such the results should be treated with caution. To confirm these findings high quality trials are needed that examine cardiovascular disease and its risk factors over a longer period of time. Furthermore, future trials may consider the use of teas rather than tea extracts due to their wider availability and lower cost. In doing this, however, future trials should also take into account the use of a placebo since in trials that use tea, the placebo is usually water and there may be beneficial affects related to an increase in water consumption. Given the limited evidence to date, this review does not make any recommendations about changing practice. Implications for research There is a lack of randomised controlled trials looking at the effects of black and green tea consumption for the primary prevention of CVD. In particular, there is a shortage of randomised controlled trials that examine the effects of black and green tea interventions over the long term and which would help to examine the effects of such interventions on CVD events. We also found no trials reporting economic evaluations of interventions involving black or green tea and found only one trial that reported health‐related quality of life outcomes. Acknowledgements We are grateful to Nicole Martin and Jo Abbot for conducting the searches for this review. We would also like to acknowledge Dr Maron and Dr Mukamal for providing additional data from their trials ( Maron 2003 ; Mukamal 2007 ). Appendices Appendix 1. Search strategies October 2012 CENTRAL, DARE, HTA, HEE on The Cochrane Library #1 MeSH descriptor: [Cardiovascular Diseases] explode all trees #2 cardio* #3 cardia* #4 heart* #5 coronary* #6 angina* #7 ventric* #8 myocard* #9 pericard* #10 isch?em* #11 emboli* #12 arrhythmi* #13 thrombo* #14 atrial next fibrillat* #15 tachycardi* #16 endocardi* #17 sick near sinus #18 MeSH descriptor: [Stroke] explode all trees #19 stroke or stokes #20 cerebrovasc* #21 cerebral next vascular #22 apoplexy #23 brain near/2 accident* #24 brain* near/2 infarct* #25 cerebral near/2 infarct* #26 lacunar near/2 infarct* #27 MeSH descriptor: [Hypertension] explode all trees #28 hypertensi* #29 peripheral next arter* next disease* #30 high near/2 blood next pressure #31 increased near/2 blood next pressure #32 elevated near/2 blood next pressure #33 MeSH descriptor: [Hyperlipidemias] explode all trees #34 hyperlipid* #35 hyperlip?emia* #36 hypercholesterol* #37 hypercholester?emia* #38 hyperlipoprotein?emia* #39 hypertriglycerid?emia* #40 MeSH descriptor: [Arteriosclerosis] explode all trees #41 MeSH descriptor: [Cholesterol] explode all trees #42 cholesterol #43 "coronary risk factor" #44 MeSH descriptor: [Blood Pressure] this term only #45 "blood pressure" #46 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or #31 or #32 or #33 or #34 or #35 or #36 or #37 or #38 or #39 or #40 or #41 or #42 or #43 or #44 or #45 #47 MeSH descriptor: [Tea] this term only #48 tea or teas #49 (green and black) near/3 (tea or teas) #50 (tea or teas) near/3 (extract) #51 MeSH descriptor: [Catechin] this term only #52 (catechuic or catechinic or catechin) #53 cyanidanol #54 zyma #55 epicatechin #56 kb 53 #57 flavanpentol #58 z 7300 #59 catergen* #60 #47 or #48 or #49 or #50 or #51 or #52 or #53 or #54 or #55 or #56 or #57 or #58 or #59 #61 #46 and #60 MEDLINE OVID 1. exp Cardiovascular Diseases/ 2. cardio.tw. 3. cardia.tw. 4. heart.tw. 5. coronary.tw. 6. angina.tw. 7. ventric.tw. 8. myocard.tw. 9. pericard.tw. 10. isch?em.tw. 11. emboli.tw. 12. arrhythmi.tw. 13. thrombo.tw. 14. atrial fibrillat.tw. 15. tachycardi.tw. 16. endocardi.tw. 17. (sick adj sinus).tw. 18. exp Stroke/ 19. (stroke or stokes).tw. 20. cerebrovasc.tw. 21. cerebral vascular.tw. 22. apoplexy.tw. 23. (brain adj2 accident).tw. 24. ((brain or cerebral or lacunar) adj2 infarct).tw. 25. exp Hypertension/ 26. hypertensi.tw. 27. peripheral arter* disease.tw. 28. ((high or increased or elevated) adj2 blood pressure).tw. 29. exp Hyperlipidemias/ 30. hyperlipid.tw. 31. hyperlip?emia.tw. 32. hypercholesterol.tw. 33. hypercholester?emia.tw. 34. hyperlipoprotein?emia.tw. 35. hypertriglycerid?emia.tw. 36. exp Arteriosclerosis/ 37. exp Cholesterol/ 38. cholesterol.tw. 39. "coronary risk factor".tw. 40. Blood Pressure/ 41. blood pressure.tw. 42. or/1‐41 43. Tea/ 44. (tea or teas).tw. 45. ((green or black) adj3 (tea or teas)).tw. 46. ((tea or teas) adj3 extract$).tw. 47. Catechin/ 48. (catechuic or catechinic or catechin).tw. 49. cyanidanol.tw. 50. zyma.tw. 51. epicatechin.tw. 52. kb 53.tw. 53. flavanpentol.tw. 54. z 7300.tw. 55. catergen$.tw. 56. or/43‐55 57. 42 and 56 58. randomized controlled trial.pt. 59. controlled clinical trial.pt. 60. randomized.ab. 61. placebo.ab. 62. drug therapy.fs. 63. randomly.ab. 64. trial.ab. 65. groups.ab. 66. 58 or 59 or 60 or 61 or 62 or 63 or 64 or 65 67. exp animals/ not humans.sh. 68. 66 not 67 69. 57 and 68 EMBASE OVID 1. exp cardiovascular disease/ 2. cardio.tw. 3. cardia.tw. 4. heart.tw. 5. coronary.tw. 6. angina.tw. 7. ventric.tw. 8. myocard.tw. 9. pericard.tw. 10. isch?em.tw. 11. emboli.tw. 12. arrhythmi.tw. 13. thrombo.tw. 14. atrial fibrillat.tw. 15. tachycardi.tw. 16. endocardi.tw. 17. (sick adj sinus).tw. 18. exp cerebrovascular disease/ 19. (stroke or stokes).tw. 20. cerebrovasc.tw. 21. cerebral vascular.tw. 22. apoplexy.tw. 23. (brain adj2 accident).tw. 24. ((brain or cerebral or lacunar) adj2 infarct).tw. 25. exp hypertension/ 26. hypertensi.tw. 27. peripheral arter* disease.tw. 28. ((high or increased or elevated) adj2 blood pressure).tw. 29. exp hyperlipidemia/ 30. hyperlipid.tw. 31. hyperlip?emia.tw. 32. hypercholesterol.tw. 33. hypercholester?emia.tw. 34. hyperlipoprotein?emia.tw. 35. hypertriglycerid?emia.tw. 36. exp Arteriosclerosis/ 37. exp Cholesterol/ 38. cholesterol.tw. 39. "coronary risk factor".tw. 40. Blood Pressure/ 41. blood pressure.tw. 42. or/1‐41 43. tea/ 44. green tea extract/ 45. black tea extract/ 46. (tea or teas).tw. 47. ((green or black) adj3 (tea or teas)).tw. 48. ((tea or teas) adj3 extract$).tw. 49. catechin/ 50. (catechuic or catechin).tw. 51. catechinic.tw. 52. cyanidanol.tw. 53. zyma.tw. 54. epicatechin.tw. 55. kb 53.tw. 56. flavanpentol.tw. 57. z 7300.tw. 58. catergen$.tw. 59. or/43‐58 60. 42 and 59 61. random$.tw. 62. factorial$.tw. 63. crossover$.tw. 64. cross over$.tw. 65. cross‐over$.tw. 66. placebo$.tw. 67. (doubl$ adj blind$).tw. 68. (singl$ adj blind$).tw. 69. assign$.tw. 70. allocat$.tw. 71. volunteer$.tw. 72. crossover procedure/ 73. double blind procedure/ 74. randomized controlled trial/ 75. single blind procedure/ 76. 61 or 62 or 63 or 64 or 65 or 66 or 67 or 68 or 69 or 70 or 71 or 72 or 73 or 74 or 75 77. (animal/ or nonhuman/) not human/ 78. 76 not 77 79. 60 and 78 Web of Science #36 #35 AND #34 AND #33 #35 #32 OR #31 OR #30 OR #29 OR #28 OR #27 OR #26 #34 #25 OR #24 OR #23 OR #22 OR #21 OR #20 OR #19 OR #18 OR #17 OR #16 OR #15 OR #14 OR #13 OR #12 OR #11 OR #10 OR #9 OR #8 OR #7 OR #6 OR #5 OR #4 OR #3 OR #2 OR #1 #33 TS=(random* or blind* or allocat* or assign* or trial* or placebo* or crossover* or cross‐over) #32 TS=(catergen or (z 7300) or flavanpentol or (kb 53) or epicatechin) #31 TS=(zyma) #30 TS=(cyanidanol) #29 TS=((catechuic or catechinic or catechin)) #28 TS=(((tea or teas) near/3 extract)) #27 TS=(((green or black) near/3 (tea or teas))) #26 TS=(tea or teas) #25 TS=(arteriosclerosis or cholesterol or "coronary risk factor" or "blood pressure") #24 TS=(hypercholester?emia* or hyperlipoprotein?emia* or hypertriglycerid?emia) #23 TS=(hyperlipid or hyperlip?emia* or hypercholesterol) #22 TS=(((brain or cerebral or lacunar) near/2 infarct)) #21 TS=(brain near/2 accident) #20 TS=(apoplexy) #19 TS=("cerebral vascular") #18 TS=(cerebrovasc) #17 TS=(stroke or strokes) #16 TS=("sick sinus") #15 TS=(endocardi) #14 TS=(tachycardi) #13 TS=((atrial fibrillat)) #12 TS=(thrombo) #11 TS=(arrhythmi) #10 TS=(emboli) #9 TS=(isch?em) #8 TS=(pericard) #7 TS=(myocard) #6 TS=(ventric) #5 TS=(angina) #4 TS=(coronary) #3 TS=(heart) #2 TS=(cardia) #1 TS=(cardio) Appendix 2. Search strategies for trial registers metaRegister of controlled trials (mRCT), Clinical trials.gov, the WHO International Clinical Trials Registry platform (ICTRP) 1. Green AND/OR Black AND Tea Notes New Data and analyses Comparison 1 Black Tea Outcome or subgroup title No. of studies No. of participants Statistical method Effect size 1 LDL‐Cholesterol 4 147 Mean Difference (IV, Random, 95% CI) ‐0.43 [‐0.56, ‐0.31] 2 HDL‐Cholesterol 4 146 Mean Difference (IV, Random, 95% CI) ‐0.01 [‐0.06, 0.04] 3 Triglycerides 4 Mean Difference (IV, Random, 95% CI) Totals not selected 4 Total Cholesterol 3 Mean Difference (IV, Fixed, 95% CI) Totals not selected 5 Systolic blood pressure 2 123 Mean Difference (IV, Fixed, 95% CI) ‐1.85 [‐3.21, ‐0.48] 6 Diastolic blood pressure 2 123 Mean Difference (IV, Fixed, 95% CI) ‐1.27 [‐3.06, 0.53] Open in a separate window Comparison 2 Green Tea Outcome or subgroup title No. of studies No. of participants Statistical method Effect size 1 Total Cholesterol 4 327 Mean Difference (IV, Fixed, 95% CI) ‐0.62 [‐0.77, ‐0.46] 2 LDL Cholesterol 4 327 Mean Difference (IV, Fixed, 95% CI) ‐0.64 [‐0.77, ‐0.52] 3 Triglycerides 4 327 Mean Difference (IV, Fixed, 95% CI) ‐0.08 [‐0.24, 0.07] 4 HDL‐Cholesterol 4 327 Mean Difference (IV, Random, 95% CI) 0.01 [‐0.08, 0.11] 5 Systolic Blood Pressure 2 167 Mean Difference (IV, Fixed, 95% CI) ‐3.18 [‐5.25, ‐1.11] 6 Diastolic Blood Pressure 2 167 Mean Difference (IV, Fixed, 95% CI) ‐3.42 [‐4.54, ‐2.30] Open in a separate window Comparison 3 All Tea Outcome or subgroup title No. of studies No. of participants Statistical method Effect size 1 Total Cholesterol 7 Mean Difference (IV, Fixed, 95% CI) Totals not selected 2 LDL‐Cholesterol 8 474 Mean Difference (IV, Random, 95% CI) ‐0.48 [‐0.61, ‐0.35] 3 HDL‐Cholesterol 8 473 Mean Difference (IV, Random, 95% CI) 0.00 [‐0.04, 0.04] 4 Triglycerides 8 476 Mean Difference (IV, Random, 95% CI) ‐0.06 [‐0.19, 0.06] 5 Systolic Blood Pressure 4 290 Mean Difference (IV, Fixed, 95% CI) ‐2.25 [‐3.39, ‐1.11] 6 Diastolic Blood Pressure 4 290 Mean Difference (IV, Fixed, 95% CI) ‐2.81 [‐3.77, ‐1.86] Open in a separate window 3.1 Analysis Comparison 3 All Tea, Outcome 1 Total Cholesterol. Characteristics of studies Characteristics of included studies [ordered by study ID] Bahorun 2012 Methods RCT of parallel group design Participants 87 healthy adults of either sex, aged 25‐60 years were enrolled. Inclusion criteria: non‐smoker or former smokers who had stopped for less than 6 months. alcohol intake of less than 2 standard drinks/day, postmenopausal women not receiving hormone replacement therapy and ejection fraction greater than 40%. Country of publication was Mauritius. Interventions Participants were required to consume 3 x 200 mL of black tea a day for 12 weeks. Those in the control group consumed the equivalent volume of hot water for 12 weeks. Follow‐up period was at the end of the intervention period of 12 weeks. Outcomes Triglycerides, total cholesterol, LDL‐cholesterol, HDL‐cholesterol. Notes This study was a post‐hoc analysis of a subgroup of patients used in a previous study that recruited both patients with Ischaemic heart disease and healthy participants. As such, it has unequal randomisation to intervention and control groups and has a high potential for bias. Risk of bias Bias Authors' judgement Support for judgement Random sequence generation (selection bias) Low risk A random generator was used by a statistician and randomisation was in a 7:3 ratio. However, this is a post‐hoc analysis of only the healthy participants and the methods of randomisation apply to all participants of the study which will include those with Ischaemic heart disease. Therefore, the number of healthy participants randomised to each group was unequal, with more participants randomised to the intervention group than to the control. Allocation concealment (selection bias) Unclear risk Method of allocation concealment not stated Blinding of participants and personnel (performance bias) All outcomes Unclear risk Not stated Blinding of outcome assessment (detection bias) All outcomes Unclear risk Not stated Incomplete outcome data (attrition bias) All outcomes High risk No ITT analysis. Reasons for attrition not reported sufficiently. Selective reporting (reporting bias) Low risk All outcomes stated are reported Other bias High risk Post‐hoc analysis of a previous study that included patients with Ischaemic heart disease. Randomisation not equal between groups and no rationale for the randomisation ratio of 7:3 was given. Open in a separate window Bahorun females 2012 Methods Please see information provided above Participants Interventions Outcomes Notes Risk of bias Bias Authors' judgement Support for judgement Random sequence generation (selection bias) Low risk A random generator was used by a statistician and randomisation was in a 7:3 ratio. However, this is a post‐hoc analysis of only the healthy participants and the methods of randomisation apply to all participants of the study which will include those with Ischaemic heart disease. Therefore, the number of healthy participants randomised to each group was unequal, with more participants randomised to the intervention group than to the control. Allocation concealment (selection bias) Unclear risk Method of allocation concealment not stated Blinding of participants and personnel (performance bias) All outcomes Unclear risk Not stated Blinding of outcome assessment (detection bias) All outcomes Unclear risk Not stated Incomplete outcome data (attrition bias) All outcomes High risk No ITT analysis. Reasons for attrition not reported sufficiently. Selective reporting (reporting bias) Low risk All outcomes stated are reported Other bias High risk Post‐hoc analysis of a previous study that included patients with Ischaemic heart disease. Randomisation not equal between groups and no rationale for the randomisation ratio of 7:3 was given. Open in a separate window Bahorun males 2012 Methods Please see information provided above Participants Interventions Outcomes Notes Risk of bias Bias Authors' judgement Support for judgement Random sequence generation (selection bias) Low risk A random generator was used by a statistician and randomisation was in a 7:3 ratio. However, this is a post‐hoc analysis of only the healthy participants and the methods of randomisation apply to all participants of the study which will include those with Ischaemic heart disease. Therefore, the number of healthy participants randomised to each group was unequal, with more participants randomised to the intervention group than to the control. Allocation concealment (selection bias) Unclear risk Method of allocation concealment not stated Blinding of participants and personnel (performance bias) All outcomes Unclear risk Not stated Blinding of outcome assessment (detection bias) All outcomes Unclear risk Not stated Incomplete outcome data (attrition bias) All outcomes High risk No ITT analysis. Reasons for attrition not reported sufficiently. Selective reporting (reporting bias) Low risk All outcomes stated are reported Other bias High risk Post‐hoc analysis of a previous study that included patients with Ischaemic heart disease. Randomisation not equal between groups and no rationale for the randomisation ratio of 7:3 was given. Open in a separate window Bogdanski 2012 Methods RCT of parallel group design Participants 56 obese adults of either sex, aged 30‐60 years with hypertension were enrolled. Exclusion criteria: those with secondary hypertension and/or secondary obesity, diabetes, history of coronary artery disease, stroke, congestive heart failure, malignancy, history of use of any dietary supplements within three months before the study, current need for modification of antihypertensive therapy, abnormal liver, kidney or thyroid gland function, clinically significant inflammatory process within respiratory, digestive or genitourinary tract, or in the oral cavity, pharynx, or paranasal sinuses, history of infection in the month before the study, nicotine or alcohol abuse and/or any other condition that would make participation not in the best interest of the subject or could prevent, limit or confound the efficacy assessment. Country of publication was Poland. Interventions Participants were required to consume 1 capsule of green tea extract or a placebo with a morning meal for 3 months. Each green tea capsule contained 379 mg of green tea extract. The placebo capsule contained pure microcrystalline cellulose. Follow‐up period was at the end of the intervention period of 3 months. Outcomes Blood pressure, total cholesterol, LDL‐cholesterol, HDL‐cholesterol, triglycerides Notes Risk of bias Bias Authors' judgement Support for judgement Random sequence generation (selection bias) Unclear risk Not stated Allocation concealment (selection bias) Low risk Used an independent statistician Blinding of participants and personnel (performance bias) All outcomes Low risk States double‐blind and placebo‐controlled Blinding of outcome assessment (detection bias) All outcomes Unclear risk States double‐blind but provides no details Incomplete outcome data (attrition bias) All outcomes Unclear risk No information provided Selective reporting (reporting bias) Low risk All expected outcomes were reported Other bias Unclear risk Insufficient information to judge Open in a separate window Fujita 2008 Methods RCT of parallel group design Participants 50 adults of either sex, aged 40‐70 years with borderline hypercholesterolaemia were enrolled in the study. Exclusion criteria: those under treatment of serious cardiac, renal, or hepatic diseases; those with history of gastrectomy, enterectomy, other gastrointestinal surgery, or hypothyroidism; those with alcohol abuse, insulin‐dependent diabetes or secondary causes of hyperglycaemia, pancreatitis, or serious hypertension. Country of publication was Japan. Interventions Participants were required to consume 2 black tea extract (BTE) tablets or placebo tablets, 3 times daily before meals for 3 months. Each BTE tablet (250 mg) contained 166.5 mg BTE (66.6%) and various bulking agents, including sugar alcohol (12.4%), cellulose (10%), polysaccharide (2%), lubricating and glossing agents (5%) and other excipients (4%). This meant that participants ingested a total of 1 g/day of BTE. The placebo tablets contained dextrin (66.6%) instead of BTE. Study was conducted between June 2006 and October 2006. Follow‐up period was at the end of the intervention period of 3 months. Outcomes Total cholesterol, LDL‐cholesterol, HDL‐cholesterol, triglycerides Notes BTE tablets were circular and placebo tablets were square. Adverse effects were monitored, however, none were reported. Risk of bias Bias Authors' judgement Support for judgement Random sequence generation (selection bias) Unclear risk Not stated Allocation concealment (selection bias) Unclear risk Not stated Blinding of participants and personnel (performance bias) All outcomes Low risk States double‐blind and placebo‐controlled Blinding of outcome assessment (detection bias) All outcomes Unclear risk States double‐blind but provides no details Incomplete outcome data (attrition bias) All outcomes Low risk Reasons for exclusions provided Selective reporting (reporting bias) Unclear risk Insufficient information to judge Other bias Unclear risk Insufficient information to judge Open in a separate window Hodgson 2012 Methods RCT of parallel group design Participants 111 healthy men and women, aged 35 to 75 years were recruited from the general population and randomised to two arms ‐ black tea (56 participants) and placebo (55 participants). Inclusion criteria: taking up to three antihypertensive medications. Any change in regular medication with the potential to influence vascular health resulted in withdrawal of the participant from the study. Baseline status within the black tea group, based on 46 participants: mean age 56.9; 33% male, 20% taking antihypertensive medication. Baseline status within the placebo group, based on 49 participants: mean age 56.3, 37% male, 29% taking antihypertensive medication. Country of publication was Australia. Interventions Participants consumed 3 cups/day of 1493 mg powdered black tea solids containing 429 mg of polyphenols and 96 mg of caffeine for 6 months, or placebo, 3 cups/day which was matched in flavour and caffeine content, containing no tea solids. Follow‐up period was at the end of the intervention period of 6 months. Outcomes Blood Pressure (systolic and diastolic) Notes Participants were regular tea drinkers Risk of bias Bias Authors' judgement Support for judgement Random sequence generation (selection bias) Low risk Used computer‐generated random numbers. Allocation concealment (selection bias) Low risk Randomisation codes sealed in envelopes, produced independent of study researchers. Envelopes opened in consecutive order as participants entered into the study. Blinding of participants and personnel (performance bias) All outcomes Low risk States placebo‐controlled and double‐blind. Blinding of outcome assessment (detection bias) All outcomes Low risk Analysis performed by biostatistician blinded to treatment allocation. Incomplete outcome data (attrition bias) All outcomes Low risk Used ITT analysis. Selective reporting (reporting bias) Unclear risk Insufficient information to judge Other bias Unclear risk Insufficient information to judge Open in a separate window Janjua 2009 Methods RCT of parallel group design Participants 56 healthy women aged 25‐75 years were randomised to two arms ‐green tea extract (29 participants) and placebo (27 participants). Inclusion criteria:Facial Glogau Photoaging scale II or III and Fitzpatrick skin type I to III. Exclusion criteria: Used systemic retinoids within 6 weeks before the start of the study, had active facial dermatological conditions that might interfere with photo‐aging assessments, history of cosmetic procedure to the face such as laser treatment, chemical peel and facelifts. Country of publication was the U.S.A. Interventions Participants were required to consume 1 capsule twice daily containing green tea extract or placebo for two years. Each active study capsule contained 250 mg of polyphenols (70%) of which were catechins. The capsules were 99.5% caffeine‐free. The placebo capsule were identical in appearance to the active capsule. Follow‐up period was at the end of the intervention period of 2 years. Outcomes Adverse events Notes Risk of bias Bias Authors' judgement Support for judgement Random sequence generation (selection bias) Low risk Computer‐generated Allocation concealment (selection bias) Unclear risk Not stated Blinding of participants and personnel (performance bias) All outcomes Low risk Double‐blind and placebo‐controlled Blinding of outcome assessment (detection bias) All outcomes Unclear risk Double‐blind but provides no details Incomplete outcome data (attrition bias) All outcomes High risk No ITT analysis and 37.9 % of tea group and 37% of placebo group dropped out of study Selective reporting (reporting bias) Low risk All expected outcomes reported Other bias Unclear risk Insufficient information to judge Open in a separate window Maron 2003 Methods RCT of parallel group design Participants 240 adults (100 males, 140 females) with mild to moderate hypercholesterolaemia and on a low‐fat diet were recruited from outpatient clinics in 6 urban hospitals in China. Participants were randomised to 2 arms ‐ tea extract (120 participants, 44.2% male, mean age 54.4) and placebo (120 participants, 39.2% male, mean age 55.0). Exclusion criteria: a baseline triglyceride level of 350 mg/dL or greater (4.0 mmol/L), having uncontrolled hypertension (160/95 mmHg), active pulmonary, hematologic, hepatic, gastrointestinal or renal disease, premalignant or malignant disease, diabetes, thyroid dysfunction, a history of coronary heart disease or other atherosclerotic disease, or any pathological values among routine clinical chemistry or hematological parameters having consumed greater than 32% of daily energy from fat or had a body mass index of 35 or higher, taking any lipid‐lowering medications or drugs that might interfere with lipid metabolism, taking cardiac or other vasoactive medications including antihypertensive drugs, thyroid hormones, oral contraceptives, cyclic hormone replacement therapy, dietary supplements (e.g., fish oils, niacin at doses 400 mg/d, or dietary fibre supplements), or antioxidants, and they were prohibited from taking these medications during the course of the study. Country of publication was China. Interventions Participants were required to consume 1 capsule containing a theaflavin‐enriched green tea extract or placebo, each morning, for 12 weeks (June 7th 2001 to October 18th 2001). Each active study capsule contained 75 mg of theaflavins, 150 mg of green tea catechins, and 150 mg of other tea polyphenols.The placebo capsules were made from inert ingredients and were identical to the theaflavin‐enriched green tea extract capsules in weight, appearance, and odour. Follow‐up period was at the end of the intervention period of 12 weeks. Outcomes Total cholesterol, LDL‐cholesterol, HDL‐cholesterol, triglycerides, adverse effects. Notes Authors were contacted for extra information on lipid levels. Authors responded. Risk of bias Bias Authors' judgement Support for judgement Random sequence generation (selection bias) Unclear risk Not stated, only states stratified by hospital Allocation concealment (selection bias) Unclear risk Not stated Blinding of participants and personnel (performance bias) All outcomes Low risk Double‐blind and placebo‐controlled Blinding of outcome assessment (detection bias) All outcomes Unclear risk Double‐blind but provides no details Incomplete outcome data (attrition bias) All outcomes High risk No ITT analysis. Reasons for attrition not reported sufficiently. 95% and 88% of participants completed the study in intervention and control groups respectively Selective reporting (reporting bias) Low risk All expected outcomes were reported Other bias Unclear risk Insufficient information to judge Open in a separate window Mukamal 2007 Methods RCT of parallel group design Participants 31 community‐dwelling adults aged 55 years and older with either diabetes (21% in tea group and 7% in control group) or 2 other cardiovascular risk factors (hypertension, current smoking, LDL cholesterol >=130 mg/dL, high‐density lipoprotein cholesterol > 40 mg/dL, or family history of premature coronary heart disease) were randomised to 2 arms ‐ black tea extract (16 participants, mean age 66.6 years, 79% on statins at baseline) and control (15 participants, mean age 64.9 years, 57% on statins at baseline). Exclusion criteria: established cardiovascular disease (congestive heart failure; myocardial infarction; coronary, carotid, or peripheral arterial revascularisation procedure; stroke; angina; or intermittent claudication), contraindications to MRI (severe claustrophobia, intolerance to previous MRI examinations, pacemaker, intraauricular implants, or intracranial clips), atrial fibrillation (due to requirement for gated MRI images), severe illness expected to cause death or disability within 6 months; blood pressure >=180/110 mm Hg; serum creatinine >2.5 mg/dL or dialysis; history of hyponatraemia; use of vitamin supplements greater than the recommended daily allowance; inability to speak English; and lack of a working telephone. Country of publication was the U.S.A. Interventions Intervention group: Dehydrated soluble black tea powder was provided to participants in unit‐dose containers. Each container included 2.0 g of powder, and 3 containers (representing a single‐day supply) were bagged together. The catechin content of the tea was 106 ± 7 mg per serving (i.e. 318 mg/d) of catechin equivalents. No restrictions were made on addition of milk or sweeteners, reconstitution with hot or cold water, or time of day of consumption. The control group consumed 3 glasses of water daily and dietary restrictions were consumption of non‐study tea (green, oolong, or black). Follow‐up period was at the end of the intervention period of 6 months. Outcomes HDL‐cholesterol, LDL‐cholesterol, triglycerides, adverse effects. Notes Authors contacted for extra information on blood pressure. Authors responded. Risk of bias Bias Authors' judgement Support for judgement Random sequence generation (selection bias) Low risk Used random permuted blocks of sizes 2 and 4 Allocation concealment (selection bias) Low risk Used opaque, sealed, sequentially numbered envelopes in a locked, off‐site location Blinding of participants and personnel (performance bias) All outcomes High risk Participants knew whether they were in the intervention or control group as they were asked to drink tea or water Blinding of outcome assessment (detection bias) All outcomes Low risk All measurements performed by technicians or investigators blinded to treatment assignment Incomplete outcome data (attrition bias) All outcomes Low risk ITT analysis used and attrition and exclusions were reported with reasons Selective reporting (reporting bias) Unclear risk Insufficient information to judge Other bias Unclear risk Insufficient information to judge Open in a separate window Nantz 2009 Methods RCT of parallel group design Participants 124 healthy adults recruited from University of Florida and Gainsville community (52 males, 72 females), mean age 29. Participants were randomised to 2 arms ‐ Camellia Sinensis capsules (61) and placebo (63). Exclusion criteria: vegetarian diet, chemotherapy or other immune suppressing therapy within the previous year, chronic antibiotics or other infectious disease prophylactic, chronic or current illness, surgery within the previous year, and pregnancy and/or lactation, those who daily consumed greater than one cup (250 mL) of tea, an average of seven or more servings of fruits and vegetables, and herbal supplements and vitamins other than a multivitamin or vitamin D. Country of publication was the U.S.A. Interventions Participants were required to consume either 1 Camellia sinensis composition (CSC) capsule or 1 placebo capsule (PBO), twice daily (1 in the morning and 1 in the evening, preferably with meals) for 3 months. CSC capsules contained 100 mg of L‐theanine and 200 mg of a decaffeinated catechin green tea extract. PBO capsules contained microcrystalline cellulose, dextrose, dicalcium phosphate, magnesium stearate, silicon dioxide, and FD&C red #40, yellow #6, and blue #1. PBO capsules were identical in appearance to the CSC capsules. Follow‐up was at the end of the intervention period of 3 months (90 days). Outcomes Blood pressure (systolic and diastolic), adverse effects Notes No participant started any new medication during the study Risk of bias Bias Authors' judgement Support for judgement Random sequence generation (selection bias) Low risk Drawing coloured marbles to allocate to intervention or control group Allocation concealment (selection bias) Unclear risk Not stated Blinding of participants and personnel (performance bias) All outcomes Low risk States double‐blind and placebo‐controlled. Particpants and investigators were blinded to treatment allocation Blinding of outcome assessment (detection bias) All outcomes Unclear risk States double‐blind but provides no details Incomplete outcome data (attrition bias) All outcomes Low risk Withdrawals and exclusions were clearly reported Selective reporting (reporting bias) Unclear risk Insufficient information to judge Other bias Unclear risk Insufficient information to judge Open in a separate window Shen 2010 Methods RCT of parallel group design Participants Postmenopausal women were recruited through flyers, local TV, radios, newspaper, municipal community centres and clinics. 171 women were randomised into 4 arms ‐ placebo; green tea polyphenols; placebo + tai chi; and green tea polyphenols + tai chi. Inclusion criteria were postmenopausal women (at least 2 years after menopause) with osteopenia; normal function of thyroid, liver and kidney; serum alkaline phosphatase, calcium and inorganic phosphorus within normal ranges; and serum 25‐hydroxy vitamin D (25(OH)D) ≥ 20 ng/mL. Exclusion criteria: participants with a disease condition or those on medication known to affect bone metabolism; a history of cancer except for treated superficial basal or squamous cell carcinoma of the skin; uncontrolled intercurrent illness or physical condition that would be a contraindication to exercise; depression; cognitive impairment; or those unwilling to accept randomisation. 47 participants were randomised to receive green tea polyphenols (mean age 56.5, 10.6% with history of diabetes) and 44 randomised to receive placebo (mean age 57.6, 2.3% with history of diabetes). Country of publication was the U.S.A. Interventions Green tea polyphenols (GTP) group: GTP 500 mg daily. The main GTP components were 46.5% of epigallocatechin‐3‐gallate (EGCG), 21.25% of epigallocatechin (ECG), 10% of epicatechin (EC), 7.5% of epicatechin‐3‐gallate (EGC), 9.5% of gallocatechin gallate (GCG), and 4.5% of catechin. Placebo group: medicinal starch 500 mg daily. The daily dose of GTP or placebo material was divided into two capsules (250 mg each). During the 24‐week intervention, all participants were provided with 500 mg elemental calcium and 200 IU vitamin D (as cholecalciferol) daily. Follow‐up period was at the end of the intervention period of 24 weeks. Outcomes Quality of life (8 domains), adverse effects. Notes Data only used from two arms: placebo, green tea polyphenol. The reported adverse effects were judged by the safety monitoring team as unlikely to be related to the study protocol. Risk of bias Bias Authors' judgement Support for judgement Random sequence generation (selection bias) Unclear risk Insufficient information to judge Allocation concealment (selection bias) Unclear risk Not stated Blinding of participants and personnel (performance bias) All outcomes Low risk Participants and investigators responsible for day‐to‐day operation and data analyses were blinded to the intervention and placebo groups Blinding of outcome assessment (detection bias) All outcomes Low risk Participants and investigators responsible for day‐to‐day operation and data analyses were blinded to the intervention and placebo groups Incomplete outcome data (attrition bias) All outcomes Unclear risk ITT analysis performed but no reasons reported for loss to follow‐up Selective reporting (reporting bias) Low risk All expected outcomes reported Other bias Unclear risk Insufficient information to judge Open in a separate window Smith 2010 Methods RCT Participants Women who volunteered to participate. 27 sedentary women classified as "overweight" were randomised into 4 arms ‐ exercise and active supplement; exercise and placebo; placebo; active supplement. Inclusion criteria were women aged 18‐45 years; < 30 min physical activity per week. Exclusion criteria: those with a history of hypertension or metabolic, renal, hepatic, musculoskeletal, autoimmune, or neurological disease; used any medication that might have significantly affected the study outcome; used nutritional supplements, other than a multivitamin, that might have affected metabolism and/or muscle mass within the four weeks prior to the start of the study. 7 participants were randomised to receive the active supplement (Green tea extract) (mean age 27.86) and 5 participants were randomised to the placebo (mean age 28.40). Country of publication was the U.S.A. Interventions Active Supplement group: Drink consisted of 10 kcal, B6 and B12, blend of taurine, guarana extract, green tea leaf extract (EGCG), caffeine, glucuronolactone and ginger extract. Placebo group: consisted of the same calorie and vitamin content as active supplement. 1 drink a day with time of beverage consumption left to subjects discretion. all beverages were labelled identically and matched for taste and colour. Outcomes Total cholesterol, LDL‐cholesterol, HDL‐cholesterol, triglycerides, blood pressure (systolic and diastolic) Notes Data only used from 2 arms: placebo and active supplementation group. Risk of bias Bias Authors' judgement Support for judgement Random sequence generation (selection bias) Unclear risk Not stated Allocation concealment (selection bias) Unclear risk Not stated Blinding of participants and personnel (performance bias) All outcomes Low risk States double‐blind and placebo controlled Blinding of outcome assessment (detection bias) All outcomes Unclear risk States double‐ blind but provides no details Incomplete outcome data (attrition bias) All outcomes Unclear risk No ITT analysis used and no loss to follow‐up reported Selective reporting (reporting bias) Low risk All expected outcomes reported Other bias Unclear risk Insufficient information to judge Open in a separate window Stendell‐Hollis 2010 Methods RCT Participants Women who volunteered to participate. 54 overweight breast cancer survivors were randomised into two arms ‐ green tea or placebo. Inclusion criteria: BMI between 25‐40 kg m ‐2 , received chemotherapy for treatment of invasive breast cancer, aged 18‐80 years, reported no current tobacco use and have no chronic illnesses. Participants had to be willing to refrain from all weight loss diets and supplements for a study period of six months. Twenty‐nine participants were randomised to receive green tea (mean age 56.6) and twenty five participants were randomised to the placebo group (mean age 57.8). Country of publication was the U.S.A. Interventions Green tea group: Consumed green tea. Green tea bags comprising of 550‐700 mg tea solids, providing an average catechin dose of 58.91 mg and 32.21 mg of EGCG per bag. Participants were to consume 960 mL green tea daily. Individiual tea bags were placed in a provided tea mug with 240 mL of boiling water and allowed to steep for 3 minutes. Green tea was to be consumed four times a day and up to two doses were allowed at any single dosing. Placebo group:Citrus‐based herbal tea that contained no EGCG. Follow‐up period was six months. Outcomes Total cholesterol, LDL‐cholesterol, HDL‐cholesterol, triglycerides. Notes Risk of bias Bias Authors' judgement Support for judgement Random sequence generation (selection bias) Low risk Used a table of random numbers Allocation concealment (selection bias) Low risk Allocation done by someone independent of study Blinding of participants and personnel (performance bias) All outcomes Low risk States double‐blind and placebo controlled Blinding of outcome assessment (detection bias) All outcomes Unclear risk States double‐blind but does not provide details Incomplete outcome data (attrition bias) All outcomes High risk No ITT analysis and 36% of participants in the control group and 20% of participants in the intervention group were lost to follow‐up Selective reporting (reporting bias) Low risk All expected outcomes reported Other bias Unclear risk Insufficient information to judge Open in a separate window BMI: body mass index HDL: high‐density lipoprotein ITT: intention‐to‐treat LDL: low‐density lipoprotein MRI: magnetic resonance imaging RCT: randomised controlled trial Characteristics of excluded studies [ordered by study ID] Study Reason for exclusion Alexopoulos 2008 Short‐term trial (follow‐up period was 120 minutes) Alexopoulos 2009 Short‐term trial (follow‐up period was 2 weeks) Arima 2009 Short‐term trial (follow‐up period was 6 hours) Auvichayapat 2008 Study focused on weight loss Basu 2010 Short‐term trial (follow‐up period was 8 weeks) Basu 2011 Short‐term trial (follow‐up period was 8 weeks) Batista 2009 Short‐term trial (follow‐up period was 8 weeks) Belza 2009 Short‐term trial (follow‐up period was 4 hours) Bingham 1997 Short‐term trial (follow‐up period was 4 weeks) Brown 2011 Short‐term trial (follow‐up period was 6 weeks) Davies 2003 Short‐term trial (follow‐up period was 3 weeks) de Maat 2000 Short‐term trial (follow‐up period was 4 weeks) Di Pierro 2009 Study focused on weight loss Eichenberger 2010 Short‐term trial (follow‐up period was 21 days) Erba 2005 Short‐term trial (follow‐up period was 42 days) Fisunoglu 2010 Short‐term trial (follow‐up period was 6 weeks) Frank 2009 Short‐term trial (follow‐up period was 3 weeks) Freese 1999 Short‐term trial (follow‐up period was 4 weeks) Gordillo‐Bastidas 2011 Study focused on weight loss Grassi 2009 Short‐term trial (follow‐up period was 1 week) Hakim 2003 No outcomes of interest Hirata 2004 Short‐term trial (follow‐up was 2 hours duration) Hodgson 1999 Short‐term trial (follow‐up period was 7 days) Hodgson 2000 No outcomes of interest Hodgson 2001 No outcomes of interest Hodgson 2002a Short‐term trial (follow‐up period was 4 weeks) Hodgson 2002b Short‐term trial (follow‐up period 7days or 4 weeks) Hodgson 2002c Short‐term trial (follow‐up period 4hrs) Hodgson 2003 Short‐term trial (follow‐up period was 4 weeks) Inami 2007 Short‐term trial (follow‐up period was 4 weeks) Ishikawa 1997 Short‐term trial (follow‐up period was 4 weeks) Kurita 2010 Short‐term trial (follow‐up period 8 weeks) Miller 2012 Short‐term trial (follow‐up period 90 minutes) Muroyama 2006 Study focused on weight loss Nagaya 2004 Short‐term trial (follow‐up period was 2 hours) Penugonda 2009 Short‐term trial (follow‐up period was 8 weeks) Princen 1998 Short‐term trial (follow‐up period was 4 weeks) Quinlan 1997 Short‐term trial (follow‐up period was 60 minutes) Quinlan 2000 Short‐term trials (follow‐up periods were between 60‐105 minutes) Rakic 1996 Short‐term trial (follow‐up period was 2 weeks) Ryu 2006 More than 25% of patients had T2D Schmidschonbein 1991 Short‐term trial (follow‐up period was 7 hours) Schultz 2009 Study focused on weight loss Steptoe 2007 Short‐term trial (follow‐up period was 6 weeks) Takase 2008 Study focused on weight loss Takeshita 2008 Study focused on weight loss Trautwein 2010 Short‐term trial (follow‐up period was 11 weeks) Unno 2005 Short‐term trial (follow‐up period was 6 hours) Vlachopoulos 2006 Short‐term trial (follow‐up period was 3 hours) Wang 2010 Study focused on weight loss Wu 2012 Short‐term trial (follow‐up period was 2 months) Yen 2010 Study focused on weight loss Yoshikawa 2012 Short‐term trial (follow‐up period was 1 week) Open in a separate window T2D: type 2 diabetes Characteristics of studies awaiting assessment [ordered by study ID] Chen 1991 Methods Article written in Chinese with no English abstract ‐ awaiting translation. Participants Interventions Outcomes Notes Open in a separate window Lu 1997 Methods Article written in Chinese with no English abstract ‐ awaiting translation. Participants Interventions Outcomes Notes Open in a separate window Characteristics of ongoing studies [ordered by study ID] Mitsuhiro Yamada 2009 Trial name or title A randomised, double‐blind, placebo‐controlled study of effect of green tea on lifestyle‐related disease prevention Methods Parallel randomised Participants Inclusion criteria: Is over 30 years old and under 75 years old and meets at least one of the followings; 1.BMI:23‐35kg/m 2 2.Waist circumference: 85 cm or more in men and 90 cm or more in women Exclusion criteria: 1) Individuals with a medical record of heart failure or cardiac infarction. 2) Individuals judged to have atrial fibrillation, Irregular Heart Beat, hepatic damage, kidney damage, cerebrovascular accident, rheumatism, diabetes mellitus, lipid disorder and/or anaemia. 3) Individuals with a medical record of allergy to food and drug. 4) Pregnant women, or women with intending to become pregnant, and lactating women. 5) Individuals judged by the doctor to be unsuitable. Age minimum: 30 years‐old Age maximum: 75 years‐old Gender: Men and women Health conditions: metabolic syndrome Interventions Ten capsules of green tea powder, three times a day (6 g/day), for 12 weeks. Ten placebo capsules, three times a day (6 g/day), for 12 weeks. Outcomes Primary 1) body weight 2) HbA1c 3) LDL‐cholesterol Secondary 1) Blood pressure, fat percentage, waist, BMI 2) FBS, insulin 3) Serum total cholesterol, HDL‐cholesterol, triglycerides 4) Serum amyloid protein A, high sensitive C_reactive protein 5) Adiponectin, TNF‐alfa, urine 8‐OHdG Starting date Date of first enrolment: 2009/02/01 Contact information Mitsuhiro Yamada Address: 9‐28, Goshohara, Kakegawa, Shizuoka, Japan Email: [email protected] Notes Open in a separate window BMI: body mass index FBS: fasting blood sugar HDL: high‐density lipoprotein LDL: low‐density lipoprotein TNF: tumour necrosis factor Differences between protocol and review It was our intention to perform stratified analysis to examine the effects of caffeine content and “dose” and duration of the intervention but the review included an insufficient number of trials to do this. Similarly, the lack of included studies meant that we were unable to examine the effects of caffeine intake. We also intended to perform funnel plots to assess publication bias. These will be addressed in future updates of this review when more evidence is available. Contributions of authors All authors contributed to the protocol development. The Trials Search Co‐ordinators of the CHG ran the searches, Review authors LH and NF screened titles and abstracts and assessed studies for formal inclusion and exclusion. LH and NF or JH abstracted data and assessed methodological rigour. NF analysed the data which were checked by KR. LH and NF wrote the first draft of the review and all authors contributed to later drafts. Sources of support Internal sources Warwick Medical School, University of Warwick, UK. Norwich Medical School, University of East Anglia, UK. External sources NIHR Cochrane Programme Grant, UK. Declarations of interest None known. References References to studies included in this review Bahorun 2012 {published data only} Bahorun T,
Luximon‐Ramma A,
Neergheen‐Bhujun VS,
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Yamagami T. Antihypercholesterolemic effect of Chinese black tea extract in human subjects with borderline hypercholesterolemia . Nutrition Research 2008; 28 ( 7 ):450‐6.

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