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Professional DotNetNuke 5: Open Source Web Application Framework for ASP.NET Paperback – Feb 24 2009
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From the Back Cover
DotNetNuke is a powerful open source framework for creating and deploying web sites with dynamic and interactive content. Written by the creator of DotNetNuke and a team of DotNetNuke community experts and ASP.NET programmers, this book provides you with the tools and insight you need to install, configure, and develop web applications with DotNetNuke 5.
After Shaun Walker's introduction to DotNetNuke and the business aspects of creating and nurturing the DotNetNuke community, product, and a new DotNetNuke corporation, the authors demonstrate how to manage and administer a DotNetNuke portal. They then show you how the application works through the DotNetNuke application architecture and its major application programming interfaces (APIs), which provide DotNetNuke's power.
You'll discover how to extend the portal framework by developing and distributing modules that plug into a DotNetNuke portal, and you'll examine the flexible skinning capabilities of DotNetNuke. This helpful exploration of the history, structure, and foundation of the DotNetNuke application affirms its place as an extremely extensible application framework.
What you will learn from this book
- The latest features and functionality of DotNetNuke 5 and the differences between DotNetNuke Community Edition and Professional Edition
The responsibilities of a host/administrator who is using DotNetNuke as a web portal, such as the uploading of skins and modules
The core modules that are included with DotNetNuke and how to use them
Ways to integrate DotNetNuke into an existing membership structure
Techniques for replacing hard-coded text with dynamic strings
The new unified model for packaging extensions for distribution
Who this book is for
This book is for nondevelopers who are interested in exploring the DotNetNuke framework as well as experienced ASP.NET developers who want to build dynamic ASP.NET sites or create add-ins to DotNetNuke.
Wrox Professional guides are planned and written by working programmers to meet the real-world needs of programmers, developers, and IT professionals. Focused and relevant, they address the issues technology professionals face every day. They provide examples, practical solutions, and expert education in new technologies, all designed to help programmers do a better job.
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Most Helpful Customer Reviews on Amazon.com (beta)
I didnt have this book when I was asked to create a DNN site with some custom content at work. I'd had no previous experience with DNN, but am an ASP.net developer with other portal app experience so was able to set up my dev DNN site pretty easily. I do wish I'd had a chance to glance over the chapters on intro/setup before doing so just because there are a few options that aren't quite intuitive. I also noticed a lot of questions asked in the forums are answered here.
The first chapter went into some background of DNN - very enjoyable for a technical book. I'm glad the authors didn't choose to put this as a foreword or I probably would have skipped over it. Reading how such an extensible open-source application came into existence is really neat. It also tells you about the decisions made along the way and why they were made.
After the intro, installation, and admin-type content, the book goes into more detail about the application design, the different provider models, APIs, etc. I really liked how the authors started out describing the chain of events that occur within the application when a web request is made (like how the friendly URLs are processed, for example). All of these more technical chapters are very clearly written and provide sufficient detail and examples.
As someone else mentioned in more detail, the start of the book is padded with largely irrelevant anecdotes about the history of dotnetnuke. Unfortunately, once you get into the meat of the book, it doesn't get any more useful. The most obvious steps are laboriously described (how to unzip a file) and the most obscure (creating a module with multiple views) are skipped over lightly with the apparent assumption that the reader is already familiar with the topic.
Specific examples, as is often the case in Wrox books, are given around a sample project; however, in the tasks described, it is rarely made clear what steps are taken exclusively in support of the specific sample case and which are the general steps necessary for any project.
The code listings in the book are lengthy but are not commented sufficiently to be useful.
Much is made of the fact that the authors are significant contributors to the DNN project, but that is actually a recommendation against the book when you consider that the help integral to the product itself is similarly poorly written... click the question mark tag next to "Module Culture" and you get the tautological "The culture for this module" instead of anything genuinely helpful. The entire book seems to follow this general premise that throwing a greater volume of words is sufficient explanation for concepts, as if the reader already knew everything the authors do but simply needed to have their memory jogged. As a tool for learning the concepts of developing for DNN, it's not particularly helpful.
While waiting for my plane to take off I made it through the first chapter of the book written by the father of DotNetNuke Shaun Walker. This chapter talks about the history of where DNN came from and trials and tribulations that Shaun and his team had giving birth to what we know today. I think that anyone that is interested in starting an open source product should spend a few minutes and learn from the lessons that Shaun learned in the creation of DNN, especially if you are trying to build an open source product that sits on the very not open source Windows platform.
The next few chapters of the book provide information on just about everything that administrator/end-user would need to know in order to go from an empty hosting account to having a DNN site. This includes installation, an overview of the modules and how to administer the lot. The next chunk of the book talks about the architecture of DNN. For years I have been telling developers looking for reference architectures to look at products like DNN. This set of chapters not only includes information on how the DNN team did what they did, but perhaps more importantly WHY they did it that way. For me knowing the why behind these types of decisions allows me to leverage the lessons learned by other developers and apply that to my applications, even non-DNN applications. The ability to learn from the experience/knowledge/mistakes of others makes us all better developers. The last chunk of the book is the how to information that you need to extend DNN. They cover modules, skinning, and distribution.
This book provides a good overview of all the major components in the DNN products. It covers the architecture of the DNN infrastructure and how to extend it with your own custom modules and skins. This book provides the developer and the administrator what they need to get their feet wet with DNN, and as an added bonus you get a great narrative on the birth of an open source software package.
Shawn Weisfed C# MVP
For someone who is trying to learn the technology as it exists today, this is trivia and a waste of valuable time. The one reason I bought the book was to learn how to compile custom modules in Visual Studio (which is advertises as explaining). In the 534 pages of piecemealed fragments of information and code, this was never explained. This book is a puzzle that you, the inexperienced DNN developer, have to piece together and hope for the best. Code examples supposedly downloadable from DNN's website were unavailable there. In a word - pathetic. Don't waste your money.


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Every year the quantity of waste the human population creates is rising, it's because of this that rubbish removal has now become such a huge industry. Before you start to see dollar signs by opening up a company within the rubbish industry, I would take a deep breath and keep reading.
There are many tasks involved when it comes to rubbish removal that you may not have thought of at first including collection, transport, storage, and recycling. Every one of these tasks requires considerable knowledge and thorough training before it can be undertaken, you must ensure that everything's in order or you may end up breaking the law without even realising it. Take into consideration the manners which waste is accumulated, the vehicles used to carry it and the places it needs to be dropped off, all of this is strictly regulated throughout Sydney to ensure the specific guidelines set by law are followed at all times.
Keep in mind the different materials you will be handling whilst on the job, for example plastic, glass and paper are materials you recycle, then you have various metals and other elements which can't be recycled so must be disposed of elsewhere, it is your job to ensure the load has been segregated correctly and the correct procedures are followed or you could get fined for not adhering to the regulations set in Sydney.
There are a number of advantages when running a firm in this sector, for instance, there will always be high demand for a work force which consists of individuals that come along and do an excellent job! The heaps of rubbish thrown out on a daily basis isn't going to stop anytime soon, this means it won't be difficult to find work if you look in the right places. There's always a possibility that you could be down at the tip and stumble upon a valuable item which has been thrown out and no longer has an owner! Yes, there is a lot involved when running a Sydney rubbish company but it pays off if it's you put the effort in first.
If you think you have the right mind-set for this line of work then go for it, not only are the pay rates high enough to live a very comfortable lifestyle but you can go home every night knowing that you've helped clean up the surrounding area making it safer for the people that live there, you've done your part for the environment by following the correct guidelines and recycling plus, you are creating more jobs for people at recycling facilities by ensuring there always busy.
If you need your rubbish removed or want to know what's involved to open your own business in the industry, then visit toptipsolutions and they will give you all the answers you need.

subset: commoncrawl


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3 PM Crochet Basics - Trivet ($45)
Date: 29-Apr-2012
Capacity: 4 (100% booked)
This class is Full.
Crochet Basics – trivet with our new instructor, Alisa: Interested in learning to crochet but not sure where to start? We'll teach you to chain, single-crochet, double-crochet, and how to read a basic pattern. These stitches are the foundation of crochet! You'll be ready to tackle something a bit more complicated after this class.
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3 of 3 people found the following review helpful
A fellow grammar girl's review,
This review is from: Grammar Girl's Quick and Dirty Tips for Better Writing (Quick & Dirty Tips) (Paperback)
As an editor and author of my own grammar book, I always enjoy reading a colleague's book on grammar and usage. Grammar Girl has quickly become the go-to grammar expert and this book is a perfect reference guide that covers all the grammar basics written in an easy to understand format. Any writer wanting to brush up on those pesky grammar rules, will find it easy to find the answers in this book. You go Girl!
Karen Reddick, author of Grammar Done Right!
Review Details
Location: Centennial, CO
Top Reviewer Ranking: 9,895,322


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Dr. Caruana graduated from the Mount Sinai School of Medicine in 1989. He works in New York, NY and 2 other locations and specializes in Otolaryngology. Dr. Caruana is affiliated with New York Presbyterian Hospital Columbia University Medical Center.
Medical School: Mount Sinai School of Medicine; Graduated 1989
Please verify insurance information directly with your doctor's office as it may change frequently.
*This physician has multiple office locations. See Office Information for details.
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Inhaled Agonists of Soluble Guanylate Cyclase Induce Selective Pulmonary Vasodilation
Evgenov, Oleg V.
Kohane, Daniel S.
Bloch, Kenneth D.
Stasch, Johannes-Peter
Volpato, Gian P.
Bellas, Evangelia
Evgenov, Natalia V.
Buys, Emmanuel S.
Gnoth, Mark J.
Graveline, Amanda R.
Liu, Rong
Hess, Dean R.
Langer, Robert
Zapol, Warren M.
American Journal of Respiratory and Critical Care Medicine
Rationale: Nitric oxide–independent agonists of soluble guanylate cyclase (sGC) have been developed.
Objectives: We tested whether inhalation of novel dry-powder microparticle formulations containing sGC stimulators (BAY 41-2272, BAY 41-8543) or an sGC activator (BAY 58-2667) would produce selective pulmonary vasodilation in lambs with acute pulmonary hypertension. We also evaluated the combined administration of BAY 41-8543 microparticles and inhaled nitric oxide (iNO). Finally, we examined whether inhaling BAY 58-2667 microparticles would produce pulmonary vasodilation when the response to iNO is impaired.
Methods: In awake, spontaneously breathing lambs instrumented with vascular catheters and a tracheostomy tube, U-46619 was infused intravenously to increase mean pulmonary arterial pressure to 35 mm Hg.
Measurements and Main Results: Inhalation of microparticles composed of either BAY 41-2272, BAY 41-8543, or BAY 58-2667 and excipients (dipalmitoylphosphatidylcholine, albumin, lactose) produced dose-dependent pulmonary vasodilation and increased transpulmonary cGMP release without significant effect on mean arterial pressure. Inhalation of microparticles containing BAY 41-8543 or BAY 58-2667 increased systemic arterial oxygenation. The magnitude and duration of pulmonary vasodilation induced by iNO were augmented after inhaling BAY 41-8543 microparticles. Intravenous administration of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), which oxidizes the prosthetic heme group of sGC, markedly reduced the pulmonary vasodilator effect of iNO. In contrast, pulmonary vasodilation and transpulmonary cGMP release induced by inhaling BAY 58-2667 microparticles were greatly enhanced after treatment with ODQ.
Conclusions: Inhalation of microparticles containing agonists of sGC may provide an effective novel treatment for patients with pulmonary hypertension, particularly when responsiveness to iNO is impaired by oxidation of sGC.
pulmonary hypertension; soluble guanylate cyclase; BAY 41-2272; BAY 41-8543; BAY 58-2667
Related Articles
Lasker, George F.
Pankey, Edward A.
Allain, Alexander V.
Dhaliwal, Jasdeep S.
Stasch, Johannes-Peter
Murthy, Subramanyam N.
Kadowitz, Philip J.
The journal of sexual medicine
Soluble guanylate cyclase (sGC) is the receptor for nitric oxide (NO) and in pathophysiologic conditions where NO formation or bioavailability is impaired, erectile dysfunction (ED) occurs.
The aim of this study was to investigate erectile responses to the sGC stimulator BAY 41-8543 in physiologic and pathophysiologic conditions.
Increases in intracavernosal pressure (ICP) in response to intracavernosal (ic) injections of BAY 41-8543 were investigated in the anesthetized rat.
Main Outcome Measures
Increases in ICP/MAP in response to ic injections of BAY 41-8543 and the interaction of BAY 41-8543 with exogenous and endogenously released NO were investigated and the effect of the sGC stimulator on cavernosal nerve injury was assessed. The mechanism of the increase in ICP/MAP in response to ic injection of acetylcholine was investigated.
The ic injections of BAY 41-8543 increased ICP/MAP and the duration of the response. BAY 41-8543 was less potent than SNP and ic injections of BAY 41-8543 and SNP produced a larger response than the algebraic sum of responses to either agent alone. Simultaneous ic injection of BAY 41-8543 and cavernosal nerve stimulation produced a greater response than either intervention alone. Atropine and cavernosal nerve crush injury decreased the response to nerve stimulation and ic injection of BAY 41-8543 restored the response.
These data show that BAY 41-8543 has significant erectile activity and can synergize with exogenous and endogenously released NO. This study shows that atropine and nerve crush attenuate the response to cavernosal nerve stimulation and that BAY 41-8543 can restore the response. The results with atropine, L-NAME and hexamethonium indicate that the response to ic injection of acetylcholine is mediated by muscarinic receptors and the release of NO with no significant role for nicotinic receptors. These results suggest that BAY 41-8543 would be useful in the treatment of ED.
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Pankey, Edward A.
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Riehl, Russel A.
Murthy, Subramanyam N.
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Kadowitz, Philip J.
Nitric Oxide
Pulmonary hypertension (PH) is a rare disorder that without treatment is progressive and often fatal within 3 years. The treatment of PH involves the use of a diverse group of drugs and lung transplantation. Although nitrite was once thought to be an inactive metabolite of endothelial-derived nitric oxide (NO), there is increasing evidence that nitrite may be useful in the treatment of PH, but the mechanism by which nitrite exerts its beneficial effect remains uncertain. The purpose of this study was to investigate the effect of chronic sodium nitrite treatment in a PH model in the rat. Following induction of PH with a single injection of monocrotaline, 60 mg; daily ip injections of sodium nitrite (3 mg/kg) starting on day 14 and continuing for 21 days, resulted in a significantly lower pulmonary arterial pressure on day 35 when compared to values in untreated animals with monocrotaline-induced PH. In monocrotaline-treated rats, daily treatment with ip nitrite injections for 21 days decreased right ventricular mass and pathologic changes in small pulmonary arteries. Nitrite therapy did not change systemic arterial pressure or cardiac output when values were measured on day 35. The decreases in pulmonary arterial pressure in response to iv injections of sodium nitroprusside, sodium nitrite, and BAY 41-8543 were not different in rats with monocrotaline-induced pulmonary hypertension and rats with chronic nitrite therapy when compared to responses in animals in which pulmonary arterial pressure was increased with U46619. These findings are consistent with the hypothesis that the mechanisms that convert nitrite to vasoactive NO, activate soluble guanylyl cyclase and mediate the vasodilator response to NO or an NO derivative are not impaired. The present data are consistent with the results of a previous study in monocrotaline-induced PH in which systemic arterial pressure and cardiac output were not evaluated and are consistent with the hypothesis that nitrite is effective in the treatment of monocrotaline-induced PH in the rodent.
pulmonary vascular bed; systemic vascular bed; pulmonary hypertension/therapy; right ventricular hypertrophy; sodium nitrite; nitric oxide; soluble guanylyl cyclase; monocrotaline
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Effects of Different Pulmonary Vasodilators on Arterial Saturation in a Model of Pulmonary Hypertension
Becker, Eva Maria
Stasch, Johannes-Peter
Bechem, Martin
Keldenich, Jörg
Klipp, Alexandra
Schaefer, Katja
Ulbrich, Hannes-Friedrich
Truebel, Hubert
PLoS ONE
Approved therapies for pulmonary arterial hypertension can induce oxygen desaturation when administered to patients with secondary forms of pulmonary hypertension (PH), probably due to an increase in ventilation/perfusion mismatch. Thus, so far these treatments have largely failed in secondary forms of PH.
We established an animal model of heterogeneous lung ventilation to evaluate the desaturation potential of mechanistically distinct vasoactive drugs launched or currently in clinical development for the treatment of PH. Single-lung ventilation was induced in five groups (N = 6) of anesthetized minipigs (7 weeks, 4 to 5 kg BW), and their hemodynamic parameters were monitored before and after intravenous injection of control (vehicle only), endothelin antagonist (bosentan; 0.3, 1, 3, 10 mg/kg), phosphodiesterase type 5 inhibitor (sildenafil; 3, 10, 30, 100 µg/kg), and soluble guanylate cyclase stimulators (BAY 41–8543 and riociguat; 1, 3, 10, 30 µg/kg). Cumulative doses were administered before successive unilateral ventilation cycles. The doses were chosen to achieve equal effect on blood pressure by the different pharmacologic principles.
Single-lung ventilation resulted in transient increases in mean pulmonary artery pressure (mPAP) and desaturation. In contrast to control, all drugs dose-dependently decreased hypoxic mPAP (a positive treatment effect) and increased area under the arterial hemoglobin saturation curve (unwanted desaturation effect). Riociguat and bosentan reduced hypoxic mPAP to the greatest extent, while the soluble guanylate cyclase stimulators riociguat and BAY 41–8543 lowered arterial oxygen saturation of hemoglobin the least.
Future investigations will be required to confirm these findings in clinical settings.
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5-HT2B Receptor Antagonists Inhibit Fibrosis and Protect from RV Heart Failure
Janssen, Wiebke
Schymura, Yves
Novoyatleva, Tatyana
Kojonazarov, Baktybek
Boehm, Mario
Wietelmann, Astrid
Luitel, Himal
Murmann, Kirsten
Krompiec, Damian Richard
Tretyn, Aleksandra
Pullamsetti, Soni Savai
Weissmann, Norbert
Seeger, Werner
Ghofrani, Hossein Ardeschir
Schermuly, Ralph Theo
BioMed Research International
Objective. The serotonin (5-HT) pathway was shown to play a role in pulmonary hypertension (PH), but its functions in right ventricular failure (RVF) remain poorly understood. The aim of the current study was to investigate the effects of Terguride (5-HT2A and 2B receptor antagonist) or SB204741 (5-HT2B receptor antagonist) on right heart function and structure upon pulmonary artery banding (PAB) in mice. Methods. Seven days after PAB, mice were treated for 14 days with Terguride (0.2 mg/kg bid) or SB204741 (5 mg/kg day). Right heart function and remodeling were assessed by right heart catheterization, magnetic resonance imaging (MRI), and histomorphometric methods. Total secreted collagen content was determined in mouse cardiac fibroblasts isolated from RV tissues. Results. Chronic treatment with Terguride or SB204741 reduced right ventricular fibrosis and showed improved heart function in mice after PAB. Moreover, 5-HT2B receptor antagonists diminished TGF-beta1 induced collagen synthesis of RV cardiac fibroblasts in vitro. Conclusion. 5-HT2B receptor antagonists reduce collagen deposition, thereby inhibiting right ventricular fibrosis. Chronic treatment prevented the development and progression of pressure overload-induced RVF in mice. Thus, 5-HT2B receptor antagonists represent a valuable novel therapeutic approach for RVF.
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ACE2 Improves Right Ventricular Function in a Pressure Overload Model
Johnson, Jennifer A.
West, James
Maynard, Karen B.
Hemnes, Anna R.
PLoS ONE
Right ventricular (RV) dysfunction is a complication of pulmonary hypertension and portends a poor prognosis. Pharmacological therapies targeting RV function in pulmonary hypertension may reduce symptoms, improve hemodynamics, and potentially increase survival. We hypothesize that recombinant human angiotensin-converting enzyme 2 (rhACE2) will improve RV function in a pressure overload model.
rhACE2 administered at 1.8 mg/kg/day improved RV systolic and diastolic function in pulmonary artery banded mice as measured by in vivo hemodynamics. Specifically, rhACE2 increased RV ejection fraction and decreased RV end diastolic pressure and diastolic time constant (p<0.05). In addition, rhACE2 decreased RV hypertrophy as measured by RV/LV+S ratio (p<0.05). There were no significant negative effects of rhACE2 administration on LV function. rhACE2 had no significant effect on fibrosis as measured by trichrome staining and collagen1α1 expression. In pulmonary artery banded mice, rhACE2 increased Mas receptor expression and normalized connexin 37 expression.
In a mouse RV load-stress model of early heart failure, rhACE2 diminished RV hypertrophy and improved RV systolic and diastolic function in association with a marker of intercellular communication. rhACE2 may be a novel treatment for RV failure.
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Maintaining tricuspid valve competence in double discordance: a challenge for the paediatric cardiologist
Acar, P
Sidi, D
Bonnet, D
Aggoun, Y
Bonhoeffer, P
Kachaner, J
Objectives—To establish the prevalence of tricuspid valve abnormalities in children with a double discordant heart (or congenitally corrected transposition of the great arteries); to study the influence of the loading conditions induced by various surgical interventions on the right and left ventricle in patients with double discordance and an abnormal tricuspid valve; and to propose a rational surgical approach. Methods—Case notes were reviewed of 141 consecutive patients admitted in the first year of life with various types of double discordance (intact ventricular septum (group 1), ventricular septal defect (group 2), ventricular septal defect and pulmonary obstruction (group 3)). A study group of 62 patients with an abnormal tricuspid valve was selected by cross sectional echocardiography. These were followed up through palliative and open heart procedures with grading of tricuspid regurgitation. Results—Tricuspid valve abnormalities were more common in groups 1 and 2 (60% and 56%) than in group 3 (31%). Preoperative tricuspid regurgitation was more common in group 2 (90%) than in groups 1 and 3 (38% and 36%). Ten patients in groups 1 and 2 died in the neonatal period with severe tricuspid regurgitation, associated with coarctation of the aorta in 60%. Eight patients in group 1 had no surgery and are doing well, with a competent tricuspid valve. Palliative procedures were undertaken in 28 patients: 14 had pulmonary artery banding, which resulted in a decrease in tricuspid regurgitation, 12 in group 2 by reducing the pulmonary blood flow and two in group 1 by changing the septal geometry; 14 in group 3 had an aortopulmonary shunt, which induced tricuspid regurgitation in two. Twenty patients are still alive after palliation, with stable tricuspid valve function. Repair of the tricuspid valve was unsuccessful in the three patients who underwent conventional surgery, leaving the right ventricle facing the systemic circulation. In two patients with a competent but abnormal tricuspid valve, conventional surgery induced severe tricuspid regurgitation. Of the 15 patients who underwent conventional surgery, only 10 survived (mortality 33%): eight with a tricuspid valve prosthesis and two with severe residual tricuspid regurgitation. However, tricuspid regurgitation decreased after anatomical correction (nine patients), restoring a systemic left ventricle and a subpulmonary right ventricle, even when the tricuspid valve was not repaired (five patients). Eight patients are doing well after anatomical correction (mortality 11%). Conclusions—Tricuspid valve function in double discordance with an abnormal tricuspid valve depends on the loading conditions of both ventricles and on the septal geometry. Interventions that increase right ventricular volume or decrease left ventricular pressure are likely to induce tricuspid regurgitation, while those that decrease right ventricular volume or increase left ventricular pressure are likely to improve tricuspid valve function. Repair of the tricuspid valve always failed when the right ventricle was left in a systemic position and always succeeded when the right ventricle was placed in a subpulmonary position. These results should be taken in to account when dealing with patients with double discordance and an abnormal tricuspid valve. Keywords: transposition of the great arteries; double discordance; double switch procedures; tricuspid valve; paediatric cardiology; congenitally corrected transposition
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Deletion of Fn14 receptor protects from right heart fibrosis and dysfunction
Novoyatleva, Tatyana
Schymura, Yves
Janssen, Wiebke
Strobl, Frederic
Swiercz, Jakub M.
Patra, Chinmoy
Posern, Guido
Wietelmann, Astrid
Zheng, Timothy S.
Schermuly, Ralph T.
Engel, Felix B.
Basic Research in Cardiology
Pulmonary arterial hypertension (PAH) is a fatal disease for which no cure is yet available. The leading cause of death in PAH is right ventricular (RV) failure. Previously, the TNF receptor superfamily member fibroblast growth factor-inducible molecule 14 (Fn14) has been associated with different fibrotic diseases. However, so far there is no study demonstrating a causal role for endogenous Fn14 signaling in RV or LV heart disease. The purpose of this study was to determine whether global ablation of Fn14 prevents RV fibrosis and remodeling improving heart function. Here, we provide evidence for a causative role of Fn14 in pulmonary artery banding (PAB)-induced RV fibrosis and dysfunction in mice. Fn14 expression was increased in the RV after PAB. Mice lacking Fn14 (Fn14−/−) displayed substantially reduced RV fibrosis and dysfunction following PAB compared to wild-type littermates. Cell culture experiments demonstrated that activation of Fn14 induces collagen expression via RhoA-dependent nuclear translocation of myocardin-related transcription factor-A (MRTF-A)/MAL. Furthermore, activation of Fn14 in vitro caused fibroblast proliferation and myofibroblast differentiation, which corresponds to suppression of PAB-induced RV fibrosis in Fn14−/− mice. Moreover, our findings suggest that Fn14 expression is regulated by endothelin-1 (ET-1) in cardiac fibroblasts. We conclude that Fn14 is an endogenous key regulator in cardiac fibrosis and suggest this receptor as potential new target for therapeutic interventions in heart failure.
Electronic supplementary material
The online version of this article (doi:10.1007/s00395-012-0325-x) contains supplementary material, which is available to authorized users.
Right heart disease; Fibrosis; Fn14; MAL; Cardiac fibroblasts
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Pulmonary Hypertension in Wild Type Mice and Animals with Genetic Deficit in KCa2.3 and KCa3.1 Channels
Wandall-Frostholm, Christine
Skaarup, Lykke Moran
Sadda, Veeranjaneyulu
Nielsen, Gorm
Hedegaard, Elise Røge
Mogensen, Susie
Köhler, Ralf
Simonsen, Ulf
PLoS ONE
In vascular biology, endothelial KCa2.3 and KCa3.1 channels contribute to arterial blood pressure regulation by producing membrane hyperpolarization and smooth muscle relaxation. The role of KCa2.3 and KCa3.1 channels in the pulmonary circulation is not fully established. Using mice with genetically encoded deficit of KCa2.3 and KCa3.1 channels, this study investigated the effect of loss of the channels in hypoxia-induced pulmonary hypertension.
Approach and Result
Male wild type and KCa3.1−/−/KCa2.3T/T(+DOX) mice were exposed to chronic hypoxia for four weeks to induce pulmonary hypertension. The degree of pulmonary hypertension was evaluated by right ventricular pressure and assessment of right ventricular hypertrophy. Segments of pulmonary arteries were mounted in a wire myograph for functional studies and morphometric studies were performed on lung sections. Chronic hypoxia induced pulmonary hypertension, right ventricular hypertrophy, increased lung weight, and increased hematocrit levels in either genotype. The KCa3.1−/−/KCa2.3T/T(+DOX) mice developed structural alterations in the heart with increased right ventricular wall thickness as well as in pulmonary vessels with increased lumen size in partially- and fully-muscularized vessels and decreased wall area, not seen in wild type mice. Exposure to chronic hypoxia up-regulated the gene expression of the KCa2.3 channel by twofold in wild type mice and increased by 2.5-fold the relaxation evoked by the KCa2.3 and KCa3.1 channel activator NS309, whereas the acetylcholine-induced relaxation - sensitive to the combination of KCa2.3 and KCa3.1 channel blockers, apamin and charybdotoxin - was reduced by 2.5-fold in chronic hypoxic mice of either genotype.
Despite the deficits of the KCa2.3 and KCa3.1 channels failed to change hypoxia-induced pulmonary hypertension, the up-regulation of KCa2.3-gene expression and increased NS309-induced relaxation in wild-type mice point to a novel mechanism to counteract pulmonary hypertension and to a potential therapeutic utility of KCa2.3/KCa3.1 activators for the treatment of pulmonary hypertension.
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A pilot study of the effect of spironolactone therapy on exercise capacity and endothelial dysfunction in pulmonary arterial hypertension: study protocol for a randomized controlled trial
Elinoff, Jason M
Rame, J Eduardo
Forfia, Paul R
Hall, Mary K
Sun, Junfeng
Gharib, Ahmed M
Abd-Elmoniem, Khaled
Graninger, Grace
Harper, Bonnie
Danner, Robert L
Solomon, Michael A
Pulmonary arterial hypertension is a rare disorder associated with poor survival. Endothelial dysfunction plays a central role in the pathogenesis and progression of pulmonary arterial hypertension. Inflammation appears to drive this dysfunctional endothelial phenotype, propagating cycles of injury and repair in genetically susceptible patients with idiopathic and disease-associated pulmonary arterial hypertension. Therapy targeting pulmonary vascular inflammation to interrupt cycles of injury and repair and thereby delay or prevent right ventricular failure and death has not been tested. Spironolactone, a mineralocorticoid and androgen receptor antagonist, has been shown to improve endothelial function and reduce inflammation. Current management of patients with pulmonary arterial hypertension and symptoms of right heart failure includes use of mineralocorticoid receptor antagonists for their diuretic and natriuretic effects. We hypothesize that initiating spironolactone therapy at an earlier stage of disease in patients with pulmonary arterial hypertension could provide additional benefits through anti-inflammatory effects and improvements in pulmonary vascular function.
Seventy patients with pulmonary arterial hypertension without clinical evidence of right ventricular failure will be enrolled in a randomized, double-blinded, placebo-controlled trial to investigate the effect of early treatment with spironolactone on exercise capacity, clinical worsening and vascular inflammation in vivo. Our primary endpoint is change in placebo-corrected 6-minute walk distance at 24 weeks and the incidence of clinical worsening in the spironolactone group compared to placebo. At a two-sided alpha level of 0.05, we will have at least 84% power to detect an effect size (group mean difference divided by standard deviation) of 0.9 for the difference in the change of 6-minute walk distance from baseline between the two groups. Secondary endpoints include the effect of spironolactone on the change in placebo-corrected maximal oxygen consumption; plasma markers of vascular inflammation and peripheral blood mononuclear cell gene expression profiles; sympathetic nervous system activation, renin-angiotensin-aldosterone system activation and sex hormone metabolism; and right ventricular structure and function using echocardiography and novel high-resolution magnetic resonance imaging-based techniques. Safety and tolerability of spironolactone will be assessed with periodic monitoring for hyperkalemia and renal insufficiency as well as the incidence of drug discontinuation for untoward effects.
Trial registration
ClinicalTrials.gov: NCT01712620
Magnetic resonance imaging; Microarray; Mineralocorticoid receptor antagonist; Neurohormonal axis; Pulmonary arterial hypertension; Right ventricular function; Vascular inflammation
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Testosterone negatively regulates right ventricular load stress responses in mice
Hemnes, Anna R.
Maynard, Karen B.
Champion, Hunter C.
Gleaves, Linda
Penner, Niki
West, James
Newman, John H.
Pulmonary Circulation
Right ventricular (RV) function is the major determinant of mortality in pulmonary arterial hypertension and male sex is a strong predictor of mortality in this disease. The effects of testosterone on RV structure and function in load stress are presently unknown. We tested whether testosterone levels affect RV hypertrophic responses, fibrosis, and function. Male C57BL/6 mice underwent castration or sham followed by pulmonary artery banding (PAB) or sham. After recovery, testosterone pellets were placed in a subset of the castrated mice and mice were maintained for at least two weeks, when they underwent hemodynamic measurements and tissues were harvested. Plasma levels of testosterone were reduced by castration and repleted by testosterone administration. In PAB, castration resulted in lower right ventricle/left ventricle + septum (RV/LV+S), and myocyte diameter (P < 0.05). Replacement of testosterone normalized these parameters and increased RV fibrosis (P < 0.05). Two weeks of PAB resulted in increased RV systolic pressure in all groups with decreased markers of RV systolic and diastolic function, specifically reduced ejection fraction and increased time constant, and dPdt minimum (P < 0.05), though there was minimal effect of testosterone on hemodynamic parameters. Survival was improved in mice that underwent castration with PAB compared with PAB alone (P < 0.05). Testosterone affects RV hypertrophic response to load stress through increased myocyte size and increased fibrosis in mice. Castration and testosterone replacement are not accompanied by significant alterations in RV in vivo hemodynamics, but testosterone deprivation appears to improve survival in PAB. Further study of the role of testosterone in RV dysfunction is warranted to better understand these findings in the context of human disease.
pulmonary hypertension; right ventricle; sex hormones; testosterone
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The Reno-Vascular A2B Adenosine Receptor Protects the Kidney from Ischemia
Grenz, Almut
Osswald, Hartmut
Eckle, Tobias
Yang, Dan
Zhang, Hua
Tran, Zung Vu
Klingel, Karin
Ravid, Katya
Eltzschig, Holger K
PLoS Medicine
Acute renal failure from ischemia significantly contributes to morbidity and mortality in clinical settings, and strategies to improve renal resistance to ischemia are urgently needed. Here, we identified a novel pathway of renal protection from ischemia using ischemic preconditioning (IP).
Methods and Findings
For this purpose, we utilized a recently developed model of renal ischemia and IP via a hanging weight system that allows repeated and atraumatic occlusion of the renal artery in mice, followed by measurements of specific parameters or renal functions. Studies in gene-targeted mice for each individual adenosine receptor (AR) confirmed renal protection by IP in A1−/−, A2A−/−, or A3AR−/− mice. In contrast, protection from ischemia was abolished in A2BAR−/− mice. This protection was associated with corresponding changes in tissue inflammation and nitric oxide production. In accordance, the A2BAR-antagonist PSB1115 blocked renal protection by IP, while treatment with the selective A2BAR-agonist BAY 60–6583 dramatically improved renal function and histology following ischemia alone. Using an A2BAR-reporter model, we found exclusive expression of A2BARs within the reno-vasculature. Studies using A2BAR bone-marrow chimera conferred kidney protection selectively to renal A2BARs.
These results identify the A2BAR as a novel therapeutic target for providing potent protection from renal ischemia.
Using gene-targeted mice, Holger Eltzschig and colleagues identify the A2B adenosine receptor as a novel therapeutic target for providing protection from renal ischemia.
Editors' Summary
Throughout life, the kidneys perform the essential task of filtering waste products and excess water from the blood to make urine. Each kidney contains about a million small structures called nephrons, each of which contains a filtration unit consisting of a glomerulus (a small blood vessel) intertwined with a urine-collecting tube called a tubule. If the nephrons stop working for any reason, the rate at which the blood is filtered (the glomerular filtration rate or GFR) decreases and dangerous amounts of waste products such as creatinine build up in the blood. Most kidney diseases destroy the nephrons slowly over years, producing an irreversible condition called chronic renal failure. But the kidneys can also stop working suddenly because of injury or poisoning. One common cause of "acute" renal failure in hospital patients is ischemia—an inadequate blood supply to an organ that results in the death of part of that organ. Heart surgery and other types of surgery in which the blood supply to the kidneys is temporarily disrupted are associated with high rates of acute renal failure.
Why Was This Study Done?
Although the kidneys usually recover from acute failure within a few weeks if the appropriate intensive treatment (for example, dialysis) is provided, acute renal failure after surgery can be fatal. Thus, new strategies to protect the kidneys from ischemia are badly needed. Like other organs, the kidneys can be protected from lethal ischemia by pre-exposure to several short, nonlethal episodes of ischemia. It is not clear how this "ischemic preconditioning" increases renal resistance to ischemia but some data suggest that the protection of tissues from ischemia might involve a signaling molecule called extracellular adenosine. This molecule binds to proteins called receptors on the surface of cells and sends signals into them that change their behavior. There are four different adenosine receptor—A1AR, A2AAR, A2BAR, and A3AR—and in this study, the researchers use ischemic preconditioning as an experimental strategy to investigate which of these receptors protects the kidneys from ischemia in mice, information that might provide clues about how to protect the kidneys from ischemia.
What Did the Researchers Do and Find?
The researchers first asked whether ischemic preconditioning protects the kidneys of mice strains that lack the genes for individual adenosine receptors (A1AR−/−, A2AAR−/−, A2BAR−/−, and A3AR−/− mice) from subsequent ischemia. Using a hanging-weight system, they intermittently blocked the renal artery of these mice before exposing them to a longer period of renal ischemia. Twenty-four hours later, they assessed the renal function of the mice by measuring their blood creatinine levels, GFRs, and urine production. Ischemic preconditioning protected all the mice from ischemia-induced loss of kidney function except the A2BAR−/− mice. It also prevented ischemia-induced structural damage and inflammation in the kidneys of wild-type but not A2BAR−/− mice. These results suggest that A2BAR may help to protect the kidneys from ischemia. Consistent with this idea, ischemic preconditioning did not prevent ischemia-induced renal damage in wild-type mice treated with a compound that specifically blocks the activity of A2BAR. However, wild-type mice (but not A2BAR−/− mice) treated with an A2BAR agonist (which activates the receptor) retained their kidney function after renal ischemia without ischemic preconditioning. Finally, the researchers report that A2BAR has to be present on the blood vessels in the kidney to prevent ischemia-induced acute renal failure.
What Do These Findings Mean?
These findings suggest that the protection of the kidneys from ischemia and the renal resistance to ischemia that is provided by ischemic preconditioning involve adenosine signaling through A2BAR. They also suggest that adenosine might provide protection against ischemia-induced damage by blocking inflammation in the kidney although other possible mechanisms of action need to be investigated. Importantly, these findings suggest that A2BAR might be a therapeutic target for the prevention of renal ischemia. However, results obtained in animals do not always reflect the situation in people, so before A2BAR agonists can be used to reduce the chances of patients developing acute renal failure after surgery, these results need confirming in people and the safety of A2BAR agonists need to be thoroughly investigated.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050137.
The US National Institute of Diabetes and Digestive and Kidney Diseases provides information on how the kidneys work and what can go wrong with them, including a list of links to further information about kidney disease
The MedlinePlus encyclopedia has a page on acute kidney failure (in English and Spanish)
Wikipedia has pages on acute renal failure, ischemia, ischemic preconditioning, and adenosine (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
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Genistein, a Soy Phytoestrogen, Reverses Severe Pulmonary Hypertension and Prevents Right Heart Failure in Rats
Matori, Humann
Umar, Soban
Nadadur, Rangarajan D.
Sharma, Salil
Partow-Navid, Rod
Afkhami, Michelle
Amjedi, Marjan
Eghbali, Mansoureh
Pretreatment with a phytoestrogen genistein has been shown to attenuate the development of pulmonary hypertension (PH). Because PH is not always diagnosed early, we examined whether genistein could also reverse preexisting established PH and prevent associated right heart failure (RHF). PH was induced in male rats by 60 mg/kg of monocrotaline. After 21 days, when PH was well established, rats received daily injection of genistein (1 mg/kg per day) for 10 days or were left untreated to develop RHF by day 30. Effects of genistein on human pulmonary artery smooth muscle cell and endothelial cell proliferation and neonatal rat ventricular myocyte hypertrophy were assessed in vitro. Severe PH was evident 21 days after monocrotaline, as peak systolic right ventricular pressure increased to 66.35±1.03 mm Hg and right ventricular ejection fraction reduced to 41.99±1.27%. PH progressed to RHF by day 30 (right ventricular pressure, 72.41 ± 1.87 mm Hg; RV ejection fraction, 29.25 ± 0.88%), and mortality was ≈75% in RHF rats. Genistein therapy resulted in significant improvement in lung and heart function as right ventricular pressure was significantly reduced to 43.34±4.08 mm Hg and right ventricular ejection fraction was fully restored to 65.67 ± 1.08% similar to control. Genistein reversed PH-induced pulmonary vascular remodeling in vivo and inhibited human pulmonary artery smooth muscle cell proliferation by ≈50% in vitro likely through estrogen receptor-β. Genistein also reversed right ventricular hypertrophy (right ventricular hypertrophy index, 0.35±0.029 versus 0.70±0.080 in RHF), inhibited neonatal rat ventricular myocyte hypertrophy, and restored PH-induced loss of capillaries in the right ventricle. These improvements in cardiopulmonary function and structure resulted in 100% survival by day 30. Genistein restored PH-induced downregulation of estrogen receptor-β expression in the right ventricle and lung. In conclusion, genistein therapy not only rescues preexisting severe PH but also prevents the progression of severe PH to RHF.
pulmonary hypertension; right heart failure; genistein; angiogenesis; estrogen receptor-β
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Zierer, Andreas
Voeller, Rochus K.
Melby, Spencer J.
Steendijk, Paul
Moon, Marc R.
European journal of anaesthesiology
Patients with chronic pulmonary hypertension (CPH) who demonstrate a pulmonary vasodilation following calcium channel blocker (CCB) administration are defined as "responders". In contrast, "non-responders" are patients who do not show such a pulmonary vasodilation with CCB therapy. The purpose of this investigation was to study the effects of CCB therapy on right heart mechanics in experimental CCB responders versus CCB non-responders.
In 12 dogs, right atrial (RA) and ventricular (RV) pressure and volume (conductance catheters) were simultaneously recorded after 3 months of progressive pulmonary artery (PA) banding. Diltiazem was given at 10 mg/hr with the PA constricted (simulated CCB non-responder). Responders were then created by releasing the PA band to unload the ventricle. RA and RV contractility and diastolic stiffness (slope of end-systolic and end-diastolic pressure-volume relations) were calculated and RA reservoir and conduit function were quantified as RA inflow with the tricuspid valve closed versus open, respectively.
With CCB, RA contractility (p<0.03) and cardiac output (p<0.004) were compromised in simulated non-responders while RA stroke work was pharmacologically depressed in the setting of an unchanged afterload. After simulating a responder by controlled PA band release, the RA became less distensible, causing a shift from reservoir to conduit function (p<0.001) towards physiologic baseline conditions and a recovery in the hyperdynamic compensatory response in both chambers (p<0.007) as evidenced in a declined RA and RV contractility with an improved cardiac output as compared to CPH and simulated non-responders. RA and RV diastolic function in both groups was not affected by CCB.
CCB did not impact RV function in simulated non-responders, but significantly impaired RA contractility and cardiac output. In simulated responders, afterload fell substantially, thereby allowing the RA and RV to recover from their pathological hyperdynamic contractile response to CPH. This affect was able to outweigh the intrinsic negative effects of CCB therapy on systolic RA function. Current data suggest that the RA in CPH is much more sensitive to CCB therapy than the RV and delineate for the first time why CCB therapy in CPH has been empirically restricted to documented responders.
calcium-channel blockers; chronic pulmonary hypertension; right heart function
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Xuan Bai Cheng Qi formula as an adjuvant treatment of acute exacerbation of chronic obstructive pulmonary disease of the syndrome type phlegm-heat obstructing the lungs: a multicenter, randomized, double-blind, placebo-controlled clinical trial
Liu, Miao
Zhong, Xianggen
Li, Yuhang
Zheng, Fengjie
Wu, Ruohan
Sun, Yan
Zhang, Jinchao
BMC Complementary and Alternative Medicine
Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a common cause of morbidity and mortality. Traditional Chinese medicine (TCM) is used to treat AECOPD as adjunctive therapy. This study aimed to evaluate the efficacy and safety of the TCM formula Xuan Bai Cheng Qi as an adjuvant therapy for AECOPD patients with the syndrome type of phlegm-heat obstructing the lungs.
A multicenter, randomized, double-blind, placebo-controlled clinical trial was conducted. A total of 244 patients were divided into the intervention group (n = 122, treated with conventional medicine and Xuan Bai Cheng Qi) and the control group (n = 122, treated with conventional medicine and placebo). Total symptom scores (cough, phlegm, wheezing, chest congestion) before treatment and at 3, 5, 7, 10 days post-treatment were recorded. Lung function, arterial blood gas, serum inflammatory cytokines, oxidation/anti-oxidation index were observed before treatment and at the end of the 10-day treatment.
A total of 242 patients completed the study. The full analysis set (FAS) population was 244 and the per-protocol analysis set (PPS) population was 229. After the 10-day treatment, symptom scores of the Xuan Bai Cheng Qi group were significantly lower over time compared with the control group (FAS: mean difference -1.84, 95% CI -2.66 to -1.03, P < .001; PPS: mean difference -1.87, 95% CI -2.71 to -1.03, P < .001). FEV1, FVC, and FEV1%pred were significantly higher over time in the Xuan Bai Cheng Qi group compared with those in the control group (day 10, FAS and PPS: P < .05). PaO2 and PaCO2 were significantly improved in the Xuan Bai Cheng Qi group (day 10, FAS and PPS: P < .05). Xuan Bai Cheng Qi was also found to ameliorate cytokine levels and oxidation/antioxidant index compared with placebo. There were no differences in safety variables and adverse events between the two groups.
Xuan Bai Cheng Qi formula appears to be a safe and beneficial treatment for AECOPD of phlegm-heat obstructing the lungs syndrome type.
Acute exacerbation; Chronic obstructive pulmonary disease; Xuan Bai Cheng Qi; Phlegm-heat obstructing lung; Syndrome; Traditional Chinese medicine
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Effect of single lung transplantation on pulmonary hypertension in patients with end stage fibrosing lung disease.
Doig, J C
Corris, P A
Hilton, C J
Dark, J H
Bexton, R S
British Heart Journal
OBJECTIVE--To investigate the effect of successful single lung transplantation on pulmonary haemodynamic variables and right ventricular function. DESIGN--Pulmonary haemodynamic variables and right ventricular function were measured at right heart catheterisation after single lung transplantation. The results were compared with the preoperative pulmonary haemodynamic variables measured at the time of assessment for transplantation. SETTING--A tertiary referral centre. PATIENTS--Five survivors of single lung transplantation performed for end stage lung disease. INTERVENTIONS--Cardiac catheterisation in all five patients at a mean of 18 months postoperatively. Preoperative catheter data were available for comparison in four. Right heart pressures and cardiac output were measured and right ventricular angiography was performed. Perfusion scans performed for clinical reasons were used to assess the percentage of cardiac output passing through each lung. MAIN OUTCOME MEASURES--Right heart pressures, cardiac output, right ventricular function, percentage perfusion to lungs. RESULTS--After operation mean peak right ventricular pressure fell from 53 mm Hg to 33 mm Hg, mean pulmonary artery pressure from 33 mm Hg to 18 mm Hg, total pulmonary resistance from 11.2 U x m2 to 5.8 U x m2, and pulmonary arteriolar resistance from 8.9 U x m2 to 3.6 U x m2. Pulmonary artery wedge pressure and cardiac index were unchanged. Right ventricular function improved in all patients. The transplanted lung received most of the cardiac output. CONCLUSION--In patients with moderate pulmonary hypertension and right ventricular dysfunction secondary to end stage fibrosing lung disease single lung transplantation was followed by an improvement in pulmonary haemodynamic variables and right ventricular function.
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Iloprost improves ventricular function in the hypertrophic and functionally impaired right heart by direct stimulation
Holmboe, Sarah
Andersen, Asger
Vildbrad, Mads D.
Nielsen, Jan M.
Ringgaard, Steffen
Nielsen-Kudsk, Jens E.
Pulmonary Circulation
Right heart function is an important predictor of morbidity and mortality in patients suffering from pulmonary arterial hypertension and congenital heart diseases. We investigated whether the prostacyclin analog iloprost has a direct inotropic effect in the pressure-overloaded hypertrophic and dysfunctional right ventricle (RV). Rats were randomized to monocrotaline injection (60 mg/kg; ), pulmonary trunk banding (PTB; ), or a sham operation (). RV function was evaluated with magnetic resonance imaging, echocardiography, and invasive pressure measurements at baseline, after intravenous administration of placebo, iloprost 10 ng/kg/min, or iloprost 100 ng/kg/min (Ilo100). Infusion of Ilo100 induced a () increase in stroke volume in the sham group and a () increase in the PTB group. RV was elevated by () in the sham group and by () in the PTB group. An elevation in cardiac output of () and an () increase in RV systolic pressure were found in the PTB group. Iloprost caused a decrease in mean arterial blood pressure (MAP) in all groups of animals. An equal reduction in MAP induced by the arterial vasodilator nitroprusside did not improve any of the measured parameters of RV function. We conclude that iloprost has inotropic properties directly improving ventricular function in the hypertrophic and dysfunctional right heart of the rat.
heart failure; prostacyclin; inotropy; pulmonary hypertension; right heart
Related Articles
Creatine supplementation during pulmonary rehabilitation in chronic obstructive pulmonary disease
Fuld, J
Kilduff, L
Neder, J
Pitsiladis, Y
Lean, M
Ward, S
Cotton, M
Background: Skeletal muscle wasting and dysfunction are strong independent predictors of mortality in patients with chronic obstructive pulmonary disease (COPD). Creatine nutritional supplementation produces increased muscle mass and exercise performance in health. A controlled study was performed to look for similar effects in 38 patients with COPD.
Methods: Thirty eight patients with COPD (mean (SD) forced expiratory volume in 1 second (FEV1) 46 (15)% predicted) were randomised to receive placebo (glucose polymer 40.7 g) or creatine (creatine monohydrate 5.7 g, glucose 35 g) supplements in a double blind trial. After 2 weeks loading (one dose three times daily), patients participated in an outpatient pulmonary rehabilitation programme combined with maintenance (once daily) supplementation. Pulmonary function, body composition, and exercise performance (peripheral muscle strength and endurance, shuttle walking, cycle ergometry) took place at baseline (n = 38), post loading (n = 36), and post rehabilitation (n = 25).
Results: No difference was found in whole body exercise performance between the groups: for example, incremental shuttle walk distance mean –23.1 m (95% CI –71.7 to 25.5) post loading and –21.5 m (95% CI –90.6 to 47.7) post rehabilitation. Creatine increased fat-free mass by 1.09 kg (95% CI 0.43 to 1.74) post loading and 1.62 kg (95% CI 0.47 to 2.77) post rehabilitation. Peripheral muscle performance improved: knee extensor strength 4.2 N.m (95% CI 1.4 to 7.1) and endurance 411.1 J (95% CI 129.9 to 692.4) post loading, knee extensor strength 7.3 N.m (95% CI 0.69 to 13.92) and endurance 854.3 J (95% CI 131.3 to 1577.4) post rehabilitation. Creatine improved health status between baseline and post rehabilitation (St George's Respiratory Questionnaire total score –7.7 (95% CI –14.9 to –0.5)).
Conclusions: Creatine supplementation led to increases in fat-free mass, peripheral muscle strength and endurance, health status, but not exercise capacity. Creatine may constitute a new ergogenic treatment in COPD.
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The peroxisome proliferator–activated receptor β/δ agonist GW0742 has direct protective effects on right heart hypertrophy
Kojonazarov, Baktybek
Luitel, Himal
Sydykov, Akylbek
Dahal, Bhola K.
Paul-Clark, Mark J.
Bonvini, Sara
Reed, Anna
Schermuly, Ralph T.
Mitchell, Jane A.
Pulmonary Circulation
Pulmonary hypertension is a debilitating disease with no cure. We have previously shown that peroxisome proliferator–activated receptor (PPAR) β/δ agonists protect the right heart in hypoxia-driven pulmonary hypertension without affecting vascular remodeling. PPARβ/δ is an important receptor in lipid metabolism, athletic performance, and the sensing of prostacyclin. Treatment of right heart hypertrophy and failure in pulmonary hypertension is an emerging target for future therapy. Here we have investigated the potential of GW0742, a PPARβ agonist, to act directly on the right heart in vivo and what transcriptomic signatures are associated with its actions. Right heart hypertrophy and failure was induced in mice using a pulmonary artery banding (PAB) model. GW0742 was administered throughout the study. Cardiovascular parameters were measured using echocardiography and pressure monitoring. Fibrosis and cellular changes were measured using immunohistochemistry. Transcriptomics were measured using the Illumina MouseRef-8v3 BeadChip array and analyzed using GeneSpring GX (ver. 11.0). PAB resulted in right heart hypertrophy and failure and in increased fibrosis. GW0742 reduced or prevented the effects of PAB on all parameters measured. GW0742 altered a number of genes in the transcriptome, with Angptl4 emerging as the top gene altered (increased) in animals with PAB. In conclusion, the PPARβ/δ agonist GW0742 has direct protective effects on the right heart in vivo. These observations identify PPARβ/δ as a viable therapeutic target to treat pulmonary hypertension that may complement current and future vasodilator drugs.
pulmonary hypertension; heart failure; peroxisome proliferator–activated receptor (PPAR) β; right ventricular function; angiopoietin-like 4
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MR and CT imaging of the structural and functional changes of pulmonary arterial hypertension
Schiebler, Mark L.
Bhalla, Sanjeev
Runo, James
Jarjour, Nizar
Roldan, Alejandro
Chesler, Naomi
François, Christopher J.
Journal of thoracic imaging
The current Dana Point classification system (2009) divides elevation of pulmonary artery pressure into Pulmonary Arterial Hypertension (PAH) and Pulmonary Hypertension (PH). Fortunately, pulmonary arterial hypertension (PAH) is not a common disease. However, with the aging of the first world's population, heart failure is now an important cause of pulmonary hypertension with up to 9% of the population involved. PAH is usually asymptomatic until late in the disease process. While there are indirect features of PAH found on noninvasive imaging studies, the diagnosis and management still requires right heart catheterization. Imaging features of PAH include: 1. Enlargement of the pulmonary trunk and main pulmonary arteries, 2. Decreased pulmonary arterial compliance, 3. Tapering of the peripheral pulmonary arteries, 4. Enlargement of the inferior vena cava, and 5. Increased mean transit time. The chronic requirement to generate high pulmonary arterial pressures measurably affects the right heart and main pulmonary artery. This change in physiology causes the following structural and functional alterations that have been shown to have prognostic significance: Relative area change of the pulmonary trunk, RVSVindex, RVSV, RVEDVindex, LVEDVindex, and baseline RVEF <35%. All of these variables can be quantified non-invasively and followed longitudinally in each patient using MRI to modify the treatment regimen. Untreated PAH frequently results in a rapid clinical decline and death within 3 years of diagnosis. Unfortunately, even with treatment, less than 1/2 of these patients are alive at four years.
Hypertension; Pulmonary; Magnetic Resonance Angiography; Multidetector Computed Tomography; Thromboembolism; Heart Catheterization
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Echocardiography may help detect pulmonary vasculopathy in the early stages of pulmonary artery hypertension associated with systemic sclerosis
Serra, Walter
Chetta, Alfredo
Santilli, Daniele
Mozzani, Flavio
Dall'Aglio, Pier Paolo
Olivieri, Dario
Cattabiani, Maria Alberta
Ardissino, Diego
Gherli, Tiziano
Cardiovascular Ultrasound
Pulmonary arterial hypertension (PAH) in patients with systemic sclerosis is associated with a poor prognosis, but this can be improved by early disease detection. Abnormal pulmonary and cardiac function can be detected early by means of echocardiography, whereas right heart catheterization is usually performed later.
The purpose of this prospective study was to detect early the presence of pulmonary artery vasculopathy in patients with verified systemic sclerosis without significant pulmonary fibrosis, normal lung volumes and a mildly reduced lung diffusion capacity of carbon monoxide (DLCO).
Nineteen consecutive female NYHA class I-II patients with scleroderma and a PAPs of < 35 mm/Hg measured by echocardiography, were enrolled between September 2007 and September 2009. They had a mean age of 51 ± 13 years, body mass index of 25 ± 5 kg/m2). They all underwent complete Doppler echocardiography, CPET, a pulmonary ventilation test (carbon monoxide lung diffusion, DLCO), HRCT. To investigate PAH by means of complete resting Doppler echocardiography estimates of systolic pulmonary artery pressure (PAPs) derived from tr icuspid regurgitation, mean PAP derived from pulmonary regurgitation, pulmonary vessel resistance (PVR) derived from the acceleration time of the pulmonary outflow tract (ACTpo), and right ventricular function derived from tricuspid annular plane systolic excursion (TAPSE). Right heart catheterisation was conducted only, if pulmonary hypertension was suggested by echocardiography and an abnormal ventilator test.
The data are given as mean values ± SD, unless otherwise stated. The correlations between the variables were analysed using Pearson's r coefficient, and the predictive value of the variables was calculated using linear regression analysis. A p value of > 0.05 was considered significant.
Right heart catheterization detected PAH in 15/19 patients; mean PAP was 30.5 mm/Hg and RVP 3.6 UW. Coronary angiography of the patients aged more than 55 years showed some evidence of significant coronary artery disease. Echocardiography showed high systolic PAP values (46 ± 8 mmHg), whereas right ventricular function was normal (TAPSE 23 ± 3 mm), and in line with the NYHA class. ACTpo was reduced in the patients with a systolic PAP of < 46 mm/Hg (p > 0.001) and positively correlated with DLCO (p > 0.001) and the hemodynamic data.
There was a good correlation between ACTpo and PVR (hemodynamic data) (r = -0615; p > 0.01).
Although they need to be confirmed by studies of larger series of patients, our findings suggest that, in comparison with hemodynamic data, non-invasive echocardiographic measurements are an excellent means of identifying early-stage PAH.
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N-acetylcysteine improves established monocrotaline-induced pulmonary hypertension in rats
Chaumais, Marie-Camille
Ranchoux, Benoît
Montani, David
Dorfmüller, Peter
Tu, Ly
Lecerf, Florence
Raymond, Nicolas
Guignabert, Christophe
Price, Laura
Simonneau, Gérald
Cohen-Kaminsky, Sylvia
Humbert, Marc
Perros, Frédéric
Respiratory Research
The outcome of patients suffering from pulmonary arterial hypertension (PAH) are predominantly determined by the response of the right ventricle to the increase afterload secondary to high vascular pulmonary resistance. However, little is known about the effects of the current available or experimental PAH treatments on the heart. Recently, inflammation has been implicated in the pathophysiology of PAH. N-acetylcysteine (NAC), a well-known safe anti-oxidant drug, has immuno-modulatory and cardioprotective properties. We therefore hypothesized that NAC could reduce the severity of pulmonary hypertension (PH) in rats exposed to monocrotaline (MCT), lowering inflammation and preserving pulmonary vascular system and right heart function.
Saline-treated control, MCT-exposed, MCT-exposed and NAC treated rats (day 14–28) were evaluated at day 28 following MCT for hemodynamic parameters (right ventricular systolic pressure, mean pulmonary arterial pressure and cardiac output), right ventricular hypertrophy, pulmonary vascular morphometry, lung inflammatory cells immunohistochemistry (monocyte/macrophages and dendritic cells), IL-6 expression, cardiomyocyte hypertrophy and cardiac fibrosis.
The treatment with NAC significantly decreased pulmonary vascular remodeling, lung inflammation, and improved total pulmonary resistance (from 0.71 ± 0.05 for MCT group to 0.50 ± 0.06 for MCT + NAC group, p < 0.05). Right ventricular function was also improved with NAC treatment associated with a significant decrease in cardiomyocyte hypertrophy (625 ± 69 vs. 439 ± 21 μm2 for MCT and MCT + NAC group respectively, p < 0.001) and heart fibrosis (14.1 ± 0.8 vs. 8.8 ± 0.1% for MCT and MCT + NAC group respectively, p < 0.001).
Through its immuno-modulatory and cardioprotective properties, NAC has beneficial effect on pulmonary vascular and right heart function in experimental PH.
Pulmonary hypertension; Immunomodulation; Inflammation; Right heart function; N-acetylcysteine
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High-Pressure Pulmonary Artery Aneurysm and Unilateral Pulmonary Artery Agenesis in an Adult
Heper, Gulumser
Korkmaz, Mehmet Emin
Texas Heart Institute Journal
The presence of a pulmonary artery aneurysm, major aortopulmonary and coronary–pulmonary collateral vessels, and severe pulmonary hypertension in an adult with unilateral pulmonary artery agenesis and previous patent ductus arteriosus ligation is very rare. A 34-year-old man experienced these conditions. When he was 10 years old, catheterization and angiography revealed right pulmonary artery agenesis, dilation of the main pulmonary artery, multiple collateral vessels extending from the aorta to the right pulmonary system, and a patent ductus arteriosus (shunt ratio, 3.57) that was then ligated; the other conditions were not corrected.
This adult patient was in New York Heart Association functional class II; mild central cyanosis was detected only during exercise. The right pulmonary arterial system was seen only at the right hilar area via collateral vessels from the subclavian, bronchial, internal mammary, and intercostal arteries. Angiography revealed collateral vessels from the right and circumflex coronary arteries to the right pulmonary system. The right intraparenchymal pulmonary arterial systems were patent but of small diameter (pulmonary artery pressure, 85 mmHg; ratio of peak right-to-left ventricular pressure, 0.94; peak pulmonary pressure unresponsive to 100% oxygen). Pulmonary vascular resistance was not estimated because of the risk of aneurysmal rupture.
We concluded that irreversible pulmonary hypertension had developed (delayed by the patent ductus arteriosus ligation in childhood) and that the patient's only chance for survival was heart-lung transplantation. To sustain the patient until surgery, we administered sildenafil. Herein, we describe the vascular conditions that accompany unilateral absence of the pulmonary artery, and therapeutic methods.
Adult; cardiovascular abnormalities; collateral circulation/physiology; coronary vessel anomalies/complications/diagnosis/physiopathology; diagnosis, differential; heart defects, congenital; hypertension, pulmonary/diagnosis/drug therapy/etiology; pulmonary artery/abnormalities/anatomy & histology/physiopathology; sildenafil; vasodilator agents/therapeutic use
Related Articles
Catecholamine-Independent Heart Rate Increases Require CaMKII
Gao, Zhan
Singh, Madhu V
Hall, Duane D
Koval, Olha M.
Luczak, Elizabeth D.
Joiner, Mei-ling A.
Chen, Biyi
Wu, Yuejin
Chaudhary, Ashok K
Martins, James B
Hund, Thomas J
Mohler, Peter J
Song, Long-Sheng
Anderson, Mark E.
Circulation. Arrhythmia and electrophysiology
Catecholamines increase heart rate by augmenting the cAMP responsive HCN4 'pacemaker current' (If) and/or by promoting inward Na+/Ca2+ exchanger current (INCX), by a 'Ca2+ clock' mechanism in sinoatrial nodal cells (SANCs). The importance, identity and function of signals that connect If and Ca2+ clock mechanisms are uncertain and controversial, but the multifunctional Ca2+ and calmodulin-dependent protein kinase II (CaMKII) is required for physiological heart rate responses to β-adrenergic receptor (β-AR) stimulation. The aim of this stuy is to measure the contribution of the Ca2+ clock and CaMKII to cardiac pacing independent of β-AR agonist stimulation.
Methods and Results
We used the L-type Ca2+ channel agonist BayK 8644 (BayK) to activate the SANC Ca2+ clock. BayK and isoproterenol were similarly effective in increasing rates in SANCs and Langendorff-perfused hearts from WT control mice. In contrast, SANCs and isolated hearts from mice with CaMKII inhibition by transgenic expression of an inhibitory peptide (AC3-I) were resistant to rate increases by BayK. BayK only activated CaMKII in control SANCs, but increased ICa equally in all SANCs, indicating that increasing ICa was insufficient and suggesting CaMKII activation was required for heart rate increases by BayK. BayK did not increase If or protein kinase A (PKA)-dependent phosphorylation of phospholamban (at Ser16), indicating that increased SANC Ca2+ by BayK did not augment cAMP/PKA signaling at these targets. Late diastolic intracellular Ca2+ release and INCX were significantly reduced in AC3-I SANCs and the response to BayK was eliminated by ryanodine in all groups.
The Ca2+ clock is capable of supporting physiological fight or flight responses, independent of β-AR stimulation or If increases. Complete Ca2+ clock and β-AR stimulation responses require CaMKII.
Ca2+/calmodulin-dependent protein kinase (CaMKII); sinoatrial node cells; L-type Ca2+ channels; pacemaker current; sarcoplasmic reticulum
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Pulmonary heart disease: The heart-lung interaction and its impact on patient phenotypes
Forfia, Paul R.
Vaidya, Anjali
Wiegers, Susan E.
Pulmonary Circulation
Pulmonary heart disease (PHD) refers to altered structure or function of the right ventricle occurring in association with abnormal respiratory function. Although nearly always associated with some degree of PH, the degree, nature, severity, and causality of PH in relation to the PHD is not necessarily linear and direct. Abnormal gas exchange is a fundamental underpinning of PHD, affecting pulmonary vascular, cardiac, renal, and neurohormonal systems. Direct and indirect effects of chronic respiratory disease can disrupt the right ventricular-pulmonary arterial (RV-PA) interaction and, likewise, factors such as sympathetic nervous system activation, altered blood viscosity, and salt and water retention can function in a feedback loop to further influence RV-PA function. Left heart function may also be affected, especially in those with pre-existing left heart disease. Thus, the physiologic interactions between abnormal respiratory and cardiovascular function are complex, with PHD representing a heterogeneous end organ effect of an integrated multisystem process. In this review, we propose to separate PHD into two distinct entities, "Type I" and "Type II" PHD. Type I PHD is most common, and refers to subjects with chronic respiratory disease (CRD) where the perturbations in respiratory function dominate over more mild cardiac and circulatory disruptions. In contrast, Type II PHD refers to the smaller subset of patients with more severe pulmonary vascular and right heart dysfunction, whom often present in a fashion similar to patients with PAH. Phenotypic differences are not made by PA pressure alone, but instead by differences in the overall physiology and clinical syndrome. Thus, key differences can be seen in symptomatology, physical signs, cardiac imaging, hemodynamics, and the cardiovascular and gas exchange responses to exercise. Such key baseline differences in the overall physiologic phenotype are likely critical to predicting response to PH specific therapy. Recognizing PHD as distinct phenotypes assists in the necessary distinction of these patients, and may also provide a key clinical and pathophysiologic framework for improved patient selection for future studies investigating the role of pulmonary hypertension-specific therapies in PHD.
pulmonary heart disease; cor pulmonale; pulmonary hypertension; group 3 pulmonary hypertension; pulmonary vascular disease; chronic respiratory disease; right ventricular function; exercise physiology; ventilatory inefficiency
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Adesnik Lab
Postdoctoral positions are available in three areas: sensory physiology, optical engineering, and the development of novel optogenetic tools. The latter two areas will be part of a collaboration with faculty in engineering. Interested candidates should send a CV and a list of three references and should have a strong record of scentific achievement.
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