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Arterial stiffness and contralateral differences in blood pressure: The Atherosclerosis Risk in Communities (ARIC) study

Abstract A large interarm difference in brachial systolic blood pressure (SBP) (≥10 or ≥15 mmHg) is strongly associated with elevated cardiovascular events and mortality. Evidence demonstrating whether such contralateral differences in SBP occur in ankle blood pressure and its association with arterial stiffness is scarce. The aims of this study were to characterize arm and ankle contralateral SBP differences in a sample of community‐dwelling older adults (5077), and to determine whether this difference is associated with arterial stiffness assessed by pulse wave velocity (PWV) between the heart and ankle (haPWV), femoral artery and ankle (faPWV), and brachial artery and ankle (baPWV) in the right and left sides. Prevalence of interarm SBP differences ≥10 and ≥15 mmHg was 5.1% and .7%, respectively; the corresponding prevalence for interankle SBP was 24.9% and 12.0%. Higher BMI and lower ankle‐brachial index (ABI) were significantly correlated with greater interarm SBP differences. Increased age, higher BMI, lower ABI, and greater contralateral differences in haPWV, faPWV, and baPWV were significantly correlated to greater interankle SBP differences. Interankle SBP difference ≥15 mmHg was significantly associated with contralateral differences of >80 cm/s in haPWV (OR = 1.94 [95% CI = 1.52–2.49]), >165 cm/s in faPWV (OR = 1.64 [95% CI = 1.27–2.12]), and >240 cm/s in baPWV (OR = 2.43 [95% CI = 1.94–3.05]). The associations remained significant after adjustment for age, sex, race, BMI, smoking status, and ABI. Compared with interarm differences, interankle differences in SBP are common in older adults. The magnitude of interankle, but not interarm, differences in SBP is associated with various measures of arterial stiffness.


INTRODUCTION
Blood pressure is a prototypical quantitative trait known to be variable.
It fluctuates beat-by-beat from daytime to nighttime. Blood pressure can be substantially different in each limb that is measured. [1][2][3][4] Several epidemiological studies have demonstrated that a large interarm difference in brachial systolic blood pressure (SBP) (i.e., ≥10 or ≥15 mmHg) is associated with elevated cardiovascular events and mortality. [2][3][4][5][6] Pathophysiology linking contralateral differences in brachial SBP and cardiovascular mortality remains unclear, but subclinical and/or clinical vascular disease affecting one side of the body (e.g., coarctation, subclavian artery stenosis) has been suggested. 3,4,7 Physiological factors such as arterial stiffness could also play a role as SBP is strongly influenced by the stiffening of arteries. 8,9 Indeed, individual variabilities in contralateral differences in pulse wave velocity (PWV) have been reported, 10 but there is of yet published no information addressing this question. Moreover, it is not known if such contralateral differences in ankle SBP are associated with those in brachial blood pressure. Considering the evidence that arterial wave reflection is a primary mechanism responsible for augmenting SBP distally, and that the lower body is believed to be the important site of wave reflection, 11 contralateral differences in SBP, if any, may be influenced by the stiffness of arteries to a greater extent in the ankle than in the arm. However, such issue has not been addressed. The Atherosclerosis Risk in Communities (ARIC) study utilized a vascular screening device that simultaneously measured blood pressure in four limbs and arterial stiffness in both sides of the body, 12 which enables a comprehensive examination of blood pressure differences and their associations with arterial stiffness.
Accordingly, the aims of the present study were to characterize arm and ankle contralateral SBP differences in a sample of communitydwelling older adults and to determine whether these differences are associated with various measures of arterial stiffness assessed at different body sites.

Study population
The ARIC Study is a community-based prospective cohort study of

Pulse wave velocity
The semiautomatic vascular screening device OMRON VP-1000 plus (Kyoto, Japan) was used to measure blood pressure simultaneously in the arms and ankles and arterial stiffness by PWV after participants were in the supine position for 5-10 min. Participant preparation included abstaining from smoking, vigorous exercise, and caffeinated beverages during the day of examination. PWV was estimated as the distance between 2 arterial recording sites divided by transit time.
PWV was assessed between the heart and ankle (haPWV), femoral artery and ankle (faPWV), and brachial artery and ankle (baPWV) on the right and left sides. Femoral arterial pressure waveforms were acquired for 30 s by applanation tonometry sensor attached to the left common femoral artery (via elastic tape around the hip). Bilateral brachial and posterior-tibial arterial pressure waveforms were detected over 10 s by extremity cuffs connected to a plethysmographic and an oscillometric pressure sensor wrapped on both arms and ankles.
Trained technicians recorded PWV and blood pressures twice, and the results of the two readings were averaged. 8

Covariates
Participants underwent a blood draw, standard 12-lead electrocardiogram, anthropometric measurements, and interviewer-administered questionnaires to obtain medical history and lifestyle information.
Age, sex, race, smoking status, and medical history were self-reported.

Statistical analyses
Data were analyzed using SAS 9.4 (SAS Institute, Cary, NC). Variables are presented as means ± SD if continuous and as count (percent) if categorical. Analysis was performed after excluding potential outliers, defined as PWV and SBP values 3 SDs above or below the mean.
Baseline characteristics were compared between individuals with and without interarm and interankle SBP difference ≥10 mmHg and ≥15 mmHg using t-tests. 13,14 Pearson correlations and multivariable logistic regression were used to examine relations between characteristics associated with contralateral differences in arm and in ankle SBP.
Odds ratio (OR) and 95% confidence intervals (CI) were calculated to determine the association between contralateral differences in arm and ankle SBP ≥10 and ≥15 mmHg and contralateral differences in haPWV > 80 cm/s, faPWV > 165 cm/s, and baPWV > 240 cm/s. The cut points for contralateral differences in PWV were arbitrarily set at the 90th percentile in our sample. We also performed the analysis using the 75th and 50th percentile (data not shown). Two models were created, Model 1 was unadjusted, and Model 2 was adjusted for age, sex, race, BMI, smoking status, and ABI. The level of significance was set at p < .05 for all tests. Additionally, using a stepwise backward elimination process, covariates that did not contribute significantly were removed and excluded from the final analysis. These are presented as parsimonious models to elucidate the relationship between the variables. Furthermore, sensitivity analysis was performed to exclude the possibility that the accuracy of PWV readings might be affected by ABI < .95 (n = 4656).

RESULTS
Of the 5077 adults studied, 41% were male, 21.5% blacks, with a mean age of 75.2 ± 5.1 years. Overall sample characteristics stratified by interarm and interankle SBP differences of ≥10 mmHg and ≥15 mmHg are shown in Table 1. The mean ± SD absolute contralateral differences in arm and ankle SBP were 3.7 ± 3.0 and 7.5 ± 7.0 mmHg, respectively.
As compared with participants with interankle SBP differences of <10 mmHg and <15 mmHg, those with differences of ≥10 mmHg and ≥15 mmHg were more likely to have worse cardiovascular risk factor profiles, such as a higher prevalence of current smoking, hypertension, and diabetes (p < .05) ( Table 1). They also had higher brachial SBP, lower ABI, and higher triglycerides (p < .05). The prevalence of ABI < .95 was also greater (15.3% and 24.1% vs. 5.9% and 6.1%, p < .05, respectively).
Similarly, those with interarm differences of ≥10 mmHg and ≥15 mmHg had a higher prevalence of current smoking and hyperten-sion (p < .05). In addition, they had higher BMI, brachial SBP, lower ABI,  (Table 3).
In this sample, neither interarm SBP difference of ≥10 mmHg nor ≥15 mmHg were significantly associated with contralateral differences of >80 cm/s in haPWV, >165 cm/s in faPWV, and >240 cm/s in baPWV (Tables 4 and 5). Similar results were obtained using the 75th and 50th percentile.

DISCUSSION
In this population-based study using a simultaneous measurement of blood pressure and arterial stiffness, we evaluated the association between contralateral SBP differences and arterial stiffness by PWV.
We found that the prevalence of interankle differences in SBP of ≥10 mmHg and ≥15 mmHg were common, namely 25 and 12%. Our TA B L E 1 Comparison of selected subject characteristics stratified by interankle and interarm differences in systolic blood pressure (SBP)

Inter-ankle SBP difference
Inter-arm SBP difference Previous studies indicated SBP differences between arms carry prognostic information and that patients should have evaluation of blood pressure in both arms. 3 In addition, the ankle has been suggested as an alternative and/or additional site for noninvasive blood pressure measurement. 15,16 In the present study, blood pressure was measured simultaneously, bilaterally at both limbs using a validated oscillometric device. 12 Compared with sequentially repeated measurements of blood pressure with a single-cuff that is typically conducted, the simultaneous measurement may be more precise as beat-by-beat differences in blood pressure can be accounted for and can improve diagnostic accuracy. 14,18 Although brachial SBP was significantly asso- ciated with ankle SBP, interarm differences in SBP were not related to interankle differences in SBP suggesting that these contralateral differences in blood pressures may be modulated by different factors.
Indeed, arterial stiffness was associated with interankle, but not with interarm, differences in SBP in the present study.
What are the explanations for the contribution of arterial stiffness to interankle SBP difference but a lack thereof to interarm differences?
Arterial stiffening is a principal determinant of SBP 8 and has been independently associated with stroke, coronary disease severity, and cardiovascular outcome. 19 As the arterial wall stiffens, arterial wave reflection is a primary mechanism responsible for augmenting SBP. 8,9 In the arterial tree, branching points (i.e., aortic bifurcation, branches of renal arteries), areas of alteration in arterial elastance (from elastic artery to muscular artery), and high-resistance arterioles can all give rise to wave reflection and the lower body is believed to be an important site of wave reflection. 11 This cumulation of reflected waves along with the longer distance of the arterial tree to the ankle versus the upper arm is the reason that SBP at the level of the ankles is elevated in comparison to pressures measured in the arms in healthy humans. 20 It appears plausible that contralateral differences in SBP may be influenced to a greater extent by the stiffness of arteries in the ankle.
In the present study involving community-dwelling older adults, the prevalence of interarm SBP differences of ≥10 mmHg was 5.1%. A previous study from India reported a prevalence of 5% despite including participants with a wider age range (19-81 years). 6 The association between interarm differences in SBP and arterial stiffness has been evaluated in the past but remains highly controversial. For example, a systematic review and meta-analysis reported no association between in those with arterial stenosis. In cases of severe atherosclerosis, the stenosis of the arteries can affect PWV measurements. At the site of arterial stenosis, changes in the waveform can delay the derived PWV and affect contralateral differences in PWV. 25 In the present study, however, sensitivity analysis showed that associations between contralateral SBP differences and PWV remained statistically significant even after excluding participants with ABI < .95.
This study is not without limitations. First, results from our population of community-dwelling older adults may not be generalizable to other populations. Second, height-based formulas to calculate baPWV and faPWV were derived and validated in a Japanese population. Third, because of the cross-sectional nature of the study, the assessment of causality could not be confirmed. Future prospective studies are needed to address this issue.
In conclusion, the present study demonstrated that interankle SBP differences of ≥10 and ≥15 mmHg are common in older adults and that the magnitude of interankle, but not interarm differences in SBP is associated with several measures of arterial stiffness in communitydwelling older adults. These results expand the existing literature on factors that influence contralateral differences in blood pressure and open the opportunity for more optimum cardiovascular risk assessment. Future studies should evaluate whether contralateral differences in PWV could be regarded as an independent marker of arterial stiffness.

ACKNOWLEDGMENTS
The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood