Relationship between Inter-arm Difference in Systolic Blood Pressure and Arterial Stiffness in Community-dwelling Older Adults

Abstract

A significant inter-arm difference in systolic blood pressure (IADSBP) has been recently associated with worse cardiovascular outcomes. We hypothesized that part of this association is mediated by arterial stiffness, and examined the relationship between significant IADSBP and carotid-femoral pulse wave velocity (CF-PWV) in a sample from the Baltimore Longitudinal Study of Aging. Of 1045 participants, 50 (4.8%) had an IADSBP≥10 mmHg at baseline, and 629 had completed data from two or more visits (for a total of 1704 visits across 8 years). CF-PWV was significantly higher in those with an IADSBP≥10 mmHg (7.3±1.9 vs. 8.2±2, p=0.002). Compared to others, those with IADSBP≥10 mmHg had also higher body mass index, waist circumference and triglycerides, higher prevalence of diabetes and lower HDL-cholesterol (p<.001 for all). A significant association with IADSBP≥10 mmHg was observed for CF-PWV in both cross-sectional (OR=1.19; 95%CI: 1.06–1.87; p=0.01) and longitudinal (OR=1.15; 95%CI: 1.03–1.29; p=0.01) multivariate analyses. Female gender, Caucasian race, high body mass index (plus diabetes and low HDL-cholesterol only cross-sectionally) were other independent correlates of IADSBP≥10 mmHg. In conclusion, significant IADSBP is associated with increased arterial stiffness in community-dwelling older adults.

INTRODUCTION

Hypertension guidelines have recommended routine bilateral blood pressure (BP) measurement for some years¹, but the justification has been poor and adoption in primary care practice negligible to date². Yet, an inter-arm difference in systolic blood pressure (IADSBP) is frequently encountered in clinical practice, and may suggest the presence of a hidden congenital heart disease, aortic dissection or atherosclerotic disease involving the supra-aortic arteries³. A stenosis of the supra-aortic arteries has been associated with significant IADSBP in patients undergoing invasive angiography for cardiovascular procedures^4–6. Thus, an IADSBP≥10 mmHg has been recently proposed as a sign of potential supra-aortic vascular disease, though a cutoff of 15 mmHg or more is more specific for significant arterial stenosis with slightly lower sensitivity⁴. Furthermore, several studies and meta-analysis mostly involving individuals with high cardiovascular risk profile recently reported significant independent associations between an IADSBP≥10 mmHg and the presence of peripheral vascular disease, pre-existing coronary artery disease^{7, 8} and increased cardiovascular morbidity and mortality^9–11. Reasons for these associations are mainly unknown, and may lie beyond the ability of the IADSBP to detect a stenotic artery^{12, 13}. Indeed, no study has ever confirmed the presence of a stenosis of supra-aortic arteries among unselected subjects with significant IADSBP and without overt atherosclerotic disease.

Carotid-femoral pulse wave velocity (CF-PWV) is considered the gold-standard measurement of arterial stiffness¹⁴, and several studies have demonstrated its strong ability to predict cardiovascular morbility and mortality in the general population^{15, 16}. To gain insights into the association between IADSBP and adverse cardiovascular outcomes, we explored the hypothesis that IADSBP is cross-sectionally and longitudinally associated with CF-PWV. If this hypothesis is correct, we may hypothesize that part of the association between IADSBP and cardiovascular risk is mediated by arterial stiffness.

METHODS

Selection of study population

The study sample for the present analysis was drawn from the Baltimore Longitudinal Study of Aging, an ongoing prospective study of normative aging in community-dwelling volunteers who undergo approximately 3 days of medical, physiological and psychological examinations at regular intervals¹⁷. Participants are enrolled if they are healthy at baseline (e.g., no evidence of diabetes, stroke, or heart disease), but remain in the study if disease develops. For the present analysis, we included 1045 participants with both sequential and simultaneous BP measurements and CF-PWV available at the same study visit. Out of these 1045 participants, only those with at least two prospective evaluations of simultaneous BP measurements were retained for longitudinal analysis. Participants lost at follow-up (n=416), as compared to those available, were younger, less likely to be African-American and to have hypertension, but more likely to be obese. The remaining 629 participants had completed data from up to 8 visits (mean visits per participant=2.7, SD=1, range 2 to 8), for a total of 1704 visits across 8 years. The mean interval between visits was 4.1 years (SD=1.6, range 1 to 8 years). All clinical variables used in the present analysis were routinely collected at each visit as per study protocol. The study protocol was approved by the Intramural Research Program of the National Institute on Aging and the Institutional Review Board of the MedStar Health Research Institute (Baltimore, MD). All participants provided informed participation consent at each visit.

Blood pressure measurements

Sequential measurements

Brachial BP was measured by trained nurse practitioners according to a highly standardized protocol, using two standard aneroid sphygmomanometers with appropriate-sized cuffs. One sphygmomanometer was placed at each arm, and after at least 5 minutes of rest in supine position, three BP measurements from each arm were taken, alternating right then left, and allowing one minute between each measurement on the same arm.

Simultaneous measurements

Simultaneous bilateral brachial BP measurements were performed as part of the routine diagnostic procedure to assess bilateral ankle-brachial index (ABI). After a 10 minutes resting period in supine position, three BP measurements were taken simultaneously and automatically using a validated automatic oscillometric device (Colin VP-2000, Colin Medical Technology, Komaki, Japan). The ABI was calculated as the average of the three resting ankle systolic pressure readings divided by the average of the three resting brachial systolic pressure readings.

For both sequential and simultaneous measures of BP, values of systolic BP differing>25 mmHg from the lowest measure at the same arm were removed from the analysis¹⁸. Thirty-one subjects with 38 sequential recordings and 7 subjects with 10 simultaneous recordings meeting these prespecified criteria were excluded from the original population of 1083 participants. For the purpose of this analysis, the IADSBP was calculated as the difference in systolic BP between the right and the left arm at each reading (first, second, third) for both sequential and simultaneous BP measurements.

Definition and prevalence of significant IADSBP

In preliminary exploratory analysis, we confirmed that the prevalence of an IADSBP≥10 mmHg decreased moving from the first to the third reading (Figure 1). The decrease in prevalence was much more significant for sequential (from 18.2% to 11.4%; 6.8% decrease) as compared to simultaneous measurements (from 8% to 6.1%; 1.9% decrease), and the prevalence of significant IADSBP was generally lower with simultaneous than sequential measurements (Figure 1), as previously reported¹⁹. Bland-Altman plots did not show any tendencies for the IADSBP at each reading to vary as a function of the mean systolic BP, though a wider spread of IADSBP values was generally observed for sequential as compared to simultaneous measurements and at the first as compared to the third set of readings (Supplemental Figure S1). The first set of readings was then discarded, and for both the sequential and the simultaneous method, IADSBP was considered equal or greater than 10 mmHg only if found by both the second and the third reading, to prevent overestimation and improve consistency. This resulted into a final prevalence of IADSBP≥10 mmHg of 3.2% with the sequential method and of 4.8% with the simultaneous method (50 out of 1045 participants, 24 with right>left, 26 with left>right). For an IADSBP≥15 mmHg, the final prevalences were 0.5% and 1.1%, respectively. Given the results of our exploratory analysis and because it has been shown that simultaneous BP measurements are more reliable and reproducible than sequential ones¹⁹, subsequent analyses were performed by considering as “cases” those participants with an IADSBP≥10 mmHg at both the second and the third simultaneous readings. The distribution of the mean IADSBP in the whole cross-sectional sample is presented in Supplemental Figure S2.

Figure 1. Prevalence of IADSBP≥10 mmHg in the cross-sectional study sample.

The chart shows the prevalence of inter-arm difference in systolic blood pressure (IADSBP)≥10 mmHg at the first, second and third blood pressure reading, separately for the sequential (black columns) and simultaneous (grey columns) method. The prevalence of IADSBP≥10 mmHg decreased moving from the first to the third sets of readings for both methods, and when using combinations of these readings.

Between-visit variations of IADSBP in the same subject were previously shown to be large^{18, 20}, and this finding was confirmed in our preliminary analysis. Out of 1704 total longitudinal observations in 629 participants (Supplemental Figure S3A), only 56 participants were found with an IADSBP≥10 mmHg. Out of these 56 participants over 200 longitudinal observations (Supplemental Figure S3B), 51 had an IADSBP≥10 mmHg at a single visit sometimes during the course of the study. Only 5 participants had an IADSBP≥10 mmHg at more than one visit (3 participants with right>left at 2 consecutive visits, 1 participant with left>right at 2 consecutive visits and 1 participant with left>right at 2 separate visits, Supplemental Figure S3B).

Carotid-femoral pulse wave velocity

CF-PWV was measured after the subject had rested in supine position in a quiet room for at least 10 min. Subjects abstained from food or from drinking coffee or other caffeine-containing beverages for at least 45 min before the test. CF-PWV was calculated as the distance traveled by the pulse wave divided by the time difference between the feet of carotid and femoral arterial waveforms gated to electrocardiogram¹⁴. Over the long follow-up period, two devices were used to record CF-PWV (2003–2010:Complior SP device, Artech Medical, Paris, France; starting 2011:SphygmoCor system, AtCor Medical, Sydney, Australia), therefore CF-PWV measures were standardized as previously described²¹.

Clinical variables

To calculate clinical systolic and diastolic BP, the first set of readings was discarded, and the second and third readings at both arms were averaged. This mean BP values were used to calculate the steady and pulsatile components of BP (expressed as mean BP = 2/3 diastolic BP + 1/3 systolic BP, and pulse pressure = systolic BP− diastolic BP, respectively), and to estimate the prevalence of hypertension. The latter was defined as the presence of a BP≥140/90 mmHg and/or the use of antihypertensive medications. Heart rate was recorded at the same time of BP measurement by the nurse practitioner. Body mass index (BMI) was calculated as weight divided by squared height (Kg/m²) and a BMI≥30 was used as an index of general obesity. Waist circumference, defined as the minimal abdominal circumference between the lower edge of the rib cage and the iliac crests, was measured according to a highly standardized procedure, and Adult Treatment Panel III (ATP III) criteria were used to estimate the prevalence of central obesity (waist circumference>102 cm in men and >88 cm in women)²². Fasting serum samples were drawn to assay plasma glucose, triglycerides, total cholesterol, and high-density lipoprotein cholesterol (HDL), while low-density lipoprotein cholesterol concentrations were estimated by using the Friedewald formula. Diabetes mellitus was defined by the American Diabetes Association criteria and/or the use of diabetes medications²³. Dyslipidemia was defined as total cholesterol ≥200 mg/dl and/or by use of lipid-lowering treatment. Metabolic syndrome was diagnosed according to the ATP III criteria²². Estimated glomerular filtration rate, calculated by the simplified modification of diet in renal disease formula, was used to determine renal function, and renal failure was defined as glomerular filtration rate<60 ml/min/1.73m². Smoking status was ascertained by a questionnaire and participants were classified as ever smoker vs. never smoker (<100 cigarette/lifetime). Cardiovascular diseases were ascertained at each visit using a standardized questionnaire. Coronary artery disease was defined as a history of myocardial infarction, heart failure, current angina associated with a positive stress test, or previous cardiac procedures (including surgical or percutaneous cardiac revascularization). Peripheral arterial disease was determined by the presence of intermittent claudication and/or an ABI≤0.9 in either leg.

Statistical analysis

Continuous data are presented as mean±standard deviation and categorical data as percentages. Comparisons between participants with and without an IADSBP≥10 mmHg were performed using the Student's t test or the chi-square test as appropriate. For cross-sectional analyses, multivariate logistic regression models were used to investigate the relationship between CF-PWV and an IADSBP≥10 mmHg after adjusting for variables that in univariate analysis were associated with an IADSBP≥10 mmHg (heart rate, BMI, diabetes, triglycerides, HDL) or known to potentially affect both IADSBP and CF-PWV (age, gender, race, smoking, antihypertensive drugs, systolic BP). Collinearity was assessed calculating the variance inflation factor, that was considered acceptable when ≤ 2. Backward selection was used to select variables significantly associated with the outcome. The longitudinal relationship between PWV and an IADSBP≥10 mmHg was examined using generalized estimating equations with a standard (marginal) model²⁴, which consider the within-person correlation when examining multiple observations per subject, do not require a balanced design, and can be used for dichotomous outcomes such as the presence or absence of an IADSBP≥10 mmHg. A binary distribution, logit link, and exchangeable correlation matrix was used and odds ratios were calculated. Analyses were adjusted for the time-varying values of age and of other covariates included in previous cross-sectional analysis. As the interaction between CF-PWV and age was found to be not significant at either the P<0.05 or P<0.10 level, this coefficient was not included in the final model. A reduced model was obtained removing variables that did not retain statistical significance. All analyses were performed using the SAS package (version 9.3, SAS Institute Inc., Cary, NC). Statistical significance was set at p<0.05.

RESULTS

Study population

Descriptive characteristics of the cross-sectional and longitudinal samples are shown in Table 1. Compared to the cross-sectional sample, individuals retained for longitudinal analysis did not differ significantly at baseline, except for the slightly older age and higher prevalence of hypertension and renal failure. In the cross sectional sample, participants’ mean age was 66 years, 51% were men and 24% were African-Americans. Mean BMI was 27±5 Kg/m², and the prevalence of obesity 23%. About 20% of participants were diagnosed with diabetes, 47% with treated hypertension, and 74% with dyslipidemia, though mean systolic (118±15 mmHg) and diastolic (66±9 mmHg) BP values were within normal ranges and only 8% of the participants had BP values ≥140/90 mmHg and 38% total cholesterol values ≥200 mg/dl (Table 1).

Table 1.

Characteristics of study population for cross-sectional and longitudinal analyses

	Cross-sectional sample (n=1045)	IADSBP <10mmHg (n=995)	IADSBP ≥10mmHg (n=50)	P	Longitudinal sample (n=629)
Age (years)	66±13	66±13	64±14	0.27	68±12
Follow-up (years)	-	-	-	-	4.1±1.6 (1–8)
Number of visit	-	-	-	-	2.7±1 (2–8)
Men (%)	51	51	42	0.21	50
African American (%)	24	25	16	0.16	28
Body mass index (kg/m2)	27±5	27±4	31±6	<.0001	27±4
Waist circumference (cm)	91±12	91±12	100±14	<.0001	92±11
Total cholesterol (mg/dl)	191±37	191±37	193±43	0.76	192±38
HDL cholesterol (mg/dl)	59±17	59±17	50±15	<.001	59±17
LDL cholesterol (mg/dl)	112±33	111±33	116±39	0.41	112±33
Triglycerides (mg/dl)	104±59	102±59	134±51	<.001	103±56
Fasting plasma glucose (mg/dl)	92±17	92±17	95±14	0.25	95±18
Glomerular filtration rate (ml/min/1.73m2)	77±17	76±18	78±20	0.53	74±17
Mean systolic blood pressure (mmHg)	118±15	118±15	120±13	0.30	120±15
Mean diastolic blood pressure (mmHg)	66±9	66±9	66±7	0.57	67±9
Mean blood pressure (mmHg)	83±10	83±10	84±7	0.82	84±9
Pulse pressure (mmHg)	51±13	51±13	54±14	0.11	53±13
Heart rate (beats/min)	66±10	65±9	69±12	0.004	65±10
Carotid-femoral pulse wave velocity (m/s)	7.4±1.9	7.3±1.9	8.2±2	0.002	7.2±1.8
Ankle-brachial index	1.18±0.1	1.18±0.1	1.19±0.1	0.38	1.18±0.1
Ankle-brachial index ≤0.9 (%)	2	2	0	0.34	2
Hypertension (%)	47	47	46	0.93	53
Blood pressure≥140/90mmHg (%)	8	8	8	0.91	10
Antihypertensive drugs (%)	44	44	44	0.99	50
Diabetes (%)	19	18	42	<.0001	22
Smoking (ever,%)	45	45	34	0.12	47
Dyslipidemia (%)	74	74	84	0.11	76
Total cholesterol ≥200 mg/dl (%)	38	38	38	0.98	39
Lipid-lowering drugs (%)	42	42	42	0.98	44
Renal failure (%)	17	17	18	0.81	21
Obesity (%)	23	21	56	<.0001	22
Central Obesity (%)	33	31	71	<.0001	34
Metabolic Syndrome (%)	10	9	24	<.001	10
Coronary artery disease (%)	11	11	12	0.74	9
Cardiac procedures (%)	6	5	8	0.38	7
Peripheral arterial disease (%)	2	2	0	0.27	2

Clinical correlates of significant IADSBP

Compared to participants with an IADSBP<10 mmHg, those with an IADSBP≥10 mmHg had higher BMI, waist circumference and triglycerides, and lower HDL (Table 1). Accordingly, prevalences of diabetes, obesity, central obesity and metabolic syndrome were also significantly higher in this group. No significant differences were found for age, systolic and diastolic BP, prevalence of hypertension and cardiovascular diseases. Heart rate and CF-PWV were also significantly higher in those with an IADSBP≥10 mmHg (Table 1).

Cross-sectional relationship between CF-PWV and significant IADSBP

Adjusting for multiple confounders, CF-PWV was significantly associated with IADSBP≥10 mmHg (OR= 1.24, 95% CI=1.05–1.48, p=0.01, Table 2). After backward selection of variables that did not reach a P value level equal or less than 0.05, CF-PWV, together with female gender, Caucasian race, high BMI, diabetes and low HDL persisted as independent correlates of an IADSBP≥10 mmHg (Table 2). No significant interaction was found between gender or race and other variables, and results remained substantially unchanged when mean BP or pulse pressure was substituted for systolic BP or obesity for BMI (data not shown).

Table 2.

Cross-sectional association between predictors and an IADSBP≥10 mmHg.

	Full model				Reduced model
	OR	95% CI		P value	OR	95% CI		P value
Pulse Wave Velocity (m/s)	1.24	1.05	1.48	0.01	1.19	1.01	1.38	0.03
Age (year)	0.99	0.96	1.01	0.31
Male Gender	0.40	0.19	0.83	0.01	0.34	0.17	0.68	0.003
African-American Race	0.31	0.13	0.76	0.01	0.32	0.14	0.76	0.01
Heart rate (bpm)	1.01	0.98	1.04	0.59
Smoking (ever)	0.56	0.29	1.11	0.10
Body mass index (Kg/m2)	1.16	1.08	1.23	<.0001	1.16	1.09	1.23	<.0001
Antihypertensive drugs	0.69	0.35	1.38	0.30
Systolic blood pressure	1.01	0.98	1.03	0.63
Diabetes	2.68	1.34	5.36	0.005	2.42	1.26	4.66	0.01
Triglyceride (mg/dl)	1.00	0.99	1.01	0.78
HDL cholesterol (mg/dl)	0.98	0.95	1.00	0.09	0.97	0.95	0.99	0.03

Longitudinal relationship between CF-PWV and significant IADSBP

Longitudinal data in standard (marginal) format were analyzed using generalized estimating equation models²⁴ adjusting for gender, race, and time-varying age, heart rate, smoking, BMI, antihypertensive drugs, systolic BP, diabetes triglycerides and HDL cholesterol. Results of the reduced model showed that each unit increase of CF-PWV, in terms of both difference between subjects or within the same subjects across subsequent assessments, was associated with IADSBP≥10 mmHg (OR= 1.15, 95% CI=1.03–1.29, p=0.01, Table 3). Female gender, Caucasian race, high BMI were also independently associated with an IADSBP≥10 mmHg, while the odds ratios for diabetes and HDL were in the expected direction but did not reach statistical significance (Table 3).

Table 3.

Longitudinal association between predictors and an IADSBP≥10 mmHg.

	Full model				Reduced model
	OR	95% CI		P value	OR	95% CI		P value
Pulse Wave Velocity (m/s)	1.17	1.04	1.31	0.007	1.15	1.03	1.29	0.01
Age (year)	0.98	0.95	1.02	0.31
Male Gender	0.34	0.16	0.73	0.006	0.43	0.22	0.83	0.01
African-American Race	0.34	0.15	0.75	0.008	0.40	0.19	0.84	0.02
Heart rate (bpm)	1.01	0.98	1.04	0.61
Smoking (ever)	0.71	0.38	1.32	0.27
Body mass index (Kg/m2)	1.13	1.06	1.20	<.001	1.16	1.09	1.23	<.001
Antihypertensive drugs	0.97	0.51	1.88	0.94
Systolic blood pressure	1.01	0.99	1.03	0.20
Diabetes	1.72	0.87	3.42	0.12
Triglyceride (mg/dl)	1.00	0.99	1.01	0.80
HDL cholesterol (mg/dl)	0.99	0.96	1.01	0.29

DISCUSSION

This is the first large-scale study that explores the prevalence of significant IADSBP in community-dwelling individuals with low cardiovascular risk and analyzes its cross-sectional and longitudinal relationship with CF-PWV.

Relationship between IADSBP and CF-PWV

Studies of patients undergoing angiography for other clinical reasons were able to confirm the presence of significant atherosclerosis involving the supra-aortic arteries as the reason for the IADSBP^{4, 5, 25}. However, this kind of evidence has never been produced either by angiography or by Doppler ultrasonography in unselected individuals from the general population, for whom the pathological basis of a significant IADSBP remains unknown. For this reason, experts recommend that the definition of “arterial stenosis” should not be used in studies according to measurement of the inter-arm difference alone⁷. In searching for an explanation of the increasingly reported association between a significant IADSBP and poor cardiovascular outcomes⁷, we tested and confirmed in multivariate cross-sectional and longitudinal analyses an independent relationship between an IADSBP≥10 mmHg and CF-PWV, a parameter considered the gold standard for noninvasive assessment of arterial stiffness¹⁴. Our primary hypothesis, although not verified, is that ongoing endothelial dysfunction and arterial stiffening underlie the association between increased CF-PWV and significant IADSBP. Previous studies have shown independent associations of significant IADSBP with other markers of atherosclerosis, namely carotid artery intima-media thickness¹², coronary artery calcium score¹², brachial-ankle pulse wave velocity¹³ and an ABI≤0.9^{12, 13, 26}. Compared to our population, despite their almost10-year younger age, these studies included individuals with worse cardiovascular profile, particularly because of the higher prevalence of hypertension and coronary artery disease (69% and 19% respectively in the study by Su et al.¹³), uncontrolled systolic BP (>140 mmHg in up to 40% in the total cohort by Shadman et al.²⁶), and lower HDL and higher triglycerides mean values^{12, 13, 26}. With this regard, the results of our study are new, because obtained in a healthier aging population and using an earlier marker of subclinical vascular damage such as CF-PWV. Increased CF-PWV has been demonstrated to be a strong predictor of cardiovascular morbility and mortality in the general population^{15, 16}. Our current findings raise the possibility that part of the association between an IADSBP≥10 mmHg and cardiovascular risk reported in the literature may be mediated by arterial stiffness.

We speculate that similar systolic BP at both arms may reflect a fine tuning-process to maintain a state of homeostasis, and a significant IADSBP may be the result of a disturbance to this homeostasis, either by mechanical obstruction (as assumed so far) or dysfunction of fine-tuning, of which endothelial function, arterial stiffness and wave reflection may be a part of. In details, if there is any association between CF-PWV and significant IADSBP beyond atherosclerosis, one may speculate that since the left and right subclavian arteries originate from different points of the aortic arch, by physics this should result in slightly different pressures, but this would be masked by proper endothelial function that will act upon the different blood flow in each arm to bring the BP to target (more or less like an electronic stability control on a car, where brakes act differently on each wheel to keep the car balanced when braking). Endothelial dysfunction and consequent arterial stiffness would unmask these differences, which may also be accentuated by wave reflection that might present in one more than the other arm due to hemodynamic differences.

Other clinical correlates of IADSBP

In our multivariate analysis, an IADSBP≥10 mmHg was associated with increasing BMI, decreasing HDL and presence of diabetes. Waist circumference, central adiposity and metabolic syndrome were also significantly higher in participants with an IADSBP≥10 mmHg, but BMI (or obesity) was preferred for multivariate analyses because of the higher odds ratios and the lower correlation with other variables included in the models (especially gender and CF-PWV). The associations with BMI^{12, 13}, diabetes¹² and HDL²⁶, all previously reported in other studies, suggest a potential causal relation between unfavorable changes in body composition and lipid metabolism and significant IADSBP. In contrast with some previous reports^{12, 13, 26} but in agreement with others^{18, 27}, hypertension (as well as continuous BP-related parameters, or antihypertensive medications) did not appear to influence the IADSBP. The lower mean systolic and diastolic BP values (with only 8% of the participants having BP values ≥140/90 mmHg) and the better cardiovascular risk profile of our population, as well as rigorous BP measurement protocol (requiring supine position, adequate resting time and multiple readings) may partially explain these contrasting findings. Finally, the higher probability of significant IADSBP in women is consistent with what has already been reported in several other studies^{12, 13, 26}. The reason is unclear, nor we have a certain explanation for the lower tendency of African-American participants in our cohort to have an IADSBP≥10 mmHg. African-Americans in our population were more likely to be hypertensive (56% vs. 44%, p=0.001) and receive antihypertensive drugs (52% vs. 42%, p=0.006), but also had higher HDL values (61±18 vs. 58±17, p=0.01) and lower triglycerides (90±51 vs. 108±61, p<.001). The absence of a relationship between hypertension and the IADSBP in our analysis made us hypothesize that, among all factors, the effect of a favorable lipid profile in this race group may had overcome that of hypertension and in part explain our findings. However, further studies are needed to disentangle the complex relationship between gender, race, and significant IADSBP.

Ascertainment of IADSBP

Despite the major emphasis placed on the prognostic value of a significant IADSBP², considerable debate exists with regard to the reproducibility and generalisability of these findings to the general community²⁸. It has been shown that the more BP measurements are taken the lower the prevalence of significant IADSBP becomes, and multiple readings appear necessary to overcome the initial so-called white-coat effect²⁹. In addition, published data clearly suggest that sequential measurement of BP overestimates the prevalence of IADSBP, and simultaneous measurement of both arms seems preferable¹⁹. Our preliminary exploratory analysis confirmed these previous findings, plus the low consistency and reproducibility of IADSBP over time when looking at longitudinal trajectories of 629 participants in our study with more than two simultaneous BP evaluations^{18, 20}.

In our analysis, we used multiple BP measurements taken simultaneously at both arms with an automated device to define participants with an IADSBP≥10 mmHg. Previous population studies used either sequential BP measurements to calculate the IADSBP¹², or combined different sequential BP measurement protocols²⁶ or did not have multiple simultaneous BP readings to estimate the IADSBP¹³, hence generally reporting higher prevalence than ours. Nevertheless, significant associations with subclinical markers of atherosclerosis were consistently reported^{12, 13, 26}. Reason for this may presumably reside on the ability of the IADSBP estimated by sequential BP readings to capture some of the short-term variability in BP, a measure that per se is independently associated with increased arterial stiffness³⁰ and cardiovascular disease³¹.

Study Limitations

There are several limitations in this study. The majority of participants included in the current analysis were treated chronically with antihypertensive and lipid-lowering medications. Though adjustments for these medications did not have any significant effect in our multivariate models, we cannot completely exclude the influence of these agents on the estimation of both the IADSBP and the CF-PWV.

Central pulse pressure and wave reflection data were not available for most of the subjects included in this analysis, and we could not explore the association between IADSBP and wave reflection parameters at this time.

Though appropriate cuff size was chosen based on the arm circumference of each participant, larger arms in individual with higher BMI increase the likelihood of inaccurate BP measurements. The same applies to larger bellies and/or breasts for the estimation of CF-PWV¹⁴.

The low number of participants with IADSBP≥10 mmHg detected at baseline and in subsequent visits prevented us from performing further subanalysis stratified by either gender, race or obesity, and different longitudinal models testing the association between CF-PWV and the development of IADSBP≥10 mmHg among those with IADSBP<10 mmHg at baseline. However, such a low prevalence and incidence were expected in a cohort of subjects with a low cardiovascular risk profile. Moreover, we preferred to eliminate most potential sources of bias in the estimation of the IADSBP by considering only the second and third simultaneous and automated BP readings, thus determining a significant reduction in the prevalence of participants with an IADSBP≥10 mmHg. Despite this careful approach, the consistency and reproducibility of the simultaneous IADSBP in our longitudinal sample remained low. Nevertheless, the association between CF-PWV and an IADSBP≥10 mmHg was consistent both in cross-sectional and longitudinal analyses, though the sensitivity and specificity of this parameter for the detection of abnormal arterial compliance are probably limited.

Perspectives

We herein demonstrate a positive relationship between CF-PWV and significant IADSBP in community-dwelling healthy aging individuals. This finding may help explaining at least part of the association between IADSBP and poor cardiovascular outcomes reported in the literature. Indeed, besides its potential ability to detect obstructive disease of the supra-aortic arteries, our results suggest that an IADSBP≥10 mmHg could potentially be considered as a marker of increased arterial stiffness and support the opportunity to assign individuals with a significant IADSBP to further cardiovascular assessment. For this purpose, the IADSBP should be measured simultaneously and multiple times, and its low consistency and reproducibility over time should be taken into account.