CLINICAL STUDY: ENDOTHELIAL FUNCTION ASSESSMENT
Reduced endothelium-dependent and -independent dilation of conductance arteries in African Americans
Umberto Campia, MD*,
Wassim K. Choucair, MD*,
Melissa B. Bryant, RN*,
Myron A. Waclawiw, PhD ,
Carmine Cardillo, MD*,1 and
Julio A. Panza, MD, FACC*,*
* Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA
Office of Biostatistics Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA
Manuscript received November 5, 2001;
revised manuscript received April 25, 2002,
accepted May 16, 2002.
* Reprint requests and correspondence: Dr. Julio A. Panza, Washington Hospital Center, 110 Irving Street Northwest, Suite 2A74, Washington, DC 20010, USA.
Julio.A.Panza{at}medstar.net
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Abstract
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OBJECTIVES: The goal of this study was to determine whether racial differences exist in the functional behavior of conduit vessels.
BACKGROUND: Compared with Caucasians, African Americans have a higher prevalence of cardiovascular disease and its complications, which may be related to reduced nitric oxide (NO)-dependent and -independent vasodilation of the microvasculature. However, whether a similar impairment is also present at the level of the conductance arteries is unknown.
METHODS: To this end, we studied endothelium-dependent (posthyperemia flow-mediated dilation) and -independent (nitroglycerin) vascular responses of the brachial artery by high-resolution ultrasound imaging. There were 46 black subjects (23 men and 23 women; age 37 ± 8 years and 38 ± 9 years, respectively) and 46 white subjects (23 men and 23 women; age 38 ± 11 years and 36 ± 9 years, respectively) in this study.
RESULTS: Baseline diameter was similar in blacks and in whites (4.4 ± 0.9 mm and 4.1 ± 0.7 mm, respectively). Mean reactive hyperemia after cuff deflation was similar in the two groups (793 ± 653% in black and 852 ± 734% in white subjects, respectively; p = 0.5). Flow-mediated dilation was significantly lower in black compared with white individuals (4.79 ± 3.5% vs. 8.87 ± 4.5%, respectively; p < 0.0001). Nitroglycerin-mediated dilation was also significantly lower in black individuals compared with white individuals (10.99 ± 4.6% vs. 14.98 ± 5.4%, respectively; p = 0.0002).
CONCLUSIONS: African Americans show reduced responsiveness of conductance vessels to both endogenous and exogenous NO compared with Caucasian Americans. These findings expand our understanding of racial differences in vascular function and suggest a mechanistic explanation for the increased incidence and severity of cardiovascular disease observed in African Americans.
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Abbreviations and Acronyms
| | ANCOVA | | analysis of covariance | | BA | | brachial artery | | BMI | | body mass index | | cGMP | | cyclic guanosine-monophosphate | | FMD | | flow-mediated dilation | | NHBLI | | National Heart, Lung, and Blood Institute | | NMD | | nitroglycerin-mediated dilation | | NO | | nitric oxide | | NTG | | nitroglycerin | | SBP | | systolic blood pressure | | sGC | | soluble guanylyl cyclase | | VSMC | | vascular smooth muscle cell |
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Several previous epidemiologic studies have shown that atherosclerosis and its complications, the leading cause of death among adults in the U.S., carry significantly higher morbidity and mortality in African Americans compared with Caucasian Americans (1–3). These observations may be partly explained by a considerably higher prevalence, among African Americans, of risk factors traditionally associated with atherosclerosis, such as essential hypertension, diabetes mellitus, and tobacco use (4–6). However, the pathophysiologic processes underlying this racial predisposition have not been fully elucidated (7).
Numerous studies have investigated the role of genetic and environmental factors in the pathogenesis of hypertension in African Americans, pointing out important racial differences in renal function, socioeconomic status, and hemodynamic responses to environmental challenges (8–10). In particular, an increased cardiovascular reactivity to stress has been reported in young normotensive blacks and has been considered to be a contributor to their greater prevalence of hypertension (11). More recently, research has focused on potential differences in arterial wall function between blacks and whites and their impact on vascular homeostasis (12). Studies conducted in our, and other, laboratories have demonstrated reduced nitric oxide (NO)-mediated vasodilation of forearm resistance vessels to mental stress (13) and to endothelium-dependent and -independent pharmacologic stimuli (14,15), indicating reduced vascular smooth muscle relaxation. This diminished response to vasodilators may result in a decreased pattern of hemodynamic reactivity leading, in the long term, to increased vascular tone and hypertension. However, because these phenomena refer to resistance vessels, they may not account for the increased predisposition of African Americans for developing atherosclerosis in large conductance arteries.
The purpose of the present investigation, therefore, was to determine whether racial differences exist in the functional behavior of conduit vessels. Because of the well-known association between atherosclerosis and impaired vascular responses to endothelium-dependent stimuli, we hypothesized that African Americans would have reduced endothelial vasodilator function.
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Methods
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Study subjects.
Ninety-two healthy subjects took part in the study. The study sample size was prospectively calculated to detect a  50% relative (or 2.1% absolute) difference in flow-mediated dilation (FMD) of the brachial artery (BA) between African Americans and Caucasians, with 80% power and an alpha of 0.05, assuming that the variance of BA dilation in blacks and whites is similar to that reported by Vogel et al. (16) in middle-aged men (i.e., [3.6]2). The participants’ characteristics and lipid profile are reported in Table 1. Before admission, subjects of each group were screened by clinical history, physical examination, electrocardiography, chest X-ray, and routine chemical analyses. Exclusion criteria were smoking, history, or evidence of hypertension (blood pressure 140/90 mm Hg), hypercholesterolemia (total plasma cholesterol 200 mg/dl), diabetes mellitus, cardiac disease, peripheral vascular disease, coagulopathy, or any other disease predisposing them to vasculitis or Raynaud’s phenomenon.
The study protocol was approved by the National Heart, Lung, and Blood Institute’s (NHBLI) Institutional Review Board (NIH protocol # 98-H-0112), and all participants gave written informed consent for all procedures. All procedures followed were in accordance with the NHLBI Institutional Guidelines.
Protocol.
All studies were performed in the morning in a quiet room with a temperature of approximately 22°C. Participants were asked to refrain from drinking alcohol or beverages containing caffeine for at least 24 h before the study. Endothelium-dependent and -independent vasodilator function was assessed as previously described (17). Briefly, subjects lay supine on a bed and were allowed to rest for at least 10 min. Then, the left BA was visualized, 2 to 15 cm proximal to the antecubital fossa, using a high-resolution ultrasound (Hewlett Packard Sonos 5500 [Andover, Massachusetts] with a 7.5 MHz linear array transducer).
After baseline images and flow measurements were obtained, a pressure cuff applied on the forearm was inflated at 200 to 250 mm Hg for 5 min. Blood flow was measured during the 15 s after cuff deflation, and arterial image acquisitions for diameter measurements were performed between 60 s and 90 s after cuff deflation.
After at least 15 min of rest, new baseline images and flow measurements were obtained, and 0.4 mg of nitroglycerin (NTG) spray were given sublingually to assess endothelium-independent vasomotor responsiveness. Blood flow and images for arterial diameter were recorded after 3 min.
Arterial diameter was measured from the anterior to the posterior "m" line (the interface between media and adventitia) at end-diastole, incident with the R-wave on the electrocardiogram. Images were analyzed by an investigator blinded to image sequence and subjects’ clinical data.
Statistical analysis.
All group data are reported as mean ± SEM. Group differences were analyzed by unpaired Student t test. Correlations between variables were calculated using Pearson’s coefficient. Univariate and multivariate analyses of associations were assessed using standard linear regression techniques. Multivariate regression models for the variables FMD and nitroglycerin-mediated dilation (NMD) always included race and other relevant covariates of interest (stated specifically in each case) as main effects along with race-by-covariate interactions. In the analyses that included only one continuous covariate other than race, a standard analysis of covariance (ANCOVA) with an interaction term was used. If the interactions with race were significant, the p values associated with model main effects (including that for race) were deemed uninterpretable, and the analyses were stratified and reported by race. All calculated p values are two-tailed, and a value of p < 0.05 was considered to indicate statistical significance. Statistical analyses were performed using SigmaStat 2.03 (SPSS Inc., Chicago, Illinois).
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Results
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Effects of race on BA diameter and on FMD.
Baseline BA diameter before hyperemia was larger in African Americans compared with Caucasians (4.4 ± 0.2 mm vs. 4.1 ± 0.1 mm, respectively), but this difference did not reach statistical significance (p = 0.102). Mean reactive hyperemia after cuff deflation was similar in the two groups (793 ± 135% in black and 852 ± 153% in white subjects, respectively; p = 0.5). Flow-mediated dilation was significantly higher in white compared with black individuals (8.87 ± 1% vs. 4.79 ± 0.7%, respectively; p < 0.0001) (Fig. 1, left panel). Similarly, NMD was significantly higher in white compared with black individuals (14.98 ± 1.1% vs. 10.99 ± 1%, respectively; p = 0.0002) (Fig. 1, right panel).
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Figure 1 Bar graph showing a comparison of flow-mediated dilation (left panel) and nitroglycerin (NTG)-mediated dilation (right panel) between African Americans (black bars) and whites (hatched bars). The p values represent the results of unpaired Student t test. Values represent mean ± SEM.
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To evaluate if the relationship between FMD and NMD varies with race, we performed an ANCOVA for FMD, with race, NMD and race x NMD as covariates. The interaction term (race x NMD) was significant (p = 0.016), meaning that the relation of FMD with NMD does, in fact, vary with race. Consequently, in univariate analysis, FMD was significantly associated with NMD in Caucasian Americans (r = 0.547; p < 0.0001), whereas no correlation was observed between FMD and NMD in African Americans (r = 0.09; p = 0.515).
Baseline diameter was a significant predictor of FMD and NMD in all patients taken together (p = 0.01 and p < 0.001, respectively). To determine a possible contribution of race in the relationship between baseline diameter and FMD, and between baseline diameter and NMD, we performed ANCOVA analyses for FMD and NMD, with race, baseline diameter and race x baseline diameter as covariates. The interaction term (race x baseline diameter) was not significant in the model for FMD (p = 0.113) nor NMD (p = 0.09). In a subset analysis, FMD showed only a weak inverse correlation with baseline diameter in Caucasian Americans (r = –0.373, p = 0.016) and no significant correlation with baseline diameter in African Americans (r = 0.193, p = 0.197). In contrast, NMD was significantly and inversely correlated with baseline diameter in both blacks (r = –0.511, p = 0.0003) and whites (r = –0.591, p < 0.0001).
Race effects on FMD and NMD persisted (p < 0.001 and p = 0.009, respectively) over and above diameter difference at baseline between African Americans and Caucasian Americans in a multivariate model including race, baseline diameter, body mass index (BMI), and systolic blood pressure (SBP).
In African Americans, BMI was significantly higher compared with Caucasians (Table 1). Therefore, to estimate a possible contribution of BMI to FMD and NMD, a multiple linear regression model using race and BMI as independent variables was applied. Flow-mediated dilation could be significantly predicted by race but not by BMI (p < 0.0001 and p = 0.8118, respectively), whereas NMD was significantly predicted by race and BMI (p = 0.0121 and p = 0.0166, respectively). However, the contribution of BMI to FMD and NMD did not differ between African Americans and Caucasians, as can be seen in the scatter regression plots (Fig. 2). To formally test for a possible effect of race in the relationships between BMI and FMD, and BMI and NMD, we performed ANCOVA analyses for FMD and NMD, with race, BMI and race x BMI as covariates. The interaction term (race x BMI) was not significant in the model for FMD (p = 0.898) nor NMD (p = 0.943).
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Figure 2 Scatterplot showing the relationship between flow-mediated dilation (FMD) (left panel) and nitroglycerin-mediated dilation (NMD) (right panel) in African Americans (closed circles and lower regression lines) and whites (open circles and upper regression lines). BMI = body mass index.
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African Americans showed a slightly, albeit statistically significant, higher SBP compared with whites (Table 1). On correlation analyses, baseline diameter was significantly correlated with SBP in blacks but not in whites (r = 0.43, p = 0.003 and r = 0.27, p = 0.07, respectively). On multivariate linear analysis, SBP was not a significant predictor of FMD or NMD whether all patients were analyzed together (p = 0.116 and p = 0.201, respectively) or whether the analysis was performed separately for each of the racial subgroups (p = 0.302 and p = 0.523, respectively, in African Americans and p = 0.901 and p = 0.91, respectively, in Caucasians). To formally evaluate potential interactions of race in the relations between SBP and FMD, and SBP and NMD, ANCOVA analyses for FMD and NMD, with race, SBP and race x SBP as covariates were performed. The interaction term (race x SBP) was not significant in the model for FMD (p = 0.631) nor NMD (p = 0.716).
On multivariate analysis no association was found between either FMD or NMD and age, total plasma cholesterol and plasma homocysteine levels in both African Americans and whites (p = NS for all variables).
Effects of gender and race on BA diameter and on FMD.
Before hyperemia baseline BA diameter was similar between African American and Caucasian women (3.7 ± 0.1 mm vs. 3.6 ± 0.1 mm, respectively; p = 0.24). Mean reactive hyperemia after cuff deflation was 663 ± 72% in black women and 784 ± 119% in white women, respectively (p = 0.39). Flow-mediated dilation was significantly lower in black women compared with white women (5.1 ± 0.7% vs. 9.1 ± 1%, respectively; p = 0.0295). Similarly, African American women showed significantly reduced NMD compared with Caucasian women (12.07 ± 1% vs. 17.07 ± 1.1%, respectively; p = 0.002) (Fig. 3).
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Figure 3 Bar graph showing a comparison of flow-mediated dilation (left panel) and nitroglycerin-mediated dilation (right panel) between African American men and women (black bars) and white men and women (hatched bars). The p values represent the results of unpaired Student t test. Values represent mean ± SEM.
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Baseline BA diameter was slightly, but significantly, lower in Caucasian men compared with African American men (4.7 ± 0.1 mm vs. 5 ± 0.1 mm, respectively; p = 0.03). Mean reactive hyperemia after cuff deflation was 923 ± 176% in black men and 645 ± 70% in white men, respectively (p = 0.15). Flow-mediated dilation was significantly lower in black men compared with white men (4.4 ± 0.7% vs. 8.7 ± 0.8%, respectively; p = 0.00075). Similarly, African-American men showed significantly reduced NMD compared with Caucasian men (9.9 ± 1% vs. 12.9 ± 1.1%, respectively; p = 0.026) (Fig. 3).
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Discussion
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The results of this study show that African Americans have significantly reduced FMD and NMD of the BA compared with Caucasian Americans. These blunted responses suggest a diminished response to NO-induced vasorelaxation because both stimuli act through either an increase in the endogenous release of NO caused by shear stress (FMD) (18) or direct formation of NO (NTG) (19). Specifically, the attenuation of the response to NTG seems to indicate that the blunted response to NO is related to an endothelium-independent mechanism. These findings are in keeping with those of previous investigations from our, and other, laboratories showing decreased endothelium-dependent and -independent blood flow responses in the forearm circulation of healthy black subjects (13–15). It is, therefore, reasonable to speculate that similar pathophysiologic differences may be operative in both the macro- and microcirculation of African Americans compared with Caucasian subjects.
Mechanisms of decreased FMD and NMD in African Americans.
Various mechanisms might explain the decreased NO-dependent vasorelaxation observed in black subjects. First, a generalized defect in vasodilator function might be present in the vasculature of African Americans. However, in a previous investigation (15), we have shown that peak hyperemic vasodilator response to forearm ischemia, which is not primarily dependent on NO availability, is similar between blacks and whites, suggesting that the blunted dilator response is unlikely related to nonspecific abnormalities in vascular reactivity. Second, the impaired NO-dependent relaxation could be related to a reduced bioavailability of NO/NTG to the smooth muscle cells due to structural changes in the arterial wall, as described in the microcirculation of normotensive blacks (20,21), or to an increased destruction of NO by overproduction of oxygen-derived free radicals in the vessel wall (22). However, these mechanisms seem unlikely because NTG is converted to NO within the smooth muscle cells (23). Further, essential hypertensive patients, who commonly have vascular wall hypertrophy, show preserved vasodilator response to systemic nitrates (24). A third and more likely explanation for the impaired dilating effect of NO is a selective defect of vascular smooth muscle cell (VSMC) function, in particular of the soluble guanylate cyclase (sGC)/cyclic guanosine monophosphate (cGMP) signaling system. A defect in one or more of the steps of this pathway might impair cGMP-mediated vasorelaxation and, thus, be responsible for the attenuation of vasodilator function observed in normotensive African Americans.
Our results differ from those recently reported by Gokce et al. (25), showing that FMD is similar, and NMD higher, in African Americans compared with whites. Participants in the Gokce et al. (25) study, however, were, on average, between seven and nine years older than our subjects and included hypertensive patients, a number of whom were treated with aspirin, antihypertensive medications and lipid-lowering drugs. It is possible that older age and drugs effects may have affected vascular function and responses. In support of this hypothesis is the finding that, when comparison between blacks and whites was performed after excluding subjects on pharmacologic treatment, the difference in NMD response lost its statistical significance (25).
In partial contrast with our findings, impairment in FMD with preserved response to sublingual NTG administration has recently been reported in young, healthy African Americans by Perregaux et al. (26). Two important differences in the study methodology may explain this discrepancy. First, subjects included in the study by Perregaux et al. (26) were, on average, seven years younger than those in our investigation. It is possible that decreased FMD precedes the reduction in NMD among African Americans, thus providing an explanation for the different results. Second, in the study of Perregaux et al. (26), only 11 subjects in each group (<50% of those included in the study) underwent assessment of NMD. Thus, it is possible that the study was underpowered to detect racial differences in NMD. Further, the baseline BA diameter of the 11 black subjects in whom NMD was assessed was substantially smaller than that measured in the 11 white subjects who underwent similar studies (3.58 ± 0.29 mm vs. 3.94 ± 0.24 mm, respectively). In fact, although the absolute BA diameter during reactive hyperemia was remarkably similar between the black and the white subjects who underwent FMD assessment (3.84 ± 0.2 mm vs. 3.85 ± 0.1 mm, respectively), the absolute BA diameter during NMD was substantially smaller in black compared with white subjects (4.26 ± 0.3 mm vs. 4.68 ± 0.22 mm, respectively). It is possible that differences in baseline BA diameter in the subsets of subjects undergoing FMD and NMD explain the observed results. In our study all subjects underwent assessment of FMD and NMD, thus allowing equal power to detect racial differences in endothelium-dependent and -independent vasodilation. Moreover, the number of subjects undergoing NMD was more than four times greater in our study than in the study by Perregaux et al. (92 vs. 22, respectively). These differences in protocol design and methodology between the studies may account for the apparent discrepancy with regard to racial differences in NMD.
In our study African Americans had higher baseline diameter compared with whites. Despite the nonstatistical significance of this difference, we wanted to ascertain a possible contribution of this variable to FMD and NMD. To this aim, we performed a multivariate analysis with race, baseline diameter, BMI, and SBP as independent variables. A highly significant contribution of race on FMD and NMD persisted over and above differences in diameter at baseline. Therefore, the presence of different baseline diameter does not weaken the contribution of racial factors to the reduced vascular reactivity observed in our subjects.
A recent study by Tounian et al. (27) reported reduced FMD and NMD in obese children compared with healthy controls. Because our groups differed with respect to BMI, we were concerned about a possible contribution of this variable to FMD and NMD. Therefore, we applied a multiple regression model using race and BMI as independent variables. In this model black race was the only significant predictor of decreased FMD. Nitroglycerin-mediated dilation could be significantly predicted by both race and BMI, although the contribution of BMI to NMD was similar in African Americans and Caucasian. Thus, despite the baseline differences in BMI between the two groups, this variable does not explain the racial differences in vascular reactivity observed in our study.
Gender, racial factors, and NO-dependent dilation.
Consistent with the results in the overall study population, both black men and black women showed reduced endothelium-dependent and -independent vasorelaxation compared with their white counterparts. These observations indicate that the role played by racial factors in the blunted NO-induced vasodilator response in African Americans is independent of gender.
Decreased NO/cGMP activity and atherosclerosis.
Vascular smooth muscle cell proliferation is an important component of vessel wall remodeling during atherosclerosis formation (28). In vitro studies indicate that the NO/cGMP system inhibits VSMC proliferation, suggesting a potential link between impaired NO/cGMP activity and atherogenesis (29). Because the same signaling cascades regulating VSMC contractile state are involved in VSMC proliferation, it is possible that a defect in the NO/cGMP system leads to an impairment of both the vascular relaxation and the proliferation control mechanisms in African Americans. Our data are in agreement with two recent studies showing impaired endothelium-dependent and -independent responses of the BA of asymptomatic subjects with risk factors for atherosclerosis (30) and in patients with coronary heart disease (31), respectively. Taken together, these findings support the hypothesis that a dysfunction of VSMC may be a previously unrecognized feature in the pathophysiology of atherosclerosis.
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Conclusions
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Our study indicates that healthy African Americans have reduced vascular responsiveness of conduit vessels to both endothelium-dependent and -independent stimuli compared with Caucasian Americans. This difference may be related to an abnormality of the sGC/cGMP signaling system in vascular smooth muscle cells and might play a role in the increased prevalence of atherosclerosis in African Americans.
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Footnotes
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1 Dr. Cardillo is presently located at the Istituto Patologia Medica, Università Cattolica del Sacro Cuore, Rome, Italy. 
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References
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Abstract
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