(Hypertension. 1997;29:706-714.)
© 1997 American Heart Association, Inc.
Articles |
Effect of African-American Race and Hypertensive Left Ventricular Hypertrophy on Coronary Vascular Reactivity and Endothelial Function
the Division of Cardiology, Department of Medicine, Albany (NY) Medical College (J.L.H., V.E.S., N.L.H., W.M.B.); School of Public Health, State University of New York at Albany (D.S.S.); and Augusta (Ga) Preventive Cardiology, PC (A.A.C.).
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Abstract |
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Excess cardiovascular morbidity and mortality among African (black) Americans remains an important yet unexplained public health problem. One possible explanation proposes that intrinsic or acquired abnormalities in coronary vascular reactivity and endothelial function result in excess ischemia among black Americans. To examine this hypothesis, we subjected 80 individuals with normal coronary arteries to invasive testing of coronary artery and microvascular relaxation using intracoronary infusions of acetylcholine and adenosine, a Doppler tipped intracoronary guide wire, and quantitative coronary angiography. We measured the percent increase in coronary blood flow and epicardial diameter after graded infusion of intracoronary acetylcholine and in coronary blood flow after intracoronary adenosine in 31 normotensive subjects (10 black, 21 white) and 49 hypertensive subjects with left ventricular hypertrophy (25 black, 24 white). Categorical and multivariate analyses revealed that in response to intracoronary adenosine and acetylcholine, the depression in endothelium-independent and -dependent microvascular relaxation during peak agonist effect was largely related to the presence of chronic hypertension and left ventricular hypertrophy. Normotensive subjects demonstrated no intrinsic racial differences in conduit and resistance vessel vasoreactivity. In response to maximal infusion of acetylcholine, epicardial coronary arteries constricted similarly in black and white subjects with hypertensive left ventricular hypertrophy and dilated similarly in normotensive black and white subjects. Thus, our study shows that in a cohort of black and white subjects referred for coronary arteriography because of chest pain, African American race is not associated with excess intrinsic or acquired depression in coronary vascular relaxation during the peak effect of the endothelium-dependent and -independent agonists acetylcholine and adenosine, after adjustment for the presence of left ventricular hypertrophy.
Key Words: blacks • race • vasorelaxation • hypertrophy, left ventricular • vascular reactivity • endothelial function
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Introduction |
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Excess cardiovascular morbidity and mortality among African (black) Americans remains an important yet unexplained public health problem.1 2 Furthermore, the paradoxical finding of a lesser degree of coronary atherosclerosis but worse prognosis after diagnosis of ischemic heart disease exists among black Americans.3 4 Although myocardial ischemia is generally secondary to coronary artery atherosclerosis, the demonstration of ischemia with normal coronary arteries (syndrome X, aortic stenosis, left ventricular hypertrophy [LVH]) has clarified the concepts of microvascular angina and nonatherosclerotic supply/demand mismatch.5 6 7 8 9 These concepts, together with an evolving understanding of the endothelium, justify investigations that emphasize the central importance of the coronary microcirculation and endothelium in the regulation of myocardial perfusion.10 11
A number of possible explanations have been advanced to address the perceived paradox of greater myocardial ischemia despite less atherosclerotic disease among blacks. One invokes societal-based factors related to socioeconomic status, such as access to medical care, compliance issues, and the duration of untreated or poorly treated cardiovascular disease.12 13 14 A second explanation proposes that comorbid diseases or processes more prevalent in black Americans, such as hypertension and diabetes mellitus, may augment ischemia by affecting supply and demand through mechanisms other than atherosclerosis.6 15 16 17 Third, intrinsic abnormalities in the coronary endothelium and microcirculation may be present in black Americans, possibly as part of a generalized defect in vascular relaxation, thus leading to abnormal perfusion of the myocardium in the absence of atherosclerosis.18 19
Our purpose in this study was to examine the effects of hypertensive LVH and race on coronary artery and arteriolar vasorelaxation in response to the endothelium-dependent agent acetylcholine and the predominantly endothelium-independent agent adenosine in a cohort of black and white Americans with angiographically normal coronary arteries. Comparisons were made among normotensive subjects and subjects with complicated hypertension, defined as hypertension plus LVH. Study subjects were identified for possible participation after clinical referral for cardiac catheterization because of suspected ischemic heart disease.
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Methods |
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Subjects
Subjects were prospectively recruited for the approved investigational study (Albany Medical College Institutional Review Board) after clinical referral for cardiac catheterization for evaluation of chest pain. Informed consent was obtained, which documented the participants' understanding of the investigational nature of the protocol. The current study is part of a larger study whose purpose is examination of the effects of hypertension, LVH, hemodynamically insignificant atherosclerosis, sex, and ethnicity on coronary artery and arteriolar relaxation. Enrolled subjects had normal epicardial coronary arteries documented during coronary angiography. Individuals were excluded from the study if they had a history of myocardial infarction, balloon angioplasty, bypass surgery, significant valvular heart disease, or other serious medical disorder. Subjects fasted for a minimum of 8 hours before the study. Current smokers were instructed to refrain from smoking for a minimum of 8 hours.
Subjects were grouped by race and presence of hypertensive LVH. Hypertension was defined as reproducible blood pressure measurements greater than or equal to 140/90 mm Hg or self-reported taking of antihypertensive medication. Diabetes mellitus was diagnosed by self-reported history or fasting serum glucose greater than 7.8 mmol/L (140 mg/dL).
All subjects were referred for cardiac catheterization for evaluation of chest pain or an angina equivalent. Chest pain was classified as angina pectoris, atypical angina, or noncardiac chest pain. Angina pectoris was defined in the classic manner as substernal chest discomfort (heaviness or pressure) brought on by exertion and relieved by rest or nitroglycerin or a prolonged episode of anginal pain at rest requiring hospitalization. Atypical angina was defined as chest pain with some features of classic angina but other characteristics not generally associated with angina pectoris, such as a sharp or pleuritic character or intermittent relationship to exercise. Noncardiac chest pain had no features of angina other than a substernal location of chest pain. An angina equivalent was defined as symptoms or findings commonly associated with ischemia in the absence of chest pain, such as dyspnea or heart failure. In normotensive subjects, 6 black (60%) and 13 white (62%) were judged to have angina pectoris; 2 black (20%) and 7 white (33%), atypical angina; 2 black (20%) and 0 white, an anginal equivalent; and 0 black and 1 white (5%), noncardiac chest pain. In hypertensive subjects with LVH, 13 black (52%) and 11 white (46%) were judged to have angina pectoris; 5 black (20%) and 9 white (38%), atypical angina; 6 black (24%) and 2 white (8%), an anginal equivalent; and 1 black (4%) and 2 white (8%), noncardiac chest pain.
Twenty-nine of 45 white subjects (64%) and 24 of 35 black subjects (69%) were taking medications for chest pain and/or hypertension. Seventeen of these 29 white subjects (59%) and 12 of these 24 black subjects (50%) were taking drugs expected to have coronary vasodilating properties alone (nitroglycerin and/or calcium channel blockers). Two white (7%) and 1 black (4%) subjects were taking a ß-blocker alone. However, 5 white (17%) and 6 black (25%) subjects were taking both a ß-blocker and coronary vasodilator. Finally, the remaining 5 white (17%) and 5 black (21%) subjects were taking an angiotensin-converting enzyme inhibitor or 
-blocker together with other drugs. Eight white (28%) and 9 black (38%) subjects used diuretics in addition to the medications already described. Whenever possible, vasoactive and antihypertensive medications were withheld for a minimum of 12 hours before the study although the study design permitted sublingual nitroglycerin if deemed clinically necessary; however, no subject required sublingual nitroglycerin within 4 hours. In 10 of 80 study subjects (5 white and 5 black), medications with vasoactive potential were used within 12 hours because of clinical indication. Medications used within 12 hours were as follows: calcium channel blockers in 2 white subjects, nitroglycerin preparations in 2 white and 2 black subjects, a short-acting angiotensin-converting enzyme inhibitor in 1 white subject, and 2 or more drugs in 3 black subjects. There were no significant racial differences in drug usage. Socioeconomic status was assessed by three indicators: years of formal education, possession of private medical insurance, and current employment status. Body mass index was calculated as weight (in kilograms) divided by height (in meters) squared. Blood was obtained with subjects in the fasting state for measurement of total cholesterol, low-density and high-density lipoprotein cholesterols, lipoprotein(a), and glucose.
Left Ventricular Mass Measurements
Left ventricular (LV) mass was calculated with M-mode echocardiographic measurements made in accordance with the Penn convention and corrected to agree with necropsy data as follows20 21 : LV Mass (grams)=1.04[(IVS+LVID+PWT)3-(LVID)3]-13.7, where IVS is interventricular septal thickness (centimeters), LVID is LV internal dimension at end diastole (centimeters), and PWT is LV posterior wall thickness (centimeters). Analyses were performed with the calculated value of LV mass indexed by body surface area (meters squared) and height (meters) raised to the 2.7th power (height2.7). Partition values for LVH were taken from the Framingham Heart Study (using body surface area for indexing: normal, <131 g/m2 for men and <100 for women)22 and from allometric criteria developed by DeSimone et al23 (using height2.7 for indexing: normal, <50 g/m2.7 for men and <47 for women). Racial comparisons were made among normotensive subjects and hypertensive subjects with LVH with the use of the two partitioning systems.
Invasive Coronary Artery Testing
After diagnostic cardiac catheterization was completed, 7000 U heparin sulfate IV was administered, and a 0.018-inch Cardiometrics Flo-Wire Doppler tipped guide wire was advanced through a 7F or 8F coronary artery guiding catheter into the proximal to mid-portion of the left anterior descending artery in 53 subjects, the circumflex artery in 23 subjects, and the distal portion of the left main artery in 4 subjects. The placement of this device was optimized on the basis of Doppler signal quality. At least 15 minutes elapsed between the end of the diagnostic study and baseline coronary velocity measurements. We sampled coronary flow velocity signals at a preset fixed distance of 5.2 mm from the device tip to minimize turbulence caused by the presence of the measuring device. After stable measurements of baseline coronary flow velocity were obtained, we administered a series of drugs into the left main artery to test the capacity for vasorelaxation by endothelium-dependent and -independent mechanisms. Coronary flow velocity was continuously recorded on Super VHS tapes during drug infusions so that peak drug effect could be identified during data processing performed at a later date. Coronary angiograms were obtained under baseline conditions and at the end of each graded infusion of acetylcholine.
Intracoronary Drug Infusion Protocols
We used the following protocol to study endothelium-independent coronary vascular relaxation. Adenosine, 8 µg, was first administered via bolus infusion through the guiding catheter into the left main artery. After return to the baseline values of coronary flow velocity, blood pressure, and heart rate, 16 and then 20 µg adenosine were similarly administered. Typically, 60 seconds elapsed between each bolus infusion of adenosine. We used the next protocol to study graded responses during endothelium-dependent coronary vascular relaxation. An infusion monorail catheter was advanced over the Doppler wire device and placed near the tip but still within the guiding catheter so that acetylcholine was infused into the left main artery (assumed blood flow equal to 150 mL/min). After verification of stable velocity tracings, 3 mL acetylcholine was infused over 2 minutes through the infusion catheter at a rate of 0.15 µg/min (10-8 mol/L) with a Medfusion syringe pump (Harvard Apparatus). A coronary angiogram was performed, and after return to the baseline values of coronary flow velocity, blood pressure, and heart rate, 3 mL acetylcholine was infused over 2 minutes at a rate of 1.5 µg/min (10-7 mol/L); a third infusion was similarly administered at a rate of 15 µg/min (10-6 mol/L). In the same manner, a final infusion at a rate of 30 µg/min (2x10-6 mol/L) was performed in 50% of the subjects. Typically, 60 seconds elapsed between the end of one infusion and the beginning of the next.
Quantitative Coronary Angiography
Baseline angiography of the coronary vessel undergoing study was performed in an optimal right anterior oblique or anteroposterior projection so that overlapping of branches and foreshortening of the region of interest were minimized. Angiography was repeated in the identical view after each infusion of acetylcholine. Angiography was not repeated after each bolus of adenosine as it was assumed that coronary diameter changes were minimal in response to this drug.24 An optimal end-diastolic cineangiographic frame was selected, and coronary artery diameter was measured at the site of Doppler velocity measurements at baseline and after each infusion of acetylcholine. Measurements were made with electronic digital calipers (Sandhill Scientific). Area was calculated assuming a circular cross-sectional profile. Percent change in coronary vessel diameter above baseline was calculated in response to each infusion of acetylcholine. The contrast agent iohexol was used for all studies.
Coronary Artery Blood Flow Measurements
Coronary artery blood flow was calculated as the product of mean coronary blood flow velocity and coronary artery cross-sectional area at the site of Doppler wire velocity measurements. Baseline values were calculated before infusion of the predominantly endothelium-independent agent adenosine and before infusion of the endothelium-dependent agent acetylcholine. Percent change in coronary blood flow above baseline was calculated in response to each infusion of adenosine and acetylcholine.
Statistical Analysis
Summary clinical data and outcomes of the research studies (percent change in coronary blood flow and coronary diameter measurements in response to endothelium-dependent and -independent agonists) are expressed as mean±SE. Unpaired Student's t test (for continuous variables) and 
2 test or Fisher's exact test (for categorical variables) were used for assessment of the statistical significance of group differences, where a value of P<.05 was considered significant. ANOVA was used for testing of differences (by race and hypertension subgroups) among study outcomes, with the Bonferroni adjustment of probability values for multiple comparisons. Multiple linear regression models were generated for assessment of the association between race and study outcomes, with simultaneous adjustment for variables that substantially differed between black and white subjects (mean arterial pressure, lipoprotein(a), body mass index, and LV mass indexed by height2.7). Scatterplots were generated relating endothelium-dependent and -independent vasodilation of the microcirculation to LV mass indexed by height.2.7 Correlations and SEE were computed.
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Results |
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Study Subjects
The study included 80 subjects with normal coronary arteries who agreed to invasive testing of the coronary artery and arteriolar relaxation by the study protocol. Of these, 31 were normotensive and 39 were hypertensive with echocardiographic evidence of LVH using Framingham partitioning criteria and LV mass indexed by body surface area.22 These 39 plus an additional 10 subjects were identified as having LVH with the use of allometric partitioning and LV mass indexed by height2.7.23
Thirty-five subjects (44%) were black and 45 (56%) were white. Forty-four (55%) were women and 36 (45%) were men. In this clinically referred study population, black Americans had less formal education (10.9±0.7 versus 12.1±0.3 years, P=.08), were less likely to have private medical insurance (34% versus 76%, P=.0003), and had a lower rate of employment (63% versus 80%, P=.1) than white Americans.
Demographic and clinical characteristics of the study group stratified by race and hypertensive LVH (using both Framingham and allometric partitioning systems) are shown in Table 1
. These demonstrate comparability between black and white subjects for age, body mass index, and the presence of risk factors for atherosclerosis when comparisons are made between normotensive subjects (10 black, 21 white) and hypertensive subjects with LVH (25 black, 24 white). Fasting serum glucose and low-density lipoprotein cholesterol did not differ significantly by race within comparison groups. Serum creatinine was identical among black and white subjects (106±9 µmol/L [1.2±0.1 mg/dL]). Lipoprotein(a) was significantly greater in blacks than whites in both normotensive and hypertensive groups. Both mean arterial pressure at the time of cardiac catheterization and indexed LV mass using body surface area and Framingham partitioning were greater (although not significantly) in hypertensive blacks with LVH than in similar hypertensive whites. With the use of height2.7 and allometric partitioning for hypertrophy, mean arterial pressure and indexed LV mass were significantly greater among hypertensive blacks. Normotensive white subjects had greater indexed LV mass (with the use of body surface area) than normotensive black subjects because of the greater proportion of men in this group. This difference was not significant when LV mass was indexed by height2.7. Angiographic LV ejection fraction was nearly identical between the groups (63±2% in blacks versus 64±2% in whites). Subgroup analysis in normotensive and hypertensive subjects revealed no racial differences in ejection fraction. Baseline heart rate was similar in black and white subjects (72±2 versus 70±2 beats per minute, P=NS).
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Endothelium-Independent Coronary Microvascular Relaxation
Fig 1 demonstrates the response of the coronary microcirculation to the endothelium-independent agent adenosine. This is expressed as maximal percent increase in coronary blood flow above baseline flow after bolus infusion of adenosine. Normotensive black and white subjects demonstrated no significant differences in peak coronary blood flow (percent increase) after adenosine. Hypertensive subjects with LVH demonstrated a general decline in peak responsiveness to adenosine regardless of the hypertrophy partitioning system used, but there were no significant racial differences in this response. During adenosine testing, baseline and peak coronary blood flows in normotensive blacks were 91±12 and 304±38 mL/min, respectively; in normotensive whites, 85±8 and 271±26; in hypertensive blacks with hypertrophy (Framingham), 114±18 and 280±27; and in hypertensive whites with hypertrophy (Framingham), 97±10 and 260±39. Baseline and peak values were not significantly different between black and white subjects after matching for hypertension. Allometric partitioning resulted in similar findings. Data from four subjects in whom blood flow measurements were made in the left main artery were not included because of the increased amplitude of absolute flow.
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Fig 2 shows the relationships between peak increase in coronary blood flow after adenosine and indexed LV mass. Black subjects demonstrated a significant linear relationship (Fig 2, top) between the dependent and independent variables, such that y=367-2.6x, where y is the percent increase in coronary blood flow after adenosine and x is LV mass indexed by height2.7 (P=.0001, r=-.61, SEE=70). The relationship was weakened when LV mass was used without indexing or after indexing by height or body surface area. White subjects demonstrated a borderline significant linear relationship (Fig 2, bottom), such that y=298-1.6x, where y is the percent increase in coronary blood flow after adenosine and x is LV mass indexed by height2.7 (P=.06, r=-.30, SEE=76). As with black subjects, the relationship was weakened when LV mass was used without indexing or after indexing by height or body surface area.
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Multivariate analysis (Table 2) was performed relating the dependent variable (and major study outcome), peak microvascular response to adenosine (endothelium-independent vasodilation), to race, mean arterial pressure, lipoprotein(a), body mass index, and LV mass indexed by height2.7. Indexed LV mass (P=.0001) and mean arterial pressure (P=.01) were significantly associated with a depression in vasodilation in response to adenosine.
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Endothelium-Dependent Coronary Microvascular Relaxation
Fig 3 demonstrates the relationship between the percent increase in coronary blood flow and graded infusion of intracoronary acetylcholine in white and black subjects. The first (0.15 µg/min), second (1.5 µg/min), and third (15 µg/min) infusion rates of acetylcholine were used in all subjects. The fourth infusion rate (30 µg/min) was used in 40 subjects (50%). The use of the higher dose did not differ significantly between black and white subjects. The higher dose was preferentially intended for those with LVH because of dilutional issues related to increased basal coronary blood flow in such individuals. The highest dose was not used in the initial phase of the larger study (subjects 1 through 49) or subsequently if sinus pauses, heart block, or severe bradycardia (<45 beats per minute) occurred.
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In Fig 3
, subjects are subdivided by race into normotensive subjects and hypertensive subjects with LVH with the use of both partitioning systems. Normotensive black and white subjects exhibited similar responses to acetylcholine (peak increase in coronary blood flow, 204±26% and 217±31%, respectively; P=NS). The presence of LVH was a marker for depressed coronary vasorelaxation within each race. The maximal response to acetylcholine was markedly depressed in black subjects with LVH (Framingham partitioning) compared with that in normotensive black subjects (P=.00007). Significant differences persisted in blacks with LVH for all tested doses of acetylcholine, suggesting severe endothelial dysfunction. In white subjects with LVH, the maximal response was significantly depressed compared with that in normotensive white subjects (P=.003). The use of allometric partitioning resulted in qualitatively similar although slightly less significant results. Endothelium-dependent microvascular relaxation during the peak effect of acetylcholine did not differ significantly by race with either of the partitioning systems for LVH. However, allometric partitioning contributed a greater number of white subjects with a lesser degree of hypertrophy, and a trend (P=.06) toward a better peak response to acetylcholine was seen with this approach. During acetylcholine testing, baseline and peak coronary blood flows in normotensive black subjects were 87±11 and 272±40 mL/min, respectively; in normotensive white subjects, 79±7 and 245±29; in hypertensive black subjects with LVH (Framingham), 112±17 and 185±20; and in hypertensive white subjects with LVH (Framingham), 93±10 and 190±30. Baseline and peak values were not significantly different between black and white subjects after matching for hypertension. Allometric partitioning resulted in similar findings. Data from four subjects in whom blood flow measurements were made in the left main artery were not included because of the increased amplitude of absolute flow.
Fig 4 shows the relationships between the peak increase in coronary blood flow after acetylcholine and indexed LV mass. Black subjects demonstrated a significant linear relationship (Fig 4, top) between the dependent and independent variables, such that y=290-2.6x, where y is the percent increase in coronary blood flow after acetylcholine and x is LV mass indexed by height2.7 (P=.0001, r=-.61, SEE=73).The relationship was weakened when LV mass was used without indexing or after indexing by height or body surface area. White subjects demonstrated a significant linear relationship (Fig 4, bottom), such that y=341-3.1x, where y is the percent increase in coronary blood flow after acetylcholine and x is LV mass indexed by height2.7 (P=.02, r=-.36, SEE=117). Once again, the relationship was weakened when LV mass was used without indexing or after indexing by height or body surface area.
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Multivariate analysis (Table 2) was performed relating the dependent variable (and major study outcome), peak microvascular response to acetylcholine, and the clinical variables of race, mean arterial pressure, lipoprotein(a), body mass index, and LV mass indexed by height2.7. Indexed LV mass was the dominant predictor of depression in the vasodilation of the microcirculation after acetylcholine in these subjects (P=.002).
Endothelium-Dependent Coronary Epicardial Relaxation
Fig 5 demonstrates percent epicardial coronary artery diameter changes (negative numbers indicate constriction) during graded acetylcholine infusion in white and black subjects. Diameter was measured at the site of flow velocity measurements. This figure shows a pattern of vasodilatation in normotensive black and white subjects and a pattern of vasoconstriction in hypertensive black and white subjects in response to the maximal infusion rate of acetylcholine. Within each race, these differences were significant (P=.01 for blacks and P=.04 for whites) with the use of Framingham partitioning. However, there were no racial differences in peak epicardial responsiveness to acetylcholine with either Framingham or allometric partitioning for LVH.
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Multivariate analysis (Table 2) was performed relating the dependent variable, epicardial coronary diameter responsiveness to peak acetylcholine infusion, and the clinical variables of race, mean arterial pressure, lipoprotein(a), body mass index, and LV mass indexed by height2.7. This analysis shows that race is not predictive of depressed epicardial vasodilation in response to acetylcholine. None of the clinical variables achieved statistical significance, although indexed LV mass (P=.075) attained borderline status as predictive of depression in epicardial vasodilation.
In our study, all individuals classified as having LVH with the use of body surface area for indexing were also identified with the use of height2.7. However, 2 additional black and 8 additional white hypertensive subjects were identified with the use of height2.7 for indexing and allometric criteria. These subjects were derived from a pool of 4 black and 24 white subjects with hypertension who were enrolled in the study but did not meet Framingham criteria for LVH. Nine of the 10 additions had body mass index in excess of 30 kg/m2. The additional subjects defined by allometric criteria were characterized by moderate to severe obesity, with a mean body mass index of 40±3 kg/m2.
Thus, the presence of chronic hypertension and its cardiac sequela LVH appears to largely explain the diminished effect of high-dose acetylcholine infusion (10-6 mol/L) on the vasodilation of the coronary microcirculation and epicardial arteries in a biracial cohort with normal coronary arteries referred for cardiac catheterization because of chest pain. Normotensive subjects did not differ in coronary vasoreactivity on the basis of race. Adenosine responsiveness of the coronary microcirculation was similar in black and white subjects after adjustment for LVH.
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Discussion |
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Adverse cardiovascular outcome among black compared with white Americans presents an important public health problem for which an explanation is lacking.1 2 3 4 One possible explanation proposes that differences in coronary artery and arteriolar vasorelaxation mediated by the endothelium or by direct vascular smooth muscle mechanisms18 19 may result in differences in ischemia or ischemic threshold. Our study addresses the issue of racial differences in coronary vasoreactivity among a select group of individuals with normal coronary angiograms referred for cardiac catheterization because of symptoms suggestive of ischemia. The study findings lead us to conclude the following. First, normotensive black Americans exhibit no intrinsic differences in endothelium-dependent coronary microvascular (Fig 3
) and epicardial (Fig 5) relaxation compared with normotensive white Americans. Second, there are no intrinsic racial differences in endothelium-independent microvascular relaxation among similar normotensive subjects, nor are there significant racial differences when the effects of hypertension and LVH are accounted for (Fig 1). Third, blunting of the endothelium effect on vasorelaxation in this cohort appears to be largely related to the effects of chronic hypertension on the coronary circulation. When LVH is adjusted for, black race is not predictive of depressed microvascular or epicardial relaxation in response to the peak effect of acetylcholine or adenosine (Table 2). A reduction in endothelium-dependent relaxation in response to acetylcholine may be secondary to decreased production, efficacy, or release of relaxing factors; increased activity of contracting factors; or increased sensitivity of vascular smooth muscle to the direct constricting effects of acetylcholine. Luscher et al25 showed that in aortic rings from spontaneously hypertensive rats, exposure to acetylcholine results in the production of endothelium-derived relaxing and contracting factors, leading to the depression of relaxation at higher concentrations of the muscarinic agonist (10-6 to 10-5 mol/L). Coronary reserve, defined as coronary blood flow during maximal endothelium-independent vasodilation divided by baseline coronary blood flow, is known to be depressed in the setting of hypertensive LVH.6 7 26 We demonstrated this previously in a biracial rural population with a significant prevalence of severe hypertension among blacks.18 Our current study shows that after matching for hypertension and its sequela LVH, black race is not predictive of excess depression in coronary vasodilation among referral individuals with normal coronary arteries.
A number of conditions may be associated with depressed endothelium or vascular smooth muscle function, thus complicating the process of ethnic comparisons.11 26 27 28 29 30 31 32 33 34 35 These include increased age, systemic hypertension, LVH, hyperlipidemia, atherosclerosis, estrogen deficiency, diabetes mellitus, and chronic tobacco use. In this study, we excluded individuals with coronary atherosclerosis via angiographic assessment. However, subtle indicators of early atherosclerosis that are beyond the resolution of coronary angiography have been described with intracoronary ultrasound36 and cannot be excluded. Individuals with diabetes mellitus, hyperlipidemia, and current tobacco use were not excluded, providing that the coronary arteries appeared normal by angiographic criteria. Although diabetes mellitus, hyperlipidemia, and tobacco use were allowed, these were similarly distributed between white and black Americans. Lipoprotein(a) was elevated in blacks compared with whites in each grouping of normotensive and hypertensive subjects. Other borderline or significant differences were detected for mean arterial pressure, indexed LV mass, and body mass index. These variables were thus selected for multivariate analysis.
Socioeconomic status may well be an unavoidable confounding issue when ethnic comparisons are made among clinically referred individuals. In our study, black subjects had significantly less formal education and less insurance coverage. The possible effects of socioeconomic status on the development of LVH and endothelial dysfunction are unknown and require further study.
Studies comparing endothelial function must consider the possibility of arteriolar smooth muscle dysfunction as a contributory effect.37 In this study, there were no significant ethnic differences in response to the endothelium-independent agent adenosine when comparisons were made for similar LV mass. This infers comparability of nonendothelial portions of the pathway.
Methodological Issues
The use of indexed LV mass as a surrogate for the severity and duration of hypertension is imperfect. Casual blood pressure measurements appear to correlate only weakly with LV mass, and some individuals do not develop LVH despite documentation of uncontrolled hypertension.38 39 Yet cardiac hypertrophy is the end-organ expression of hypertension in many individuals and, when ethnic comparisons are being made, may be useful in the assessment of the clinical severity of hypertension. Furthermore, multiple studies, including our own,18 show that LVH is a marker for depressed coronary vasodilation. The use of two different partitioning systems for the establishment of LVH resulted in no significant differences in the major findings. The Framingham criteria, however, resulted in a lower identification rate of LVH. This is expected because indexation by body surface area (which is mostly determined by body weight) can result in underestimation of LVH in obese individuals. Additionally, indexation by height2.7 provides better allometric, or growth, normalization of LV mass. Finally, multivariate analysis (with the use of both unindexed and indexed LV mass as a continuous variable in addition to other potentially significant clinical variables) confirmed findings obtained by the categorical analyses.
Drug infusions were all performed in the left main artery, raising the concern that mixing of drugs in the left anterior descending and circumflex arteries may have been variable. However, this does not appear to be a significant issue in our study as subset analysis of the 31 subjects without significant differences in vasoreactivity parameters (normotensive white and black subjects) showed no significant differences in the microcirculation or epicardial findings when comparisons were made between responses of circumflex (n=9) and left anterior descending (n=22) artery studies.
Other issues related to drug infusion methodology include the selection of a bolus protocol with adenosine versus another endothelium-independent agent and the issue of bolus versus continuous infusion. A previous investigation has established that the use of intracoronary adenosine in a bolus amount similar to ours produces maximal coronary hyperemia like that produced by an intracoronary bolus of papaverine or an intracoronary infusion of adenosine (rates 
80 µg/min) in the left coronary artery.40 A final issue related to the adenosine drug infusion protocol is the assumption that an intracoronary bolus of adenosine results in insignificant changes in the diameter of the epicardial vessels in response to this drug. This issue was recently addressed by Reddy et al,24 who, using intracoronary ultrasound, found that adenosine administration resulted in minimal epicardial coronary dilatation (1% to 3% increase in diameter).
Finally, the effect of multiple intracoronary injections of radiographic contrast medium on coronary vascular reactivity must be addressed. Egashira et al41 showed that nonionic low osmolarity contrast medium administered by bolus infusion into the circumflex artery caused on average a 4% increase in coronary diameter in six dogs with a baseline coronary diameter of 3.06±0.19 mm. This effect was transient, with a return to baseline values within 5 minutes. Resistance vessels were also noted to dilate, but this effect resolved more quickly, with a rapid return to baseline flow velocities. Thus, serial research angiograms, performed within 5 minutes of one another, may introduce some error caused by transient minor epicardial vasodilation. In our study, the baseline research angiogram was performed at least 15 minutes after the previous diagnostic left coronary angiograms. The subsequent three to four research angiograms were performed after each 2-minute infusion of acetylcholine. Thus, for an individual study, some error is expected because of the performance of these angiograms within 5 minutes of each other. However, uniformity of the protocol among groups mitigates against error during group comparisons.
We have demonstrated that there are no intrinsic or acquired racial differences in coronary conduit and resistance vessel functions after adjustment for LVH during the peak effect of the endothelium-dependent and -independent agents acetylcholine and adenosine in individuals referred for cardiac catheterization because of chest pain but without angiographic coronary disease. However, our study does not exclude racial differences in the sensitivity to submaximal infusions of adenosine and acetylcholine or in responsiveness to other agonists. In addition, although the individuals in our study had normal coronary arteriograms, their referral for cardiac catheterization because of chest pain differentiates them from a purely volunteer group with normal coronary arteries, so these results may not be generalizable. Further study is needed to investigate these issues.
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Acknowledgments |
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This study was supported by grant HL-50262 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md. The authors are greatly indebted to Dawn Burke for manuscript and figure preparation and to Patricia A. Kuhner for technical assistance. This article is dedicated to the memory of Dr Martin J. Frank, MD, without whose encouragement this work would never have been initiated.
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Footnotes |
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Reprints requests to Dr Jan Laws Houghton, MD, Division of Cardiology, A-44, Albany Medical College, Albany, NY 12208.
Received September 11, 1996; first decision October 3, 1996; accepted October 3, 1996.
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References |
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