P.A. Kuhner

Heterogeneous Vasomotor Responses of Coronary Conduit and Resistance Vessels in Hypertension

OBJECTIVES The purpose of our study was to investigate the relation between conductance and resistance coronary vasomotor responsiveness in hypertensive patients without atherosclerosis. BACKGROUND Although similar in morphology, conduit and resistance coronary vessels differ importantly in size, function and local environment and appear to be differentially affected in certain disease processes, such as atherosclerosis and hypertension. However, little is known about the effect of hypertension on contiguous coronary conduit and resistance vessels in humans. METHODS Changes in coronary blood flow (a measure of resistance vessel reactivity) and coronary artery diameter (a measure of conduit vessel reactivity) were investigated in response to graded infusion of the endothelium-dependent agonist acetylcholine (ACh) in 98 patients with normal coronary arteries. RESULTS In 31 normotensive, euglycemic patients, conduit and resistance coronary artery responses to intracoronary infusion of ACh were significantly correlated (r = 0.73, p = 1 x 10[-6]), although eight patients (26%) had constriction of conduit but dilation of resistance arteries at peak effect. In 28 hypertensive patients without left ventricular hypertrophy (LVH), conduit and resistance artery responses to ACh remained significantly correlated (r = 0.5, p = 0.006), although 12 patients (43%) had discordant findings. Finally, in 39 hypertensive patients with LVH, conduit and resistance artery responses to ACh displayed the lowest correlation (r = 0.38, p = 0.02), with 22 patients (56%) demonstrating conduit artery constriction and resistance artery dilation. CONCLUSIONS Despite angiographically normal coronary arteries, heterogeneous vasomotor responses (dilation and constriction) were demonstrated in contiguous conduit and resistance arteries in normotensive and hypertensive patients referred for cardiac catheterization because of chest pain. In addition to more severe endothelial dysfunction among conduit and resistance arteries, a greater frequency of discordant conduit and resistance artery responses and resistance vessel constriction was found with increasing severity of hypertension. Our study suggests differing mechanisms of endothelium responsiveness to ACh among conduit and resistance coronary arteries.

The presence of African American race predicts improvement in coronary endothelial function after supplementary L-arginine☆

OBJECTIVES The purpose of our study was to determine if the presence of African American ethnicity modulates improvement in coronary vascular endothelial function after supplementary L-arginine. BACKGROUND Endothelial dysfunction is an early stage in the development of coronary atherosclerosis and has been implicated in the pathogenesis of hypertension and cardiomyopathy. Amelioration of endothelial dysfunction has been demonstrated in patients with established coronary atherosclerosis or with risk factors in response to infusion of L-arginine, the precursor of nitric oxide. Racial and gender patterns in L-arginine responsiveness have not, heretofore, been studied. METHODS Invasive testing of coronary artery and microvascular reactivity in response to graded intracoronary infusions of acetylcholine (ACh) +/- L-arginine was carried out in 33 matched pairs of African American and white subjects with no angiographic coronary artery disease. Pairs were matched for age, gender, indexed left ventricular mass, body mass index and low-density lipoprotein cholesterol. RESULTS In addition to the matching parameters, there were no significant differences in peak coronary blood flow (CBF) response to intracoronary adenosine or in the peak CBF response to ACh before L-arginine infusion. However, absolute percentile improvement in CBF response to ACh infusion after L-arginine, as compared with before, was significantly greater among African Americans as a group (45 +/- 10% vs. 4 +/- 6%, p = 0.0016) and after partitioning by gender. The mechanism of this increase was mediated through further reduction in coronary microvascular resistance. L-arginine infusion also resulted in greater epicardial dilator response after ACh among African Americans. CONCLUSIONS We conclude that intracoronary infusion of L-arginine provides significantly greater augmentation of endothelium-dependent vascular relaxation in those of African American ethnicity when compared with matched white subjects drawn from a cohort electively referred for coronary angiography. Our findings suggest that there are target populations in which supplementary L-arginine may be of therapeutic benefit in the amelioration of microvascular endothelial dysfunction. In view of the excess prevalence of cardiomyopathy among African Americans, pharmacologic correction of microcirculatory endothelial dysfunction in this group is an important area of further investigation and may ultimately prove to be clinically indicated.

African Americans With LVH Demonstrate Depressed Sensitivity of the Coronary Microcirculation to Stimulated Relaxation

Abstract—Excess coronary heart disease morbidity and mortality among African Americans remains an important yet unexplained public health problem. We hypothesized that adverse outcome is in part due to intrinsic or acquired abnormalities in coronary endothelial function and vasoreactivity. We compared dose-response curves relating changes in coronary blood flow and epicardial diameter to graded infusions of acetylcholine in 50 African American and 65 white subjects with hypertensive left ventricular hypertrophy (LVH) and normal coronary arteries. These groups were similar for age, body mass index, mean arterial pressure, and indexed left ventricular mass. The same protocol was conducted in 24 normotensive African American and 56 similar white subjects. We found significant depression in the coronary blood flow dose-response curve relation among African Americans when compared with white subjects with similar LVH (P <0.03). Racial differences were observed at all doses of acetylcholine but were less precisely estimated at the highest dose. The same testing among normotensive subjects revealed similar dose-response curves with no significant effect of race. Qualitatively similar results were found with respect to coronary diameter. Adenosine responses, a measure of endothelium-independent function, were similar after partitioning by LVH. Our study demonstrates that there are racial differences in sensitivity of coronary arteries to acetylcholine-stimulated relaxation among those with LVH. These results provide a mechanism whereby racial differences in coronary vasoreactivity might contribute to adverse coronary heart disease outcome among African Americans, a group in whom LVH is prevalent.

Coronary vasomotor reactivity among normotensive African and white American subjects with chest pain

BACKGROUND AND OBJECTIVES Excess cardiovascular morbidity and mortality among African (black) Americans is the subject of intensive investigation but the etiology remains speculative. One hypothesis proposes that inherent, or intrinsic, differences in coronary vascular reactivity and endothelial function predispose African Americans to enhanced vasoconstriction and/or depressed vasodilation, resulting in excess ischemia. The objective of this study was to establish whether coronary vasoreactivity differs among normotensive, nondiabetic African and white Americans with normal arteries referred for coronary arteriography because of chest pain. PATIENTS AND METHODS Eleven African American (8 female, 3 male) and 28 white American (9 female, 19 male) normotensive, euglycemic patients with normal coronary arteries were prospectively recruited for invasive testing of coronary artery and microvascular relaxation using the endothelium-dependent and -independent agents, acetylcholine and adenosine; a Doppler tipped intracoronary guidewire; and quantitative coronary angiography. RESULTS The study cohort consisted of 17 women (44%) and 22 men (56%) with a mean age of 46 +/- 10 yrs. Of 8 African American women, 6 were premenopausal and 2 were postmenopausal on estrogen replacement therapy. Of 9 white American women, 2 were premenopausal, 1 was 46-year old with a previous history of hysterectomy without ovariectomy, 2 were postmenopausal on estrogen replacement therapy, 2 were perimenopausal and 44- and 54-year old, and 2 were postmenopausal without estrogen replacement therapy. In response to maximal infusion of acetylcholine, epicardial coronary arteries and resistance vessels dilated similarly in black and white subjects. Dose-response curves revealed no significant racial differences during submaximal graded infusion of acetylcholine. In response to peak effect of adenosine, there were no racial differences in dilation of the microcirculation. CONCLUSIONS In the absence of hypertension, diabetes mellitus, and angiographic evidence of coronary artery disease, African American women demonstrate no evidence of intrinsic predisposition to enhanced coronary conduit vasoconstriction or depressed microcirculatory dilation in response to the endothelium-dependent and -independent vasodilator agonists-acetylcholine and adenosine-when compared with responses of similar white men and women. Because of low enrollment of black males, definitive conclusions cannot be drawn regarding this group.

Coronary endothelial function: The impact of aging in a matched study group with normal coronary arteries

Make Kelm Julius Rath, P&a Kleinbongard, Tienush Rassaf, Michael Preik, Bodo E. Strauer, Universitatsklinikum Diisseldorf, Diisseldorf, Germany Background: Nitric oxide (NO) has been shown to dilate vessels and to inhibit platelet function, both effects highly desirable during percutaneous intervention (PCI) in patients with coronary artery disease (CAD). Whether or not NO applied directly into human coro- nary circulation exerts biological effects is unknown so far. Therefore, the aims of our study were: (i) to develop a method for reproducible production of sterile solutions con- taining authentic NO, (ii) to find a save mode of intracoronary (ic.) application, and (iii) and to characterize potential dilatory effects in conduit and resistance coronary arteries. Methods: Changes in coronary blood flow (CBF) were quantified by quantitative coro- nary angiography (QCA) and intracoronary Doppler guide wares (ICD) in 13 patients with- out flow limiting CAD after application of either saline controls, aqueous NO solutions (NO.1 -6 wmol), adenosin (ADO, 2.4mg/min) or tsosorbiddinitrate (ISDN, 0.3 mg) in ran- dom order. Results: NO dilated epicardial arteries I” a dose-dependent manner up to lo+_1 %, equiv- alent to that seen upon ISDN. In parallel average peak velocity (APV) increased from 21 to 51+4 cm/s. Thus NO dilated coronary microvasculature to almost the same degree as seen after infusion of adenosine, whereas ISDN increased APV only slightly. Conse- quently. coronary blood flow increased according to the following rank order: NO and ADO > ISDN, whereas saline controls ware without effect. NO induced increases in CBF lasted much longer than expected from Its biochemical life span in human blood. Heart rate or blood pressure remained unaffected. Conclusions:Aqueous NO solutions can be applied directly into human coronary circu- lation and dilate uniformly epicardial