Charles L. Eastham

Does Visual Interpretation of the Coronary Arteriogram Predict the Physiologic Importance of a Coronary Stenosis

To assess visual interpretation of the coronary arteriogram as a means of predicting the physiologic effects of coronary obstructions in human beings, we compared caliper measurements of the degree of coronary stenosis with the reactive hyperemic response of coronary flow velocity studied with a Doppler technique at operation, after 20 seconds of coronary arterial occlusion. In 39 patients (44 vessels) with isolated, discrete coronary lesions varying in severity from 10 to 95 per cent stenosis, measurement of the percentage of stenosis from coronary angiograms was not significantly correlated (r = -0.25) with the reactive hyperemic response. Results were the same for obstructions in the left anterior descending, diagonal, and right coronary arteries. Underestimation of lesion severity occurred in 95 per cent of vessels with greater than 60 per cent stenosis of the diameter by arteriography. Both overestimation and underestimation of lesions with less than 60 per cent stenosis were common. These results, together with the high interobserver and intraobserver variability of standard visual analysis of angiograms, suggest that the physiologic effects of the majority of coronary obstructions cannot be determined accurately by conventional angiographic approaches. The need for improved analytical methods for the physiologic assessment of angiographically detected coronary obstructions is apparent.

Decreased coronary reserve: a mechanism for angina pectoris in patients with aortic stenosis and normal coronary arteries.

The pathogenesis of angina pectoris in patients with aortic stenosis and normal coronary arteries remains uncertain. Using a specially designed Doppler probe, we measured the maximal velocity of coronary blood flow in the left-anterior descending coronary artery at the time of elective open-heart surgery in 14 patients with aortic stenosis and left ventricular hypertrophy (13 had angina) and in 8 controls without left ventricular hypertrophy. The ratio peak velocity of coronary blood flow, after a 20-second occlusion, to resting velocity was decreased by more than 50 per cent (P less than 0.05) in the patients with aortic stenosis. In 7 of the patients this ratio was decreased by more than 75 per cent. Studies of the velocity of coronary blood flow in vessels perfusing the right ventricle in these patients showed only mild abnormalities. These data demonstrate a selective and marked decrease in coronary reserve to the hypertrophied left ventricle in patients with severe aortic stenosis. The impairment in coronary reserve is probably an important contributor to the pathogenesis of angina pectoris in these patients.

The value of lesion cross-sectional area determined by quantitative coronary angiography in assessing the physiologic significance of proximal left anterior descending coronary arterial stenoses.

The results of previous work from this laboratory have shown a poor correlation between percent stenosis (determined visually with calipers) and the coronary reactive hyperemic response (an index of maximal coronary vasodilator capacity) determined during cardiac surgery. This study was performed to determine whether other parameters of lesion severity could predict the reactive hyperemic response and thus the hemodynamic significance of coronary stenoses in human beings. Twenty-three patients with lesions in the proximal left anterior descending coronary artery were studied. To account for differences in expected vessel size, patients with large diagonal branches (greater than one-half the diameter of the left anterior descending artery) arising before the lesion were excluded. Computer-assisted quantitative coronary angiography was used to measure percent diameter stenosis, percent area stenosis, and minimal stenosis cross-sectional area. With a pulsed Doppler velocity probe, reactive hyperemic responses were recorded after a 20 sec coronary occlusion of the left anterior descending artery at cardiac surgery before cardiopulmonary bypass and were quantified by the peak/resting velocity ratio (normal greater than 3.5:1). Percent area stenosis ranged from 7% to 54% for vessels with normal reactive hyperemic responses and from 27% to 94% for vessels with abnormal reactive hyperemic responses. With both percent diameter stenosis and percent area stenosis there was substantial overlap between vessels with normal and abnormal reactive hyperemic responses. In contrast, nine of nine vessels with normal reactive hyperemic responses had lesion minimal cross-sectional areas of greater than 3.5 mm2 and 13 of 14 vessels with abnormal reactive hyperemic responses had minimal cross-sectional areas of less than 3.5 mm2.(ABSTRACT TRUNCATED AT 250 WORDS)

Understanding the coronary circulation through studies at the microvascular level.

Studies of the coronary circulation have divided vascular resistances into three large components: large vessels, small resistance vessels, and veins. Studies of the epicardial microcirculation in the beating heart using stroboscopic illumination have suggested that resistance is more precisely controlled in different segments of the circulation. Measurements of coronary pressure in different sized arteries and arterioles have indicated that under normal conditions, 45–50% of total coronary vascular resistance resides in vessels larger than 100 μm. This distribution of vascular resistance can be altered in a nonuniform manner by a variety of physiological (autoregulation, increases in myocardial oxygen consumption, sympathetic stimulation) and pharmacological stimuli (norepinephrine, papaverine, dipyridamole, serotonin, vasopressin, nitroglycerin, adenosine, and endothelin). Studies of exchange of macromolecules in the microcirculation using fluorescent-labeled dextrans have also identified the size of the small pore (35–50 AÅ) in coronary microvessels that can be altered by myocardial ischemia. Studies of the coronary microcirculation have demonstrated that the control of vascular resistance is extremely complex, and mechanisms responsible for these heterogeneous responses need further examination.

Measurements of coronary velocity and reactive hyperemia in the coronary circulation of humans.

An acceptable method for measuring phasic coronary velocity and reactive hyperemia in humans has not been available. We have developed a doppler probe which can be coupled to surface coronary vessel* at the time of cardiac surgery with a small suction cup. Phasic coronary velocity can be measured with a signal to noise ratio that exceeds 20:1. Animal studies have shown that the probe does not alter myocardial perfusion or cause tissue damage. In addition, changes in mean coronary velocity are closely related (r = 0.97) to changes in coronary flow over a wide range (15–400 ml/min). The characteristics of reactive hyperemia in the coronary circulation of dogs determined with the doppler system are similar to those obtained simultaneously with an electromagnetic flow meter. Transient occlusions of branch coronary vessels in patients with normal coronary arteries are not associated with significant changes in heart rate, left atrial, or mean arterial pressure. The characteristics of reactive hyperemia in normal vessels of 13 patients were as follows: although reactive hyperemia responses were demonstrable following 1 to 2-aecond coronary occlusions, maximal responses usually occurred with 20-second coronary occlusions; following 20 seconds of coronary occlusion, the ratio of peak to resting velocity was 5.8 ± 0.6 (mean ± SE); the ratio of repayment to debt area was 3.1 ± 0.2, and the duration of the reactive hyperemia response was 20.8 ± 0.3 seconds. These studies provide the first quantitative measurements of coronary reactive hyperemia in humans.

Increased size of myocardial infarction in dogs with chronic hypertension and left ventricular hypertrophy.

Impaired coronary reserve in animals and patients with left ventricular hypertrophy (LVH) might be expected to augment infarct size following coronary occlusion (CO). To test this hypothesis, the circumflex coronary artery was acutely occluded in 30 control dogs and in 28 renal hypertensive (HT)-LVH dogs during the conscious state. Hemodynamics and regional myocardial flow (microspheres) were measured. After 48 hours of CO, we assessed infarct size pathologically and area at risk by postmortem coronary angiography. Mean arterial pressure (130 ± 5 mm Hg) and LV:body weight ratio (6.1 ± 0.1 g/kg) in HT-LVH dogs were about 35% greater than in control dogs (P < 0.05). During the 48 hours following CO, mortality rate was markedly increased in HT-LVH (54%) compared to control (17%) (P < 0.01). We performed a linear regression analysis of the relationship between area at risk (AR; % of LV mass) and infarct size (IS; % of LV mass); control, IS = 1.20AR - 25.6 (r = 0.96); HT-LVH, IS = 1.19AR - 16.3* (r = 0.95) (*P < 0.05 vs. control). Although the slopes of these relationships were similar, the intercepts were different. Consequently, the minimal AR associated with infarction was 35% smaller in HT-LVH (15 ± 2% of LV mass) than in control (22 ± 1%), and over the entire range of AR, the IS was increased in HT-LVH. The distance between the lateral extent of infarct size and area at risk in different layers of LV was measured. The increase in infarct size in the HT-LVH group reflected primarily an increase in midwall layer infarction. Increase in collateral flow to the risk area was attenuated in HT-LVH. In conclusion, infarct size relative to the area at risk is increased significantly in HT-LVH. This interaction between LVH and myocardial ischemia may significantly influence the outcome of myocardial infarction in patients with hypertension and LVH.

Abnormalities in the coronary circulation that occur as a consequence of cardiac hypertrophy

Myocardial ischemia is frequently observed in patients with cardiac hypertrophy even when the conduit coronary arteries are normal. Recent studies indicate that impaired coronary reserve in hypertrophied hearts probably occurs because growth of the coronary bed does not keep pace with increases in cardiac mass. The imbalance between vascular proliferation and muscle growth is probably most severe when cardiac hypertrophy is produced by pressure overload. Experimental studies also suggest that abnormalities intrinsic to pressure-hypertrophied heart muscle (decreased capillary density; decreased coronary reserve; electrophysiologic abnormalities) adversely affect the response of the enlarged heart to sudden coronary occlusion. When animals with hypertension and left ventricular hypertrophy are subjected to sudden coronary occlusion, the incidence of sudden cardiac death is increased severalfold and infarct size is substantially augmented. These observations suggest that abnormalities in the coronary microcirculation that accompany cardiac hypertrophy play a significant role in the pathogenesis of the complications associated with cardiac hypertrophy.

Comparison of the effects of increased myocardial oxygen consumption and adenosine on the coronary microvascular resistance.

The purposes of this study were to determine if coronary dilation secondary to an increase in myocardial oxygen consumption (MVO2) affects the microcirculation in a homogeneous or heterogeneous manner and to determine if comparable degrees of coronary dilation produced by increasing MVO2 or exogenous (intravenous adenosine) or endogenous (intravenous dipyridamole) adenosine have similar effects In the coronary microcirculation. The epimyocardial coronary microcirculation was observed through an intravital microscope by stroboscopic epi-illumination in anesthetized open-chest dogs. Aortic pressure and heart rate were controlled by an aortic snare and atrioventricular sequential pacing, respectively, during experimental procedures. In group 1 (n = 15), coronary arterial microvessel diameters were measured under control condition and during rapid pacing at 300 beats/min, which doubled MVO2. Increases in MVO2 caused heterogeneous vasodilation in coronary arterial microvessels (40-380 μm). There was an inverse relation between control diameter and percent increase in diameter. In group 2 (n =15) or group 3 (n =10), adenosine or dipyridamole was infused intravenously to increase myocardial perfusion to the same level as that obtained with rapid pacing. Adenosine and dipyridamole did not change MVO2. Adenosine and dipyridamole also caused heterogeneous vasodilation, but the effects of adenosine and dipyridamole were restricted to arterial microvessels smaller than 150 μm. From these results, we conclude that increases in MVO2 produce widespread but heterogeneous vasodilation, that is, greater dilation in smaller arterial microvessels. Comparable increases in coronary flow produced by increasing MVO2 or endogenous and exogenous adenosine do not produce identical changes in the distribution of coronary microvascular resistance.

Effects of chronic hypertension and left ventricular hypertrophy on the incidence of sudden cardiac death after coronary artery occlusion in conscious dogs

When acute myocardial infarction occurs in patients with hypertension and left ventricular hypertrophy (LVH), the incidence of sudden cardiac death increases markedly. Possible explanations include increased size of the occluded vascular bed secondary to more extensive atherosclerotic coronary vascular disease in the presence of hypertension, decreased coronary reserve secondary to LVH, and intrinsic electrophysiologic abnormalities in hypertrophied cardiac muscle. To explore these possibilities, we produced acute circumflex coronary occlusion during the resting, conscious state in 32 control dogs and in 28 dogs with hypertensive LVH. Before coronary occlusion, mean arterial pressure was 96 ± 0.1 mm Hg in control dogs and 125 ± 5 mm Hg in dogs with hypertensive LVH (p < 0.01). The control left ventricular/body weight ratio was 4.5 ± 0.1 g/kg, compared with 6.1 ± 0.1 g/kg in hypertensive LVH (p < 0.01). Cumulative mortality at 6, 24 and 48 hours was 9%, 13% and 16% in control dogs and 32%, 43% and 54%, respectively, in dogs with hypertensive LVH (all p < 0.01 vs control). The perfusion fields of the occluded vessel defined by postmortem coronary angiography were similar in the two groups (31 ± 2% of left ventricular mass for control vs 29 ± 2% for hypertensive LVH). Thus, the increased incidence of sudden cardiac death after coronary artery occlusion in hypertensive LVH dogs cannot be explained by increased size of the occluded vascular bed and is probably related to the decreased coronary reserve or intrinsic electrophysiologic abnormalities that characterize pressure-induced hypertrophied cardiac muscle.

Role of ATP-sensitive potassium channels in coronary microvascular autoregulatory responses.

The purpose of the present study was to test the hypothesis that ATP-sensitive potassium channels mediate autoregulatory vasodilatation of coronary arterioles in vivo. Experiments were performed in 23 open-chest anesthetized dogs. Coronary arterial microvascular diameters were directly measured with fluorescence microangiography using an intravital microscope and stroboscopic epi-illumination synchronized to the cardiac cycle. A mild coronary stenosis (perfusion pressure = 60 mm Hg), a critical coronary stenosis (perfusion pressure = 40 mm Hg), and complete coronary artery occlusion were produced with an occluder around the left anterior descending coronary artery in the presence or absence of glibenclamide (10(-5) M, topically), which inhibits ATP-sensitive potassium channels, or of vehicle. During topical application of vehicle (0.01% dimethyl sulfoxide), there was dilatation of small (less than 100 microns diameter) arterioles during reductions in perfusion pressure (percent change in diameter: 6.7 +/- 1.5%, 11.7 +/- 3.5%, and 10.4 +/- 5.1% during mild stenosis, critical stenosis, and complete occlusion, respectively). In the presence of glibenclamide, arteriolar dilatations during coronary stenoses and occlusions were abolished. Glibenclamide did not affect responses of arterioles greater than 100 microns. Glibenclamide did not alter microvascular responses to nitroprusside. These data suggest that ATP-sensitive potassium channels play an important role in determining the coronary microvascular response to reductions in perfusion pressure.