Melvin L. Marcus

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.

Transluminal, subselective measurement of coronary artery blood flow velocity and vasodilator reserve in man.

Assessment of coronary blood flow and the vasodilator reserve capacity of individual coronary arteries in the catheterization laboratory has been hampered by methodologic limitations. We have developed and validated a small Doppler catheter that can subselectively measure phasic coronary blood flow velocity (CBFV). In seven anesthetized calves, CBFV was varied from 0.1 to 5.7 times control CBFV. Changes in mean CBFV measured intraluminally by catheter in the left anterior descending and left circumflex arteries were similar to those measured simultaneously with an epicardial Doppler probe on the surface of the same vessel (n = 85, r = .95, slope = 1.04) and to changes in coronary sinus flow (n = 69, r = .97, slope = 1.06) measured with timed venous collections. Identical maximal coronary reactive hyperemic responses with the catheter present and absent in the artery being studied demonstrated that coronary obstruction by the catheter was minimal. Safety studies in six additional calves demonstrated that the catheter caused small changes in coronary endothelial permeability. Histologic studies revealed no endothelial denudation or thrombus formation. Stable phasic recordings of coronary blood flow velocity have been obtained in 58 of 70 patients studied. One of the 70 patients studied had abrupt coronary occlusion probably related to catheter-induced vasospasm. In 10 normal patients, intracoronary meglumine diatrizoate increased CBFV to 3.5 times that at rest (range 2.8 to 5.0). CBFV rose 5.0-fold after an intravenous infusion of dipyridamole (range 3.8 to 7.0). In each patient, dipyridamole produced greater vasodilation than meglumine diatrizoate. The time- and dose-response characteristics to dipyridamole infusion were heterogeneous, underscoring the advantage of continuous on-line measurement of CBFV in the measurement of vasodilator reserve. This method of measuring CBFV and assessing vasodilator reserve in the catheterization laboratory should facilitate studies of the coronary circulation in man.

Augmented responses to vasoconstrictor stimuli in hypercholesterolemic and atherosclerotic monkeys.

We examined effects of hypercholesterolemia and atherosclerosis on vasoconstrictor responses to norepinephrine and serotonin. Responses were compared in normal, atherosclerotic, and hypercholesterolemic but non-atherosclerotic cynomolgus monkeys. The hindlimb was per fused at constant flow so that changes in perfusion pressure indicated changes in vascular resistance. We measured the pressure gradient from the iliac to the dorsal pedal artery so that responses of the large artery segment could be determined. Serotonin decreased total hindlimb resistance in normal and hypercholesterolemic monkeys, but increased total resistance in athero sclerotic monkeys. There was a greater than 10-fold increase in constrictor responses of large arteries to serotonin in atherosclerotic monkeys, compared with normal and hypercholesterolemic monkeys. In contrast, we found that vasoconstrictor responses tc norepinephrine are normal in atherosclerotic monkeys and increased in hypercholesterolemic monkeys prior to development of atherosclerosis. Hypercholesterolemia augmented responses of small vessels to norepinephrine. We conclude that, during early stages of hypercholesterolemia in cynomolgus monkeys, vasocon strictor responses to norepinephrine are increased in small vessels. At a later stage, as atheroscle rosis develops, responses to norepinephrine return to normal, but vasoconstrictor effects of large arteries to serotonin are greatly potentiated.

The effect of coronary angioplasty on coronary flow reserve.

To determine the effects of coronary angioplasty on coronary flow reserve (CFR), we studied 32 patients before and immediately after single-vessel coronary angioplasty and 31 patients evaluated late after angioplasty (7.5 +/- 1.2 months, mean +/- SEM). The geometry (percent area stenosis and minimal cross-sectional area) of each lesion was determined by quantitative coronary angiography (Brown/Dodge method) and the integrated optical density was measured by videodensitometry. CFR was measured with a No. 3F coronary Doppler catheter placed immediately proximal to the lesion and a maximally vasodilating dose of intracoronary papaverine. The translesional pressure gradient was obtained in all lesions before and immediately after angioplasty and in 18 of 31 vessels late after angioplasty. CFR immediately after angioplasty returned to normal levels (greater than 3.5 peak/resting velocity ratio) in 14 of 31 patients and was improved, although not normalized, in the remaining 17 patients. CFR immediately after dilation was not significantly correlated with any of the angiographic variables of arterial stenosis nor the resting pressure gradient. Moreover, the pressure gradient and absolute distal coronary pressure at peak hyperemia were not significantly different in vessels with normal and those with abnormal flow reserve immediately after dilation, suggesting that the residual stenosis did not significantly limit hyperemia. Late after angioplasty, however, a significant relationship emerged between CFR and all four indexes of residual arterial stenosis (percent area stenosis r = .70, p less than .01; minimum arterial cross-sectional area r = .70, p less than .01; integrated optical density r = .60, p less than .01; and translesional pressure gradient r = .77, p less than .01). Furthermore, in the absence of restenosis, CFR eventually normalized in all patients. These findings demonstrate that in one-half of patients there is a transient reduction in coronary flow reserve immediately after angioplasty. In the absence of restenosis, coronary flow reserve later normalizes. Consequently, measurements of coronary flow reserve immediately after angioplasty may not reflect the eventual success of the procedure in removing physiologic obstruction to coronary blood flow.

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)

Rethrombosis after reperfusion with streptokinase: importance of geometry of residual lesions.

We tested the hypothesis that lesion rethrombosis after streptokinase reperfusion is related to luminal size of the residual stenosis. Two independent techniques of analyzing coronary angiograms, quantitative coronary angiography and computer-based videodensitometry, were used to estimate the size of the residual lumen immediately after discontinuation of streptokinase. These techniques were selected because they provide independent estimates of cross-sectional area of a lesion with high degrees of reproducibility and minimal observer variability. Twenty-four patients who had undergone successful reperfusion with streptokinase were studied. Seven patients had lesion rethrombosis documented either on a repeat angiogram, at autopsy, or, in one case, by the fact that the patient had an acute transmural infarction resulting in death. Vessel patency was documented by repeat coronary angiography 8 to 14 days after initial streptokinase reperfusion in the other 17 patients. As assessed by quantitative coronary angiography, seven of 13 patients (54%) with minimal luminal cross-sectional areas of less than 0.4 mm2 had rethrombosis. None of the 11 patients with lumens greater than 0.4 mm2 had rethrombosis. In the 17 patients with vessels that remained patent the size of the residual lesion at repeat catheterization was compared with its size immediately after reperfusion with streptokinase. Over the intervening 8 to 14 day interval, an average percentage increase in minimal cross-sectional area of 116 +/- 34% was observed. In seven patients minimal luminal cross-sectional area more than doubled. Integrated optical density, an index of the severity of coronary stenosis derived from computer-based videodensitometry, was also useful in identifying a subgroup of patients at high risk for rethrombosis of lesion.(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.

Methods of measurement of myocardial blood flow in patients: a critical review.

During the past decade, major progress has been made in the evolution of technology directed toward the accurate measurement of regional myocardial perfusion in patients. The deficiencies of some of the older methods (thermodilution and gas clearance) are better appreciated and improved approaches (Doppler catheters, positron-emission tomography, and digital subtraction angiography) have been developed. The new approaches should play a major role in research and for most applications the older methods will gradually be replaced. Efforts to bring these new methods to community hospitals and practicing cardiologists should be stimulated. Doppler catheters, positron-emission tomography, and digital-subtraction angiography are commercially available and Doppler catheters and digital-subtraction angiography could be easily incorporated into routine cardiac catheterization procedures. The Doppler catheter is the most inexpensive and probably the simplest to apply. In our opinion, routine measurements of coronary flow reserve will significantly improve the care of patients with coronary obstructive disease and other diseases that impair myocardial perfusion. If coronary reserve measurements are used frequently, patient selection for coronary angioplasty and bypass surgery will no longer depend entirely on visual assessment of percent diameter stenosis, a very poor criterion in many situations. Also, patients with chest pain syndromes, normal coronary vessels, and impaired coronary reserve will be identified and perhaps some effective treatment for this condition will be devised.(ABSTRACT TRUNCATED AT 250 WORDS)