The mechanism of angina pectoris in aortic stenosis is unclear. In their report in this issue of Circulation, Julius et al1 describe several hemodynamic factors in patients with angina pectoris that differ from those in persons without angina in the presence of aortic stenosis. Those patients with aortic stenosis and angina pectoris had lower left ventricular (LV) mass, increased LV peak systolic pressure, increased systolic-diastolic wall stress, smaller left coronary artery diameter, and lower coronary flow reserve compared with persons without angina. The authors conclude that myocardial ischemia and angina pectoris in aortic stenosis are due to inadequate LV hypertrophy, with high systolic and diastolic wall stresses causing reduced coronary flow reserve.
Although these factors do differ between the groups of patients with and without angina pectoris in aortic stenosis, there is such great overlap between the groups that these hemodynamic measurements do not correlate specifically with angina pectoris in individuals. Furthermore, it is difficult to explain ischemia on the basis of limited coronary flow reserve when, in fact, there is remaining coronary flow reserve, as indicated by average flow reserves of 1.5 and 1.9 in those with and without angina, ie, 50% to 90% increases in blood flow after dipyridamole administration. Given the wide range of variability and overlap between the groups, it is difficult to ascribe myocardial ischemia to differences in coronary flow reserve when flow reserve was so markedly reduced in both groups. Coronary flow reserve is so comparably reduced in both groups with so much overlap that explaining angina pectoris on the basis of reduced flow reserve is unconvincing.
Although the authors have contributed valuable information to this question, their conclusions remain moot. There is a missing link that the authors do not address which is a more specific mechanism for myocardial ischemia and angina pectoris in aortic stenosis that still incorporates their observations.
Pathophysiology of Coronary Perfusion
Systolic contraction stops coronary artery flow or even reverses it momentarily. Coronary artery flow remains low throughout systole. In early diastole, coronary flow increases rapidly to an early diastolic peak and slowly falls during diastole in proportion to slowly falling diastolic aortic pressure. At normal heart rates, in the absence of hypertrophy or arterial stenoses, diastolic flow provides enough blood flow to compensate for the low flow during systolic compression. Any impairment of the rapid increase in early diastolic flow may limit the total average increase in diastolic coronary flow during increased oxygen demands. Blunting of the rapid increase in early diastolic perfusion through the myocardial wall may particularly affect the subendocardium.2 Pathology that limits the rapid diastolic rise in coronary flow includes LV hypertrophy,3 4 5 6 impaired LV relaxation,7 and coronary artery stenoses.8 9
Experimentally, at a fixed heart rate of 60 bpm, decreased coronary perfusion pressure reduces perfusion uniformly in subendocardium and subepicardium.2 10 No selective underperfusion of subendocardium is observed as perfusion pressure falls until a distal coronary perfusion pressure of 25 mm Hg is reached. At pressures above this level, pharmacological vasodilator reserve remains uniform transmurally in both subepicardium and subendocardium. At pressures <25 mm Hg, pharmacological vasodilation does not increase subendocardial flow further while epicardial flow rises, indicating remaining epicardial flow reserve. Therefore, in the absence of tachycardia, endocardial vasodilator reserve persists and subendocardial perfusion remains normal down to a pressure of 25 to 35 mm Hg. At lower pressures, subendocardial vasodilator reserve is exhausted before epicardial vasodilator reserve.10
Normal reactive hyperemia after temporary coronary occlusion occurs first in the subepicardium, with a delay in reactive hyperemia of the subendocardium.11 12 Therefore, after systolic compression empties the vascular bed, the surge of diastolic flow reaches the subepicardium first, with a delay in early diastolic flow reaching the subendocardium. Therefore, tachycardia and associated shortened diastolic flow time impair subendocardial flow for a given lowered distal coronary perfusion pressure that alone, without tachycardia, would not cause subendocardial ischemia.
The degree of delay in the early diastolic flow surge after systolic compression depends on coronary perfusion pressure. At normal perfusion pressure, this delay is not significant enough to impair subendocardial flow even with a short diastolic duration of tachycardia. With low perfusion pressure, however, the time required to perfuse the subendocardium after systolic compression is longer than the diastole filling time during tachycardia, thereby causing subendocardial ischemia.
This delayed subendocardial diastolic perfusion after systolic compression explains the susceptibility of subendocardium to ischemia. Neither tachycardia alone nor lowered coronary perfusion pressure distal to a stenosis alone (down to 25 mm Hg) will reduce subendocardial flow.10 However, tachycardia and lowered perfusion pressure distal to a flow-limiting stenosis impair the rapid diastolic rise and diastolic perfusion to subendocardium. Because the subepicardium is not subject to the same compressive systolic forces or to a delay in diastolic perfusion, its perfusion is not as tenuous as for the subendocardium.
Coronary artery stenosis is the commonest limitation to rapid diastolic subendocardial perfusion after systole because the stenosis prevents or damps out the rapid diastolic flow increase usually present.8 9 During tachycardia of atrial pacing or exercise in patients with coronary artery disease, diastolic perfusion time at onset of stress-induced myocardial ischemia is tightly and inversely related to stenosis severity by arteriography, as described by Ferro et al.13 This relation between diastolic perfusion time at the onset of stress-induced ischemia is so tightly related to stenosis severity that it can be used to predict severity of stenosis in patients with known single-vessel coronary artery disease. In contrast to diastolic perfusion time, the heart rate, R-R interval, or pressure-rate product at the onset of stress-induced ischemia is poorly related to stenosis severity, indicating the specific importance of diastolic perfusion time regardless of the type of stress.
Factors other than coronary artery stenoses that delay subendocardial diastolic perfusion after systolic compression contribute to subendocardial ischemia during tachycardia. In addition to coronary artery stenosis, LV hypertrophy, delayed LV diastolic relaxation, elevated LV end-diastolic pressure, and elevated diastolic wall stress may all cause delayed subendocardial diastolic perfusion after systolic compression. These factors, combined with tachycardia, then cause subendocardial ischemia.
Thus, at normal resting heart rates, diastolic perfusion time is long enough that impairment of the early rapid diastolic rise in flow may not reduce average coronary flow. Normally, as tachycardia shortens diastolic perfusion time, the rapid rise in diastolic perfusion increases further, higher flow lasts throughout diastole, and adequate perfusion is maintained despite reduced diastolic perfusion time. However, tachycardia that shortens diastolic perfusion time added to one of those pathologies that impair the rapid rise in diastolic perfusion may prevent adequate increase in coronary flow to meet increased demands. Because the normal compensatory rise in diastolic perfusion with tachycardia cannot occur, perfusion is impaired, causing ischemia.
The most likely mechanism for myocardial ischemia and angina pectoris in aortic stenosis is tachycardia associated with shortened diastolic perfusion time in combination with LV hypertrophy, impaired LV relaxation, and high diastolic wall stresses that delay the rapid rise of diastolic perfusion to the endocardium after systolic compression. This mechanism explains exertional ischemia in aortic stenosis with normal coronary arteries and abnormal exercise perfusion tests reported14 in the absence of coronary artery disease. No single hemodynamic parameter for an individual patient predicts angina pectoris. The hemodynamic factors identified by Julius et al1 are associated with an increased probability of angina pectoris but are not specific to explain myocardial ischemia in individual patients because of such great overlap between the groups. However, if tachycardia is added to the combination of these other hemodynamic abnormalities, the mechanism of angina pectoris may be more precisely defined in individuals and groups of patients with aortic stenosis. Although this article contributes useful information to our understanding of angina pectoris in aortic stenosis, more work needs to be done on the interaction of the hemodynamic abnormalities identified as important and diastolic perfusion time.
How would the study be done? Patients with aortic stenosis could be safely paced to angina. The diastolic perfusion time could be measured as described by Ferro et al13 in relation to severity of coronary artery stenosis. However, in aortic stenosis without coronary artery disease, the diastolic perfusion time at the threshold pacing-induced angina would then be correlated with LV systolic and diastolic wall stresses, peak systolic pressure, LV mass, wall thickness, and coronary flow reserve. The one (or more) of these measurements that related best with diastolic perfusion time at threshold of pacing-induced angina would identify the most important mechanism of angina pectoris in individuals and groups of patients with aortic stenosis and normal coronary arteriograms. Because of the inhomogeneous distribution of wall stress throughout the left ventricle, a perfusion radionuclide could be injected at the threshold of pacing angina to image the regional perfusion abnormalities causing angina despite normal coronary arteriograms. Perhaps then the mechanism of angina pectoris in aortic stenosis with normal coronary arteries would have been definitively defined.
Reprint requests to K. Lance Gould, MD, University of Texas Medical School, Division of Cardiology, 6431 Fannin St, Room 4.258 MSB, Houston, TX 77030.
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
- Copyright © 1997 by American Heart Association
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