Flow-limiting Coronary Artery Stenosis Research Articles

Incidence of flow-limiting coronary artery stenoses in patients with diabetes - a coronary angiography natural history study

Abstract Background Diabetes is an established risk factor for the development of coronary atherosclerosis. We sought to assess the association between diabetes and the incidence of coronary artery atherosclerosis progression on coronary angiography. Methods Using the Swedish Coronary Angiography and Angioplasty Registry (SCAAR), we included all coronary artery segments with mild to no atherosclerosis defined as <50% luminal obstruction in patients undergoing a first-time coronary angiography in Sweden between 1989 and 2017. Patients with two or more vessel disease were excluded as were patients with a previous history of coronary artery disease. In patients with one vessel disease, the diseased vessel including all its branches were excluded. Patients were followed for 15 years until a clinically indicated re-angiography was done, death occurred or end of follow-up (April 2018). The primary outcome was plaque progression to flow-limiting coronary artery stenosis defined as ≥50% luminal obstruction on repeat angiography assessed using epidemiological tables, Kaplan Meier event rates, and Cox proportional hazard models. The importance of selected risk factors (smoking, hypertension, hyperlipidemia, and established coronary artery disease) was assessed. Results A total of 2 661 245 coronary segments in 248 736 patients were included in the study. Diabetes was present in 30 533 patients and 320 815 coronary artery segments. Kaplan-Meier event rates and incidence rates (IR) per 1000 segment-years were higher in patients with diabetes (5.5%, IR 2.78 [95% CI 2.70–2.85] vs. 3.0%, 1.44 [1.42–1.46]) resulting in an almost two-folded hazard ratio (HR) of plaque progression (HR 1.93 [95% CI 1.87– 2.00]). The anatomical distribution of plaque progression was similar between the two cohorts on all levels of analysis (coronary artery level, main artery and branches level, and coronary segment level artery). Diabetic patients with established coronary artery disease had a significantly higher risk of future events compared to those without clinically significant coronary artery disease. Conclusions Diabetes was associated with an almost twofold higher incidence rate of plaque progression but did not appear to alter the anatomical location of plaque development compared to the absence of diabetes. Once coronary artery disease is established, the rate of atherosclerotic events accelerates. Therefore, adopting aggressive primary prevention strategies is crucial to reduce the risk of adverse outcomes in diabetic patients.Event rates and anatomical distributionProgression of stenoses by risk factor

Exercise and pharmacologic stress-induced interlead T-wave heterogeneity analysis to detect clinically significant coronary artery stenosis

BackgroundDespite widespread use of ETT and vasodilator-stress with myocardial perfusion imaging (MPI) for noninvasive detection of flow-limiting coronary artery disease, there is continued need to improve diagnostic accuracy. We examined whether measurement of interlead T-wave heterogeneity (TWH) during exercise tolerance testing (ETT) or pharmacologic stress testing improves detection of stenoses in large epicardial coronary arteries. MethodsAll 137 patients at our institution who underwent diagnostic coronary angiography within 0 to 5 days after ETT (N = 81) or dipyridamole IV infusion (N = 58) in 2016 were studied, including 2 patients with both tests. Cases (N = 93) had angiographically significant stenosis (≥50% of left main or ≥ 70% of an epicardial coronary artery ≥2 mm in diameter); controls (N = 44) did not. TWH, i.e., interlead splay of T waves, was determined by second central moment analysis from precordial leads by an investigator blinded to angiographic results. ResultsAt rest, TWH levels were similar for cases and controls. ETT and dipyridamole stress testing increased TWH by 69% (p < 0.0001) and 27% (p < 0.0001), respectively, in cases. In controls, TWH did not change. Areas under the ROC curves for TWH increase for any flow-limiting coronary artery stenosis were 0.737 (p < 0.0001) for ETT and 0.818 (p < 0.0001) for dipyridamole stress testing. By contrast, neither ST-segment changes during ETT (p = 0.12) nor MPI during dipyridamole stress testing (p = 0.60) discriminated cases from controls. ConclusionsTWH measurement is a novel method that improves detection of angiographically confirmed flow-limiting stenoses in large epicardial coronary arteries during both ETT and MPI during pharmacologic stress testing with dipyridamole.

STRESS-INDUCED T-WAVE HETEROGENEITY WITH REGADENOSON DETECTS CLINICALLY SIGNIFICANT CORONARY ARTERY STENOSIS

Stress testing for symptoms or ST-segment changes with or without imaging is the main noninvasive technique for detection of flow-limiting coronary artery stenosis despite limited accuracy. Interlead T-wave heterogeneity (TWH) may offer a more precise approach. All 44 patients at our institution

The Cornucopia of “Pleiotropic” Actions of Statins

See related article, pages 255–264 Initially described in patients with coronary artery disease undergoing coronary artery bypass graft (CABG) surgery, myocardial “hibernation” denotes a state of adaptive reduction in myocardial contractile function in response to limited energy supply caused by reduced blood flow.1,2 In this precarious equilibrium, the myocardium can remain viable for sustained periods of time (although not indefinitely) and slowly resumes contractile activity on restoration of perfusion.2,3 Hibernating myocardium resulting from a flow-limiting coronary artery stenosis is a common clinical entity that contributes to myocardial dysfunction in many patients with ischemic heart disease1,2; its clinical importance stems from the fact that is it is potentially reversible. The pathophysiological basis of this syndrome was proposed as a conceptual framework in 19924 and subsequently tested in various animal models5–8: it is likely to involve recurrent brief episodes of ischemia, which initially result in repetitive “stunning” with normal resting flow and eventually cause a persistent decrease in resting function and flow.2,4–6,8 Over time, these changes lead to myocyte loss resulting from degenerative changes and apoptosis.2,8 Because mechanical dysfunction is caused by a restriction in blood flow, revascularization has traditionally been the cornerstone of therapy for myocardial hibernation. Indeed, restoration of blood flow via CABG or percutaneous coronary interventions often improves the mechanical performance of hibernating myocardium.1–3,8,9 In those cases in which these procedures are not feasible, however, there is a need for alternative approaches. Direct transmyocardial laser revascularization10 and intramyocardial gene transfer of phVEGF16511 or fibroblast growth factor-57 have been reported to enhance perfusion and contractile reserve and improve regional function in experimental models of hibernation. Transplantation of circulating progenitor cells following revascularization has also been reported to attenuate hibernation (ie, to increase coronary flow reserve …

Does coronary vasodilation after adenosine override endothelin-1-induced coronary vasoconstriction?

Endothelin-1 is a powerful coronary vasoconstrictor that is overexpressed in coronary artery disease. Adenosine is a powerful coronary vasodilator used for myocardial perfusion imaging to identify flow-limiting coronary artery stenosis. Therefore, in an animal model we tested the hypothesis that intracoronary endothelin-1 may cause myocardial perfusion abnormalities by positron emission tomography (PET) at resting conditions that may persist or only partially improve after intravenous adenosine stress in the absence of myocardial scar and flow-limiting stenosis. Fourteen dogs underwent serial PET perfusion imaging with rubidium-82 before and after subselective intracoronary infusion of endothelin-1, followed by intravenous and then intracoronary adenosine. Small physiological doses of endothelin-1 infused into the mid-left circumflex coronary artery caused quantitatively significant resting perfusion abnormalities that normalized after intracoronary adenosine but not consistently after intravenous adenosine used for diagnostic imaging. After effects of adenosine abated, resting perfusion defects returned, lasting up to 5 h in some animals. Cumulative doses of endothelin-1 caused perfusion defects that did not normalize after intravenous adenosine. In an animal model without myocardial scar or flow-limiting stenosis, intracoronary endothelin-1 causes visually apparent, quantitatively significant, long-lasting myocardial perfusion defects at resting conditions that may persist or only partially improve after intravenous adenosine used for diagnostic imaging. These results may potentially explain resting perfusion abnormalities or heterogeneity by clinical PET that may persist or only partially improve after adenosine stress perfusion imaging in the absence of myocardial scar and flow-limiting stenosis.

Clinical validation of intravascular ultrasound imaging for assessment of coronary stenosis severity: Comparison with stress myocardial perfusion imaging

OBJECTIVESTo validate intravascular ultrasound (IVUS) measurements for differentiating functionally significant from nonsignificant coronary stenosis.BACKGROUNDTo date, there are no validated criteria for the definition of a flow-limiting coronary artery stenosis by IVUS.METHODSPreinterventional IVUS imaging (30-MHz imaging catheter) of 70 de novo coronary lesions was performed. The lesion lumen area and three IVUS-derived stenosis indixes comparing lesion lumen area with the lesion external elastic lamina (EEL) area, the mean reference lumen area and the mean reference EEL area were compared with the results of stress myocardial perfusion imaging.RESULTSThe lesion lumen area and three IVUS-derived stenosis indexes showed sensitivities and specificities ranging between 80% and 90% using stress myocardial perfusion imaging as the gold standard. The lesion lumen area ≤4 mm2is a simple and highly accurate criterion for significant coronary narrowing.CONCLUSIONSQuantitative IVUS indices can be reliably used for identifying significant epicardial coronary artery stenoses.

Endogenous nitric oxide masks alpha 2-adrenergic coronary vasoconstriction during exercise in the ischemic heart.

Previously, we observed that alpha 1-but not alpha 2-adrenergic vasoconstriction restricted blood flow distal to a coronary artery stenosis that resulted in myocardial hypoperfusion during exercise. This study was performed to test the hypothesis that vascular smooth muscle alpha 2-adrenergic vasoconstriction during exercise does exert a flow-limiting effect distal to a coronary artery stenosis but that this action is counterbalanced by simultaneous endothelial alpha 2-adrenergic stimulation of NO production. Eight dogs instrumented with a Doppler velocity probe, hydraulic occluder, and indwelling microcatheter in the left anterior descending coronary artery (LAD) were studied during treadmill exercise in the presence of a coronary artery stenosis before and during infusion of the alpha 2-adrenergic receptor antagonist idazoxan (1.0 microgram.kg-1.min-1 IC) before and after NO synthase blockade with NG-monomethyl-L-arginine (LNNA, 1.5 mg/kg IC). Coronary pressure distal to the stenosis was maintained constant during the control period and after administration of idazoxan before and after LNNA. Neither idazoxan nor LNNA altered any of the systemic hemodynamic variables either at rest or during exercise. During exercise in the absence of a stenosis, idazoxan and LNNA had no effect on coronary blood flow. In the presence of a stenosis that decreased distal coronary pressure to 52 +/- 3 mm Hg, mean myocardial blood flow measured with microspheres was 0.87 +/- 0.17 mL.min-1.g-1 in the LAD-dependent region and 2.52 +/- 0.30 mL.min-1.g-1 in the posterior control region, respectively. With no change in distal coronary pressure, idazoxan had no effect on mean myocardial blood flow in the LAD region (0.86 +/- 0.17 mL.min-1.g-1), but LNNA decreased mean myocardial blood flow to 0.49 +/- 0.09 (P < .01). However, when idazoxan was infused during exercise in the presence of a coronary artery stenosis after LNNA administration, idazoxan increased mean myocardial blood flow to 0.62 +/- 0.13 mL.min-1.g-1 (P < .01). These data demonstrate that alpha 2-adrenergic stimulation of endothelial NO production, which occurs during exercise in the presence of a flow-limiting coronary artery stenosis, acts to counterbalance vascular smooth muscle alpha 2-adrenergic vasoconstriction.

Inhibition of nitric oxide production aggravates myocardial hypoperfusion during exercise in the presence of a coronary artery stenosis.

Regulation of coronary vasomotor tone during myocardial hypoperfusion is incompletely understood. The present study was performed to test the hypothesis that endogenous production of nitric oxide contributes to resistance vessel dilation distal to a coronary artery stenosis that results in myocardial ischemia during exercise. Seven dogs instrumented with a Doppler velocity probe, hydraulic occluder, and indwelling microcatheter in the left anterior descending coronary artery (LAD) were studied during treadmill exercise in the presence of a coronary artery stenosis before and after intracoronary infusion of NG-nitro-L-arginine (LNNA, 20 mg/kg). This dose of LNNA inhibited the maximal increase in LAD flow produced by intracoronary acetylcholine by 82 +/- 5% but did not alter the response to intracoronary nitroprusside. Coronary pressure distal to the stenosis was maintained constant during the control period and after administration of LNNA. LNNA increased aortic and left ventricular systolic and end-diastolic pressures at rest and during exercise. During control in the absence of a stenosis, LNNA had no effect on coronary blood flow. In the presence of a stenosis that decreased distal coronary pressure to 55 +/- 2 mm Hg, mean myocardial blood flow measured with microspheres was 1.09 +/- 0.13 mL.min-1.g-1 in the LAD-dependent and 2.57 +/- 0.50 mL.min-1.g-1 in the posterior control region, respectively. With no change in distal coronary pressure, LNNA decreased mean myocardial blood flow in the LAD region to 0.68 +/- 0.11 mL.min-1.g-1 (P < .01). To avoid systemic hemodynamic effects, LNNA was administered in a dose of 1.5 mg/kg IC to four additional dogs. This low dose inhibited the coronary blood flow increases produced by acetylcholine by 61 +/- 5% but was devoid of systemic hemodynamic effects. During exercise in the presence of a coronary stenosis that decreased coronary pressure to 52 +/- 1 mm Hg, this dose of LNNA decreased mean myocardial blood flow from 0.89 +/- 0.23 to 0.66 +/- 0.21 mL.min-1.g-1 (P < .02). These data demonstrate that nitric oxide contributes to the maintenance of myocardial perfusion distal to a flow-limiting coronary artery stenosis during exercise.

Effect of superoxide dismutase and catalase on regional dysfunction after exercise-induced ischemia.

This study was designed to test the hypothesis that the oxygen free radical scavengers superoxide dismutase (SOD) and catalase may reduce myocardial "stunning" after exercise-induced ischemia. To test this hypothesis, 8 mongrel dogs performed treadmill exercise for 10 min in the presence of a flow-limiting coronary artery stenosis. Regional left ventricular function was measured with ultrasonic microcrystals implanted to measure regional wall thickening. Regional myocardial perfusion was measured with radioactive microspheres. The combination of SOD (5 mg/kg iv) and catalase (5 mg/kg iv) did not affect heart rate, blood pressure, coronary artery flow, or regional myocardial blood flow at rest, during exercise, or in the postexercise period. SOD and catalase had no effect on regional wall thickening at rest before exercise. During exercise in the absence of a coronary artery stenosis, thickening was slightly lower during SOD and catalase infusion (27 +/- 11.0 vs. 30.8 +/- 11.5%, SOD vs. control P = 0.05). During exercise in the presence of a coronary artery stenosis, there was no difference in thickening. Infusion of SOD and catalase affected neither the transient rebound function occurring early after exercise nor the prolonged period of stunning. These results indicate that the myocardial stunning that follows exercise-induced ischemia is unlikely to be mediated by oxygen free radicals.

Postischemic recovery in the stunned myocardium after reperfusion in the presence or absence of a flow-limiting coronary artery stenosis

Hyperemic flow occurs after release of a transient coronary artery occlusion in excess of the acquired oxygen debt if the vessel has sufficient vasodilator reserve. The purpose of this study was to determine whether differences exist in the degree of postischemic functional and metabolic recovery in the stunned myocardium when a reactive hyperemia is allowed to occur as opposed to reperfusion in the presence of a flow-limiting coronary artery stenosis. Anesthetized dogs were subjected to 15-minute episodes of coronary artery occlusion, followed by either 10 minutes (short reperfusion) or 3 hours (long reperfusion) of reperfusion to investigate early and late differences in tissue blood flow. At reperfusion a micrometer-driven occluder was either released fully within 1 minute (full-reactive [FR] group) or the occluder was slowly released to return coronary blood flow to preocclusion levels (no-reactive [NR] group). Areas at risk, myocardial blood flow (radioactive microspheres), hemodynamics, myocardial segment shortening (sonomicrometry) during occlusion, and high-energy phosphate levels (tissue biopsies) at 3 hours of reperfusion were similar in both groups. Recovery of function in the short-reperfusion group was significantly greater in the FR than the NR group until 3 minutes of reperfusion, which corresponded to the peak reactive hyperemic response. After this time there were no differences between the two groups in functional recovery until 2 and 3 hours after reperfusion when the percentage of segment shortening had deterlorated to a significantly greater extent ( p < 0.05) in the NR group than in the FR group. The reason for this finding may involve prolonged subendocardial ischemia if reperfusion is introduced into a flow-limiting stenosis, as suggested by the greater tissue blood flows in the ischemic reperfused region during early reperfusion in the FR versus NR group. These data suggest that coronary artery patency, in part, determines functional recovery in the stunned myocardium.

Transmural differences in sympathetic coronary constriction during exercise in the presence of coronary stenosis.

The goal of this study was to determine the effect of sympathetic neural activation on the transmural distribution of myocardial perfusion distal to a flow-limiting coronary artery stenosis. Treadmill exercise in conscious dogs was used as a physiological stimulus to activate the sympathetic nervous system. In the experimental model, the anterior region of the circumflex artery was innervated, but the posterior circumflex region was treated with phenol to produce regional sympathectomy within the stenotic territory. Myocardial perfusion to innervated and sympathectomized left ventricular regions was measured before and after inflation of the occluder to reduce distal coronary pressure to 45 mm Hg. Measurements were obtained during control conditions with the animal standing on the treadmill, during inflation of the occluder with the animal standing, during exercise alone, during exercise with beta-adrenergic blockade, and during exercise with combined alpha- and beta-adrenergic blockade. Exercise (6 km/hr) resulted in a marked increase in heart rate from 128 +/- 9 (standing) to 218 +/- 7 beats/min. beta-Adrenergic blockade blunted the tachycardia during exercise (146 +/- 6 beats/min). Under control conditions (while standing), there were no differences in myocardial perfusion between the innervated and sympathectomized regions, 187 +/- 26 and 181 +/- 24 ml.min-1.100 g-1, respectively. During exercise or in combination with beta-adrenergic blockade, subepicardial perfusion was significantly less (18-25%) in the innervated stenotic region than that in the sympathectomized stenotic region. In contrast, subendocardial perfusion was significantly greater in the innervated stenotic region (17-26%) than that in the sympathectomized stenotic region. The subendocardial-to-subepicardial blood flow ratio during exercise was 0.60 +/- 0.08 in the innervated stenotic region and 0.42 +/- 0.07 in the sympathectomized stenotic region (p less than 0.05). During exercise with beta-adrenergic blockade, the endocardial-to-epicardial blood flow ratios in the innervated and sympathectomized stenotic regions were 0.47 +/- 0.09 and 0.37 +/- 0.07, respectively (p less than 0.05). These differences were abolished during alpha- and beta-adrenergic blockade. These data indicate that alpha-adrenergic coronary constriction distal to a flow-limiting stenosis facilitates redistribution of blood flow toward the subendocardium. This redistribution was produced by alpha-adrenergic constriction in the outer layers of the left ventricle.

Effect of diltiazem on coronary reactive hyperemia in patients with flow-limiting coronary artery stenosis

The acute effects of diltiazem on coronary reactive hyperemia were studied in 12 patients with flow-limiting coronary stenosis. Reactive hyperemia was elicited by injection of 8 ml contrast medium into the left coronary artery, while coronary sinus blood flow and left ventricular and aortic pressures were continuously recorded. Relative magnitude of hyperemia was estimated by the ratio of coronary flow at peak hyperemia to baseline flow (hyperemic ratio). Coronary resistance was calculated as the ratio between mean aortic pressure minus left ventricular mean diastolic pressure and coronary sinus blood flow. The 12 patients studied had flow-limiting coronary stenosis since their hyperemic ratio was significantly restrained when compared to that of seven control subjects (1.45 ± 0.17 vs 2.02 ± 0.24, respectively; < 0.001). The intravenous infusion of ditiazem (0.30 mg · kg −1) reduced heart rate, mean aortic pressure, and myocardial oxygen consumption (all p < 0.001). After diltiazem the hyperemic ratio was blunted when compared to the basal state (1.36 ± 0.15 vs 1.45 ± 0.17, respectively; p < 0.05), and hyperemia volume was reduced (−33%; p < 0.001). The decrease in coronary resistance at peak hyperemia was also reduced from −30 ± 8% to −25 ± 8% ( p < 0.05). We conclude that diltiazem blunts coronary reactive hyperemia in patients with demonstrated flow-limiting coronary stenosis. This reduction of coronary flow response to a hyperemic stimulus could favorably influence blood flow distribution in patients with significant coronary stenosis.

Enhanced Subendocardial Perfusion Distal to a Flow-Limiting Coronary Artery Stenosis in Dogs: Comparative Effects of Nicorandil, a Potential New Antianginal Agent, and Nitroglycerin

The purpose of this study was to compare the effects of nicorandil [SG-75; 2-nicotinamidoethyl nitrate (ester)] and nitroglycerin on the distribution of blood flow between subendocardium and subepicardium [endocardial/epicardial blood flow ration (endo/epi)] distal to a proximal flow-limiting coronary artery stenosis in anesthetized dogs. Myocardial blood flow distribution was determined by use of 15-micron radioactive microspheres. Various indices of reactive hyperemia (peak flow, duration, volume) and poststenotic coronary pressures were used to assess the severity of ischemia in the area distal to the stenosis. Partial ischemia was produced by a 10-s total left circumflex coronary occlusion followed by 110 s of reflow to 50-60% of the control flow. Microspheres were injected during steady-state conditions during the partial reflow period. In the absence of drug, coronary artery stenosis produced marked underperfusion of the subendocardium (endo/epi, 0.55 +/- 0.05). Following administration of nicorandil (60 micrograms/kg i.v.) or nitroglycerin (15 micrograms/kg i.v.), the endo-epi during a subsequent partial reflow (stenosis present) period was significantly increased (0.67 +/- 0.06). The duration of reactive hyperemia and reactive hyperemic flow were also decreased by both compounds following release of the stenosis. These results suggest that nicorandil and nitroglycerin reduce subendocardial ischemia distal to a flow-limiting coronary artery stenosis. This beneficial effect may partially explain the efficacy of these two compounds in the therapy of angina pectoris.

Effect of perfusion pressure distal to a coronary stenosis on transmural myocardial blood flow.

We tested the hypothesis that reductions of perfusion pressure distal to a flow-limiting coronary artery stenosis can directly impair perfusion of the subendocardial myocardium. Dogs were instrumented with an electromagnetic flowmeter probe and a variable occluder on the proximal left circumflex coronary artery. Coronary perfusion pressure was measured with a catheter distal to the occluder. Coronary autoregulation was abolished by intraarterial infusion of adenosine to produce maximal coronary vasodilation. The transmural distribution of myocardial blood flow was measured with radioactive microspheres during unimpeded arterial inflow, when the occluder was progressively narrowed to reduce distal coronary pressure to approximately 70%, 50% and 35% of the control coronary perfusion pressure, and during total coronary occlusion. Heart rate, left ventricular diastolic pressure and the fraction of coronary artery flow during systole remained constant throughout the study. Progressive reductions of coronary perfusion pressure were accompanied by direct reductions of the subendocardial/subepicardial blood flow ratio (r = 0.83). Examination of the relationship between myocardial blood flow and coronary perfusion pressure showed that blood flow decreased linearly with perfusion pressure, with flow ceasing at a positive pressure (zero-flow pressure). Blood flow data from four transmural myocardial layers from epicardium to endocardium showed that this zero-flow pressure increased progressively from 10 +/- 2.1 mm Hg in the subepicardium to 18 +/- 2.3 mm Hg in the subendocardium (p less than -.01). Consequently, as coronary pressure was reduced, the zero-flow pressure represented a progressively greater fraction of coronary pressure in the subendocardium than in the subepicardium. This effect appeared to account for the progressive redistribution of blood flow away from the subendocardium that occurred as coronary pressure was decreased. Myocardial vascular resistance did not change as a result of changes in coronary perfusion pressure.

Myocardial blood flow distribution during ischemia-induced coronary vasodilation in the unanesthetized dog.

This study was designed to determine whether coronary vasodilation distal to a flow-limiting coronary artery stenosis could result in redistribution of myocardial blood flow to produce subendocardial underperfusion. Studies were performed in 10 awake dogs chronically prepared with electromagnetic flow-meters and hydraulic occluders on the left circumflex coronary artery. Regional myocardial blood flow was measured using radionuclide-labeled microspheres, 7-10 mum in diameter, injected into the left atrium. A 5(-s) coronary artery occlusion was followed by reactive hyperemia with excess inflow of arterial blood effecting 375+/-20% repayment of the blood flow debt incurred during occlusion. When, after a 5(-s) occlusion, the occluder was only partially released to hold arterial inflow to the preocclusion level for 20 s before complete release, the delayed reactive hyperemia was augmented (mean blood flow repayment = 610+/-45%, P < 0.01). This augmentation of the reactive hyperemia suggested that ischemia was continuing during the interval of coronary vasodilation when coronary inflow was at the preocclusion level. Measurements of regional myocardial blood flow demonstrated that endocardial flow slightly exceeded epicardial flow during control conditions. When arterial inflow was limited to the preocclusion rate during vasodilation after a 5(-s) total coronary artery occlusion, however, flow to the subepicardial myocardium was increased at the expense of underperfusion of the subendocardial myocardium. Thus, in the presence of a flow-limiting proximal coronary artery stenosis, ischemia-induced coronary vasodilation resulted in redistribution of myocardial blood flow with production of subendocardial ischemia in the presence of a net volume of arterial inflow which, if properly distributed, would have been adequate to prevent myocardial ischemia.