Coronary Vasoconstriction During Myocardial Ischemia Induced by Rises in Metabolic Demand in Patients With Coronary Artery Disease
Background In patients with coronary artery disease, a maximal vasodilation of the coronary microcirculation is generally assumed to occur during myocardial ischemia induced by rises in metabolic demand. However, vasoconstriction has been documented during severe prolonged ischemia in animals. The aim of this study was to investigate coronary vasomotor tone during pacing-induced ischemia in humans.
Methods and Results The study included 11 patients with exercise-induced ischemia and single-vessel disease of the left anterior descending artery and 7 control subjects with normal coronary arteries. Blood flow velocity was monitored with a Doppler catheter in the left anterior descending artery. Coronary resistance index was calculated as the ratio between mean arterial pressure and flow velocity. Measurements were obtained at baseline, after intracoronary adenosine (2 mg), and during maximal atrial pacing in the absence and presence of adenosine. After adenosine administration at rest, coronary resistance decreased more in control subjects than in patients (25±7% of baseline versus 61±19%; P<.01). Coronary resistance decreased in all control subjects (P<.01) both at maximal pacing (60±17% of baseline) and after administration of adenosine during tachycardia (31±13% of baseline). By contrast, all 10 ischemic patients displayed increased coronary resistance at maximal heart rate (221±131% of baseline; P<.01 versus baseline, P<.01 versus control subjects). At this stage, adenosine decreased coronary resistance to 44±20% of values observed before injection. Additionally, it reduced ST-segment depression in 5 of 8 patients.
Conclusions In patients with coronary artery disease, transient myocardial ischemia induced by increased metabolic demand is not associated with maximal vasodilation. Rather, an inappropriate severe microvascular vasoconstriction is present that can be abolished by intracoronary adenosine.
In patients with chronic coronary artery disease, myocardial ischemia occurs when increases in myocardial oxygen demand are not met by adequate increases in coronary blood flow. This phenomenon is generally attributed to the additional resistance of the epicardial stenosis that does not allow an adequate increase in flow.1 According to this concept, maximal vasodilation of coronary resistance vessels is usually thought to be present in the ischemic vascular bed.2
However, this assumption has been challenged by a number of experimental and clinical studies. In animal models of severe stenosis and myocardial hypoperfusion3 4 or dysfunction,5 it has been demonstrated that the vasomotor tone is not exhausted and a vasodilator reserve can still be documented by several pharmacological agents. In experimental models of prolonged severe flow reduction and ischemia, an active vasoconstriction6 7 and a persistent responsiveness7 of the coronary microvasculature to adenosine have also been documented. This paradox has been interpreted either as a primary microvascular response to reduced pressure,8 an active downregulation of myocardial metabolism,9 or the consequence of an adrenergic activation particularly evident in anesthetized animals.10 Whatever the mechanism, a persistent vasodilator reserve has also been demonstrated in myocardial regions with chronic hypoperfusion distal to a severe stenosis11 in patients with coronary artery disease.
Despite these observations, the behavior of coronary vasomotor tone during acute demand/supply mismatch has not been directly explored in humans to the best of our knowledge. Several authors12 13 14 have reported an absolute flow reduction during ischemia caused by pacing tachycardia in patients with severe coronary stenosis. However, these studies do not provide any insight into the mechanisms underlying this phenomenon. In fact, the flow reduction might reflect either an active vasoconstriction or, alternatively, an increase in the extravascular components of coronary resistance. The reduction in diastolic time could mask the effect of distal vasodilation; conversely, the ischemic contractile impairment could lead to a rise in left ventricular end-diastolic pressure, thus increasing extravascular compressing forces.2 15 16
To characterize the behavior of vasomotor tone during transient ischemia, flow response to maximally vasodilating drugs should be evaluated under this condition. Intracoronary Doppler technology enables the assessment of even rapid changes in blood flow in response to short-acting vasodilators,17 thus rendering such measurements safe and feasible.
The present study was designed to evaluate the vasomotor response of the coronary microvasculature to acute myocardial ischemia induced by increases in heart rate in patients with single-vessel coronary artery disease and stable effort angina.
Eleven candidates for coronary angioplasty (mean age, 56±7 years) were included in the study according to the following criteria: (1) history of angina pectoris; (2) evidence of ischemia either during exercise stress test (ST-segment depression ≥1.5 mm; n=10) or during dipyridamole echocardiography test (according to conventional criteria; n=1); (3) absence of clinical or ECG evidence of previous myocardial infarction; (4) single-vessel disease of the left anterior descending coronary artery; (5) absence of arterial hypertension and/or left ventricular hypertrophy (septal and posterior wall thickness ≤11 mm on two-dimensional echocardiography); and (6) absence of diabetes.
Seven age-matched subjects (mean age, 59±3 years) with atypical chest pain and negative exercise stress tests were studied as a control population. These patients were referred for coronary arteriography to exclude an organic cause of their symptoms and had normal coronary angiograms and left ventriculograms.
In patients, the study protocol was performed before coronary angioplasty, ≤2 weeks after diagnostic angiography; control subjects were studied 30 minutes after diagnostic angiography. The single stenosis in the left anterior descending artery was quantified by an automated edge-detection system (Mipron; Kontron), resulting in an average percent cross-sectional area reduction of 80±5%. Left ventriculography (30° right anterior projection) showed mild to moderate dyssynergy in anterior segments in 7 of 11 patients and normal function in all control subjects. Left ventricular ejection fraction was 0.58±0.06 in patients and 0.57±0.05 in control subjects.
Both patients and control subjects were studied after an overnight fast and while receiving active treatment with oral diltiazem 60 mg TID, isosorbide mononitrate 20 mg TID, and aspirin. An 8F guiding catheter was advanced into the left main coronary artery, a control left coronary arteriography was performed, and the best projection was selected. A 5F unipolar pacing catheter was placed in contact with the high lateral wall of the right atrium. A bolus of isosorbide dinitrate (0.6 mg IC) was injected and heparin (10 000 IU) was injected intravenously. A 2.5F catheter (Millar Instruments, Inc) was placed by means of a 0.014-in guidewire in the prestenotic segment in patients and in the proximal left anterior descending artery in control subjects. Care was taken to place the catheter in the center of the lumen to maintain a stable flow-velocity signal with minimal noise and without artifacts due to major side vessels. Thereafter, the guidewire was pulled back, and the position of the Doppler catheter was checked again under fluoroscopy. The quality of the velocity signal was controlled.
During the study, the following signals were monitored and recorded on photographic paper when required: (1) an ECG lead (in patients, the lead displaying the greatest ischemic modifications during stress test); (2) phasic and mean arterial pressures; and (3) phasic and mean blood flow velocities.
Steady-state conditions of blood flow and systemic hemodynamics were verified for ≥5 minutes before baseline recordings were obtained.
Adenosine (2 mg) was selectively injected into the left anterior descending coronary artery through the Doppler catheter to induce maximal regional vasodilation. A period of 5 minutes was allowed to ensure the restoration of a steady baseline condition. Thereafter, heart rate was increased by atrial pacing starting from 10 bpm above the patient's heart rate, with 20-bpm increments every 30 seconds. The heart rate was increased up to twice the baseline heart rate until angina or ST-segment depression was produced or to a maximum of 150 bpm. No premedication with atropine was used. Wenckebach block was not observed in patients or control subjects. At maximum pacing, the heart rate was kept constant for 30 seconds, and a second bolus of 2 mg of adenosine was selectively injected into the left descending coronary artery. Forty-five seconds later, the heart rate was decreased, and the external pacemaker was switched off within 2 minutes.
Contrast injections were avoided during this phase of the study to prevent interference with blood flow velocity. After the study, all patients underwent successful coronary angioplasty of the left anterior descending coronary artery.
Seven periods of high-velocity recordings (2.5 cm/s) were obtained at the following times: (1) baseline, (2) 30 seconds after intracoronary adenosine, (3) 4 minutes after adenosine, (4) 1 minute after pacing started, (5) 2 minutes after pacing started, (6) at the maximum heart rate, and (7) 30 seconds after intracoronary adenosine at maximal heart rate.
Coronary resistance index was calculated as the ratio of mean coronary arterial pressure to mean blood flow velocity. Flow velocity and resistance index in each condition of the study protocol were expressed as percent of baseline values.
All data are expressed as mean±SD. ANOVA followed by Newman-Keuls procedure for multiple comparisons was used to compare heart rate, arterial pressure, and raw and percent values of both mean flow velocity and coronary resistance index at the various stages of the protocol between patients and control subjects. In addition, ANOVA followed by Newman-Keuls procedure for multiple comparisons and repeated measures was used in each population to identify significant changes in coronary blood flow and coronary resistance index at the various stages of the protocol. Linear regression analysis was performed by the least-squares method. A probability value <.05 was considered significant.
Clinical and Hemodynamic Characteristics
No serious side effects occurred during the study. No control patient displayed clinical or ECG signs of ischemia. During pacing, angina and/or ECG changes were observed in 10 of 11 patients. Six patients had angina, 8 developed ST-segment depression, and 2 displayed ST-segment elevation. One patient showed neither ECG changes nor symptoms during pacing. Therefore, this patient was considered not ischemic during the study and was excluded from further data analysis. There were no significant changes in systolic, diastolic, and mean arterial pressures in patients or control subjects (Fig 1⇓).
Atrial pacing significantly (P<.01) increased heart rate from 68±11 to 130±9 bpm in control subjects and from 75±10 to 128±14 bpm in patients. At each step of the protocol, heart rate and blood pressure were similar in patients and control subjects (Fig 1⇑). In patients, rate-pressure products during maximal pacing were slightly but not significantly lower than at peak exercise (16 778±3134 versus 18 930±3850 mm Hg·bpm, respectively; P=NS).
Intracoronary adenosine did not affect heart rate at rest or during pacing tachycardia (Fig 1⇑). During pacing-induced ischemia, intracoronary adenosine did not induce any ECG change in the two patients with ST-segment elevation. By contrast, it reduced ST-segment depression (measured 0.08 seconds after the J-point) from ≥1 to <0.5 mm in five of eight patients. In these patients, average ST-segment depression decreased from −1.07±0.38 to −0.25±0.18 mm (P<.01). Because of the short time interval between intracoronary adenosine and interruption of pacing, the effect of adenosine on chest pain could not be evaluated accurately.
Blood Flow Measurements
Flow velocities are shown in Fig 2⇓. In control subjects, blood flow velocity was 8±3 cm/s. Intracoronary adenosine increased blood flow velocity to 440±129% of baseline. In all control subjects, blood flow velocity increased during pacing by 188±51% at maximum heart rate. At this stage, adenosine further increased flow velocity to 390±153% of baseline.
In patients, average blood flow velocity was 6±2.7 cm/s. Intracoronary adenosine increased blood flow velocity to 186±65% of baseline (P<.01 versus baseline, P<.01 versus control subjects). One minute after the onset of pacing, blood flow velocity showed an absolute decrease from baseline values in 5 of 10 patients; at 2 minutes, this phenomenon was observed in 9 of 10 patients. At maximum heart rate, blood flow velocity decreased in all 10 patients (62±22% of baseline; P<.05 versus baseline, P<.01 versus control subjects) with evidence of ischemia (Figs 2⇑ and 3⇓). When adenosine was administered at this stage, it markedly increased blood flow velocity in all patients (152±69% of baseline; P<.05 versus baseline, P<.01 versus control subjects). During pacing-induced ischemia, maximal flow capacity (documented by adenosine) was 267±107% of ischemic flow before pharmacological vasodilation (P<.01 versus maximum pacing). Interestingly, the nonischemic patient did not show any flow reduction during pacing (Fig 2⇑, dashed line).
Coronary Resistance Index Evaluation
At rest, adenosine decreased coronary resistance in all control subjects to 25±7% of baseline. Similarly, maximal tachycardia consistently reduced coronary resistance index to 60±17% of baseline. At this stage, adenosine further decreased coronary resistance index to 31±13% of baseline.
In all patients, intracoronary adenosine decreased resting coronary resistance index (61±19% of baseline values; P<.05 versus baseline, P<.01 versus control subjects). However, after 1 and 2 minutes of pacing, coronary resistance index was increased in 8 of 10 patients. At maximum pacing, coronary resistance was increased in all 10 ischemic patients (221±131% of baseline; P<.01 versus baseline, P<.01 versus control subjects). Adenosine injection during pacing-induced ischemia decreased coronary resistance index in all patients to 85±33% of baseline. Therefore, at maximal pacing heart rate, the ratio between minimal resistance (documented by adenosine) and resistance during ischemia before pharmacological vasodilation was 44±20% (range, 24% to 78%).
Effect of Tachycardia and Ischemia on Blood Flow Regulation
During pacing-induced ischemia, coronary resistance markedly increased in patients when vasomotor tone was intact. By contrast, maximal flow capacity and minimal resistance index during tachycardia and ischemia were not significantly different from the values observed when adenosine was administered at sinus rhythm (Fig 2⇑) both in patients and in control subjects.
Nevertheless, tachycardia and ischemia had a small effect on minimal coronary resistance. In patients, percent increases in heart rate were significantly correlated with percent increase in minimal resistance (r=.83, P<.02), whereas such a correlation was not observed in control subjects (r=.03, P=NS).
The data of the present study confirm that in the absence of coronary atherosclerotic lesions, increases in heart rate are paralleled by microvascular dilation and decreases in coronary resistance. By contrast, in the territories perfused by a severely stenosed vessel, coronary resistance increases during pacing and reaches its maximum at the appearance of ischemia. Intracoronary adenosine almost completely reverses this paradoxical behavior. These findings document that during ischemia induced by increased oxygen consumption, a maximal microvascular vasodilation does not occur. Rather, a progressive, inappropriate vasoconstriction has to be conceived.
Coronary Vasomotor Tone During Ischemia Induced by Atrial Pacing Tachycardia
The effect of heart rate on minimal coronary resistance has been evaluated in various experimental and clinical studies. In awake dogs, Bache and Cobb18 observed that maximal subendocardial blood flow capacity can be reduced at heart rates <200 bpm. However, maximal transmural blood flow decreased only at a heart rate exceeding 200 to 250 bpm. Similarly, minimal resistance index showed little if any change in nonstenotic human coronary arteries when heart rate was increased up to 100 to 120 bpm.19 In the present study, percent increases in heart rate in different patients were directly correlated with percent increases in minimal (adenosine) coronary resistance. This observation is probably explained by the fact that we evaluated severely stenotic coronary arteries and that ischemia was present in all 10 patients during pacing. An increase in extravascular forces, which might explain in part the reduction in myocardial blood flow during pacing-induced ischemia, has already been reported in the literature.12 13 14 In agreement with these previous reports, pacing-induced ischemia also markedly increased coronary resistance in the present study. However, a marked vasodilation was observed when intracoronary adenosine was injected during ischemia induced by atrial pacing. Moreover, when the vasomotor tone was abolished, the effect of ischemia and tachycardia on minimal resistance was only minor and not significant. Thus, these findings document that myocardial ischemia is associated with an inappropriate severe vasoconstriction and indirectly document the minor role of extravascular compressive forces.
Mechanisms Underlying Coronary Vasoconstriction During Ischemia
Vasoconstriction during acute ischemia might reflect different mechanisms.
Residual vasomotor tone might have been confined to the normoperfused subepicardial layers, whereas the ischemic subendocardium was already maximally vasodilated even before adenosine administration. A nonuniform distribution of myocardial ischemia and vasodilator reserve has been observed in regions supplied by a severely stenotic coronary artery.20 However, according to this hypothesis, we should have observed a reduced decrease in transmural coronary resistance during tachycardia. By contrast, the marked progressive increase in coronary resistance during pacing-induced ischemia strongly suggests an active vasoconstriction, although we were not able to document its spatial distribution in the myocardial wall. Additionally, the exhaustion of subendocardial vasodilator capability has been observed only in combination with a marked reduction of transmural vasodilator reserve.20 21 In the present study, intracoronary adenosine augmented coronary blood flow up to 267% of values observed at the same heart rate when autoregulation was present during ischemia. Finally, pharmacological vasodilation relieved ST-segment depression in five of eight patients, suggesting a flow increase to the hypoperfused ischemic myocardium.
The patients' flow responses to atrial pacing might indicate the presence of an altered myocardial metabolism. Bristow and coworkers9 demonstrated that moderately ischemic myocardium downregulates its oxygen demand below the actual flow availability. Under these conditions, pacing tachycardia does not induce vasodilation despite the presence of a residual coronary reserve.9 Although this possibility cannot be ruled out completely on the basis of the present data, this phenomenon has mainly been observed after sustained moderate ischemia. In the present study, we evaluated the very first minutes of acute demand/supply mismatch. If tachycardia and ischemia could have been maintained for a longer time, myocardial metabolism probably could have reached a different steady state,9 resulting in an altered coronary resistance. However, it should also be considered that the close coupling between myocardial oxygen consumption and vessel tone is adjusted on a second-to-second basis, as confirmed by experimental findings22 and by the results obtained in the control population in the present study. Thus, the present data indicate an altered relationship between microvascular resistance and transient increases in oxygen consumption in myocardial regions supplied by severely stenotic vessels.
The increase in coronary resistance might reflect a vasoconstriction (or a collapse) at the site of epicardial stenosis.23 This possibility cannot be excluded, because angiograms were not obtained during ischemia to avoid interference of contrast medium with blood flow measurements. However, the pretreatment of all patients with both oral calcium channel blockers and intracoronary nitrates should have prevented vasoconstriction of the stenotic segment.23 Moreover, the marked response to adenosine suggests that vasoconstriction was present at the microvascular level because the great epicardial arteries are relatively insensitive to this agent,24 and it excludes stenosis collapse, which would have been aggravated by the increased flow.
The observed vasoconstriction might reflect a primary response of the coronary microvasculature to ischemia, as suggested by a number of experimental studies,6 7 8 although in the present study, vasoconstriction seemed to precede the occurrence of ECG ischemic changes. The mechanisms underlying this increase in vasomotor tone remain largely hypothetical. Possible contributing factors are vasoconstrictor agents released by the ischemic myocardium,25 mechanisms mediated by α1-adrenergic receptors,26 or atherosclerotic endothelial dysfunction.27 28 29 30 Previous studies28 29 showed that endothelial production of nitric oxide in coronary resistance vessels is a crucial mechanism for regulating myocardial perfusion during ischemia, whereas its role in regulating blood flow under physiological conditions is less certain. It has been hypothesized that endothelium-mediated microvessel vasodilation might play an important role under conditions of reduced driving pressure.28 31 Nitric oxide effects are more evident in proximal small arteries that are not under direct metabolic control.31 Thus, in the presence of normal driving pressure, an endothelial dysfunction may be counterbalanced by a metabolic dilation of distal arterioles. However, when driving pressure is abnormally low (ie, downstream from a severe stenosis) distal arterioles are already maximally dilated at baseline. In this setting, the lack of endothelium-dependent nitric oxide release might prevent an appropriate adaptation of microvascular resistance during increased oxygen consumption. An alternative hypothesis is the production, during increased cardiac work, of vasoactive substances that dilate the microvasculature when the endothelium is intact while they constrict microvessels in the presence of endothelial damage. The link between microvascular endothelial dysfunction and exercise-induced ischemia has been confirmed recently in patients with coronary atherosclerosis.32 In the present study, we did not directly evaluate endothelial function. However, the observation of a marked inappropriate vasoconstriction during increases in heart rate strongly supports the relevance of a microvascular disorder in the precipitation of myocardial ischemia downstream from a severe stenosis.
Several limitations of the present study deserve further discussion. All patients were evaluated during active treatment with aspirin, diltiazem, and nitrates. Moreover, before blood flow measurements, all patients received intracoronary nitrates and heparin. This procedure might have interfered with blood flow regulation, but it was imposed by ethical considerations. However, it should be stressed that under the same drug regimen, control subjects showed a progressive vasodilation during pacing, whereas patients with coronary artery disease showed a progressive vasoconstriction. The inhibition of prostaglandin synthesis by aspirin should have had little if any effect on the match between myocardial flow demand and supply.33 Similarly, treatment with calcium antagonists should have limited the vasoconstriction of both the coronary microvasculature34 and the large epicardial coronary vessels.23
A second consideration concerns atrial pacing. Although this stress is not sufficient to induce a maximal vasodilation, as confirmed in the control group of the present study, it prevents the profound neurohumoral changes elicited by exercise, allowing a more direct evaluation of microvascular response to increases in oxygen consumption. In our population, ST-segment depression during exercise occurred at rate-pressure products slightly but not significantly higher than those obtained by atrial pacing. It seems conceivable that the increase in arterial pressure, induced by physical exercise, might counterbalance the increase in coronary resistance and move the ischemic threshold to higher rate-pressure products with respect to pacing.35
Patients with evidence of previous myocardial infarction were carefully excluded. However, we cannot rule out the presence, at least in some of these patients, of subendocardial infarction or patchy fibrosis responsible for impaired flow response to pacing. However, all patients had evidence of ischemic and therefore viable myocardium in the regions supplied by the stenotic left anterior descending coronary artery. The present data do not enable us to identify whether the mild dyssynergies observed in 7 of 11 patients reflected either stunning or hibernating myocardium. However, it should be considered that vasoconstriction during ischemia was remarkably similar in patients with or without resting wall-motion abnormality.
Because of ethical considerations, pacing-induced ischemia was maintained for only 30 seconds in the present study before intracoronary injection of adenosine. Belloni and Sparks36 documented that a full and steady-state decrease in coronary resistance after a step increase in heart rate is reached within this time frame in anesthetized dogs. To the best of our knowledge, it has not been ascertained whether coronary atherosclerosis affects the time constant of coronary vascular response to increases in myocardial oxygen consumption. A delay in the time course of this vasodilation might be responsible for the relative vasoconstriction observed in the early phase of ischemia. In this instance, this paradoxical behavior might subside with time. Although the present data cannot exclude this hypothesis, it should also be considered that in agreement with experimental findings,36 flow velocity was remarkably stable during the last 10 seconds of each heart rate period, allowing accurate measurements in both control subjects and patients.
Finally, the adenosine dose was quite larger than that commonly used in clinical studies,37 but it has previously been shown by our laboratory that such a dose is needed to guarantee the maximal effect.38 It is conceivable that at this dose, adenosine might induce a generalized vasodilation even in microvascular segments less sensitive to this agent.31 39 40 Accordingly, the present study does not identify the microvascular compartment responsible for vasoconstriction.
The relevance of coronary stenosis as a major factor in the pathogenesis of myocardial ischemia is unquestioned. Procedures that remove its impact, such as coronary artery bypass grafting or coronary angioplasty, are strongly effective in reducing the occurrence of ischemic episodes. It is widely accepted that the severity of epicardial obstruction correlates with the impairment in coronary flow reserve and the incidence of ischemia.1 Nevertheless, in the majority of clinical studies, this relationship is characterized by a consistent scatter of individual data points.11 41 42 Accordingly, the need for a more precise characterization of blood flow regulation in regions supplied by a severely stenotic coronary artery has become apparent.43 The findings of the present study document the relevance of coronary vasomotor tone in the pathogenesis of myocardial ischemia in addition to the severity of coronary obstruction.
Although these data need confirmation by different techniques, they challenge the common view that attributes the course of myocardial ischemia exclusively to stenosis severity. Recently, Kitakaze and coworkers44 reported the beneficial effect of pharmacological intervention, such as ACE inhibition, on the coronary microvasculature during myocardial ischemia in an animal model. The identification of specific functional microvascular alterations yields the potential for a better targeting of therapy in patients with coronary artery disease.
This study was supported in part by the CNR-Targeted Project “Prevention and Control of Disease Factors,” subproject “Control of Cardiovascular Disease,” from the National Research Council, Rome, Italy. Dr Schneider-Eicke is the recipient of a training grant from the Human Capital and Mobility Project of the European Community. The authors are indebted to the staff of the catheterization laboratory for their skillful cooperation, to Claudio Michelassi and Guido Nassi for their assistance in the statistical analysis of the data, and to Ilaria Citti for her careful secretarial assistance.
- Received August 22, 1996.
- Revision received December 5, 1996.
- Accepted January 2, 1997.
- Copyright © 1997 by American Heart Association
Dole WP, Yamada N, Bishop WS, Holsson RA. Role of adenosine in coronary blood flow regulation after reduction in perfusion pressure. Circ Res. 1985;56:517-524.
Gould KL, Lipscomb K, Calvert C. Compensatory changes of the distal coronary vascular bed during progressive coronary vasoconstriction. Circulation. 1975;51:1085-1094.
Canty JM, Klocke FJ. Reduced regional myocardial perfusion in the presence of pharmacologic vasodilator reserve. Circulation. 1985;71:370-377.
Aversano T, Becker LC. Persistence of coronary vasodilator reserve despite functionally significant flow reduction. Am J Physiol. 1985;248:H403-H411.
Gorman MW, Sparks HV. Progressive coronary vasoconstriction during relative ischemia in canine myocardium. Circ Res. 1982;51:411-420.
Chilian WM, Layne SM. Coronary microvascular responses to reductions in perfusion pressure: evidence for persistent arteriolar vasomotor tone during coronary hypoperfusion. Circ Res. 1990;66:1227-1238.
Bristow JD, Arai AE, Anselone CG, Pantely GA. Response to myocardial ischemia as a regulated process. Circulation. 1991;84:2580-2587.
Canty JM, Smith TP. Adenosine-recruitable flow reserve is absent during myocardial ischemia in unanesthetized dogs studied in the basal state. Circ Res. 1995;76:1079-1087.
Sambuceti G, Marzullo P, Giorgetti A, Neglia D, Marzilli M, Salvadori P, L'Abbate A, Parodi O. Global alteration in perfusion response to increasing oxygen consumption in patients with single-vessel coronary artery disease. Circulation. 1994;90:1696-1705.
Maseri A, L'Abbate A, Pesola A, Michelassi C, Marzilli M, DeNes M. Regional myocardial perfusion in patients with atherosclerotic coronary artery disease at rest and during angina pectoris induced by tachycardia. Circulation. 1977;55:423-433.
Selwyin AP, Forse G, Fox K, Jonathan A, Steiner R. Patterns of disturbed myocardial perfusion in patients with coronary artery disease: regional myocardial perfusion in angina pectoris. Circulation. 1981;64:83-90.
Nabel E, Selwyin AP, Ganz P. Paradoxical narrowing of atherosclerotic coronary arteries induced by increases in heart rate. Circulation. 1990;81:850-859.
Hoffmann JIE. Determinants and prediction of transmural myocardial perfusion. Circulation. 1978;58:381-391.
Wilson RF, Laughlin DE, Ackell PH, Chilian WM, Holida MD, Hartley CJ, Armstrong ML, Marcus ML. Transluminal, subselective measurement of coronary blood flow velocity and vasodilator reserve in man. Circulation. 1985;72:82-92.
Bache RJ, Cobb FR. Effect of maximal coronary vasodilation on transmural myocardial perfusion during tachycardia in the awake dog. Circ Res. 1977;41:648-653.
Schwartz GG, McHale PA, Greenfield JC. Coronary vasodilation after a single ventricular extra-activation in the conscious dog. Circ Res. 1982;50:38-46.
Gage JE, Hess OM, Murakami T, Ritter M, Grimm J, Krayenbuehl HP. Vasoconstriction of stenotic coronary arteries during dynamic exercise in patients with classic angina pectoris: reversibility by nitroglycerin. Circulation. 1986;73:865-876.
Harder DR, Belardinelli L, Sperelakis N, Rubio R, Berne RM. Differential effects of adenosine and nitroglycerin on the action potentials of large and small coronary arteries. Circ Res. 1979;44:176-182.
Scott JB, Frolich ED, Hardin RA, Haddy FJ. Na, K, Ca and Mg action on coronary vascular resistance in dog heart. Am J Physiol. 1961;201:1095-1100.
Bache RJ, Laxson DD. Coronary arteriolar vasoconstriction in myocardial ischemia: coronary vasodilator reserve during ischemia. Eur Heart J. 1989;10(suppl F):105-110.
Kuo L, Davis MJ, Cannon MS, Chilian WM. Pathophysiological consequences of atherosclerosis extend into the coronary microvasculature: restoration of endothelium-dependent responses by l-arginine. Circ Res. 1992;70:465-476.
Smith TP, Canty JM. Modulation of coronary autoregulatory responses by nitric oxide. Circ Res. 1993;73:232-240.
Dunker DJ, Bache RJ. Inhibition of nitric oxide production aggravates myocardial hypoperfusion during exercise in the presence of a coronary artery stenosis. Circ Res. 1994;74:629-640.
Zeiher AM, Drexler H, Wollschlaeger H, Just H. Endothelial dysfunction of coronary microvasculature is associated with impaired flow regulation in patients with early atherosclerosis. Circulation. 1991;84:1984-1992.
Jones CJH, Kuo L, Davis MJ, Defily DV, Chilian WM. Role of nitric oxide in the coronary microvascular responses to adenosine and increased metabolic demand. Circulation. 1995;91:1807-1813.
Zeiher AM, Krause T, Schaechinger V, Minners J, Moser E. Impaired endothelium-dependent vasodilation of coronary resistance vessels is associated with exercise-induced myocardial ischemia. Circulation. 1995;91:2345-2352.
Hintze A, Kaley G. Prostaglandins in the control of blood flow in the canine myocardium. Circ Res. 1977;40:313-320.
Bourassa MG, Cote P, Theroux P, Tubau JF, Genain C, Waters DD. Hemodynamics and coronary flow following diltiazem administration in anesthetized dogs and humans. Chest. 1980;78(suppl):224-230.
Hoffman JIE. Maximal coronary flow and the concept of coronary reserve. Circulation. 1984;70:153-159.
Belloni FL, Sparks HV. Dynamics of myocardial oxygen consumption and coronary vascular resistance. Am J Physiol. 1977;233:H34-H43.
Wilson RF, Wyche K, Christensen BV, Zimmer S, Laxson DD. Effects of adenosine on human coronary arterial circulation. Circulation. 1990;82:1595-1606.
Marzilli M, Klassen GA, Marraccini P, Camici P, Trivella MG, L'Abbate A. Coronary effects of adenosine in conscious man. Eur Heart J. 1989;10(suppl F):78-81.
Kanatsuka H, Lamping KG, Eastham CL, Dellesperger KC, Marcus ML. Comparison of the effects of increased myocardial oxygen consumption and adenosine on the coronary microvascular resistance. Circ Res. 1989;65:1296-1305.
Kuo L, Davis MJ, Chilian WM. Longitudinal gradients for endothelium-dependent and -independent vascular responses in coronary microcirculation. Circulation. 1995;92:518-525.
Topol EJ, Ellis SG, Cosgrove DM, Bates ER, Muller DWM, Schork NJ, Schork AM, Loop FD. Analysis of coronary angioplasty practice in the United States with an insurance-claims data base. Circulation. 1993;87:1489-1497.
Kitakaze M, Minamino T, Node K, Komamura K, Shinozaki Y, Mori H, Kosaka H, Inoue M, Hori M, Kamada T. Beneficial effects of inhibition of angiotensin-converting enzyme on ischemic myocardium during coronary hypoperfusion in dogs. Circulation. 1995;92:950-961.