Demonstration of an imbalance between coronary perfusion and excessive load as a mechanism of ischemia during stress in patients with aortic stenosis

Patients with aortic stenosis are susceptible to myocardial ischemia during hemodynamic stress, which may be caused by two mechanisms. First, vascular abnormalities inherent in myocardial hypertrophy may impair coronary vasodilation, limiting the ability to increase coronary blood flow to meet increased metabolic demands. Second, aortic stenosis itself may cause an imbalance between oxygen supply and demand during hemodynamic stress by decreasing aortic pressure (decreasing coronary perfusion or oxygen supply) and increasing left ventricular pressure (increasing oxygen demand). By decreasing aortic valve gradient without immediately altering ventricular hypertrophy, aortic balloon valvuloplasty offers the opportunity to distinguish these mechanisms. We hypothesized that aortic valvuloplasty would improve the balance between myocardial oxygen supply and demand, especially during isoproterenol infusion. Nine patients undergoing aortic balloon valvuloplasty were assessed at baseline and during isoproterenol infusion (5 +/- 2 micrograms/min, mean +/- SD) before and after valvuloplasty. Valvuloplasty increased myocardial oxygen supply. After valvuloplasty, isoproterenol decreased diastolic pressure time index (DPTI) less and increased coronary sinus blood flow more than before valvuloplasty (-630 +/- 367 vs. -292 +/- 224 mm Hg.sec/min, p = 0.02 and 53 +/- 137 vs. 179 +/- 145 ml/min, p = 0.001, respectively). Valvuloplasty also decreased oxygen demand, decreasing systolic pressure time index (SPTI) from 4,135 +/- 511 to 3,021 +/- 492 mm Hg.sec/min (p = 0.0002). Valvuloplasty improved the balance between myocardial oxygen supply and demand, increasing baseline DPTI:SPTI, decreasing aortocoronary sinus oxygen content difference (0.51 +/- 0.15 to 0.68 +/- 0.14, p = 0.005 and 96 +/- 14 to 78 +/- 15 ml O2/l, p = 0.002, respectively), and decreasing myocardial lactate production during isoproterenol infusion (mean lactate extraction fraction, -0.26 +/- 0.40 to 0.14 +/- 0.17; p = 0.01). We conclude that aortic valvuloplasty improves the balance between myocardial oxygen supply and demand during hemodynamic stress induced by isoproterenol infusion. We speculate that the clinical improvement, which often occurs in these patients after valvuloplasty despite persistence of hemodynamically "critical" aortic stenosis, is in part attributable to immediate improvement in the myocardial oxygen supply:demand ratio.     

Effects of afterload elevation on the ischemic myocardium in isolated, paced canine heart with partial coronary stenosis

The effect of afterload elevation on the ischemic myocardium was examined in an isolated, paced canine heart with a partial coronary stenosis. The coronary blood flow of the left circumflex coronary artery was reduced to approximately one-third of the values before stenosis. The left circumflex coronary stenosis produced a decrease in global ventricular function, a decrease in systolic shortening and deviation of the ST-segment of the epicardial electrocardiogram and an increase in myocardial carbon dioxide (CO2) tension of the ischemic region. Then, afterload elevation with constant preload decreased the myocardial CO2 tension and improved the ST-segment deviation of the ischemic myocardium. Mechanical function, estimated by the relation between mean aortic pressure and systolic shortening, also improved with elevation of mean aortic pressure. In contrast, afterload elevation combined with preload elevation did not improve ischemic injury, as estimated by myocardial CO2 tension, and did not improve ST-segment deviation or mechanical function despite an increase in left circumflex coronary flow. These results suggest that the elevation of afterload pressure under constant preload improves ischemia produced by a partial coronary stenosis due to increased coronary blood supply; however, the preload elevation counterbalances the beneficial effects of afterload elevation.     

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; p less than 0.001). The intravenous infusion of diltiazem (0.30 mg X kg-1) reduced heart rate, mean aortic pressure, and myocardial oxygen consumption (all p less than 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 less than 0.05), and hyperemia volume was reduced (-33%; p less than 0.001). The decrease in coronary resistance at peak hyperemia was also reduced from -30 +/- 8% to -25 +/- 8% (p less than 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.     

The effect of positive end-expiratory pressure on the coronary blood flow

Positive end-expiratory pressure (PEEP) is used liberally whenever a ventilated patient shows signs of increased pulmonary venous shunting. Clinicians using PEEP to improve blood oxygenation may face the cardiovascular side effects which limit utilization of the desired respiratory effects of PEEP. We measured the pressure flow characteristics of the cardiovascular system and the coronary arterial system as a function of PEEP, using closed-chest surgically instrumented dogs, in order to assess its effects on myocardial blood flow with respect to the left ventricular energy demands. The aortic left ventricular blood pressure as well as the aortic blood flow decreased with increasing PEEP values. The coronary blood flow decreased by 5% for PEEP values of 4 cm H2O, and by 25% for 14 cm H2O of PEEP. PEEP values under 10 cm H2O reduced the left ventricular end-diastolic pressure (LVEDP), while higher PEEP values caused an increase in LVEDP. The relation between the alterations of coronary and aortic blood flows changed with PEEP values. Low PEEP values (less than 10 cm H2O) had a tendency for higher relative reduction of aortic blood flow, whereas higher PEEP values (higher than 10 cm H2O) reduced the coronary blood flow more than the reduction occurring in the aortic blood flow. Our results suggest that low PEEP values may have beneficial effects on the relation between aortic blood flow and coronary blood flow, therefore low PEEP application may minimize hypoxic myocardial alterations. Further studies that will measure left ventricular workload or another metabolic index for estimating myocardial perfusion relative to its metabolic demand are essential before clinical conclusions can be drawn from our results.     

Importance of maintaining systemic blood pressure during nitroglycerin administration for reducing ischemic injury in patients with coronary disease. Effects on coronary blood flow, myocardial energetics and left ventricular function.

Because of the controversy concerning the effects on myocardial ischemia of maintaining systemic pressure concomitant with administration of nitroglycerin, this study was undertaken of the actions of nitroglycerin, with and without simultaneous phenylephrine infusion, on coronary blood flow, myocardial energetics and left ventricular function in 17 patients with multivessel coronary artery disease. Five minutes after sublingual administration of 0.4 mg of nitroglycerin, mean arterial pressure, left ventricular filling pressure, cardiac index and coronary sinus blood flow were reduced (P < 0.05) from control values. With mean arterial pressure raised to control level with phenylephrine in 10 patients (Group I), values for coronary sinus blood flow, myocardial perfusion gradient, cardiac efficiency index and ratio of coronary sinus flow/cardiac output all increased (P < 0.05) compared with values in 7 patients receiving only nitroglycerin (Group II) and in patients receiving nitroglycerin before phenylephrine in Group I and with the values in 7 patients who received no phenylephrine. Left ventricular function and coronary vascular resistance were unchanged (P > 0.05) from control values by the addition of phenylephrine to nitroglycerin. Because myocardial oxygen extraction decreased while coronary sinus flow increased, the phenylephrine-induced increase in coronary flow was not due to augmented cardiac oxygen demands. Thus, preservation of systemic pressure concomitant with nitroglycerin enhances myocardial perfusion. From these findings, with greater nitroglycerininduced decreases in mean arterial pressure and coronary flow in patients with acute ischemia, it appears that phenylephrine with nitroglycerin may particularly improve myocardial energetics.     

Alterations in regional myocardial blood flow after nitroprusside and nitroglycerin in patients with and without significant coronary artery disease

To evaluate vasodilator-induced redistribution of regional myocardial blood flow, intravenous sodium nitroprusside and nitroglycerin were administered in doses producing matched reductions (15%) in mean arterial pressure at constant heart rate. Anterior left ventricular great cardiac vein blood flow (thermodilution) was measured in 14 patients without angiographic anterior collateral supply. Global coronary sinus blood flow remained constant with both nitroprusside and nitroglycerin administration, despite significant reductions in mean arterial pressure. However, nitroglycerin reduced great vein flow by 25 +/- 17% and nitroprusside by 10 +/- 16% (p less than 0.01). Subgroup analysis indicated that the nitroglycerin-nitroprusside regional blood flow differences were more pronounced in patients without significant left anterior descending coronary artery narrowing. Neither vasodilator produced significant differences in arterial-coronary sinus oxygen or lactate contents, calculated myocardial oxygen consumption, left ventricular dP/dt, or electrocardiographic or clinical signs of myocardial ischemia. Despite qualitatively similar hemodynamic effects, comparisons of vasodilator-induced relative reductions in normally supplied anterior left ventricular regional coronary blood flow suggest a mechanism of the reported beneficial effects of nitroglycerin on potentially ischemic myocardial regions.     

Diurnal changes in coronary blood flow in conscious dogs

The purpose of the present study was to evaluate potential diurnal changes in resting coronary blood flow under conditions of comparable myocardial oxygen requirements. We studied 21 conscious, resting dogs instrumented for the measurement of coronary flow, left ventricular pressure, and regional myocardial segment length. Recordings were taken in the early morning and late afternoon. In the afternoon, left circumflex coronary blood flow was 12.8% higher than in the morning, without detectable changes in the major hemodynamic determinants of myocardial oxygen consumption, i.e., heart rate, left ventricular pressure, peak positive dP/dt, end-diastolic regional myocardial dimension, and regional myocardial stroke work. These results are consistent with a circadian variation of coronary vascular tone accompanied by compensatory alteration in myocardial oxygen extraction and may have clinical relevance, since the coronary vascular tone may change dynamically in patients with critical coronary stenosis.     

Effect of coronary stenosis on myocardial blood flow during exercise in the chronically pressure-overloaded hypertrophied left ventricle

This study was performed to determine if a coronary artery stenosis would result in more-severe perfusion abnormalities in hypertrophied compared with normal canine hearts during exercise. Studies were performed in eight normal control dogs and in seven adult dogs in which a 67% increase in left ventricular mass wa produced by banding the ascending aorta at 9 weeks of age. Myocardial blood flow was measured by the microsphere method during treadmill exercise in the presence of a coronary artery stenosis that decreased distal coronary perfusion pressure to 55 or 42 mm Hg. At a coronary pressure of 55 mm Hg, mean myocardial blood flow was decreased by 23 +/- 5% in normal control dogs but was decreased by 53 +/- 10% in dogs with left ventricular hypertrophy (LVH) (p less than 0.05, comparing normal vs. LVH dogs). Similarly, at a coronary pressure of 42 mm Hg, mean blood flow was decreased by 53 +/- 6% below control in normal dogs but was decreased by 76 +/- 5% below control values in dogs with LVH (p less than 0.01, comparing normal vs. LVH dogs). In both groups of dogs, the stenosis caused a gradient of hypoperfusion, worsening from epicardium to endocardium. However, for each level of stenosis, subendocardial blood flow and the ratio of subendocardial to subepicardial blood flow was less in LVH than in normal canine hearts. These findings demonstrate that the presence of LVH secondary to long-term pressure overload is associated with an increased vulnerability to myocardial hypoperfusion during exercise in the presence of a coronary artery stenosis.     

Effects of pulsed external augmentation of diastolic pressure on coronary and systemic hemodynamics in patients with coronary artery disease

The purpose of this study was to define the effects of pulsed external diastolic pressure augmentation on coronary and systemic hemodynamics in 14 men with coronary artery disease and normal left ventricular function. Coronary sinus and great vein blood flow (thermodilution) and systemic hemodynamics were measured before, during, and after timed lower extremity compression, augmenting peak diastolic pressure to within 5 mm Hg of systolic pressure. Systolic and diastolic pressure-time indices were calculated from the high-fidelity micromanometer left ventricular-aortic recordings. External counterpulsation increased mean arterial pressure (108 +/- 11 [1 SD] to 114 +/- 12 mm Hg, p less than 0.01) and the diastolic pressure-time index (440 +/- 51 to 498 +/- 82 units, p less than 0.01), with no change in the systolic pressure-time index, absolute coronary sinus, or great cardiac vein blood flow. External diastolic pressure augmentation did not affect heart rate, right heart hemodynamics, cardiac output, or calculated myocardial oxygen consumption. An unanticipated finding was a greater than or equal to 10% reduction in peak systolic pressure during external diastolic pressure augmentation in 8 of 14 patients. Despite minimal changes in absolute myocardial blood flow and oxygen consumption, the increase in the diastolic pressure-time/systolic pressure-time index ratio suggests that subendocardial perfusion may be favorably influenced by diastolic pressure augmentation and may explain the previously reported clinical benefits of external counterpulsation in some patients with ischemic heart disease.     

The effect of coronary artery lesions on the relationship between coronary perfusion pressure and myocardial blood flow during cardiopulmonary resuscitation in pigs

In subjects without coronary disease, coronary perfusion pressure generated with closed-chest cardiopulmonary resuscitation (CPR) bears a direct relationship to myocardial blood flow. The effect of coronary lesions on this relationship was studied in an experimental porcine model not requiring thoracotomy. Coronary stenoses (a 50% reduction in coronary cross-sectional area) or total coronary occlusions were created by percutaneous, transarterial catheter placement of a Teflon cylinder in the left anterior descending artery of 21 swine (30 to 60 kg). Coronary perfusion pressure, defined as the aortic diastolic pressure minus right atrial diastolic pressure, was correlated with myocardial blood flow measured with nonradioactive, colored microspheres during external chest compression CPR. Complete occlusion of the left anterior coronary artery resulted in essentially no CPR-generated blood flow to the anterior myocardium distal to the site of occlusion. Coronary perfusion pressure showed a positive correlation with myocardial blood flow above the area of occlusion (r = 0.783; p less than 0.01) but did not correlate with myocardial blood flow below the occlusion site (r = 0.239). In the presence of a patent coronary artery stenosis, coronary perfusion pressure correlated with myocardial blood flow both above (r = 0.841; p less than 0.001) and below (r = 0.508; p less than 0.05) the stenosis. During closed-chest CPR producing coronary perfusion pressures between 30 and 60 mm Hg, anterior myocardial blood flow was 109 +/- 16 ml/min/100 gm above a patent stenosis and 66 +/- 13 ml/min/100 gm below the stenosis (p less than 0.005). Over a wide range of coronary perfusion pressures, myocardial blood flow below a coronary lesion was significantly less than that above the lesion. Coronary occlusions and stenoses can substantially affect the amount of CPR-generated coronary perfusion pressure needed to produce distal myocardial blood flow.     

Systemic, left ventricular and coronary hemodynamic effects of intravenous diltiazem in coronary artery disease

Systemic and coronary hemodynamic effects of intravenous diltiazem, administered as a bolus of 250 micrograms/kg followed by an infusion of 1.4 micrograms/kg/min, were examined in 14 patients with effort angina. There was no change in heart rate despite significant decreases in systolic, diastolic and mean systemic pressures (13%, 10% and 11%, respectively, all p less than 0.01). The blood pressure decrease was closely correlated with the initial blood pressure (r = 0.81, p less than 0.05). Neither left ventricular end-diastolic pressure nor peak dP/dt changed significantly, but peripheral vascular resistance decreased 16% (p less than 0.001) and stroke volume index increased 10% (p less than 0.05). The pressure-rate product decreased 15% (p less than 0.005), but coronary blood flow was maintained as coronary resistance decreased 14% (p less than 0.025). Diltiazem increased regional coronary flow in some patients. Thus, intravenous diltiazem dilates coronary and systemic resistance vessels, without an increase in heart rate, favorably altering indexes of myocardial oxygen supply and demand.     

Coronary artery stenosis controlled by distal perfusion pressure: Description of the servo-system and time-dependent changes in regional myocardial blood flow

An animal model for the induction of coronary artery stenosis is described. In this model the degree of stenosis, as induced with commercially available hydraulic occluders, can be easily controlled by keeping constant the mean perfusion pressure (pcor) distal to the site of stenosis. This pcor is the input signal for a servo-system feeding a motor-pump, which determines the degree of inflation of the cuff around the left anterior interventricular coronary artery (LAICA). In each experiment pcor did not vary more than 2 mm Hg from the preset value of about 25 mm Hg. In 60 anesthetized open-chest dogs the time course of standard hemodynamic variables and regional myocardial blood flow in the center of the underperfused area, using the radioactive microsphere technique, were determined. Within 1 min after induction of stenosis heart rate and end-diastolic left ventricular pressure (plved) increased (by 20 and 60%, respectively) and mean aortic pressure and dplv/dtmax decreased (by 10 and 25%, respectively). After the initial decrease median myocardial blood flow further decreased between 1 and 5 min of stenosis from 0.63 to 0.32 ml.min-1.g-1 in the outer layers (P less than 0.05) and from 0.26 to 0.15 ml.min-1.g-1 in the inner layers (P less than 0.05), despite constant hemodynamic conditions and pcor. Between 5 and 120 min of stenosis these values remained unchanged in the outer layers, but decreased further in the inner layers to 0.08 ml.min-1.g-1 (P less than 0.05). The accurate control of pcor, the reproducibility of the levels of residual blood flow and the ease of handling the stenosis system indicate that coronary artery stenosis controlled by perfusion pressure distal to the stenosis is a useful animal model to study events during regional myocardial ischemia. With the use of this model of low flow ischemia a biphasic increase of myocardial vascular resistance was observed, which is initiated during the first minutes of coronary artery stenosis.     

C5a decreases regional coronary blood flow and myocardial function in pigs: implications for a granulocyte mechanism

Granulocytes cause some of the pathophysiological effects associated with the capillary no-reflow phenomenon during ischemia and in ischemia-reperfusion injury. However, no study has examined the consequences of in vivo granulocyte activation during normal perfusion pressures. In this study, we examined the effects of intracoronary administration of the complement component C5a, which is known to be a potent granulocyte activating factor. Nine open-chest, anesthetized pigs were instrumented to monitor regional coronary blood flow and segment shortening, left ventricular dP/dt, heart rate, and pulmonary artery and aortic blood pressures and to sample arterial and regional coronary venous blood for oxygen content and complete blood counts. Intracoronary infusion of human or porcine C5a in doses ranging from 10 to 500 ng produced a significant reduction in regional coronary blood flow and myocardial function. Although perfusion pressure and heart rate remained constant, venous oxygen content fell, indicating an imbalance between myocardial oxygen supply and demand. In addition, the arteriovenous difference of white blood cells was increased significantly after anaphylatoxin infusion, indicating intravascular trapping in the myocardium. Granulocytes accounted entirely for the differences in leukocyte counts because no significant changes in platelet, lymphocyte, or hematocrit levels were observed. Injection of vehicle alone did not alter any of the monitored variables.(ABSTRACT TRUNCATED AT 250 WORDS)     

Regional myocardial function is not affected by severe coronary depressurization provided coronary blood flow is maintained

It has been suggested that vasodilation distal to a stenosis may cause a profound decrease in perfusion pressure and adversely affect regional left ventricular function. This phenomenon could explain the clinical concept of reversal of regional dysfunction by coronary revascularization. To evaluate the hypothesis that regional myocardial function parallels regional coronary blood pressure in the absence of changes in coronary flow, dogs chronically instrumented with left circumflex coronary artery flow probes, cuff occluders, pressure catheters and segmental function sonomicrometers were studied. By decreasing regional coronary vascular resistance with selective intracoronary dipyridamole and controlling blood flow with a proximal coronary cuff occluder, the mean left circumflex artery pressure was reduced from 83 +/- 3 to 38 +/- 2 mm Hg while circumflex coronary blood flow was maintained constant. Regional contractile function as measured by circumflex sonomicrometers was unchanged at constant circumflex subendocardial blood flow as measured by radioactive microspheres. These findings suggest that regional contractile function is dependent on subendocardial blood flow and is independent of coronary perfusion pressure.     

Changes in ischemic blood flow distribution and dynamic severity of a coronary stenosis induced by beta blockade in the canine heart

The effects of equipotent beta 1-receptor-blocking doses of propranolol, metoprolol and sotalol on distal coronary pressure, stenosis resistance and regional myocardial blood flow (endo/epi) were studied in anesthetized dogs with a severe noncircumferential stenosis of the left circumflex coronary artery. No significant differences between the three beta blockers were observed for overall hemodynamics and regional myocardial blood flow. After drug treatment, subendocardial blood flow (0.47 +/- 0.05 to 0.78 +/- 0.05 ml/min/g) and endo/epi (0.67 +/-0.04 to 1.18 +/- 0.04) increased significantly (p less than 0.05) in the ischemic region. These changes were associated with a marked increase in distal coronary perfusion pressure and a decrease in heart rate. Resistance across the stenosis decreased significantly (p less than 0.05) after beta-receptor blockade (3.2 +/- 0.3 to 1.4 +/- 0.2 units). Atrial pacing to control heart rate only partially attenuated these changes. These results suggest that a favorable redistribution of ischemic blood flow after beta blockade is the result of an increase in distal diastolic pressure-time index and an autoregulation-induced increase in distal bed vascular resistance due to a decrease in myocardial oxygen demand associated with beta blockade. The latter effect also resulted in a decrease in the dynamic severity of a proximal coronary stenosis.     

Alterations of myocardial blood flow associated with experimental canine left ventricular hypertrophy secondary to valvular aortic stenosis

Experimental renovascular hypertension or supravalvular aortic constriction results in left ventricular hypertrophy and impaired minimum coronary vascular resistance. However, these experimental models expose the coronary arteries to increased intra-arterial pressure, so that hypertensive vascular changes might be responsible for the impaired minimum coronary resistance. This study was performed to test the hypothesis that left ventricular hypertrophy in the absence of increased coronary pressure results in abnormalities of myocardial perfusion. Aortic valve stenosis was produced by plication of the noncoronary aortic cusp of 11 dogs at 6-8 weeks of age. Studies were carried out when the animals reached adulthood; mean left ventricular:body weight ratio was 7.1 +/- 0.4 as compared to 4.4 +/- 0.3 g/kg in 11 normal dogs (P less than 0.01). Under quiet resting conditions, myocardial blood flow measured with microspheres was significantly greater than normal in dogs with aortic stenosis. However, during maximum coronary vasodilation with adenosine, mean left ventricular blood flow in dogs with hypertrophy (3.29 +/- 0.39) was substantially less than in normal dogs (6.19 +/- 0.54 ml/min per g; P less than 0.01), whereas minimum coronary resistance was increased from 14.1 +/- 1.7 in normal dogs to 23.7 +/- 5.4 mmHg. min X g/ml (P less than 0.01). To examine the response of myocardial perfusion to cardiac stress, blood flow was measured during pacing at 200 and 250 beats/min. Compared with normal dogs, animals with hypertrophy had a subnormal increase in myocardial blood flow during tachycardia; this perfusion deficit was most marked in the subendocardium. These data demonstrate that left ventricular hypertrophy alone, without increased coronary artery pressure, is associated with impaired minimum coronary vascular resistance and with abnormalities of myocardial blood flow during pacing stress.     

Relationship between coronary blood flow velocity waveform and transmural distribution of myocardial blood flow in coronary artery

It is important to know the transmural distribution of myocardial blood flow in assessing the severity of ischemia in coronary heart disease. We analyzed the relation between phasic waveform of epicardial coronary flow velocity with a Doppler flow probe in the left anterior descending artery in dogs and regional myocardial blood flow using a colored microsphere technique. Time-velocity integral in an average of 5 cardiac cycles was measured as an index of coronary blood flow during diastole (TVId) and systole (TVIs). The diastolic fraction of coronary blood flow (%DF) was defined as TVId/(TVId + TVIs). Myocardial specimens were divided into inner (subendocardial), middle, and outer (subepicardial) layers, and the inner layer to outer layer myocardial blood flow ratio (endo/epi ratio) was used as an index of transmural distribution of myocardial perfusion. The mean endo/epi ratio and the mean %DF decreased as the pressure gradient increased. There was a moderate but significant correlation (r = 0.57) between the endo/epi ratio and the %DF. In conclusion, analysis of the phasic pattern of coronary blood flow velocity provides some information about the transmural distribution of blood flow in the myocardium. The %DF may be a useful index for evaluating subendocardial ischemia.     

Coronary flow limitation during the development of ischemia: Effect of atrial pacing in patients with left anterior descending coronary artery disease

Atrial pacing-induced tachycardia causes increased myocardial oxygen demand and leads to the development of angina in patients with significant coronary arterial narrowing, when the ability to augment coronary flow is limited. This study evaluated the response of coronary flow in a single coronary bed as that bed was rendered ischemic by progressive increases in oxygen demand. Thermodilution measurements of great cardiac vein flow, representing the efflux from the territory of the left anterior descending coronary artery, were obtained in 20 patients as heart rate was increased by incremental atrial pacing until the maximal heart rate was reached or angina developed. Ten of the 20 patients had no significant coronary narrowing on angiography, and 10 had a lesion obstructing more than 50 percent of the diameter of the left anterior descending coronary artery but no other significant coronary narrowing. No significant difference was found between the two groups in resting heart rate, aortic pressure, left ventricular end-diastolic pressure or great cardiac vein flow. With each increment in heart rate throughout the pacing test, the patients without significant coronary stenosis showed a steady increase in great cardiac vein flow. During all submaximal pacing increments, the increase in great cardiac vein flow per increment in heart rate was similar in those with and without significant stenosis (mean ± standard deviation 1.05 ± 0.48 ml/beat versus 0.79 ± 0.31 ml/beat, respectively). However, over the final pacing increment, the patients with coronary stenosis had no increase in great cardiac vein flow, whereas those without disease continued to have increased flow (Δ = 0.10 ± 0.19 ml/beat versus 1.3 ± 0.69 ml/beat, respectively, p < 0.001). This flow limitation phenomenon was observed in all 10 patients with coronary stenosis and was accompanied by angina or S-T segment changes, or both, in all 10. This striking difference in coronary flow patterns between patients with and without significant left anterior descending coronary artery disease may prove useful in (1) further studies of the pathophysiology and therapy of myocardial ischemia in human beings, and (2) clinical evaluation of the hemodynamic importance of left anterior descending coronary arterial lesions in selected patients.     

Effect of graded reductions of coronary pressure and flow on myocardial metabolism and performance: a model of "hibernating" myocardium

The term "hibernating" myocardium has been applied to chronic left ventricular dysfunction without angina or ischemic electrocardiographic changes in patients with coronary artery disease that is reversed by therapy that increases myocardial blood flow. To investigate the relation between coronary blood flow and ventricular function experimentally, graded reductions in coronary artery pressure were produced in isolated perfused rat hearts as contractile performance (peak systolic pressure and its first derivative [dP/dt]) and metabolic variables were measured using phosphorus-31 nuclear magnetic resonance (NMR) spectroscopy. As coronary pressure and flow were reduced, significant reductions in myocardial oxygen consumption and contractile performance were observed, which returned to control levels when coronary artery pressure and flow were restored to baseline values. Two phases of metabolic abnormality were observed. With modest reductions in coronary perfusion, proportionate reductions in myocardial oxygen consumption and contractile behavior were accompanied by a slight reduction in creatine phosphate but no significant lactate production. With greater reductions in coronary artery pressure and flow, creatine phosphate decreased more, adenosine triphosphate levels and myocardial pH decreased significantly and myocardial lactate production increased. The balanced reductions in myocardial contractility and oxygen consumption without metabolic abnormalities traditionally associated with "ischemia" observed in the first phase provides evidence in normal hearts for resetting of the myocardial contractile behavior and oxygen consumption in the presence of reduced coronary flow (that is, hibernating myocardium). The data suggest that reductions in adenosine diphosphate and the index of the reduced form of nicotinamide adenine dinucleotide (NADH) (lactate formation) do not explain the coupling between coronary artery pressure and flow and myocardial oxygen consumption as contractile performance decreases.     

Improvement by propranolol of regional myocardial dysfunction and abnormal coronary flow pattern in conscious dogs with coronary narrowing

The effects of propranolol on regional myocardial function and the pattern of coronary blood flow velocity were studied during partial coronary arterial constriction in conscious resting dogs. Miniature ultrasonic crystals were implanted subendocardially in the left ventricle for measurement of segment length in control and ischemic areas. Coronary blood flow was limited by inflation of an hydraulic-cuff around the left circumflex coronary artery to produce stable hypofunction in the ischemic segment. With coronary stenosis, which reduced mean flow by an average of 31 percent of the control value, the heart rate increased by 17 beats from 78 ± 4 beats/min (mean ± standard error of the mean) and the flow pattern changed from a dominant diastotic to a dominant systolic pattern (peak velocity ratio of systole to diastole, 0.35 ± 0.06 to 1.06 ± 0.09) without change in left ventricular systolic pressure. After administration of propranolol (0.5 mg/kg Intravenously), heart rate decreased to 72 ± 4 from 95 ± 4 beats/min and contraction in the Ischemic segment increased markedly, as did left ventricular wall thickening. Simultaneously, coronary flow returned to a normal velocity pattern. These favorable effects were only partially diminished by cardiac pacing to increase the heart rate to that before treatment with propranolol. This study provides evidence for a substantial beneficial effect of propranolol when myocardial dysfunction results from transient coronary arterial stenosis, and it suggests several mechanisms that may be operative under these conditions.