Prolonged impairment of coronary vasodilation after reversible ischemia. Evidence for microvascular "stunning"

Reperfusion after brief, reversible myocardial ischemia is associated with prolonged depression of contractile function (myocardial "stunning"); however, the effect on coronary vascular function has not been defined. Thus, open-chest dogs (n = 14) underwent a 15-minute left anterior descending coronary artery (LAD) occlusion followed by reflow. Four hours after reperfusion, regional myocardial blood flow (microspheres) was significantly (p less than 0.01) lower and coronary vascular resistance significantly (p less than 0.01) higher in the postischemic as compared with the nonischemic endocardium. Furthermore, during maximal vasodilation elicited by intravenous adenosine (n = 6), myocardial blood flow was lower (p less than 0.05) and coronary vascular resistance higher (p less than 0.05) in the postischemic as compared with the nonischemic myocardium, both in the endocardial and in the epicardial layers. Similarly, during maximal dilation elicited by intravenous papaverine (n = 8), myocardial blood flow was lower (p less than 0.05) and vascular resistance higher (p less than 0.05) in the postischemic as compared with the nonischemic endocardium; a directionally similar trend was observed in the epicardium. Four hours after reperfusion, all indexes of reactive hyperemia after a 40-second coronary occlusion were significantly lower in the LAD than in the control circumflex coronary artery (n = 8). There was no appreciable correlation between systolic wall thickening in the stunned myocardium and 1) the resting myocardial perfusion, 2) the hyperemia attained during adenosine or papaverine, and 3) the hyperemic response to a 40-second coronary occlusion. In control dogs that did not undergo a 15-minute LAD occlusion (n = 15), there were no differences in myocardial blood flow or vascular resistance between the LAD-dependent and the circumflex-dependent bed, either before or during adenosine (n = 7) or papaverine (n = 8). Furthermore, reactive hyperemia after a 40-second occlusion did not differ between the LAD and the circumflex artery (n = 8). In conclusion, a brief (15 minute), reversible ischemic insult causes a prolonged increase in resting vascular resistance and a prolonged impairment in vasodilator responsiveness, both of which persist for at least 4 hours. The severity of these vascular derangements is not related to the severity of contractile depression, suggesting that they may represent a relatively independent phenomenon. It is proposed that, in addition to myocardial "stunning," reversible ischemia also causes a microvascular "stunning."     

Role of adenosine in coronary vasodilation during exercise

This study examined the hypothesis that increases in myocardial blood flow during exercise are mediated by adenosine-induced coronary vasodilation. Active hyperemia associated with graded treadmill exercise and coronary reactive hyperemia were examined in chronically instrumented awake dogs during control conditions, after intracoronary infusion of adenosine deaminase (5 units/kg/min for 10 minutes), and after adenosine receptor blockade with 8-phenyltheophylline. Both adenosine deaminase and 8-phenyltheophylline caused a rightward shift of the dose-response curve to intracoronary adenosine; 8-phenyltheophylline was significantly more potent than adenosine deaminase. Adenosine deaminase caused a 33 +/- 7 to 39 +/- 3% decrease in reactive hyperemia blood flow following coronary occlusions of 5-20 seconds duration, respectively, while 8-phenyltheophylline produced a 40 +/- 6 to 62 +/- 8% decrease in reactive hyperemia. Increasing myocardial oxygen consumption during treadmill exercise was associated with progressive increase of coronary blood flow. Neither adenosine deaminase nor 8-phenyltheophylline attenuated the increase in coronary blood flow or the decrease of coronary vascular resistance during exercise. Neither agent altered the relation between myocardial oxygen consumption and coronary blood flow. Thus, although both adenosine deaminase and 8-phenyltheophylline antagonized coronary vasodilation in response to exogenous adenosine and blunted coronary reactive hyperemia, neither agent impaired coronary vasodilation associated with increased myocardial oxygen requirements produced by exercise. These findings fail to support a substantial role for adenosine in mediating coronary vasodilation during exercise.     

Myocardial lactate release during ischemia in swine. Relation to regional blood flow

To determine the relation between regional myocardial blood flow, contractile function, and myocardial lactate release during mild-to-moderate regional myocardial ischemia, nine open-chest swine were instrumented for measurement of regional myocardial blood flow (microsphere method), contractile function (sonomicrometry), and hemodynamics. L-[1-14C]Lactate or L-[U-13C]lactate was infused intravenously using a primed continuous infusion technique to quantify regional myocardial lactate release. D-[U-13C]glucose or D-[6-14C]glucose was simultaneously infused to determine the contribution of exogenous glucose to lactate release. Graded coronary ischemia (two to three levels) was created in the left anterior descending coronary arterial distribution by mechanically constricting the artery in five animals or by decreasing flow through a cannulated left anterior descending artery in four animals. In all nine animals, subendocardial blood flow was 0.99 +/- 0.21 (ml/min)/g during control and 0.34 +/- 0.14 (ml/min)/g during the most severe grade of underperfusion (p less than 0.001) in the left anterior descending coronary arterial distribution. Regional myocardial lactate release was 0.15 +/- 0.09 and 1.19 +/- 0.75 mumols/ml, respectively (p less than 0.003). A highly significant inverse correlation was observed between subendocardial blood flow and myocardial lactate release during the graded reductions in blood flow (r = -0.71, p less than 0.001). Results from sonomicrometry showed a significant reduction in contractile ventricular function in the anterior wall during the graded reductions in blood flow. The regional arterial-venous glucose difference increased significantly with underperfusion in the left anterior descending coronary arterial distribution, from 0.14 +/- 0.15 to 0.56 +/- 0.37 mumols/ml (p less than 0.003). The contribution of exogenous glucose to lactate release also increased significantly; 0.04 +/- 0.03 mumols/ml of the lactate came from exogenous glucose during control compared with 0.64 +/- 0.59 mumols/ml during the most severe underperfusion (p less than 0.02). A significant positive correlation exists between lactate release and lactate from exogenous glucose during graded underperfusion (r = 0.96, p less than 0.001). In summary, these data demonstrate a close inverse relation between regional myocardial lactate release and regional subendocardial blood flow during graded ischemia.     

Coronary hemodynamics and subendocardial perfusion distal to stenoses

We compared distal coronary hemodynamics and regional myocardial perfusion in anesthetized dogs in the presence of a single or two coronary artery stenoses in series. After application of either a single or two stenoses on the left anterior descending coronary artery, regional myocardial blood flow was measured with radioactive microspheres. Moderate degrees of single-vessel stenosis (no change in resting coronary blood flow but reduction in reactive hyperemic response of 70%) resulted in no significant change in regional myocardial perfusion at rest despite a pressure drop across the stenosis of 24 +/- 3 mm Hg. When two such stenoses were applied in series, there was a 91% decrease in reactive hyperemia, a significant reduction in resting diastolic coronary blood flow and a 51 +/- 7 mm Hg pressure drop across the two stenoses. Alone, each stenosis produced no change in regional myocardial perfusion; however, together the two stenoses resulted in a significant decrease in subendocardial blood flow and a redistribution of transmural perfusion within the ischemic zone favoring the subepicardium (endo/epi from 0.95 +/- 0.03 to 0.72 +/- 0.03). The results indicate that whereas resting subendocardial perfusion is not significantly affected by moderate degrees of a single coronary artery stenosis, multiple stenoses of the same severity may dramatically reduce subendocardial perfusion.     

Effect of nifedipine on the myocardial and vascular response to myocardial ischemia

Summary Nifedipine reduces reactive hyperemia following brief coronary artery occlusions. To determine whether this is related to improvement in collateral blood flow to ischemic myocardium or alterations in myocardial oxygen consumption, ten chloralose anesthetized dogs were instrumented with coronary sinus catheters, circumflex artery flowmeters, and ultrasonic microcrystals for measurement of myocardial segment shortening. Myocardial oxygen consumption and circumflex coronary artery flow were determined at rest and during incremental infusions of isoproterenol. Myocardial blood flow measured with microspheres and segmental function were assessed during and following 30- and 60-second coronary artery occlusions. Thirty minutes after the intravenous administration of nifedipine, 10 g/kg iv, all measurements were repeated. Nifedipine did not alter myocardial oxygen consumption or the relationship between oxygen consumption and circumflex coronary artery flow either at rest or during isoproterenol infusion. Following 60-second coronary occlusions, nifedipine reduced peak circumflex coronary artery flow (176±99 vs. 128±68 cc/min) and reactive hyperemia debt repayment (221±84 vs. 158±66%; p<0.01). Nifedipine did not alter flow to ischemic segments during coronary artery occlusions (0.16±0.10 vs. 0.19±0.13 ml/min/g mean transmural flow). Furthermore, nifedipine did not affect the severity of ischemic segment dysfunction, nor the rate of recovery of ischemic segment function following release of coronary artery occlusion. We conclude that the reduction in reactive hyperemia induced by nifedipine was not related to alterations in the severity of hypoperfusion in ischemic areas, or alterations in myocardial oxygen consumption. Reductions in reactive hyperemia produced by nifedipine did not impair recovery of mechanical function in postischemic myocardium.This study was supported in part by grants HL01162 and HL20598 from the National Heart, Lung and Blood Institute of the National Institutes of Health, Bethesda, Maryland; and by a grant-in-aid from the American Heart Association, Minnesota Affiliate, Inc. Dr. Homans was a fellow of the American Heart Association, Minnesota Affiliate, and recipient of National Research Service Award (HL06575) from the National Heart, Lung and Blood Institute of the National Institute of Health at the time that this work was performed.     

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.     

Influence of hypertonic mannitol on regional myocardial blood flow and ventricular performance in awake, intact dogs with prolonged coronary artery occlusion.

The influence of hypertonic mannitol on regional myocardial blood flow and ventricular performance in awake, intact, unsedated dogs with myocardial infarction resulting from chronic occlusion of the proximal left anterior descending coronary artery was studied. tmannitol given to increase serum osmolality 20 mOsm increased regional myocardial blood flow to that portion of the left ventricle supplied by the occluded left anterior descending coronary artery by 22 +/- 2.8% (1.06 +/- 0.19 to 1.36 +/- 0.23 ml/min with g-1) without changing the inner:outer wall flow ratio. Mannitol also significantly increased regional myocardial blood flow to other areas of the left ventricle and the ventricular septum. Mean aortic pressure, maximal LV dP/dt, LV dP/dt/P, and cardiac output also increased significantly after mannitol. Thus hypertonic mannitol increases regional myocardial blood flow and ventricular performance in the awake, unsedated dog with prolonged occlusion of the proximal left anterior descending coronary artery. The increase in regional myocardial blood flow after mannitol under these circumstances probably is at least in part secondary to the increase in blood pressure and contractility. The increases in regional myocardial blood flow after mannitol in this study are less impressive than those that have been previously reported in the setting of either no myocardial ischaemia or acute myocardial ischaemia; this is probably due to the vasodilatation that chronic myocardial ischaemia itself produces in the canine heart.     

Effects of high arterial oxygen tension on function, blood flow distribution, and metabolism in ischemic myocardium.

BACKGROUND. Although oxygen inhalation therapy has long been used in the treatment of acute myocardial ischemia, experimental evidence that increased arterial PO2 has any beneficial effect in the absence of hypoxemia is equivocal. In this study, we used a swine model of subendocardial myocardial ischemia to determine the effects of arterial hyperoxia on regional myocardial contractile function (sonomicrometry), myocardial blood flow distribution (microspheres), and regional myocardial glycolytic metabolism (carbon isotope-labeled substrates). METHODS AND RESULTS. In 10 domestic swine, the left anterior descending coronary artery was cannulated and flow to this artery was strictly controlled via a roller pump in the perfusion circuit. Arterial PO2 was controlled by manipulating inspired oxygen concentration (FIO2). Low-flow myocardial ischemia was induced by reducing pump flow to 50% of the control value, which diminished regional endocardial systolic shortening to 30-50% of normal. After a 15-minute period of flow stability, each animal was exposed in randomized order to two additional 15-minute experimental periods: coronary normoxia (PO2 = 90-110 mm Hg) and coronary hyperoxia (PO2 greater than 400 mm Hg). At each level of oxygenation, we measured regional myocardial function, regional myocardial blood flow and metabolism, and hemodynamic indexes of myocardial oxygen demand. Myocardial ischemia during normoxia reduced systolic shortening to 10.9 +/- 5.3% in the ischemic zone. Hyperoxia increased ischemic zone systolic shortening substantially to 15.2 +/- 4.6%. During myocardial ischemia, endocardial blood flow was decreased to 0.26 +/- 0.06 ml.g-1.min-1 in the ischemic zone. During hyperoxia, endocardial blood flow rose to 0.34 +/- 0.10 ml.g-1.m-1. The endocardial: epicardial flow ratio was 0.45 +/- 0.18 in the initial ischemia period and rose to 0.61 +/- 0.23 in the hyperoxic period. Myocardial ischemia increased regional uptake of glucose, conversion of glucose to released lactate, and net myocardial lactate release. In the ischemic myocardium, coronary hyperoxia decreased both chemically measured lactate production and isotopically measured lactate release and decreased glucose extraction and the conversion of glucose to lactate. CONCLUSIONS. These data demonstrate for the first time that increasing arterial PO2 to high levels during acute low-flow myocardial ischemia improves both function and flow distribution in the ischemic myocardium and decreases glycolytic metabolism in the ischemic zone. The degree of improvement in contractile function (5% absolute increase in systolic shortening or 25% change normalized to preischemic values) is consistent with the observed increase in subendocardial blood flow.     

Regional differences in postischemic recovery in the stunned canine myocardium

To determine if differences exist in the degree of ischemic damage and in postischemic recovery when different coronary arteries are occluded and reperfused, 40 barbital-anesthetized dogs were subjected to brief 15-minute periods of coronary artery occlusion followed by 3 hours of reperfusion ("stunned" myocardium) of the left anterior descending (LAD) or the left circumflex (LCX) coronary arteries. Myocardial segment shortening (%SS) in the subendocardium of nonischemic and ischemic reperfused areas was measured by sonomicrometry, and regional myocardial blood flow was measured by radioactive microspheres. Transmural tissue biopsies were taken at the end of reperfusion for the measurement of adenine nucleotides and total tissue water content. Arterial and local coronary venous blood samples were collected during preocclusion, during occlusion, and at 30 and 180 minutes of reperfusion for determination of blood oxygen content and oxygen consumption in the ischemic area. During occlusion, subendocardial blood flow (LAD flow = 0.11 +/- 0.02; LCX flow = 0.15 +/- 0.04 ml/min/gm), myocardial oxygen consumption (LAD = 2.4 +/- 0.7; LCX = 2.7 +/- 0.7 ml/min/100 gm), and areas of the left ventricle at risk (LAD = 27.4 +/- 2.3%; LCX = 32.4 +/- 2.4) were similar in both groups, thus indicating equivalent degrees of ischemia. There were no differences between groups in hemodynamics throughout the experiment or in the loss of myocardial high-energy phosphates or increase in total tissue water in the ischemic reperfused area at 3 hours of reperfusion. There was a significantly greater loss (p less than 0.05) of systolic wall function during LAD versus LCX occlusion and a greater recovery of segment function from 5 minutes throughout 1 hour of reperfusion after LCX occlusion (p less than 0.05), with no difference in %SS at 2 and 3 hours following reperfusion. Thus, although similar changes occurred in blood flow, metabolite parameters, tissue edema, wall function, and overall hemodynamics when either the LAD or LCX perfusion territories were occluded and reperfused, the loss of systolic wall function and recovery of segment shortening were more variable after regional stunning of the LCX perfusion bed. These data suggest that evaluation of pharmacologic or surgical interventions to improve postischemic functional recovery may be more reliably performed when the LAD coronary artery is the vessel occluded.     

Attenuation of dysfunction in the postischemic 'stunned' myocardium by dimethylthiourea

The mechanism for the prolonged contractile dysfunction observed in myocardium reperfused after reversible regional ischemia ("stunned" myocardium) is unclear. Recent studies suggest that myocardial stunning may be mediated by oxygen-derived free radicals, but the precise molecular species involved remain unknown. Thus we explored the role of the highly cytotoxic hydroxyl radical in regional postischemic dysfunction by using dimethylthiourea (DMTU), an effective and highly permeable hydroxyl radical scavenger. Open-chest dogs undergoing a 15 min occlusion of the left anterior descending coronary artery followed by 4 hr of reperfusion received either DMTU (0.5 g/kg iv over 45 min starting 30 min before occlusion, n = 14) or saline (n = 15). Control and treated dogs were comparable with respect to variables that may affect postischemic dysfunction, including heart rate, aortic pressure, left atrial pressure, arterial blood gases and hemoglobin concentration, size of the occluded bed (determined by postmortem perfusion), and collateral blood flow (determined by radioactive microspheres). Regional myocardial function was assessed by measuring wall thickening with an epicardial Doppler probe. The two groups exhibited comparable systolic thickening under baseline conditions and similar degrees of dyskinesis during ischemia. After reperfusion, however, wall thickening (expressed as percent of baseline) was considerably greater in treated as compared with control dogs: 53 +/- 9% (mean +/- SEM) vs 9 +/- 14% (p less than .03) at 1 hr, 55 +/- 9% vs 23 +/- 13% (p less than .05) at 2 hr, 60 +/- 9% vs 28 +/- 14% (p less than .05) at 3 hr, and 67 +/- 5% vs 36 +/- 13% (p less than .05) at 4 hr. Thus DMTU produced a significant and sustained improvement in recovery of contractile function. In concentrations greater than the plasma levels attained in vivo, DMTU did not scavenge either hydrogen peroxide or superoxide anion in vitro. These results suggest that the myocardial dysfunction occurring after a brief episode of regional ischemia is mediated in part by the hydroxyl radical.     

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.     

Effect of elevations of coronary artery partial pressure of carbon dioxide (PCO2) on coronary blood flow

This study was designed to examine the effect of increases in the partial pressure of carbon dioxide (PCO2) in coronary artery blood on coronary blood flow, coronary reactive hyperemia and the coronary response to intracoronary adenosine administration. The left anterior descending coronary artery was cannulated and perfused over a wide range of perfusion pressure (P) and flow (F) with blood equilibrated with 0 to 40% carbon dioxide in 16 open chest dogs. Increases in coronary artery PCO2 from 20 +/- 2 to 93 +/- 8 to 211 +/- 22 mm Hg (mean +/- SEM) increased the coronary flow from 28 +/- 3 to 68 +/- 16 to 87 +/- 22 ml/min, respectively, at a perfusion pressure of 60 mm Hg and from 49 +/- 6 to 139 +/- 30 to 206 +/- 48 ml/min, respectively, at a perfusion pressure of 100 mm Hg. Coronary reactive hyperemia following a 30 second coronary perfusion line occlusion and the response to an intracoronary bolus of adenosine (60 micrograms) were prominent at a low PCO2 but absent at a high PCO2. Beta-adrenergic blockade did not abolish the increase in coronary flow that occurred at increased PCO2. Thus, progressive elevations of regional coronary PCO2 produced substantial increases in coronary blood flow and maximal or near maximal coronary vasodilation.     

Protection by superoxide dismutase from myocardial dysfunction and attenuation of vasodilator reserve after coronary occlusion and reperfusion in dog

Previous studies indicate impairment of coronary arterial ring relaxation and loss of coronary vasodilator reserve after coronary artery occlusion and reperfusion. These changes are mediated in part through loss of endothelium-derived relaxing factor (EDRF) and/or myocardial neutrophil accumulation. To examine if superoxide dismutase (SOD), a scavenger of superoxide radicals, would modify the diminished coronary vasodilator reserve after temporary coronary occlusion in the intact animal, open-chest mongrel dogs were subjected to 1 hour of circumflex (Cx) coronary artery occlusion followed by 1 hour of reperfusion and treated with saline or SOD. Before Cx occlusion, coronary blood flow increased, and vascular resistance decreased (both p less than 0.01) in response to EDRF-dependent vasodilator acetylcholine as well as EDRF-independent vasodilator nitroglycerin. After Cx reperfusion, resting Cx coronary blood flow and vascular resistance were similar to the preocclusion values. In the saline-treated animals, there was evidence of myocardial dysfunction, which was measured by segmental shortening (-6 +/- 2% vs. 10 +/- 2%). Furthermore, increase in Cx coronary blood flow and reduction in vascular resistance in response to both vasodilators were significantly (p less than 0.01) impaired; these occurrences suggested loss of coronary vasodilator reserve. Myocardial histology showed extensive capillary plugging by neutrophils in the Cx-supplied myocardium. Myocardial myeloperoxidase activity, an index of neutrophil infiltration, was also increased in the Cx compared with the left anterior descending coronary artery region (p less than 0.02). Treatment of dogs with SOD, started at the end of Cx occlusion and continued during reperfusion, exerted significant (p less than 0.01) protective effect against reperfusion-induced attenuation of coronary vasodilator reserve in response to both acetylcholine and nitroglycerin. Loss of myocardial function (segmental shortening 5 +/- 1% vs. 10 +/- 1%) was less than in the saline-treated animals (p less than 0.01). Cx region-myocardial neutrophil accumulation and myeloperoxidase activity were also less (p less than 0.02) in the SOD-treated than in the saline-treated dogs. These observations suggest that coronary reperfusion impairs coronary vasodilator reserve in intact dogs. This impairment can be modified by treatment of animals with SOD before reperfusion. Capillary plugging by neutrophils may contribute to the altered coronary vasodilator reserve observed in the immediate postreperfusion period, and SOD modifies this reperfusion-induced impairment.     

Coronary blood flow reserve measured by contrast media injection depends on myocardial viability

Coronary blood flow reserve may be affected by several physiological variables besides hydraulic impediment to flow. A hyperaemic response induced by hyperosmolar radiopaque contrast medium was recorded in the left anterior descending and left circumflex arteries with a steerable pulsed Doppler system in four patients with Q wave anterior myocardial infarction chronic scar and non-stenotic coronary arteries. Resting flow velocities were similar in both arteries. The magnitude of the hyperaemic response induced by contrast media in the circumflex artery (mean flow velocity increase from 5.9 +/- 2.5 baseline to 12.2 +/- 0.6 cm s-1 at peak flow, P less than 0.05) was almost twice that induced in the left anterior descending artery (mean flow velocity increase from 6.1 +/- 2.2 baseline to 7.4 +/- 2.6 cm s-1 at peak flow, P = N.S.). The peak flow to baseline flow velocities ratios were 1.22 +/- 0.15 in the left anterior descending artery vs 2.23 +/- 0.75 in the circumflex artery. Thus when a post-myocardial infarction chronic scar is supplied by a non-stenotic coronary artery, the coronary blood flow hyperaemic response to contrast media-induced transient ischaemia is decreased, suggesting that coronary blood flow reserve depends on a myocardial metabolic stimulus which is impaired by ischaemic cell death.     

Reduction in coronary vasodilator reserve following coronary occlusion and reperfusion in anesthetized dog: role of endothelium-derived relaxing factor, myocardial neutrophil infiltration and prostaglandins

To examine the effects of acute myocardial ischemia and reperfusion on regional coronary vasodilator (or flow) reserve, peak reactive hyperemic blood flow following a 10 s occlusion was obtained in dogs subjected to circumflex (Cx) coronary artery occlusion for 1 h followed by reperfusion for 1 h. Acute myocardial ischemia resulting from Cx artery occlusion-reperfusion caused an attenuation in peak reactive hyperemic Cx flow (mean +/- S.E., from 215 +/- 29% to 87 +/- 17%, P less than or equal to 0.001). Acetylcholine-induced increase in Cx flow was also significantly (P less than or equal to 0.01) attenuated following Cx occlusion-reperfusion. These alterations were not observed in the left anterior descending (LAD) coronary artery, which was not subjected to occlusion. Pre-treatment of four dogs with indomethacin inhibited prostaglandin release (P less than or equal to 0.01), but did not affect peak reactive hyperemic coronary flow or acetylcholine-induced increase in coronary flow before or after occlusion-reperfusion. Histopathology revealed extensive myocardial neutrophil infiltration in the Cx-supplied region compared to the LAD-supplied region. Myocardial myeloperoxidase activity, an index of neutrophil infiltration, was also increased in the Cx compared to the LAD region (P less than or equal to 0.02). Myocardial neutrophil accumulation and myeloperoxidase activity were similar in the control and indomethacin-treated animals. These observations suggest that acute myocardial ischemia resulting from coronary artery occlusion-reperfusion impairs coronary vasodilator reserve in anesthetized dogs. This impairment, which was not modified by prostaglandin inhibition, may be related to the loss of endothelium-derived relaxing factor and/or decreased microvascular cross-sectional area resulting from capillary plugging by neutrophils.     

Nifedipine administered after reperfusion ablates systolic contractile dysfunction of postischemic "stunned" myocardium

Recent evidence suggests that postischemic contractile dysfunction of viable myocardium salvaged by reperfusion ("stunned myocardium") may be a consequence of abnormal calcium flux within the previously ischemic cells. Calcium channel blocking agents have been shown to enhance contractile function of stunned postischemic tissue, but it is not certain whether these improvements in function are due to the profound hemodynamic and vasodilator effects of these agents or to a direct effect on calcium flux within the stunned myocytes. Therefore, the effects of 1) high doses of nifedipine, given intravenously at 30 min after reperfusion, and 2) minute doses of nifedipine, infused directly into the coronary circulation at 30 min after reflow, were assessed and compared in anesthetized open chest dogs subjected to 15 min of transient coronary artery occlusion. As anticipated, intravenous nifedipine significantly reduced arterial pressure and increased regional myocardial blood flow. In addition, intravenous nifedipine restored systolic contractile function of the stunned, previously ischemic tissue to essentially normal preocclusion values: segment shortening averaged 102 +/- 8% versus 26 +/- 11% of baseline at 2 h after treatment in treated versus control dogs, respectively (p less than 0.003). Low dose intracoronary infusion of nifedipine did not alter hemodynamic variables or myocardial blood flow, but did improve segment shortening (90 +/- 9% versus 37 +/- 10% of preocclusion values at 1 h after treatment versus 25 min after reperfusion [that is, pretreatment], respectively; p less than 0.03). These data indicate that the calcium channel blocking agent nifedipine, given 30 min after reperfusion, enhances systolic contractile function of postischemic stunned myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)     

Improvement by 5-amino-4-imidazole carboxamide riboside of the contractile dysfunction that follows brief periods of ischemia through increases in ecto-5-nucleotidase activity and adenosine release in canine hearts.

5-Amino-4-imidazole carboxamide (AICA) riboside increases adenosine release in ischemic myocardium, suggesting that AICA riboside improves contractile dysfunction. In 49 open-chest dogs, contractile function assessed by fractional shortening (FS) was observed 3 h after the onset of reperfusion following 15 min of occlusion of the left anterior descending coronary artery. During reperfusion, the treatment with AICA riboside increased adenosine concentration in the coronary venous blood (536+/-44 vs. 281+/-21 pmol/ml at 3 min of reperfusion, p<0.001) and peak coronary hyperemic flow (367+/-13 vs. 300+/-21 ml/100 g per min, p<0.001) when compared with the untreated group. FS at 3h of reperfusion increased in the AICA riboside group (21.1+/-2.3 vs. 12.8+/-0.6% in the untreated group, p<0.001). AICA riboside increased myocardial ecto-5'-nucleotidase activity. Administration of adenosine also augmented coronary hyperemic flow and increased FS to the levels of the AICA riboside group. Either 8-phenyltheophylline (an antagonist of adenosine receptors) or alpha,beta-methylene-adenosine 5'-diphosphate (an inhibitor of ecto-5'-nucleotidase) completely abolished the increased coronary hyperemic flow and improvements of myocardial contractile function due to AICA riboside. Thus it was concluded that AICA riboside improves the contractile dysfunction that follows a brief period of ischemia via adenosine-dependent mechanisms.     

Exercise-induced regional dysfunction with subcritical coronary stenosis

The hypothesis was tested that regional myocardial contractile dysfunction can detect subtle regional coronary blood flow maldistribution induced by exercise. In seven dogs, left ventricular pressure (micromanometer), regional systolic wall thickening (WTh, sonomicrometry), and myocardial blood flow (MBF, microspheres) were measured when mild degrees of coronary artery stenosis were produced during treadmill exercise. During exercise without coronary stenosis, WTh increased by 21 +/- 12% (SD), and transmural MBF increased uniformly. In each dog, two levels of coronary stenosis were produced during exercise by adjusting the coronary hydraulic cuff: (1) St-Ex I, where WTh during exercise failed to increase significantly (average change 0 +/- 7%), and (2) St-Ex II, where WTh during exercise decreased moderately from the resting control value (average -20 +/- 8%). In the potentially ischemic zone coronary hyperemia occurred with each run: resting subendocardial MBF was 1.09 +/- 0.30 mg/g/min, and it was 3.04 +/- 0.83 during control exercise, 2.48 +/- 0.75 during St-Ex I, and 1.55 +/- 0.59 ml/g/min during St-Ex II (p less than .01 compared with control exercise and control area). The subendocardial-subepicardial blood flow ratio fell from 1.32 +/- 0.27 during control exercise to 1.07 +/- 0.20 (p less than .05) during St-Ex I, and to 0.64 +/- 0.15 (p less than .01) with St-Ex II. Changes in the subendocardial electrogram and reactive hyperemia occurred more consistently during St-Ex II than St-Ex I. Thus, failure of regional function to increase during exercise detected slight maldistribution of regional MBF, whereas reduction of regional function during exercise of 10% or more below the resting value was a reliable marker of a regional flow defect and was always associated with other evidence of ischemia. Therefore, regional dysfunction during exercise can detect subcritical but functionally significant coronary stenosis, which may allow regional wall motion to be used for detecting coronary artery disease at a relatively early stage.     

Coronary pressure-flow, pressure-function, and function-myocardial oxygen consumption relations in postischaemic myocardium.

STUDY OBJECTIVE--The aim was to study coronary pressure-flow, pressure-myocardial wall motion and myocardial wall motion-myocardial oxygen consumption relations in postischaemic myocardium with prolonged myocardial dysfunction (stunned myocardium) in comparison with normal myocardium. DESIGN--Regional myocardial wall thickening was measured with ultrasonic crystals, and postischaemic myocardial dysfunction was achieved by occlusion of a carotid-left anterior descending coronary artery bypass (15 min) and reperfusion (30 min). Coronary perfusion pressure was decreased in 10 mm Hg steps by constricting the bypass before and after producing postischaemic myocardial dysfunction. At each constriction step, coronary flow, regional wall thickening, and regional myocardial oxygen consumption in the area perfused by the left anterior descending artery were measured. EXPERIMENTAL MATERIAL--12 anaesthetised open chest mongrel dogs, weighing 12-16 kg, were studied. MEASUREMENTS AND MAIN RESULTS--At the basal level, myocardial wall thickening of postischaemic myocardium was depressed compared to normal myocardium, at 18.5(SD 8.9)% v 1.3(7.1)%, p less than 0.01. With coronary stenosis, wall thickening gradually decreased at a coronary pressure below 60 mm Hg in normal myocardium, but remained unchanged until mean coronary pressure was reduced to 50 mm Hg in postischaemic myocardium. Myocardial wall thickening of postischaemic myocardium was always more depressed than normal myocardium. At any level of coronary pressure, coronary flow in postischaemic myocardium was not different from normal myocardium. There was no difference in regional myocardial oxygen consumption between normal and postischaemic myocardium at any level of coronary pressure. However, regional myocardial oxygen consumption in postischaemic myocardium was higher than in normal myocardium performing similar levels of myocardial wall thickening. CONCLUSION--The coronary pressure-function relation but not the pressure-flow relation changed in postischaemic myocardium after a 15 min coronary occlusion. Regional myocardial oxygen consumption was relatively increased in postischaemic myocardium.     

Regional coronary flow and contractile reserve in patients with idiopathic dilated cardiomyopathy

OBJECTIVES: The purpose of this study was to assess regional coronary flow and contractile reserve in patients with idiopathic dilated cardiomyopathy (IDCM). BACKGROUND: Although IDCM has been associated with alterations in coronary blood flow and contractile reserve, little is known about their regional distribution and correlation. METHODS: Fourteen patients with IDCM and 11 control subjects underwent coronary flow velocity (APV) measurements in the left anterior descending (LAD), left circumflex (LCx), and right coronary (RCA) arteries at baseline (b) and at maximal hyperemia (h). Coronary flow reserve (CFR) was defined as h-APV/b-APV. Wall thickening was assessed in 16 segments (7 assigned to LAD, 5 to LCx, and 4 to RCA) both at rest and under peak stress during low-dose dobutamine echocardiography. Regional contractile reserve was defined as the percentage difference in wall motion score index between rest and stress in each vascular territory. RESULTS: Although there were no significant differences in b-APV, patients with IDCM had significantly lower h-APV than controls in all three vascular territories and reduced CFR (LAD: 2.79 +/- 0.43 vs. 3.48 +/- 0.51, p < 0.05; LCx: 2.71 +/- 0.39 vs. 3.36 +/- 0.65, p < 0.05; and RCA: 3.43 +/- 0.55 vs. 4.02 +/- 0.73, p < 0.05). There was also a significant correlation between CFR and the corresponding contractile reserve in the vascular territory of the LAD (r = 0.75, p = 0.002) and the LCx (r = 0.64, p = 0.014). CONCLUSIONS: Patients with IDCM have alterations in regional coronary flow and reduced CFR. Furthermore, the correlation between regional CFR and the corresponding contractile reserve indicates that microvascular dysfunction may have a pathophysiologic role in the evolution of the disease.