Lower Coronary Flow Research Articles

Coronary autoregulation protects against harmful effects of commonly used cardioplegia delivery pressure.

Hearts or parts of hearts are often ischemic prior to infusion of the cardioplegic solution and have a more or less dilated coronary bed. We made an investigation whether coronary dilation just prior to induction of cardiac arrest by aortic clamping and infusion of crystalloid cardioplegic solution would influence cardioprotection. Isolated buffer-perfused rat hearts (100 cm H2O pressure (= 73.5 mmHg), 37 degrees C) were used. After a stabilization period the perfusion of 8 rats (group 1) was stopped and the hearts arrested with 5 ml CS (100 cm H2O, 12 degrees C). Equal amounts of cardioplegic solution were then delivered every 20 minutes for the entire 3 1/2 hour hypothermic ischemic period. Following ischemia the hearts were reperfused for 60 minutes. In group 2 (n = 8) 1 ml 10(-2) mmol Papaverine was given into the aortic root just prior to the first cardioplegic solution infusion in order to induce coronary vasodilation. The procedure was identical in the two groups during ischemia and reperfusion. During the ischemic period coronary resistance increased in group 2. During reperfusion group 2 had lower coronary flow (P = 0.001), left ventricle developed pressure (P = 0.002) and a higher creatine kinase release (P = 0.003) than group 1 hearts. Group 2 also had a lower adenosine-triphosphate (6.51 +/- 0.40 mumol.g-1 and 14.03 +/- 0.59 mumol.g-1, respectively, P = 0.011), creatine phosphate (24.70 +/- 1.02 mumol.g-1 and 36.50 +/- 1.31 mumol.g-1, respectively, P = 0.020) and a larger fall in dry/wet-weight ratio (1.7 +/- 0.4 and 0.8 +/- 0.5, respectively, P = 0.043). Vasodilation (i.e. ischemia) just prior to infusion of crystalloid cardioplegic solution may impair myocardial protection even when the cardioplegic solution is delivered at a relatively low and presumably safe pressure.

Regulation of bioenergetics in O2-limited isolated rat hearts

Assessing the role of O2 supply in the regulation of cardiac function in O2-limited hearts is crucial to understanding myocardial ischemic preconditioning and adaptation to hypoxia. We exposed isolated Langendorff-perfused rat hearts to either ischemia (low coronary flow) or hypoxemia (low PO2 in the perfusing medium) with matched O2 supply (10% of baseline). Myocardial contractile work and ATP turnover were greater in hypoxemic than in ischemic hearts (P < 0.05; n = 12). Thus, the energy demand was higher during hypoxemia than during ischemia, suggesting that ischemic hearts are more downregulated than hypoxemic hearts. Venous PO2 was 12 +/- 2 and 120 +/- 15 Torr (P < 0.0001) for ischemic and hypoxemic hearts, respectively, but O2 uptake was the same. Lactate release was higher during hypoxemia than during ischemia (9.7 +/- 0.9 vs. 1.4 +/- 0.2 mumol/min, respectively; P < 0.0001). Electrical stimulation (300 min-1; to increase energy demand) increased performance in ischemic (P < 0.005) but not in hypoxemic hearts without changes in venous PO2 or O2 uptake. However, venous lactate concentration and lactate release increased in ischemic (P < 0.002) but not in hypoxemic hearts, suggesting that anaerobic glycolysis provides the energy necessary to meet the increased energy demand in ischemic hearts only. We conclude that high intracellular lactate or H+ concentration during ischemia plays a major role as a downregulating factor. Downregulation disappears in hypoxemic hearts secondary to enhanced washout of lactate or H+.

Stunning, preconditioning, and functional recovery after global myocardial ischemia

Stunning (reversible myocardial ischemia without necrosis) occurs with induced global ischemia during cardiac operation and depresses the ability of the heart to utilize oxygen efficiently because less contractile work is developed per unit of oxygen utilized. Interestingly, regional studies have demonstrated dramatic infarct size reduction with stunning episodes before prolonged ischemia, a phenomenon known as myocardial preconditioning. It is postulated that the postischemic contractile dysfunction noted after stunning causes reduced energy demands, which “preconditions” myocardium to withstand a subsequent longer ischemic episode. Some evidence from regional studies suggests that preconditioning may improve functional recovery after ischemia. This study examined the complex relationship between stunning and preconditioning to functional recovery in a surgical setting of global ischemia. To study the effect of stunning, myocardial oxygen consumption, oxygen extraction, and functional indices of contractility were measured before and after isolated rabbit hearts were subjected to 10, 20, or 45 minutes of normothermic 37 °C global ischemic stun intervals. This demonstrated that while oxygen consumption and extraction quickly recover to prestun levels, contractility remains depressed well beyond the stun interval. To study the effect of preconditioning using stunning, isolated hearts were then subjected to 120 minutes of 34°C cardioplegic-induced ischemia after preconditioning. Hearts received either modified St. Thomas cardioplegic solution as a control or cardioplegia administered after preconditioning with 37 °C ischemic stunning for 5, 10, 15, 20, or 45 minutes or multiple 5- or 10-minute stuns, with reperfusion before cardioplegic-induced ischemia. Additionally, two groups of hearts were subjected to “graded” stunning (low or intermediate coronary flow for 10 minutes) before cardioplegia-induced ischemia. In all groups, contractility and metabolic recovery were all significantly worsened with preconditioning stunning. In contrast with the benefit of myocardial preconditioning upon necrosis and infarct size in regional ischemia, the present study suggests that preconditioning by stunning does not enhance postischemic myocardial functional recovery in a simple model of global ischemia.

Oxidative injury in reoxygenated and reperfused hearts

In this study, we separated the effects of low oxygen supply and low coronary flow in isolated perfused rat hearts to focus on the genesis of free radicals-induced reperfusion injury. Hearts were exposed to either hypoxemia/reoxygenation or ischemia/reperfusion in various sequences, with hypoxemia and ischemia matched for duration (20 min), temperature (37°C), and oxygen supply (10% of baseline). Hypoxemia/reoxygenation ( n = 7) resulted in lower (developed pressure) × (heart rate) ( p < 0.001) and higher end-diastolic pressure ( p < 0.001) than ischemia/reperfusion (= 9). The presence of 40 IU/ml superoxide dismutase and 104 IU/ml catalase nearly blunted the rise of the end-diastolic pressure ( p = 0.02 vs. baseline), but could only partially prevent the depression of myocardial contractility ( p < 0.001 vs. baseline, n = 7). Similar patterns were observed when hearts were made ischemic after hypoxemia, eliminating the intermediate reoxygenation step. We conclude that the major determinant of the reperfusion injury is associated with low oxygen supply rather than low coronary flow. Part of the injury is mediated by oxygen-derived free radicals, but a substantial portion of it is associated with energetic processes.

Restoration of coronary blood flow in severely narrowed and chronically occluded coronary arteries before and after angioplasty: Implications regarding restenosis

The restenosis rate after recanalization of chronic totally occluded coronary arteries is high. This may be due to a competitive flow or a low coronary flow velocity. This study was designed to assess differences in coronary blood flow velocity between severely narrowed and occluded arteries before and after successful percutaneous transluminal coronary angioplasty. Thirty-five patients were studied including 12 with an occuluded vessel (group 1) and 23 with a stenosis (group 2). Rest and peak hyperemic (papaverine) coronary blood flow velocities were measured. Before successful percutaneous transluminal coronary angioplasty, velocity was lower in occlusions than in stenoses (3.8 ± 2.1 vs 7.9 ± 4.8 cm/sec; p < 0.02), whereas resistance was higher (31.7 ± 20.8 vs 13.7 ± 7.0 mm hg/cm/sec, respectively; p = 0.0009). There was no significant difference in vasodilator reserve between the two groups. After successful percutaneous transluminal coronary angioplasty, the velocity increased in both groups and the resistance index decreased. Velocity and resistance were similar in the two groups. The vasodilator reserve did not change after the procedure. It was concluded that the coronary flow velocity achieved after successful recanalization of chronic totally occluded arteries is similar to that observed after dilatation of stenoses. These results do not support the hypothesis that the high rate of restenosis in recanalized chronically occluded vessels is due to differences in post-percutaneous transluminal coronary angioplasty blood flow velocity.

Sensitivity to ischaemic ATP breakdown in different models of cardiac hypertrophy in rats

To evaluate the sensitivity to ischaemia of rat hearts made hypertrophic by pressure overload [two-kidney, one clip (2-K,1C) rats], volume overload (aortocaval arteriovenous shunt), minoxidil or isoproterenol. Ischaemia was induced in the isolated perfused hearts by a stepwise lowering of the perfusion pressure; at each step the coronary effluent was assessed for the products of ATP breakdown. Hypertension increased cardiac weight by 35 and 56% after 2.5 and 12 weeks, respectively. Volume overload increased heart weight by 25 and 55% after 1 and 12 weeks, respectively. Minoxidil (for 5 weeks) or isoproterenol (for 1 week) increased cardiac weight by 22 and 16%, respectively. The hearts from 2-K,1C rats started to release ATP catabolites in the coronary effluent at a substantially higher perfusion pressure, and with significantly higher maximal levels, than the control hearts. In contrast, in volume overload cardiac ATP breakdown was similar to that in the controls, and isoproterenol administration caused significantly lower levels of ATP breakdown. At identical flow rates, normalized per gram dry tissue, the purine concentration in the coronary effluent was similar in all of the models of cardiac hypertrophy studied and in the respective controls, and was even lower in the long-term volume-overloaded and isoproterenol-induced hypertrophic hearts. We conclude that hearts from hypertensive rats are more sensitive to ischaemic ATP breakdown during lowering of perfusion pressure than hearts from volume-overloaded or control rats. This is independent of the duration of the hypertrophic process, and can be explained by a lower coronary flow per gram heart tissue at a given perfusion pressure. This conclusion is strengthened by the observation that hypertrophic hearts from volume-overloaded rats had similar amounts of cardiac hypertrophy to the hearts from the hypertensive rats, without a change in flow, coronary vascular resistance or ischaemic sensitivity, whereas the hearts from isoproterenol-treated rats had lower ischaemic sensitivity and coronary vascular resistance.

The role of heart rate in myocardial ischemia and infarction: Implications of myocardial perfusion-contraction matching

The pathophysiology of myocardial ischemia traditionally has been attributed to disturbances of oxygen demand, as observed in classic effort-induced angina pectoris, or to a primary disruption of coronary blood supply, as in unstable angina or acute myocardial infarction. Laboratory research eliciting various types of perfusion-contraction matching has challenged such a historical distinction between supply and demand-induced determinants of myocardial ischemia. A growing number of clinical studies analyzing the role of heart rate in the course of coronary heart disease suggest the possibility that a common perfusion-contraction scheme may underlie these diverse clinical manifestations. During experimental myocardial ischemia, produced by a low coronary blood flow, regional perfusion-contraction matching exists in which the energy demands and regional contraction are reduced to match the diminished myocardial substrate supply. Heart rate is a major factor influencing transmural blood flow distribution and regional function, because when coronary vasodilation is maximal there is an inverse relation between the level of heart rate and subendocardial perfusion. Thus, in experimental regional ischemia, increasing heart rate reduces subendocardial flow and contraction, whereas slowing of heart rate causes improvement of contraction associated with increased subendocardial blood flow, accompanied by a decrease in outer wall blood flow. Also, “interventricular steal” of blood from the left ventricle by the right ventricle during ischemia can be reversed by slowing the heart rate in the presence of regional ischemia. Improvement of contraction by heart rate slowing is more than would be expected on the basis of the increase in subendocardial perfusion alone, reflecting a combination of decreased oxygen demand and increased oxygen supply, and separate curves relating blood flow per minute to contractile function are observed at different heart rates. However, when perfusion is normalized for heart rate by expressing subendocardial blood flow in units per beat, a single relation is observed at different heart rates. This observation supports the concept of a close coupling between subendocardial blood flow per beat and regional performance, or perfusion-contraction matching, during various levels of ischemia. Based on these principles, it can be predicted that exercise-induced regional ischemia in the presence of coronary stenosis will be attenuated by several mechanisms when heart rate is slowed using either a β-blocking agent, or a specific bradycardic drug. In this setting, an exercise-induced decrease in subendocardial flow is offset after such therapy by a substantial increase in subendocardial perfusion (augmentation of subendocardial blood per beat) associated with decreased subepicardial blood flow and improved regional contraction in the ischemic zone. In various clinical settings, it seems likely that increases in heart rate in patients with coronary disease are associated not only with increases of myocardial oxygen demand, but also with decreases in subendocardial blood flow, as evidenced by the close correlation between diastolic perfusion time and anginal threshold during exercise. β-Blockade and calcium antagonists that slow heart rate reduce the number of episodes of transient ischemia in patients with stable angina pectoris, in whom silent ischemic episodes observed with ambulatory ECG monitoring are often associated with an increase in heart rate. In normal human subjects, tachycardia produces a progressive increase of coronary blood flow and flow-mediated dilation of the epicardial coronary arteries. However, in patients with an atherosclerotic lesion, reduction in coronary blood flow occurs together with a progressive loss of luminal area during exercise which is prevented by β-blockade, supporting the perfusion-contraction matching concept. In the setting of acute myocardial infarction, heart rate is an independent predictor of mortality, and the level of heart rate elevation at hospital admission or during the hospital stay is significantly correlated with early as well as 1-year mortality. A beneficial effect on mortality incidence from acute myocardial infarction of β-blockers has been reported in a number of larger trials, and this benefit is significantly related to the reduction in the heart rate produced by these agents. These laboratory and clinical findings emphasize the key role of heart rate in perfusion-contraction matching and in a number of the clinical manifestations of coronary heart disease.

Increased oxyhemoglobin affinity by carbamylation: coronary autoregulation and O2 transport.

Hemoglobin carbamylation with sodium cyanate was used to study myocardial O2 delivery during increased oxyhemoglobin affinity. A group of control dogs was compared with a group of dogs, in which their hemoglobin had been carbamylated by daily ingestion of sodium cyanate over a period of 6-8 wk. The O2 tension at 50% saturation of hemoglobin (P50) averaged 23 mmHg in the carbamylated group compared with an average P50 of 31 mmHg in the control group. The left main coronary artery was cannulated and perfused via an extracorporeal, pressure-controlled reservoir. Coronary pressure, coronary flow, and blood gas measurements were made at coronary perfusion pressures spanning the autoregulatory range. The increased oxyhemoglobin affinity produced no significant difference in convective O2 transport to the coronary capillaries, although the carbamylated group had a significantly higher arterial O2 content and significantly lower coronary flow. The autoregulatory process was not significantly altered by carbamylation-induced shifts in the O2 dissociation curve. Despite a significantly lower coronary sinus PO2 in the carbamylated group, the increase in oxyhemoglobin affinity was associated with significantly lower O2 extractions in the carbamylated group. Significant extraction reserve was present in both the control and carbamylated groups as demonstrated by the fact that O2 extraction could still increase well above control levels when perfusion pressure was lowered. We conclude that there is no significant vasodilatory compensation for moderate increases in oxyhemoglobin affinity, despite the continued presence of autoregulatory vasodilatory reserve.

Adenosine formation and energy status in isolated guinea pig hearts perfused with erythrocytes

The purpose of this study was to examine adenosine release and high-energy phosphate concentrations during norepinephrine (NE) infusion in isolated guinea pig hearts perfused with a physiological salt solution (PSS) containing erythrocytes (RBC). Phosphate concentrations were monitored using 31P-nuclear magnetic resonance spectroscopy while NE was infused at 6 x 10(-10) mol/min. Compared with perfusion with PSS alone, RBC-perfused hearts consumed more oxygen and developed higher left ventricular pressure and first time derivative of left ventricular pressure at lower coronary flow rates. Adenosine release rates were very similar with both perfusates. NE infusion did not produce a decline in ATP concentration ([ATP]) or an increase in calculated [ADP] and [AMP] in RBC-perfused hearts. However, phosphorylation potential ([ATP]/[ADP][Pi]) declined because of increased [Pi]. We conclude that NE infusion does not change adenine nucleotide concentrations in well-oxygenated guinea pig hearts and that changes in nucleotide concentrations are not necessary for increased adenosine release. Phosphorylation potential is a better predictor of adenosine release than any individual nucleotide or phosphate concentration.

The transient nature of the effect of ischemic preconditioning on myocardial infarct size and ventricular arrhythmia

We sought to determine whether short periods of preconditioning ischemia limited infarct size in a model of low coronary collateral flow and whether the effects of preconditioning were transient or long-lasting. Rats underwent 90 minutes of coronary occlusion followed by reperfusion. In one group, the rats were preconditioned by three 3-minute occlusions, each separated by 5 minutes of reperfusion. The size of the myocardial infarcts were smaller in the preconditioned group (24.9 ± 7.8% of the risk zone developed necrosis) versus the nonpreconditioned group (60.7 ± 5.3%, p < 0.01). In addition, the incidence of ventricular arrthmias was reduced by preconditioning. However, when there was a delay of 1 hour or more between he brief episodes of preconditioning and the longer 90-minute occlusion, the beneficial effects of preconditioning were lost. Thus preconditioning reduced the volume of myocardium infarcted and the incidence of ventricular arrhythmias during a subsequent period of prolonged ischemia; however, these beneficial effects were transient.

The isolated, buffer-perfused ferret heart: A new model for the study of cardiac physiology and metabolism

The isolated, buffer-perfused ferret heart is a new model for the study of cardiac physiology and metabolism. Compared to the more commonly used isolated heart preparation, the rat heart, the ferret has a lower rate-pressure product due to lower heart rate, a remarkably low coronary flow and almost complete oxygen extraction. The ferret heart remains in stable haemodynamic and metabolic conditions for a longer period of time than the rat heart. ATP contents of the two species are similar, but creatine phosphate content is higher in the ferret while NAD content is much lower.

Influence of metabolic substrate on rat heart function and metabolism at different coronary flows

The influence of metabolic substrate on contractile strength, myocardial oxygen consumption (MVO2), high- and low-energy phosphate levels, and intracellular pH were determined in isovolumically contracting isolated rat hearts perfused with solutions containing either glucose or hexanoate at both high and low coronary perfusion pressures (CPP). Contractile strength was not significantly influenced by substrate at a CPP of 80 mmHg. As coronary flow was decreased, developed pressure measured at a fixed left ventricular volume (LVV) was lower during hexanoate than glucose perfusion. The relationship between MVO2 and mechanical work determined at a CPP of 80 mmHg over a range of LVVs was shifted upward in a parallel manner when substrate was switched from glucose to hexanoate. The MVO2-work relationship measured at a fixed LVV but over a range of coronary flows (7-20 ml/min) was also parallel shifted upward on switching from glucose to hexanoate. Basal MVO2 was greater during hexanoate than glucose perfusion by an amount that accounted for two-thirds the total increase in MVO2 observed between the substrates under unloaded beating conditions. The remainder of the difference was attributed to increased energy requirements for excitation-contraction coupling. Inorganic phosphate concentrations increased more and phosphocreatine concentrations decreased more during low-flow conditions (3 ml/min) when hearts were perfused with hexanoate compared with glucose. Thus hexanoate decreases myocardial efficiency compared with glucose in large part by increasing non-work-related oxygen demands. This inefficiency impacts adversely on contractile strength and high-energy phosphate concentrations at low coronary flows.

Myocardial perfusion-contraction matching. Implications for coronary heart disease and hibernation.

Experimental studies demonstrate that short-term regional perfusion-contraction matching, in which the energy demands of regional myocardial contraction are reduced to match the diminished myocardial substrate supply, occurs during states of low coronary blood flow under resting conditions and during exercise-induced ischemia. This phenomenon is rapidly reversible and appears to occur in several clinical settings. Sustained perfusion-contraction matching is observed in states of partial experimental ischemia of intermediate duration lasting several hours. This condition might be called short-term hibernation and resembles clinical conditions such as unstable angina pectoris or myocardial infarction with some residual perfusion in which the contractile defect can be improved by reperfusion provided the ischemia is not severe enough to cause transmural necrosis. Such experimental and clinical observations may or may not relate to the setting of regional dysfunction at rest in patients with chronic coronary heart disease, in whom manifestations of acute ischemia may be absent but improvement of wall motion abnormalities occurs after CABG or balloon angioplasty. This condition may constitute the hypothetical state of chronic myocardial hibernation, for which tentative evidence exists from metabolic and perfusion studies using PET. Whether such a condition of prolonged perfusion-contraction matching might be associated with adaptive processes that could allow its persistence for long periods without manifest ischemia remains to be investigated.

Experimental studies of the physiologic properties of technetium-99m isonitriles

Recently, efforts have been directed at the development of technetium-99m (Tc-99m)-labeled isonitrile compounds for assessment of regional perfusion and viability after experimental myocardial infarction or ischemia. One of the most promising of these agents, Tc-99m sestamibi, has undergone rather extensive laboratory investigation. Like thallium-201 (Tl-201), the uptake of Tc-99m sestamibi in myocardial tissue is proportional to myocardial blood flow after intravenous injection. Similar to other diffusible indicators, Tc-99m sestamibi underestimates blood flow at high flow rates. In low flow regions, the myocardial uptake of this agent is higher relative to nonischemic uptake than is microsphere-determined blood flow. This is attributed to increased extraction at low flows. This first-pass myocardial extraction fraction for Tc-99m sestamibi is less than that for Tl-201. However, Tc-99m sestamibi has a higher parenchymal cell permeability and higher volume of distribution than Tl-201. Tc-99m sestamibi shows minimal “delayed redistribution” after initial intravenous administration. Uptake of Tc-99m sestamibi is not altered by myocardial “stunning” or with ischemic dysfunction produced by sustained low coronary flow. The uptake of the isonitrile is still proportional to blood flow in these situations. In intact animal models, myocardial uptake of Tc-99m sestamibi during coronary occlusion delineates the in vivo area at risk. When Tc-99m sestamibi is administered after reperfusion following variable periods of preceding coronary occlusion, Tc-99m sestamibi uptake delineates the area of viable myocardium that is salvaged and not simply the degree of reflow. This suggests that serial Tc-99m sestamibi imaging might be useful in assessing the efficacy of coronary reperfusion after thrombolytic therapy.

Vascular washout reduces Ca2+ overload and improves function of reperfused ischemic hearts

Relationships between myocardial Ca2+ uptake, recovery of ventricular function, and restoration of tissue metabolites were determined during 30 min of reperfusion following ischemic and anoxic perfusion with either zero or low coronary flow, zero flow with intermittent perfusion, and low-flow perfusion without substrates. When zero-flow ischemia was maintained for 30 or 40 min, tissue lactate levels increased approximately 100-fold; with reperfusion of these hearts, developed pressure recovered to only 70 and 40% of preischemic function, respectively, and Ca2+ uptake increased by 7- and 15-fold. In contrast, 30 min of low-flow (1 ml/min) anoxic perfusion resulted in accumulation of less lactate (15-fold increase), less reperfusion Ca2+ uptake, and recovery of developed pressure to the preanoxic level. Omission of energy substrates during the low-flow anoxic perfusion caused a reduced recovery of heart rate with lower high-energy phosphate levels and increased Ca2+ uptake, but contractile function recovered to the same extent as in low-flow perfusion with substrate. Even very low flow rates (0.06-0.16 ml/min) of oxygen-deficient perfusate increased high-energy phosphate content and contractile function and decreased Ca2+ uptake. Intermittent perfusion with either oxygenated or anoxic buffer between four 10-min episodes of ischemia reduced lactate accumulation, maintained function, and left Ca2+ uptake essentially unchanged. Recovery of developed pressure during reperfusion was negatively correlated with the amount of lactate that accumulated during ischemia or anoxia and with reperfusion Ca2+ uptake, regardless of the duration or type of ischemia or anoxia.(ABSTRACT TRUNCATED AT 250 WORDS)

Na + accumulation increases Ca 2+ overload and impairs function in anoxic rat heart

Maintenance of low coronary flow (1 ml/min) during 40 or 70 min of anoxia maintained function and prevented Ca 2+ overload during reoxygenation in isolated rat hearts. In comparison, recovery from 40 min of global ischemia resulted in only 20% of preischemic function and an increase in end-diastolic pressure (LVEDP) to 39 mmHg. Reperfusion Ca 2+ uptake rose from 0.6 to 10.2 μmol/g dry tissue. Intracellular Na + ( Na i +) increased from 13 to 61 μmol/g dry tissue after 40 min of global ischemia, but was unchanged in hearts with low flow anoxia. When glucose and pyruvate were omitted from buffer used for anoxic perfusion, recovery was only 15% of preanoxic values, LVEDP rose to 32 mmHg, and reperfusion Ca 2+ uptake was 7.2 μmol/g dry. In addition, Na i + increased (47.4 μmol/g dry tissue) and ATP was depleted (1.0 μmol/g dry tissue) in the absence of substrate. In anoxic hearts supplied substrate, Na i + stayed low (12 μmol/g dry tissue) and ATP was preserved (11.6 μmol/g dry tissue). Addition of ouabain (100 or 200 μ m) and provision of zero-K + buffer increased Na i + and resulted in impaired functional recovery, increased LVEDP, and greater reperfusion Ca 2+ uptake. These interventions also decreased energy availability in anoxic hearts. To distinguish between effects of Na + accumulation and ATP depletion, monensin, a Na + ionophore, was added during low flow anoxia. Monensin increased Na i +, decreased functional recovery and increased reperfusion Ca 2+ uptake in a dose-dependent manner (1–10 μ m) without changing ATP content. These results suggested that reduction of Na i + accumulation by maintenance of Na +, K + pump activity was the major mechanism of the beneficial effects of low coronary flow on reperfusion injury.

Effect of ischemia and postischemic dysfunction on myocardial uptake of technetium-99m-labeled methoxyisobutyl isonitrile and thallium-201

The myocardial uptake of a new technetium-99m-labeled myocardial perfusion agent, methoxyisobutyl isonitrile (Tc-99m MIBI), and thallium-201 was correlated with microsphere flow in an open chest canine model of low coronary flow and postischemic dysfunction. Eighteen dogs were given an injection of thallium-201 (0.5 mCi) and Tc-99m MIBI (5 mCi) either after 40 min of partial left anterior descending artery occlusion (Group I, 10 dogs) or during reperfusion after 15 min of left anterior descending artery occlusion (Group II, 8 dogs). Regional dysfunction was documented during injection in both groups by quantitative two-dimensional echocardiography. Regional blood flow was assessed by radiolabeled microspheres. The heart was excised 15 min after radionuclide injection and the left ventricle divided into 96 segments for gamma well counting.Among Group I dogs, central ischemic thallium-201 and Tc-99m MIBI activity (expressed as a percent of the activity in the corresponding nonischemic zone) was comparable, respectively, for endocardial (54 ± 17% and 52 ± 17%), mid-wall (71 ± 20% and 69 ± 17%) and epicardial (89 ± 13% and 94 ± 9%) segments and increased proportionally with flow. There was a good linear correlation among these endocardial segments between flow and both thallium-201 (r = 0.78) and Tc-99m MIBI (r = 0.85) activity. Among Group II dogs, central ischemic endocardial flow (59 ± 14%) was comparable to thallium-201 (70 ± 18%) and Tc-99m MIBI (74 ± 12%) activity. Similarly, relative endocardial flow in the intermediate ischemic region (71 ± 11%) was comparable to thallium-201 (77 ± 11%) and Tc-99m MIBI (81 ± 10%) activity.Thus, myocardial uptake of Tc-99m MIBI and thallium-201 is comparable under conditions of low coronary flow and postischemic dysfunction and closely parallels flow alterations.

Thromboxane A2 and serotonin mediate coronary blood flow reductions in unsedated dogs.

We have shown in anesthetized open-chest dogs that recurrent platelet aggregation at the site of coronary artery stenosis and endothelial injury results in a pattern of cyclical variations in coronary blood flow (CFVs) and that serotonin and thromboxane A2 are important mediators of CFVs. In the present study, we tested the following hypotheses: 1) severe spontaneous reductions in coronary blood flow occur in awake closed-chest dogs with coronary artery stenoses and endothelial injury; 2) there is a progression from CFVs to persistent low coronary blood flow; and 3) serotonin and thromboxane A2 are important mediators of coronary blood flow reductions in this model. In 17 of 20 awake closed-chest unsedated dogs with experimental coronary artery stenoses and endothelial injury, either intermittent CFVs (n = 3), persistent low flow (n = 4), or progression from CFVs to low flow (n = 10) occurred during the first postoperative week. A serotonin receptor antagonist (ketanserin or LY 53857) or a thromboxane synthesis inhibitor (dazoxiben) or receptor antagonist (SQ 29548) abolished platelet-dependent CFVs in 80% of dogs. Thus 1) severe spontaneous reductions in coronary blood flow occur in awake closed-chest unsedated dogs with coronary artery stenoses and endothelial injury; 2) there is a progression from CFVs to persistent low coronary blood flow and final coronary artery occlusion; and 3) serotonin and thromboxane A2 are important mediators of coronary blood flow reductions in this experimental model.

Differences in coronary flow and myocardial metabolism at rest and during pacing between patients with obstructive and patients with nonobstructive hypertrophic cardiomyopathy

Fifty patients with hypertrophic cardiomyopathy underwent invasive study of coronary and myocardial hemodynamics in the basal state and during the stress of pacing. The 23 patients with basal obstruction (average left ventricular outflow gradient, 77 +/- 33 mm Hg; left ventricular systolic pressure, 196 +/- 33 mm Hg, mean +/- 1 SD) had significantly lower coronary resistance (0.85 +/- 0.18 versus 1.32 +/- 0.44 mm Hg X min/ml, p less than 0.001) and higher basal coronary flow (106 +/- 20 versus 80 +/- 25 ml/min, p less than 0.001) in the anterior left ventricle, associated with higher regional myocardial oxygen consumption (12.4 +/- 3.6 versus 8.9 +/- 3.3 ml oxygen/min, p less than 0.001) compared with the 27 patients without obstruction (mean left ventricular systolic pressure 134 +/- 18 mm Hg, p less than 0.001). Myocardial oxygen consumption and coronary blood flow were also significantly higher at paced heart rates of 100 and 130 beats/min (the anginal threshold for 41 of the 50 patients) in patients with obstruction compared with those without. In patients with obstruction, transmural coronary flow reserve was exhausted at a heart rate of 130 beats/min; higher heart rates resulted in more severe metabolic evidence of ischemia with all patients experiencing chest pain, associated with an actual increase in coronary resistance. Patients without obstruction also demonstrated evidence of ischemia at heart rates of 130 and 150 beats/min, with 25 of 27 patients experiencing chest pain. In this group, myocardial ischemia occurred at significantly lower coronary flow, higher coronary resistance and lower myocardial oxygen consumption, suggesting more severely impaired flow delivery in this group compared with those with obstruction. Abnormalities in myocardial oxygen extraction and marked elevation in filling pressures during stress were noted in both groups. Thus, obstruction to left ventricular outflow is associated with high left ventricular systolic pressure and oxygen consumption and therefore has important pathogenetic importance to the precipitation of ischemia in patients with hypertrophic cardiomyopathy. Patients without obstruction may have greater impairment in coronary flow delivery during stress.

Acute alterations in diastolic left ventricular chamber distensibility: mechanistic differences between hypoxemia and ischemia in isolated perfused rabbit and rat hearts.

Changes in diastolic chamber distensibility (DCD) during hypoxemia and ischemia were studied in isolated-buffer-perfused rabbit hearts. Two minutes of hypoxemia (low PO2 coronary flow) resulted in a shift of the diastolic pressure-volume curve to the left, i.e., distensibility was decreased (hypoxemic contracture). In contrast, 2 minutes of ischemia (zero coronary flow) resulted in an initial shift of the diastolic pressure-volume curve to the right indicating increased distensibility, which was followed by a later (30 minutes) shift to the left (ischemic contracture). Two minutes of ischemia superimposed on hypoxemia caused complete reversal of contracture. A quick stretch and release applied to the myocardium reversed late ischemic contracture but did not effect early hypoxemic contracture. The role of intracellular pH in modulating changes in DCD during hypoxia and ischemia was studied using phosphorus-31 nuclear magnetic resonance spectroscopy of isolated-buffer-perfused rat hearts that demonstrated changes in DCD similar to rabbit hearts during hypoxemia and ischemia. Intracellular pH decreased from 7.03 +/- 0.02 to 6.87 +/- 0.03 (p less than .01) during 2 minutes of ischemia but did not change significantly during 4 minutes of hypoxemia. When 2 minutes of ischemia were superimposed on hypoxemia, pH decreased from 6.99 +/- 0.01 during hypoxemia to 6.88 +/- 0.02 after 2 minutes of ischemia (p less than .01), concomitant with the complete reversal of hypoxemic contracture. These results suggest different mechanisms for late ischemic and early hypoxemic contracture and also suggest an explanation for the opposite initial changes in DCD seen after brief periods of ischemia and hypoxemia. The early development of contracture during hypoxemia and rapid redevelopment of diastolic tension after quick stretching are consistent with the hypothesis that hypoxemic contracture results from persistent Ca++-activated diastolic tension secondary to impaired calcium resequestration by the sarcoplasmic reticulum. In contrast, the late development of contracture during global ischemia and reversal by quick stretching is compatible with rigor bond formation. The initial increase in distensibility during early ischemia and the reversal of hypoxemic contracture by a brief period of superimposed ischemia probably is the result of two factors present during ischemia but not during hypoxemia: the collapse of the coronary vasculature and loss of the "erectile" effect and, the rapid development of intracellular acidosis, which has been shown to affect myofibrillar calcium sensitivity, and this may lead to a decrease in Ca++ activated diastolic tension.