Glutathione protects cardiac and skeletal muscle from cyclophosphamide-induced toxicity.

Administration of cyclophosphamide at a dose which is lethal to 10% of control athymic nude mice resulted in sudden death within 3 h in all mice that had been pretreated with the glutathione synthesis inhibitor L-buthionine-SR-sulfoximine. In Fischer 344 rats pretreated with L-buthionine-SR-sulfoximine, the cyclophosphamide dose producing 100% acute toxicity was lowered from 500-150 mg/kg; cardiac monitoring revealed ventricular fibrillation to be the cause of death. These and additional studies reported demonstrate that cytoplasmic glutathione is an important protectant against the cardiac and skeletal muscle toxicity of cyclophosphamide and indicate that such toxicity may be substantially increased by glutathione depletion. Since diet and many drugs (including cyclophosphamide itself) are known to affect glutathione levels, the present studies suggest that cardiac and skeletal muscle glutathione content is likely to be a clinically significant determinant of the frequency and severity of the adverse drug interactions and systemic toxicity sometimes observed during cyclophosphamide therapy.

Effect of repetitive brief episodes of ischemia on cell volume, electrolytes and ultrastructure.

The effects of repeated brief episodes of ischemia on myocardial cell volume, electrolytes and ultrastructure were studied in dogs. Seventeen animals were divided into five groups. Group 1 underwent a single 10 minute occlusion of the circumflex coronary artery, with no subsequent reperfusion. Group 2 was similarly subjected to a 10 minute coronary occlusion, but was allowed a 20 minute reperfusion period. Group 3 underwent two 10 minute occlusions separated by 20 minutes of reperfusion and Group 4 underwent four 10 minute occlusions, each separated from the next by 20 minutes of reperfusion. Group 5 was subjected to a single, uninterrupted 40 minute occlusion. The anterior and posterior papillary muscles in each heart were sampled to compare nonischemic versus ischemic myocardium. No changes in myocardial water or electrolytes occurred during ischemia. However, reperfusion was associated with slight increases in tissue water and potassium, loss of magnesium and minimal changes in sodium or calcium ions. Electron microscopic analysis revealed signs of mild ischemic injury (absence of normal intramitochondrial granules, partial loss of glycogen and slight clumping of the nuclear chromatin) in posterior papillary muscle from Groups 1, 3 and 4. Group 2 showed complete recovery with 20 minutes of reperfusion, whereas Group 5 showed evidence of irreversible injury. There was no difference in the appearance of myocardium that had been subjected to one, two or four 10 minute occlusions. It is concluded that intermittent periods of reperfusion between brief episodes of coronary ischemia have a protective effect and prevent a cumulative deterioration of myocardial ultrastructure.

The spectrum of pathology associated with percutaneous transluminal coronary angioplasty during acute myocardial infarction.

The purpose of this study was to determine at necropsy the morphologic consequences of percutaneous transluminal coronary angioplasty performed during acute myocardial infarction. The heart was examined in four patients who died between 6 hours and 4 days after coronary angioplasty. The patients had angioplasty of the left main coronary artery (one patient), left anterior descending coronary artery (two patients) and left circumflex coronary artery (one patient). Necropsy revealed residual stenosis, intimal hemorrhage and plaque disruption in all four patients. Also noted were distal embolization of plaque elements (two patients) and thrombotic occlusion of the coronary artery (one patient). In conclusion, the morphologic changes after angioplasty are varied. These changes illustrate the mechanisms of angioplasty and some of the complications that can be expected in a small number of cases. The morphologic changes associated with coronary angioplasty are similar in patients undergoing elective or emergency angioplasty although medial dissection was not observed in these patients with an evolving myocardial infarction.

The xanthine oxidase inhibitor oxypurinol does not limit infarct size in a canine model of 40 minutes of ischemia with reperfusion.

Free radicals such as superoxide (.O2-) produced by xanthine oxidase might cause cell death during reperfusion after myocardial ischemia. The effect of the xanthine oxidase inhibitor allopurinol on infarct size in ischemia-reperfusion models has been variable, possibly because of differences in treatment duration. Adequate inhibition of xanthine oxidase may require a sufficient pretreatment period to permit conversion of allopurinol to oxypurinol, the actual inhibitor of superoxide production. To test more definitively whether xanthine oxidase-derived free radicals cause cell death during reperfusion, the effect of oxypurinol on infarct size was evaluated in an ischemia-reperfusion model. Open chest dogs underwent 40 min of circumflex coronary artery occlusion followed by reperfusion for 4 days. Twelve dogs were treated with oxypurinol (10 mg/kg body weight intravenously 10 min before occlusion and 10 mg/kg intravenously 10 min before reperfusion) and 11 control dogs received drug vehicle alone (pH 10 normal saline solution). Nine control dogs from a concurrent study also were included. Infarct size was measured histologically and analyzed with respect to its major baseline predictors, including anatomic area at risk and collateral blood flow (measured with radioactive microspheres). Infarct size as a percent of the area at risk averaged 23.8 +/- 2.7% (mean +/- SEM) in the oxypurinol group (n = 10) and 23.1 +/- 4.2% in the control group (n = 17) (p = NS). Collateral blood flow to the inner two thirds of the ischemic wall averaged 0.08 +/- 0.01 ml/min per g in the oxypurinol group and 0.09 +/- 0.02 ml/min per g in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac rupture, mortality and the timing of thrombolytic therapy: a meta-analysis.

This study examined the relation between the risk of cardiac rupture and the timing of thrombolytic therapy for acute myocardial infarction. To test the hypothesis that cardiac rupture is prevented by early thrombolytic therapy but is promoted by late treatment, randomized controlled trials of thrombolytic agents for myocardial infarction were pooled. A logistic regression model including 58 cases of cardiac rupture among 1,638 patients from four trials showed that the odds ratio (treated/control) of cardiac rupture was directly correlated with time to treatment (p = 0.01); at 7 h, the odds ratio was 0.4 (95% confidence limits 0.17 to 0.93); at 11 h, it was 0.93 (0.53 to 1.60) and at 17 h, it was 3.21 (1.10 to 10.1). Analysis of data from the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI) trial independently confirmed the relation between time to thrombolytic therapy and risk of cardiac rupture (p = 0.03). Analysis of 4,692 deaths in 44,346 patients demonstrated that the odds ratio of death was also directly correlated with time to treatment (p = 0.006); at 3 h, the odds ratio for death was 0.72 (0.67 to 0.77); at 14 h, it was 0.88 (0.77 to 1.00) and at 21 h, it was 1 (0.82 to 1.37). Thrombolytic therapy early after acute myocardial infarction improves survival and decreases the risk of cardiac rupture. Late administration of thrombolytic therapy also appears to improve survival but may increase the risk of cardiac rupture.

Effect of adenosine therapy at reperfusion on myocardial infarct size in dogs.

OBJECTIVES: The concept of lethal reperfusion injury in ischemic myocardium has been the subject of controversy. Adenosine administered during reperfusion has been reported to limit lethal reperfusion injury in several studies. On the contrary, it has been reported that cardioprotection may not be achieved with adenosine alone but may occur if adenosine is co-administered with lidocaine. Still other investigators have reported no beneficial effect of adenosine, given with or without lidocaine. If the positive reports are reproducible, they are important both because they provide evidence for the existence of reperfusion injury and establish a rationale for preventing it. Thus, the present study was done to determine if adenosine could limit lethal reperfusion injury in a canine model of regional myocardial ischemia and reperfusion, carefully controlled for baseline predictors of infarct size. METHODS: Dogs (n = 37) of either sex were subjected to 90 min of coronary occlusion followed by 3 h of reperfusion. Two groups of dogs received adenosine (150 micrograms/kg/min) intravenously for 155 min starting 5 min prior to the reperfusion. One treated group received adenosine only and a second group received adenosine plus lidocaine (2 mg/kg). Control dogs received a saline infusion. After 3 h of reflow, hearts were excised and infarct size was measured and expressed as a percentage of the ischemic area at risk (AAR). To control for variation in infarct size due to variation in collateral blood flow (CBF), infarct size among groups was compared using ANCOVA, using CBF as the independent variable and infarct size as the dependent variable. RESULTS: Transmural collateral blood flow and AAR were not significantly different between any of the groups. Mean infarct size (adjusted by ANCOVA) in control dogs (n = 9) was 38.1 +/- 5.3% of the AAR. Neither adenosine (n = 9) nor adenosine plus lidocaine (n = 7) significantly limited infarct size (35.6 +/- 5.6% AAR and 38.1 +/- 7.7% AAR, respectively; both P = NS). CONCLUSIONS: Intravenous adenosine therapy (150 micrograms/kg/min) during reperfusion, whether administered alone or in dogs previously treated with lidocaine, did not limit infarct size after 90 min of regional ischemia in canine myocardium.

Adenosine slows ischaemic metabolism in canine myocardium in vitro: relationship to ischaemic preconditioning.

OBJECTIVE: Studies in rabbits suggest that the cardioprotective effects of adenosine against lethal cell injury may be related to production of adenosine and subsequent activation of adenosine A1 receptors. However, it is not known whether intracoronary adenosine therapy can mimic the metabolic sparing effects of preconditioning in rabbits or dogs. The purpose of this study was to determine the effect of intracoronary adenosine on ischaemic metabolism in totally ischaemic canine myocardium. METHODS: Dog hearts (n = 13) were excised and the coronary arteries were perfused with an oxygenated Krebs' buffer containing glucose. Adenosine was added to the buffer perfusing the circumflex (treated) region. Following perfusion, control and treated beds from each heart were subjected to 90 min total ischaemia at 37 degrees C. Tissue levels of ATP and glycolytic intermediates were determined at several time points during the ischaemic incubation. RESULTS: Adenosine significantly slowed the rate of ATP depletion, glycogen utilisation, and lactate accumulation during the first 20 minutes of total ischaemia. CONCLUSIONS: The results suggest that adenosine is capable of slowing ischaemic metabolism and they are consistent with the hypothesis that adenosine may mediate ischaemic preconditioning.

The novel calcium antagonist Ro 40-5967 limits myocardial infarct size in the dog.

OBJECTIVE: The aim was to compare the infarct limiting effect of Ro 40-5967 (Ro40), a new calcium antagonist with little negative inotropic activity, with that of verapamil and with ischaemic preconditioning, a potent endogenous cardioprotective mechanism. METHODS: Dogs (n = 53) of either sex were subjected to 60 min of coronary occlusion followed by 3 h of reperfusion. Drug treated dogs received either verapamil (1.0 mg.kg-1) or Ro40 (3.0 mg.kg-1) intravenously for 100 min starting 15 min prior to the occlusion. Control dogs received a saline infusion. Ischaemic preconditioning consisted of four 5 min cycles of ischaemia alternating with four 5 min cycles of reperfusion. After 3 h of reflow, hearts were excised and infarct size was measured using tripheyltetrazolium chloride macrochemistry and expressed as percent of the ischaemic area at risk (AAR). To control for variation in infarct size due to variation in collateral blood flow, infarct size among groups was compared using ANCOVA, in which infarct size and collateral blood flow, measured at 30 min of occlusion, were dependent and independent variables, respectively. RESULTS: Transmural collateral blood flow and AAR were not significantly different between any of the groups. Mean infarct size (adjusted by ANCOVA for slight differences in collateral blood flow among groups) in control dogs (n = 13) was 25.9(SEM 3.2)% of the AAR. Both verapamil (n = 11) and Ro40 (n = 9) limited infarct size [14.2(3.2)% AAR and 16.7(2.9)% AAR, respectively; both p < 0.05]. Preconditioning (n = 17) also significantly limited infarct size [8.1(1.8)%; p < 0.01]. CONCLUSIONS: The new calcium antagonist, Ro 40-5967, was as effective as verapamil in limiting infarct size after 60 min of regional ischaemia followed by 3 h of reperfusion, although neither calcium antagonist was as effective as ischaemic preconditioning.

Effect of coronary occlusion site on ischaemic bed size and collateral blood flow in dogs.

The ischaemic bed size (myocardium at risk) and collateral flow are major determinants of experimental myocardial infarct size. These parameters were compared in dogs with coronary occlusions at four commonly used sites. Regional blood flow was measured 5 min after proximal coronary occlusion of the circumflex (LCC) or anterior descending (LAD) arteries, or after distal occlusion of the LAD, or its apical branch. Occlusions were done sequentially in random order separated by 30 min intervals. The anatomic regions normally supplied by each occluded artery (ischaemic beds) were identified by simultaneous postmortem coronary perfusion with different coloured dyes. Proximal occlusions of the LCC and LAD produced equivalent areas of ischaemia (37 and 36% of the left ventricle) and these ischaemic beds had similar amounts of collateral flow (0.12 and 0.16 cm3.min-1.g-1). In comparison, distal LAD and apical branch occlusions involved 23 and 11% of the LV and collateral flow averaged 0.23 and 0.36 cm3.min-1.g-1. Thus, proximal LAD or LCC occlusion produce comparable areas of severe ischaemia. Experimental models using distal occlusions are characterised by more variable but often less severe ischaemia.

Distribution of coronary collateral flow in acute myocardial ischaemic injury: effect of propranolol.

The local distribution of coronary collateral flow was mapped using 8 mu tracer microspheres following circumflex coronary occlusions in dogs. Overall flow to the ischaemic posterior papillary muscle and subjacent myocardium decreased to 21% of anterior free wall flow. Collateral flow was non-uniform, however, and was lower in the subendocardium (14%) than in the subepicardium (27%). Brief temporary occlusions with and without propranolol therapy showed that collateral flow was less and the inner/outer wall ratio was unaltered in treated animals. Although propranolol reduces infarct size after coronary occlusions, this effect appears not to be related to increases in collateral flow.

Cardiac protection by ischaemic preconditioning is not mediated by myocardial stunning.

OBJECTIVE: Previous studies have shown that cardiac protection by ischaemic preconditioning wanes before contractile function recovers; thus stunning is insufficient to cause preconditioning. To test whether reduced contractile effort is necessary for preconditioning induced protection, the effect on myocardial infarct size of restoring contractile function with dobutamine was examined in preconditioned and control dogs. METHODS: In two experimental groups (groups P and P+D), preconditioning was produced by four 5 min occlusions of the left anterior descending coronary artery, each separated by 5 min of reperfusion. Contractile function was assessed by sonomicrometry 5 min after completion of the preconditioning protocol. In group P+D, dobutamine (average dose = 5 micrograms.kg-1.min-1) was then infused intravenously to restore systolic shortening to baseline. The artery then was reoccluded for 40 min of sustained ischaemia followed by 4 d of reperfusion. Two additional groups of non-preconditioned control dogs (groups C and C+D) also underwent 40 min of coronary occlusion and 4 d of reperfusion. Group C+D received a dobutamine infusion beginning 15 min before and during the 40 min occlusion to match the dobutamine received in group P+D, whereas group C received normal saline. RESULTS: Preconditioning caused mild postischaemic contractile dysfunction (50% decrease in systolic shortening) which was easily reversed by dobutamine treatment. Dobutamine also increased both the rate-pressure product and the left ventricular dP/dt in both treated groups (C+D and P+D). Histological infarct size was 12.3(SEM 2.0)% of the area at risk in the untreated control group (n = 11), and was reduced to 4.4(1.7)% in the untreated preconditioning group (n = 8; p < 0.05). Dobutamine increased non-preconditioned infarct size (group C+D) to 22.1(3.4)% (n = 7; p < 0.05). Infarct size in the dobutamine treated preconditioning group (P+D) was not significantly different from infarct size in group P (n = 8), at 6.1(2.5%). CONCLUSIONS: In preconditioned hearts, dobutamine restored postischaemic contractile function but did not increase infarct size significantly. Thus reduced contractile effort is not required for the cardioprotective effect on ischaemic preconditioning.

Effect of catecholamine depletion on myocardial infarct size in dogs: role of catecholamines in ischemic preconditioning.

OBJECTIVES: Cardioprotective adaptation to brief periods of ischemia and reperfusion is termed ischemic preconditioning (PC). Limitation of infarct size by preconditioning is associated with marked slowing of ischemic metabolism. The cause of metabolic slowing has not been determined but may involve either pro- or anti-adrenergic mechanisms. Hypothetically, adrenergic stimulation could signal the adaptive response. Alternatively, metabolic slowing during the sustained ischemic challenge could occur through a reduction in beta-adrenergic stimulation. This study was designed to test the role of cardiac norepinephrine (NE) in PC. METHODS: The effect of PC on myocardial infarct size was studied in control dogs and dogs depleted of catecholamines by pretreatment with reserpine (RES; 0.25 mg/kg i.v.). PC was induced by four cycles of 5 min of ischemia and 5 min of reperfusion. Infarcts were produced by 60 min of ischemia and 3 h of reperfusion. Cardiac NE depletion was verified by radioimmunoassay of tissue samples and by absence of hemodynamic response to a tyramine bolus (1.4 mg/kg) administered at the end of each experiment. Infarct size, expressed as percent of area at risk, was controlled for variation in collateral blood flow using analysis of covariance (ANCOVA). RESULTS: Adjusted mean infarct size was 25.5 +/- 3.2% in untreated controls vs. 19.1 +/- 3.3% in RES-treated controls (P = NS). PC limited infarct size in untreated dogs (7.4 +/- 1.8 vs. 25.5 +/- 3.2%; PC vs. control; P < 0.01) but not in RES-treated dogs (15.7 +/- 3.0% vs. 19.1 +/- 3.3%; RES + PC vs. RES; P = NS). Infarct size was larger in dogs with RES + PC than with PC alone, even though there was a trend toward a slight beneficial effect with RES alone. CONCLUSION: The cardioprotective effect of ischemic preconditioning cannot be explained entirely as an anti-adrenergic effect. On the contrary, adrenergic receptor stimulation may be required for the full expression of ischemic preconditioning in canine myocardium.

Intracoronary administration of the alpha 1-receptor agonist, methoxamine, does not reproduce the infarct-limiting effect of ischemic preconditioning in dogs.

BACKGROUND: The cardioprotective effect of ischemic preconditioning has been hypothesized to occur through one or more signalling mechanisms which activate protein kinase C. Stimulation of alpha 1-adrenergic receptors by catecholamines released during the preconditioning episodes of ischemia is one of these putative signalling mechanisms. METHODS: To determine whether stimulation of alpha 1-adrenergic receptors before an ischemic challenge can mimic preconditioning, anesthetized dogs were treated with 4 intracoronary infusions of methoxamine HCl (10 micrograms/kg/min; n = 8), each 5 min in duration and followed by 5 min of washout. Control dogs (n = 10) were given similar infusions of 0.9% NaCl. A third group of dogs was preconditioned with 4 cycles of 5 min ischemia, each followed by 5 min of reperfusion (n = 8). All dogs then underwent 60 min of ischemia (circumflex coronary occlusion) followed by 3 h of reperfusion. Infarct size (expressed as % of area-at-risk) was measured with TTC macrochemistery and analyzed (using analysis of covariance [ANCOVA]) with respect to coronary collateral blood flow (measured using radioactive microspheres). RESULTS: Methoxamine markedly increased systemic arterial and left atrial pressures prior to but not during the ischemic challenge. Baseline predictors of infarct size were not different among the groups. Mean infarct size (adjusted from ANCOVA) did not differ between control and methoxamine-treated groups, 28.3 +/- 2.8% vs. 29.7 +/- 3.2%, respectively (P = NS), but was only 12.7 +/- 3.2% in the preconditioned group (P < 0.01 vs. control and methoxamine). CONCLUSIONS: A series of methoxamine infusions before an ischemic challenge did not affect infarct size. Thus, stimulation of alpha 1-adrenergic receptors alone is insufficient to mimic the cardioprotective effect of ischemic preconditioning in this canine model.

Hypoxic reperfusion to remove ischaemic catabolites prior to arterial reperfusion does not limit the size of myocardial infarcts in dogs.

STUDY OBJECTIVE: Although timely reperfusion limits myocardial infarct size, it has been postulated that reperfusion itself may kill some myocytes which were alive at the end of an episode of ischaemia (lethal reperfusion injury). The aim of this study was to test the hypothesis that ischaemic catabolites may "prime" myocardium for such injury and that preliminary hypoxic washout of such catabolites, prior to arterial reperfusion, would limit myocardial infarct size. DESIGN: Dogs underwent a 40 min occlusion of the left circumflex coronary artery, followed by 4 d reperfusion. In a treated group, a 5 min episode of coronary artery perfusion with hypoxic buffer was instituted at the end of this ischaemic episode, before blood reperfusion was restored. Control dogs received a similar volume of hypoxic buffer intravenously. Systemic fluid overload was attenuated by haemofiltration. The effect of this preliminary hypoxic washout on myocardial infarct size was assessed. EXPERIMENTAL MATERIAL: 18 anaesthetised, open chest dogs were used. After the acute study they recovered from surgery for 4 d and were then killed for further study. MEASUREMENTS AND MAIN RESULTS: Infarct size, determined by microscopic evaluation, was not significantly different in the two groups, at (control) 31.3 (SEM 6.2)% v (hypoxic reperfusion) 25.8(3.9)% of the vascular area at risk. In control dogs, infarct size was inversely related to the amount of collateral blood flow (measured using microspheres); hypoxic reperfusion did not shift this relation (analysis of covariance, F = 0.236, NS). CONCLUSIONS: The washout of ischaemic catabolites by hypoxic perfusate prior to reoxygenation did not limit infarct size.

Effects of calcium-channel blockers on myocardial preservation during experimental acute myocardial infarction.

Calcium antagonists have become accepted agents for the attenuation of myocardial ischemia when it becomes manifest as angina pectoris. However, it is not known whether these agents can protect ischemic myocardium during the early evolution of an acute myocardial infarct. Calcium antagonists could potentially improve myocardial perfusion, by relieving coronary spasm or improving collateral blood flow, and reduce the energy demands of the ischemic myocardium either directly or by reducing heart rate or contractility. In some studies, calcium antagonists have decreased the rate of adenosine triphosphate depletion in ischemia and reduced functional or structural indexes of ischemic injury after relatively brief periods (up to 2 hours) of injury. We have assessed the ability of verapamil to protect severely ischemic myocardium in dogs with a 40-minute test period of circumflex occlusion followed by reperfusion. After 4 days of recovery, infarcts were sized by histologic methods. Untreated dogs had subendocardial infarcts (the more moderately ischemic subepicardial region being salvaged by reperfusion). Pretreatment with verapamil reduced the size of these subendocardial infarcts from 34 +/- 8 to 8 +/- 3% of the ischemic circumflex vascular bed (anatomic area at risk). Thus, verapamil prevented cell death in a substantial proportion of the severely ischemic subendocardial region that otherwise would have died as a result of the 40-minute test period of ischemia. To establish whether verapamil could prevent cell death for a longer period of time in the less severely ischemic subepicardial region, a 3-hour period of coronary occlusion with reperfusion was studied.

Reperfusion in acute myocardial infarction: effect of timing and modulating factors in experimental models.

Timely reperfusion of ischemic myocardium in experimental animals halts the advancing transmural "wavefront" of ischemic cell death and thereby limits myocardial infarct size by limiting its transmural extent. The time window of opportunity for such salvage in most experimental models of regional ischemia is the first 3 hours. The number of myocytes that can be salvaged by reperfusion decreases exponentially during this period, such that at 3 hours, reperfusion limits infarct size by only about 10%. The rate of lethal ischemic cell injury and therefore the amount of myocardium that can be salvaged by reperfusion after a particular duration of ischemia is dependent both on the degree of blood flow deficit and the rate of ischemic metabolism. In experimental animal models, several interventions, including hypothermia, calcium antagonists, and "ischemic preconditioning," have been shown to reduce the rate of ischemic metabolism and to limit myocardial infarct size when assessed after a defined period of ischemia and reperfusion. Hypothetically, interventions that could prevent additional myocyte necrosis caused by some deleterious aspects of reperfusion ("lethal reperfusion injury") also could serve as valuable adjunctive therapy. However, studies of therapies designed to prevent lethal reperfusion injury have produced conflicting results. Thus, the concept that lethal reperfusion injury occurs remains controversial. Experimental evidence indicates that reperfusion accelerates both the initial inflammatory response and later process of infarct repair. Late reperfusion of infarcts in dogs, which does not limit myocardial infarct size, appears to accelerate the replacement of necrotic myocardium by scar without altering the size of the final scar.

Pathobiology of acute myocardial ischemia: metabolic, functional and ultrastructural studies.

Acute myocardial ischemia induced by coronary occlusion in dogs is most severe in the subendocardial region, whereas more collateral blood flow is often present in the subepicardial region. Initially, all ischemic myocytes are reversibly injured, but beginning at 15 to 20 minutes after the onset, and continuing for 3 to 6 hours, there is a wave front of cell death from the subendocardial region to the less ischemic subepicardial region, such that by 6 hours, the final transmural extent of the infarct is established. Thus, ischemic myocardium cannot be salvaged by reperfusion after greater than or equal to 6 hours of coronary occlusion in open-chest anesthetized dogs. In the severely ischemic subendocardial region, most of the creatine phosphate is lost within the first 3 minutes of ischemia in vivo, and adenosine triphosphate (ATP) is depleted to 35% of control by 15 minutes (when cellular injury is still reversible), and to less than 10% of control at 40 minutes (when injury is irreversible). Tissue ATP content and other indexes of subcellular damage have also been compared after different periods of ischemia using a model of total myocardial ischemia in vitro. As long as the ATP of the tissue was not depleted below 5 mumols/g dry weight, incubated slices of injured myocardium resynthesized high-energy phosphates and excluded inulin. However, lower tissue ATP was associated with depressed high-energy phosphate resynthesis and failure of cell volume regulation. Overt membrane damage, as measured by an increased inulin-diffusible space, was detected only after the tissue ATP decreased to less than 2.0 mumols/g of dry weight. Thus, marked ATP depletion is associated with the onset of structural and functional indexes of irreversible injury. However, whether irreversibility is caused by the marked ATP depletion or by other concomitant metabolic consequences of ischemia is not known. Myocardial ischemic cellular injury is reversible despite depletion of 70% of the control ATP. Nevertheless, when myocyte injury is reversible, there is slow repletion of adenine nucleotides. This slow metabolic recovery may explain the delayed recovery of contractile function observed after reperfusion of ischemic myocardium.

On the nature of protection by propranolol against myocardial necrosis after temporary coronary occlusion in dogs.

Propranolol has been shown to reduce the extent of necrosis that develops after temporary coronary occlusion in dogs. To determine whether this protective action was related to beta adrenergic blockade or to direct effects, necrosis was quantitated in the posterior papillary muscle 2 to 4 days after 40 minute periods of coronary occlusion in anesthetized open chest dogs. Groups of dogs either were untreated or were pretreated with doses of d,l-propranolol, 0.005 to 5 mg/kg body weight, or doses of d-propranolol 2.5 or 5 mg/kg. Necrosis was greatly reduced in dogs treated with 5 mg/kg of d, l-propranolol. This protective effect was significant but quantitatively less with 0.5 and 0.05 mg/kg of d, l-propranolol. A dose of 0.005 mg/kg d, l-propranolol and d-propranolol failed to alter myocardial necrosis significantly. The dose-related reduction of necrosis with d, l-propranolol correlated with a similar dose relation for beta adrenergic blockade and suggested that a protective effect was related to beta blockade. The reduction of necrosis with 0.05 and 0.5 mg/kg of d, l-propranolol (a level at which direct "membrane stabilizing" effects are insignificant) suggested that direct effects were not essential for protection. The negative results with d-propranolol further support our conclusion that propranolol reduces myocardial ischemic injury through beta adrenergic blockade rather than through direct myocardial actions.

Sensitivity of a set of myocardial infarction screening criteria in patients with anatomically documented single and multiple infarcts.

A subset of 3 screening criteria (Q wave greater than or equal to 30 ms in lead aVF, any Q or R wave less than or equal to 10 ms and less than or equal to 0.1 mV in lead V2, and R wave greater than or equal to 40 ms in V1) has been proposed to identify single nonacute myocardial infarcts. Cumulatively, these 3 criteria achieved 95% specificity, and 84 and 77% sensitivities for inferior and anterior myocardial infarcts, respectively, among patients identified by coronary angiography and left ventriculography. This study establishes the true sensitivities of the set of screening criteria in 71 patients with anatomically proven single myocardial infarcts and 32 patients with multiple myocardial infarcts. In the single inferior infarct group, the aVF criterion was 90% sensitive. The V2 criterion (any Q or R wave less than or equal to 10 ms and less than or equal to 0.1 mV) was 67% sensitive in the single anterior infarct group. No single criterion proved sensitive in identifying a posterolateral infarct. The set of screening criteria performed just as well for multiple infarcts as it did for single infarcts, with a cumulative sensitivity of 72%. The overall sensitivity of the screening set in the 103 patients in all groups was 71%.

Anatomic validation of electrocardiographic estimation of the size of acute or healed myocardial infarcts.

Seventeen new criteria added to the simplified version of the Selvester QRS scoring system to comprise the complete version were evaluated to determine their value in estimating the size of single infarcts. These non-Q-wave criteria might be particularly useful regarding posterolateral infarcts in the distribution of the left circumflex artery. The study population was made up of 21 anterior, 30 inferior and 20 posterolateral single myocardial infarction (MI) patients with no evidences of bundle branch or fascicular blocks, ventricular hypertrophy or previous MI on their final stable electrocardiogram. The complete system's maximum 32 points is capable of indicating MI in 96% of the left ventricle and it estimated a mean electrocardiographic MI size that better approximated the anatomic size compared with the simplified version in all MI locations. The correlation between anatomic and electrocardiographic MI size using the complete system was better and statistically significant for the posterolateral MI group (simplified r = 0.55, p less than 0.01 vs complete r = 0.70, p less than 0.0006). Criteria such as Q and S amplitude less than or equal to 0.3 mV in V1 and less than or equal to 0.4 mV in V2 were particularly helpful. This study documents the improved ability provided by the 17 additional non-Q-wave criteria which have been added in the complete version of this scoring system regarding the sizing of infarcts in the region of the left ventricle supplied by the left circumflex artery.