Morphologic and hemodynamic changes that occur following coronary occlusion are examined. The effectiveness of hyperosmotic mannitol in lessening the extent of myocardial damage is assessed and mechanisms for its action discussed. Forty and 60 min of coronary vascular occlusion followed by 15 and 45 min of reflow were associated with a persistence of ischemia following reflow of blood, as established by infusions of silastic into the aortic root. Electron microscopic studies demonstrated myocardial and endothelial cell swelling at the end of the reflow period. The process of cell swelling appeared to be initiated during the period of arterial occlusion. This cell swelling was reduced by elevation of serum osmolality by 30-40 mOsm above control with the administration of mannitol during and following occlusion. There was an associated 40-50% reduction of vascular resistance following occlusion if mannitol was administered. In addition, the extent of necrosis, which was widespread in untreated hearts 12 hours after occlusion, was strikingly less in the hearts of dogs which received mannitol. Thus, in ischemic myocardium, elevation of osmolality by mannitol reduces myocardial necrosis, probably through its restoration of normal cell volume.
Previously, we demonstrated that there were effects of elevated plasma osmolality on both early cell swelling and eventual cell necrosis in ischemic cardiac muscle. The present study quantifies the extent of cell volume derangement, determines whether or not there is a quantitative relationship between cell swelling and eventual necrosis, and defines the time limits of ischemia within which prevention of early swelling by hyperosmotic intervention can reduce eventual necrosis. Computer-assisted analysis of tissue pathology was used for quantification of myocardial cell swelling early during ischemia. The results then were correlated with the extent of eventual necrosis. When canine posterior papillary muscle was sampled for electron microscopy soon after the restoration of blood flow following proximal circumflex artery occlusion, stereological methods revealed a substantial increase in myocardial cell volume. The data define the spectrum of volume gain in ischemic myocardial cells. The effectiveness of an osmotic intervention with mannitol in preventing cell swelling and eventual necrosis was limited to ischemic periods of less than 90 minutes. There was a strong linear correlation between the fractions of cells with increased volume (whether the increase was measured as cytoplasmic space, mitochondrial volume, or overall volume expansion), and the fraction of cells necrotic 12 hours after restoration of blood flow. The pattern of action of osmotic intervention in the prevention of ischemic cell swelling and in diminishing eventual necrosis in this model suggests strongly that there is an important relationship between a failure in cell volume regulation and eventual cell death in myocardial ischemia. Circ Res 47: [653][654][655][656][657][658][659][660][661][662][663][664][665] 1980
A B S T R A C T The purpose of this study was to evaluate the effect of hyperosmolality on the performance of, and the collateral blood flow to, ischemic myocardium. The myocardial response to mannitol, a hyperosmolar agent which remains extracellular, was evaluated in anesthetized dogs. Mannitol was infused into the aortic roots of 31 isovolumic hearts and of 15 dogs on right heart bypass, before and during ischemia. Myocardial ischemia was produced by temporary ligation of either the proximal or mid-left anterior descending coronary artery.Mannitol significantly improved the depressed ventricular function curves which occurred with left anterior descending coronary artery occlusion. Mannitol also significantly lessened the S-T segment elevation (epicardial electrocardiogram) occurring during myocardial ischemia in the isovolumic hearts and this reduction was associated with significant increases in total coronary blood flow (P < 0.005) and with increased collateral coronary blood flow to the ischemia area (P < 0.005).Thus, increases in serum osmolality produced by mannitol result in the following beneficial changes during myocardial ischemia: (a) improved myocardial function, (b) reduced S-T segment elevation, (c) increased total coronary blood flow, and (d) increased collateral coronary blood flow.
The effect of intra-aortic Counterpulsation (IACP) with a balloon upon myocardial oxygen consumption (MV · o 2 ), coronary blood flow (TCF), and left ventricular performance was studied in 23 anesthetized canine right heart bypass preparations at constant heart rate and cardiac output. In nonhypotensive, nonTCF-limited preparations, IACP produced a fall in left ventricular peak systolic pressure (LVP) and a decrease in MV · o 2 (-1.1 ± 0.2 (SE) ml/min/100 g LV). In these animals there was little steady state change in TCF (-5.6±5.9 ml/min), secondary to autoregulation by the coronary vascular bed. Left ventricular end-diastolic pressure (LVEDP) fell if elevated but exhibited little change if initially normal. However, in hypotensive preparations, in which left ventricular performance was substantially limited by a decreased TCF, IACP produced a striking increase in TCF (+40.9 ± 8.6 ml/min) accompanied by an increase in MV · o 2 (+1.2±0.3 ml/min/100 g LV). Elevated LVEDPs fell substantially toward normal. Directionally similar changes in LVEDP could be produced by increasing TCF alone in the absence of balloon pumping. When TCF was maintained constant in the hypotensive, TCF-limited preparation, IACP produced a fall in peak LVP and LVEDP. These data document two effects of intra-aortic balloon Counterpulsation upon cardiac dynamics: (1) IACP can decrease left ventricular peak systolic pressure and LVEDP independent of changes in coronary flow; (2) a major effect of IACP in the hypotensive, failing, TCF-limited preparation is to improve cardiac performance by increasing TCF with an associated increase in MV · o 2 .
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