The mandatory use of pharmacotherapy in human heart failure (HF) impedes further study of natural history and remodeling mechanisms. We created a sheep model of chronic, severe, ischemic HF [left ventricular (LV) ejection fraction (LVEF) <35% stable over 4 wk] by selective coronary microembolization under general anesthesia and followed hemodynamic, energetic, neurohumoral, structural, and cellular responses over 6 mo. Thirty-eight sheep were induced into HF (58% success), with 23 sheep followed for 6 mo (21 sheep with sufficient data for analysis) after the LVEF stabilized (median of 3 embolizations). Early doubling of LV end-diastolic pressure persisted, as did increases in LV end-diastolic volume, LV wall stress, and LV wall thinning. Contractile impairment (LV end-systolic elastance, LV preload recruitable stroke work, and dobutamine-responsive contractile reserve) and diastolic dysfunction also remained stable. Cardiac mechanical energy efficiency did not recover. Plasma atrial natriuretic peptide levels remained elevated, but rises in plasma aldosterone and renin activity were transient. Collagen content increased 170%, the type I-to-III phenotype ratio doubled in the LV, but right ventricular collagen remained unaltered. Fas ligand cytokine levels correlated with expression of both caspase-3 and -2, suggesting a link in the apoptotic "death cascade." Caspase-3 activity also bore a close relationship to LV meridional wall stress calculated from echocardiographic and intraventricular pressure measurements. We concluded that the stability of chronic untreated severe ischemic HF depends on the recruitment of myocardial remodeling mechanisms that involve an interaction among hemodynamic load, contractile efficiency/energetics, neurohumoral activation, response of the extracellular matrix, wall stress, and the myocyte apoptotic pathway.

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In cardiopulmonary bypass (CPB), despite heparin regimens in which the activated clotting time (ACT) is kept at more than 400 s, there is biochemical evidence of thrombin generation indicating activation of the coagulation system and increased fibrinolytic activity. Therefore, to reduce the coagulant activation has been one of the main issues in the improvement of CPB. The purpose of this study was to compare the heparin concentration with the ACT and to evaluate the effect of keeping higher heparin concentration on the coagulation and fibrinolytic systems during hypothermic CPB, employing moderate hypothermia (MHT) or deep hypothermic circulatory arrest (DHT). Heparin was either administered to maintain an ACT >400 s (ACT group) or to maintain a whole blood heparin concentration of 3 mg/kg (heparin group). At the lowest core temperature during CPB, the ACT and the heparinase ACT (unrelated to heparin concentration) were increased the most whereas the whole blood heparin concentration was less than half the initial concentration in both ACT groups of MHT and DHT. The thrombin-antithrombin III (TAT) content just after CPB in both MHT and DHT was significantly lower in the heparin group than in the ACT group. In conclusion, ACT does not reflect the whole blood heparin concentration during hypothermic CPB. Furthermore, maintenance of the higher heparin concentration during hypothermic CPB may suppress the activation of the coagulation system via thrombin inhibition. That effect was more remarkable in deep hypothermic CPB. Therefore, we believe that anticoagulation management during hypothermic CPB should be based on the maintenance of the higher blood heparin concentration.

This is the first study to demonstrate that diabetes alters ventricular energetics in vivo. LV oxygen utilization efficiency is impaired as a consequence of decreased contractile efficiency and stroke work efficiency. Impaired efficiency of oxygen utilization may explain in part the increased sensitivity of the diabetic heart to ischemia and the accelerated deterioration of ventricular function in diabetic patients.

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