No abstract

Resting coronary blood flow was measured using the fluorescent microsphere technique. Contractile function, defined by rate-pressure product, and myocardial oxygen consumption were measured in a Langendorff preparation. The mitochondrial function was evaluated on permeabilized skinned fibers. Three weeks after surgery, ischemic hearts showed a significant decrease in coronary blood flow compared with sham. Hemodynamic measurements showed a significant systolic and diastolic dysfunction. Alterations in mitochondrial function in ischemic hearts were mainly characterized by a significant decrease in the maximal velocity and apparent half-saturation constant for ADP, loss of the stimulatory effect of creatine, and a stimulatory effect of exogenous cytochrome c. These functional alterations were supported by structural alterations characterized by mitochondrial clustering and swelling associated with membrane rupture. We conclude that the alterations in systolic function after chronic ischemia are supported by severe modifications of mitochondrial structure and function. contractile function; energy metabolism; mitochondria IN A LARGE NUMBER OF PATIENTS affected by chronic coronary artery disease, the magnitude of constriction of the epicardial coronary arteries by atherosclerosis does not correspond to the severity of the clinical manifestations of myocardial dysfunction and failure (5, 28). Similar degrees of coronary stenosis detected angiographically have been found to be associated with variable hemodynamic abnormalities, thus raising questions regarding the significance of these fixed obstructions of the coronary tree in the prediction of the short-and long-term clinical outcomes of ischemic heart disease (5). This apparent inconsistency becomes even greater when anatomic findings are taken into account (5, 27). Similarly, the magnitude of tissue damage represented by multiple focal sites of myocyte loss has been found to be inadequate to explain the marked depression in cardiac performance or the appearance of overt failure (40). Coronary narrowing, involving a reduction in luminal diameter, affects coronary blood flow (CBF), which in turn supports the hypothesis of a decreased oxygen availability. This decrease in blood flow is responsible for an imbalance between energy supply and demand (3). Because energy production in the heart is mainly supported by mitochondrial function, investigations have focused on mitochondrial alterations and energy production during acute ischemia and reperfusion in vitro (17-19). Other works have drawn attention to the interrelations between ventricular contractile performance and the myocardial creatine kinase system (10,12,16,24,26,36). However, to our knowledge, the relationships between mitochondrial and energy transfer alterations have never been addressed in vivo in a model of chronic ischemic failure. To study this phenomenon, coronary artery constriction was surgically produced in rats. CBF, contractile reserve, and mitochondrial function were analyzed 3 wk after surgery...

1 In order to develop a predictive model for the preclinical evaluation of anthracycline cardiotoxicity and the means of preventing it, we have studied the functional parameters of perfused hearts isolated from rats receiving repeated doses of several anthracyclines. 2 The anthracyclines studied were doxorubicin, epirubicin, pirarubicin and daunorubicin, and we also studied a liposomal formulation of daunorubicin (DaunoXome) and the co-administration of dexrazoxane (ICRF-187) and doxorubicin. 3 Anthracyclines were administered i.p. at equimolar doses corresponding to 3 mg kg-' per injection of doxorubicin, every other day for a total of six doses. Dexrazoxane was used at the dose of 30 mg kg-' per injection and was administered either 30 min before or 30 min after doxorubicin. We evaluated any general toxicity towards the animals as well as alterations of left ventricular contractility and relaxation ex vivo.4 Epirubicin and daunorubicin were significantly less cardiotoxic than doxorubicin, and neither pirarubicin nor DaunoXome caused significant alterations in cardiac function. There was a direct relationship between the decrease in cardiac contractility or relaxation and anthracycline accumulation in the heart, evaluated after the same treatment schedule. 5 Dexrazoxane induced a significant protection against doxorubicin-induced cardiac toxicity when administered 30 min before doxorubicin, whereas this protection was ineffective when administered 30 min after doxorubicin. Direct perfusion of DaunoXome in isolated hearts of untreated animals resulted in a 12-fold reduction of the accumulation of daunorubicin in heart tissue as compared to the perfusion of free daunorubicin, and did not cause alterations in cardiac function at a dosage for which free daunorubicin induced major alterations. 6 The isolated perfused rat heart appears to be a valuable model for screening of new anthracyclines and of strategies for circumventing anthracycline cardiotoxicity.

The known shift in collagen synthesis from procollagen type I to type III in patients with atherosclerosis, suggested measurement of serum procollagen III peptide (PIIIP) levels in patients with coronary artery disease (CAD). Two groups of patients were studied: group I--thirty-six patients with CAD (male, mean age 56.9 +/- 7.5 years, hospitalized for coronary angiography. Risk factors included 16 patients with high blood pressure, four diabetics, 31 smokers and 15 with hypercholesterolaemia. Five patients had no significant lesions, seven had one vessel with over 50% stenosis, 10 had two vessels and 14 had three vessels. Group II--35 patients (male, mean age 39.4 +/- 13.3 years), with normal physical examination and ECG according to WHO criteria, formed the control group: the risk factors included nine patients with high blood pressure, 14 smokers and one with hypercholesterolaemia. Procollagen III peptide levels were determined by radioimmunoassay. In group I, PIIIP levels were 26.8 +/- 16 ng ml-1 vs. 10.4 +/- 3.2 for group II. Sixty-one per cent of group I had pathological levels of PIIIP with an absence of correlation with the severity of atherosclerosis or risk factors. Only 2.8% of patients in group II had pathological levels. Procollagen III peptide determination would appear to be a sensitive, specific and predictive test for atherosclerosis in patients with CAD.