A decrease in the myocardial level of the mRNA encoding the Ca2+-ATPase of the sarcoplasmic reticulum (SR) has been recently reported during experimental cardiac hypertrophy and failure. To determine if such a deficit occurs in human endstage heart failure, we compared the SR Ca2+-ATPase mRNA levels in left (LV) and right ventricular (RV) specimens from 13 patients undergoing cardiac transplantation (6 idiopathic dilated cardiomyopathies; 4 coronary artery diseases with myocardial infarctions; 3 diverse etiologies) with control heart samples using a rat cardiac SR Ca2+-ATPase cDNA probe. We observed a marked decrease in the mRNA for the Ca2+-ATPase relative to both the 18S ribosomal RNA and the myosin heavy chain mRNA in LV specimens of patients with heart failure compared to controls (-48%, P < 0.01 and -47%, P < 0.05, respectively). The LV ratio of Ca2+-ATPase mRNA to 18S RNA positively correlated with cardiac index (P < 0.02).The RV ratio correlated negatively with systolic, diastolic and mean pulmonary arterial pressures (P < 0.02, P < 0.02, and P < 0.01, respectively). We suggest that a decrease of the SR Ca2+-ATPase mRNA in the myocardium plays an important role in alterations of Ca2+ movements and myocardial relaxation reported during human end-stage heart failure. (J. Clin. Invest. 1990. 85:305-309.) gene expression * heart failurehuman left ventricle -myosin heavy chain mRNA * sarcoplasmic reticulum Ca2+-ATPase mRNA

We studied the effect of chronic mechanical overloading on the isoenzyme composition of rat cardiac myosin in several experimental models: aortic stenosis (AS), aortic incompetence (AI), aortocaval fistula (ACF), overload of the non-infarcted area after left coronary ligation (INF), and overload of the spontaneously hypertensive rats (SHR). Samples of the left and right ventricles were isolated from these hearts, and myosins were analyzed by electrophoresis in non-dissociating conditions. The myosin isoenzymes were called V1, V2, and V3 in order of decreasing mobility, according to the nomenclature of Hoh et al. Controls of the Wistar and Wistar Kyoto (WKY) strains were almost exclusively V1, A slow age-dependent shift toward V3 was observed in the left ventricles of adult Wistar rats, which at 30 weeks of age (body weight 600 g) contained approximately 15% of this form. In all models of cardiac hypertrophy, an isoenzymic redistribution was observed with a significant increase in V3. The level of V3 was statistically correlated with the degree of hypertrophy in the AS, (n = 11, r - 0.6, P less than 0.05), the AI (n = 14, 4 = 0.88, P less than 0.001), and the AS + AI(n = 14, 4 = 0.69, P less than 0.01) but not in the ACF (n = 16, r = 0.46). The isoenzymic changes could account for the decreases in both myosin ATPase activity and cardiac contractility described previously in our laboratory and by others. They also demonstrate that changes in myosin isoenzymes represent a general response of the rat heart, to chronic mechanical overloading.

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Pressure overload induces cardiac growth in the rat, which implies the hypertrophy of cardiac muscle cells and proliferation of nonmuscle cells. The cardiac cell loss observed in parallel has generally been attributed to necrosis. Using an in situ assay, we demonstrated a phase of apoptosis or programmed cell death during the first 7 d after pressure overload with a peak at day 4 while cardiac growth continued for over 30 d. The increase in apoptosis was confirmed by quantification of 180-1500-bp DNA oligonucleosomes with agarose gel electrophoresis and in situ labeling via 3 Ј -terminal deoxynucleotidyl transferase assay. While some apoptosis was observed in the basal state in nonmuscle cells, pressure overload induced apoptosis mainly in cardiomyocytes. These data suggest that cardiac hypertrophy is initiated by a wave of apoptosis of cardiomyocytes. Thus, apoptosis may be involved in the pathogenesis of heart remodeling. ( J. Clin. Invest. 1996. 97:2891-2897.) Key words: apoptosis • heart • hypertrophy • aortic stenosis • pressure overload