Energetic correlates of cardiac failure: changes in the creatine kinase system in the failing myocardium.

To address the hypothesis that impaired ATP synthesis rates caused by changes in the creatine kinase system is an important mechanism underlying cardiac failure, we measured total creatine kinase activity, isoenzyme composition and creatine content in two animal models of hypertrophy with cardiac dysfunction, the spontaneously hypertensive rat in the transition to failure and the creatine-depleted hyperthyroid rat heart challenged by hypoxia. During the transition from stable compensated hypertrophy to failure characterized by decreased functional capacity, we found that total creatine kinase activity and particularly mitochondrial creatine kinase activity decreased. The decrease in functional capacity, the further increase in heart size and the derangements in the creatine kinase system did not occur if these animals were treated for 6 months with the antihypertensive agents, guanethidine or hydralazine. These results suggest that changes in the creatine kinase system occur coordinately with the transition to failure. To assess whether the changes in the creatine system may be causally linked to decreased functional capacity, we used 31P NMR spectroscopy of isolated perfused hearts to define the high energy phosphate content and cardiac performance of creatine-depleted (approximately 50%) hypertrophied hearts challenged by hypoxia. These hearts displayed greater susceptibility to hypoxic injury with regard to both systolic and diastolic function during and following hypoxia. We also measured total creatine kinase activity in right ventricular biopsy specimens from patients with various forms of cardiomyopathy and low ejection fractions, and found a positive correlation between total creatine kinase activity and ejection fraction. Taken together, these results support the hypothesis that decreasing the energy reserve for ATP synthesis renders the heart more susceptible to systolic and diastolic failure.

Extent of myocardial fibrosis and cellular hypertrophy in dilated cardiomyopathy.

The distribution of fibrosis and cellular hypertrophy was studied in the hearts of patients with dilated cardiomyopathy (DC). Transmural sections were removed from the left and right ventricular free walls and the ventricular septum of 9 patients with heart failure and 6 control subjects. These sections were stained with hematoxylin-eosin (to determine cell size) and trichrome (to determine percent fibrosis). The sections were separated into equal areas from epicardium to endocardium in the free walls and right to left across the septum. Percent fibrosis was greater in patients with DC (20 +/- 4%) than control subjects (4 +/- 1%, p = 0.0001). A pattern of increasing fibrosis in the left ventricular free wall from epicardium (14 +/- 6%) to endocardium (22 +/- 9%, p less than 0.05) was documented. Fibrosis was greater on the left (21 +/- 12%) than the right (15 +/- 6%, p less than 0.05) side of the septum. No pattern was evident in the right ventricular free wall or in the control group. Myocardial cell diameter was greater in the heart failure group (22 +/- 5 micron) than the control group (17 +/- 2 micron, p less than 0.05), but no pattern of hypertrophy across the walls was seen. The increased fibrosis, the pattern of fibrosis and the increased cell diameter in patients with DC help to characterize DC.

Factors influencing the one-year mortality of dilated cardiomyopathy.

This study was designed to determine prognostic risk indicators of nonischemic dilated cardiomyopathy (DC). Sixty-nine patients were studied. Each patient underwent physical examination (including a history), electrocardiography, echocardiography, cardiac catheterization, 24-hour monitoring and endomyocardial biopsy. The mortality rate at 1 year was 35% (24 deaths). Univariate analysis revealed that the most powerful predictor of prognosis was the left intraventricular conduction delay (p = 0.003). The pulmonary capillary wedge pressure was also predictive of mortality (p = 0.005). Other significant factors, in order of importance, were ventricular arrhythmias (p = 0.007), mean right atrial pressure (p = 0.008), angiographic ejection fraction (p = 0.03), atrial fibrillation or flutter (p = 0.01) and the presence of an S3 gallop (p = 0.05). Factors such as duration of symptoms, presence of mitral regurgitation, end-diastolic diameter, myocardial cell size and percent fibrosis in the biopsy and treatment with vasodilators, antiarrhythmic and anticoagulant drugs were not significant predictors. Multivariate analysis was used to determine which combination of factors could most accurately predict survival and death. The most important factors were left conduction delay, ventricular arrhythmias and mean right atrial pressure. An equation was derived that can be applied to the prognosis of patients with DC. Thus, the clinical assessment of patients with DC can accurately predict the probability of surviving or dying in 1 year.

Human myocardial histologic characteristics in congestive heart failure.

The purpose of this study was to identify the histologic characteristics of human myocardium in congestive heart failure (CHF) by cellular hypertrophy, nuclear area, endocardial thickness, and percentage of fibrosis and to correlate histologic findings to cause, severity, and duration of disease. Right ventricular endomyocardial biopsies from 109 patients were quantitatively analyzed. Ten patients with normal cardiac history, physical examination results, and cardiac function served as the control group. The remaining patients were divided into the following groups: those treated with doxorubicin (n = 18), and those with chest pain with normal coronary arteries (n = 8), familial CHF (n = 3), CHF associated with myotonic dystrophy (n = 3), peripartal CHF (n = 2), valvular CHF (n = 9), alcohol-induced CHF (n = 13), postviral CHF (n = 6), or idiopathic CHF (n = 36). Linear regression analyses showed a strong correlation between cell diameter and nuclear area (r = .70, p less than .001) and weaker correlations between amount of fibrosis and cell diameter (r = .30, p less than .005) and fibrosis and nuclear area (r = .29, p less than .005). Results of function studies and histologic measurements (e.g., echocardiographically measured change in the minor-axis dimension of the left ventricle with systole and cell diameter) correlated poorly (r = -.33, p less than .005). Duration of dyspnea did not correlate with any histologic factor. Within the normal group there was a direct correlation of cell diameter with age (r = .67, p less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)