Abstract
Volume overload leads to development of eccentric cardiac hypertrophy and heart failure. In our previous report, we have shown myocyte hypertrophy with no fibrosis and decrease in gap junctional coupling via connexin43 in a rat model of aorto-caval fistula at 21 weeks. Here we set to analyze the electrophysiological and protein expression changes in the left ventricle and correlate them with phenotypic severity based upon ventricles to body weight ratio. ECG analysis showed increased amplitude and duration of the P wave, prolongation of PR and QRS interval, ST segment elevation and decreased T wave amplitude in the fistula group. Optical mapping showed a prolongation of action potential duration in the hypertrophied hearts. Minimal conduction velocity (CV) showed a bell-shaped curve, with a significant increase in the mild cases and there was a negative correlation of both minimal and maximal CV with heart to body weight ratio. Since the CV is influenced by gap junctional coupling as well as the autonomic nervous system, we measured the amounts of tyrosine hydroxylase (TH) and choline acetyl transferase (ChAT) as a proxy for sympathetic and parasympathetic innervation, respectively. At the protein level, we confirmed a significant decrease in total and phosphorylated connexin43 that was proportional to the level of hypertrophy, and similarly decreased levels of TH and ChAT. Even at a single time-point, severity of morphological phenotype correlates with progression of molecular and electrophysiological changes, with the most hypertrophied hearts showing the most severe changes that might be related to arrhythmogenesis.
Highlights
Heart failure is a pathological state in which the heart is unable to pump blood sufficiently to supply the organism with oxygen and nutrients
Two aortocaval fistula (ACF) animals died prior to study termination; autopsy performed in one revealed increased heart weight and grossly increased lung weight with presence of ascites and hydrothorax, suggesting heart failure as the cause of death
We explored changes in ventricular myocardium in the settings of volume-overload heart failure as a potential substrate for arrhythmias
Summary
Heart failure is a pathological state in which the heart is unable to pump blood sufficiently to supply the organism with oxygen and nutrients. Independent of its etiology, it decreases patient’s quality of life and increases the risk of sudden death (reviewed in Stevens et al, 2013). Electrophysiological Remodeling in Volume-Overloaded Rat Heart studies in heart failure patients showed a fivefold increase in the risk of sudden death (Kannel et al, 1988) and low left ventricular ejection fraction and incidence of ventricular tachycardia on Holter monitoring as predictors of both overall mortality and sudden cardiac death (Gradman et al, 1989). A significant decrease in quality of life of heart failure patients was demonstrated in community settings (Hobbs et al, 2002), and health-related quality of life was found to independently predict mortality and hospitalization after adjustment for ejection fraction, age, and functional classification (Konstam et al, 1996)
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