Abstract 9424: Caloric Restriction Augments Cardiomyocyte Autophagy to Mitigate Postinfarction Cardiac Remodeling and Heart Failure

Abstract

We previously reported that cardiomyocyte autophagy is an innate mechanism that protects against progression of postinfarction cardiac remodeling. In the present study, we examined effect of caloric restriction (CR), a potent inducer of autophagy, on post infarction cardiac remodeling. Myocardial infarction (MI) was induced in mice by ligating the left coronary artery. After one week of MI, mice were randomly divided into the following four groups. The control group was fed ad libitum (100%). Others were fed restricted diet: 80%, 60%, and 40% of the total calorie which was taken by control mice. The water was provided ad libitum. Three weeks later, we performed echocardiography and catheter to evaluate the left ventricular (LV) function. There was no mouse that died through the period. The body weight was decreased in CR groups (post/pre ratio: 1.08±0.01 in control, 0.83±0.01 in 80% CR, 0.76±0.01 in 60% CR, 0.70±0.01 in 40% CR, p<0.001). However, there was no difference in heart/body weight ratio. The dilatation and hypofunction of the LV were apparent in the control group: left ventricular diastolic dimension (LVDd) = 4.9±0.1 mm; left ventricular ejection fraction (LVEF) = 27±3.3%; and dP/dT = 4677±277 mmHg/s. However, both dilatation and hypofunction were significantly mitigated in groups undergoing CR: in 80%, 60%, and 40% CR, respectively, LVDd = 4.0±0.1 mm, 3.4±0.2 mm and 4.0±0.1 mm; LVEF = 36±2.8%, 51±4.3% and 43±1.5%; and dP/dT = 6849±221 mmHg/s, 7758±638 mmHg/s and 6923±553 mmHg/s, among which the 60% CR group showed the strongest therapeutic effect on postinfarction cardiac remodeling (control vs. 60% CR: p<0.001). Cardiomyocyte autophagy was markedly activated in CR groups as evidenced by the overexpressed microtubule-associated protein 1 light chain 3-II (LC3-II) and specific ultrastructural findings including autophagosome formation. In conclusion, caloric restriction enhances cardiomyocyte autophagy and mitigates postinfarction cardiac remodeling and dysfunction; the optimal caloric restriction is suggested to be 60%. These findings suggest an important clinical implication that a dietary protocol can be a preventive strategy against progression of postinfarction left ventricular remodeling and heart failure.