Mitochondrial Reversible Changes Determine Diastolic Function Adaptations During Myocardial (Reverse) Remodeling

Abstract

Background: Often, pressure overload-induced myocardial remodeling does not undergo complete reverse remodeling after decreasing afterload. Recently, mitochondrial abnormalities and oxidative stress have been successively implicated in the pathogenesis of several chronic pressure overload cardiac diseases. Therefore, we aim to clarify the myocardial energetic dysregulation in (reverse) remodeling, mainly focusing on the mitochondria. Methods: Thirty-five Wistar Han male rats randomly underwent sham or ascending (supravalvular) aortic banding procedure. Echocardiography revealed that banding induced concentric hypertrophy and diastolic dysfunction (early diastolic transmitral flow velocity to peak early-diastolic annular velocity ratio, E/E′: sham, 13.6±2.1, banding, 18.5±4.1, P=0.014) accompanied by increased oxidative stress (dihydroethidium fluorescence: sham, 1.6×108±6.1×107, banding, 2.6×108±4.5×107, P<0.001) and augmented mitochondrial function. After 8 to 9 weeks, half of the banding animals underwent overload relief by an aortic debanding surgery (n=10). Results: Two weeks later, hypertrophy decreased with the decline of oxidative stress (dihydroethidium fluorescence: banding, 2.6×108±4.5×107, debanding, 1.96×108±6.8×107, P<0.001) and diastolic dysfunction improved simultaneously (E/E′: banding, 18.5±4.1, debanding, 15.1±1.8, P=0.029). The reduction of energetic demands imposed by overload relief allowed the mitochondria to reduce its activity and myocardial levels of phosphocreatine, phosphocreatine/ATP, and ATP/ADP to normalize in debanding towards sham values (phosphocreatine: sham, 38.4±7.4, debanding, 35.6±8.7, P=0.71; phosphocreatine/ATP: sham, 1.22±0.23 debanding, 1.11±0.24, P=0.59; ATP/ADP: sham, 6.2±0.9, debanding, 5.6±1.6, P=0.66). Despite the decreased mitochondrial area, complex III and V expression increased in debanding compared with sham or banding. Autophagy and mitophagy-related markers increased in banding and remained higher in debanding rats. Conclusions: During compensatory and maladaptive hypertrophy, mitochondria become more active. However, as the disease progresses, the myocardial energetic demands increase and the myocardium becomes energy deficient. During reverse remodeling, the concomitant attenuation of cardiac hypertrophy and oxidative stress allowed myocardial energetics, left ventricle hypertrophy, and diastolic dysfunction to recover. Autophagy and mitophagy are probably involved in the myocardial adaptation to overload and to unload. We conclude that these mitochondrial reversible changes underlie diastolic function adaptations during myocardial (reverse) remodeling.