Increased passive stiffness promotes diastolic dysfunction despite improved Ca2+ handling during left ventricular concentric hypertrophy

Abstract

AimsConcentric hypertrophy following pressure-overload is linked to preserved systolic function but impaired diastolic function, and is an important substrate for heart failure with preserved ejection fraction. While increased passive stiffness of the myocardium is a suggested mechanism underlying diastolic dysfunction in these hearts, the contribution of active diastolic Ca2+ cycling in cardiomyocytes remains unclear. In this study, we sought to dissect contributions of passive and active mechanisms to diastolic dysfunction in the concentrically hypertrophied heart following pressure-overload.Methods and resultsRats were subjected to aortic banding (AB), and experiments were performed 6 weeks after surgery using sham-operated rats as controls. In vivo ejection fraction and fractional shortening were normal, confirming preservation of systolic function. Left ventricular concentric hypertrophy and diastolic dysfunction following AB were indicated by thickening of the ventricular wall, reduced peak early diastolic tissue velocity, and higher E/e’ values. Slowed relaxation was also observed in left ventricular muscle strips isolated from AB hearts, during both isometric and isotonic stimulation, and accompanied by increases in passive tension, viscosity, and extracellular collagen. An altered titin phosphorylation profile was observed with hypophosphorylation of the phosphosites S4080 and S3991 sites within the N2Bus, and S12884 within the PEVK region. Increased titin-based stiffness was confirmed by salt-extraction experiments. In contrast, isolated, unloaded cardiomyocytes exhibited accelerated relaxation in AB compared to sham, and less contracture at high pacing frequencies. Parallel enhancement of diastolic Ca2+ handling was observed, with augmented NCX and SERCA2 activity and lowered resting cytosolic [Ca2+].ConclusionIn the hypertrophied heart with preserved systolic function, in vivo diastolic dysfunction develops as cardiac fibrosis and alterations in titin phosphorylation compromise left ventricular compliance, and despite compensatory changes in cardiomyocyte Ca2+ homeostasis.

Hjertesvikt med bevart ejeksjonsfraksjon

“…However, we showed in a recently published study that disrupted calcium homeostasis is not a precondition for diastolic dysfunction (14). The increase in left ventricular passive stiffness is therefore probably of greater importance (14).…”

Compensatory and decompensatory alterations in cardiomyocyte Ca2+ dynamics in hearts with diastolic dysfunction following aortic banding

“…However the cells are able to compensate Ca 2+ homeostasis and efficiently minimize diastolic dysfunction caused by passive stiffening of the myocardium (Røe et al . ).…”

“…In their paper, Røe et al . () reported a decreased magnitude of the caffeine‐induced Ca 2+ transient suggesting a decreased SR load. A decrease in SR load, despite an increase in SERCA, could be explained by a sustained elevated leak from the SR.…”

“…To study compensation under elevated ventricular pressure, models are based on experimental recordings from Røe et al . (), conducted in a focused selection of animals that exhibit maintained systolic function yet diastolic dysfunction 6 weeks post‐AB. A full description of the in vivo phenotype including representative MRI pictures and echocardiographic M‐mode recordings is provided in Fig.…”

N-Acetylcysteine Influence on Oxidative Stress and Cardiac Remodeling in Rats During Transition from Compensated Left Ventricular Hypertrophy to Heart Failure

“…Probably as a consequence of the reduced oxidative stress and p-ERK and p-JNK signaling, myocardial fibrosis was attenuated by NAC treatment. As myocardial fibrosis is strongly related to poor outcome in cardiovascular diseases [2, 45], this result is important for future clinical studies.…”