Abnormal calcium homeostasis in heart failure with preserved ejection fraction is related to both reduced contractile function and incomplete relaxation: an electromechanically detailed biophysical modeling study

Abstract

Heart failure with preserved ejection fraction (HFpEF) accounts for about 50% of heart failure cases. It has features of incomplete relaxation and increased stiffness of the left ventricle. Studies from clinical electrophysiology and animal experiments have found that HFpEF is associated with impaired calcium homeostasis, ion channel remodeling and concentric left ventricle hypertrophy (LVH). However, it is still unclear how the abnormal calcium homeostasis, ion channel and structural remodeling affect the electro-mechanical dynamics of the ventricles. In this study we have developed multiscale models of the human left ventricle from single cells to the 3D organ, which take into consideration HFpEF-induced changes in calcium handling, ion channel remodeling and concentric LVH. Our simulation results suggest that at the cellular level, HFpEF reduces the systolic calcium level resulting in a reduced systolic contractile force, but elevates the diastolic calcium level resulting in an abnormal residual diastolic force. In our simulations, these abnormal electro-mechanical features of the ventricular cells became more pronounced with the increase of the heart rate. However, at the 3D organ level, the ejection fraction of the left ventricle was maintained due to the concentric LVH. The simulation results of this study mirror clinically observed features of HFpEF and provide new insights toward the understanding of the cellular bases of impaired cardiac electromechanical functions in heart failure.

The influence of low calcium dialysate on left ventricular diastolic function in peritoneal dialysis patients

“…Calcium has an important role in the contraction and relaxation of cardiac myocytes, in heart failure 3D organ models, elevated calcium level in diastolic period reduced abnormal residual diastolic force. 20 In restrictive cardiomyopathy mouse model, calcium desensitizer catechin improved the diastolic function by reducing calcium hypersensitivity but not systolic function. 21 Moreover, our results indicate that standard calcium dialysate is associated with decreased RRF level and low calcium dialysate could keep the stability on RRF after 12-month follow-up.…”

Insights from echocardiography, magnetic resonance imaging, and microcomputed tomography relative to the mid‐myocardial left ventricular echogenic zone

“…Inroads are now being made such that the ejection fraction can be mathematically derived from myocardial strain and wall thickness . Normal and abnormal left ventricular mechanics, such as twist, as well as systolic and diastolic function, furthermore, can readily be explained without invoking the concept of a helical ventricular myocardial band . The twist of the left ventricle is explained by the known anatomical arrangements of cardiomyocytes .…”

“…46 Normal and abnormal left ventricular mechanics, such as twist, as well as systolic and diastolic function, furthermore, can readily be explained without invoking the concept of a helical ventricular myocardial band. 43,47 The twist of the left ventricle is explained by the known anatomical arrangements of cardiomyocytes. 43 Abnormalities of calcium homeostasis and collagen deposition may both result in abnormal relaxation and compliance.…”

Heart Failure With Preserved Ejection Fraction: A Perioperative Review

“…38,39 The underlying cause of impairment in diastolic relaxation can be linked to abnormal calcium handling. 40 Although the anesthetized patient has been shown to have preserved myocardial performance measures through maintenance of ventriculoarterial coupling when exposed to both volatile and intravenous anesthetic agents, 41,42 abnormal vascular tone from external or native sympathetic-driven activation can lead to elevations in left ventricular end-diastolic pressure and left atrial pressure. 43 To further complicate the difficulty associated with the performance of intraoperative evaluation of LVDD, there are data to suggest that abnormal calcium homeostasis in the anesthetized state may affect the diastolic filling of the left ventricle.…”