Mathematical Modeling of Delayed Relaxation in Heart Failure with Preserved Ejection Fraction (HF‐pEF)‐ an Effect or a Cause?

Abstract

The pathophysiological mechanisms underlying heart failure with preserved ejection fraction (HF-pEF) remain incompletely understood. One proposed hypothesis is that prolonged pressure decay of left ventricle during isovolumic relaxation, due to loss of enhancement of the ventricle, may lead to elevation of left ventricular end-diastolic pressure (LVEDP) and a reduction in stroke volume in HF-pEF subjects. However, while impaired relaxation is commonly observed in HF-pEF, it is unclear whether it is a contributing cause of HF-pEF or perhaps a consequence of other impairments. We sought to evaluate whether direct impairment in cardiac relaxation can contribute to a state of HF-pEF using a mathematical modeling approach. We utilized an existing mathematical model of cardio-renal hemodynamics in which a rectified sinusoidal twitch shape function drives left ventricular contraction and relaxation. To evaluate the effect of impaired relaxation, we altered the falling side of the twitch shape function so that isovolumetric relaxation time (IVRT) increased from 100 ms to 150 ms. In addition, we also evaluated the effect of delayed relaxation coupled with other ventricular changes associated with HF-pEF, including increased ventricular stiffness. Our simulations showed that when IVRT was increased, left ventricular pressure (LV pressure) fell more slowly during diastole. However, there was minimal effect on LVEDP. Pulmonary venous pressure also fell more slowly during diastole, and the peak pulmonary venous pressure during systole was slightly increased. Ejection fraction (EF) was minimally changed. The simulated presence of hypertension, hypertrophy, and/or increased cardiac stiffness did not impact the effect of slowed relaxation. While experimental validation is needed, our simulations suggest that impaired relaxation alone may not be a primary cause for increased preload experienced by many HF-pEF patients. It is possible that delayed relaxation is a consequence of other contributing mechanisms (e.g. impaired bioenergetics, calcium handling, or fibrosis which may impact ventricle stiffness and contractility) rather than a direct cause for elevated LV preload. While impaired relaxation had minimal effect on LVEDP, the small increases in peak pulmonary venous pressure and slower fall during diastole could impact pulmonary and atrial function in HF-pEF.