Pathophysiological Mechanisms for Heart Failure with Preserved Ejection Fraction (HF‐pEF): A Mathematical Modeling Analysis

Abstract

While there are many treatment options for heart failure with reduced ejection fraction (HF-rEF), therapeutic improvements in long-term outcomes for patients with heart failure with preserved ejection fraction (HF-pEF) have proven elusive. Part of the challenge is the heterogeneous phenotype and poorly understood mechanisms responsible for HF-pEF. A wide range of pathophysiological mechanisms have been proposed to cause or contribute to HF-pEF such as cardiac interstitial fibrosis, cardiac hypertrophy, impaired cardiac metabolism and bioenergetics, impaired LV relaxation, endothelial dysfunction, impaired nitric oxide (NO) bioavailability, vascular stiffening, and systemic inflammation, among others. In this study, we used a mathematical modeling approach to evaluate the contribution of a subset of these hypothesized mechanisms in producing a hemodynamic phenotype of HF-pEF. Utilizing an existing model of cardiorenal function, we created a virtual reference patient with baseline hypertension and associated LV hypertrophy as a comorbidity, since a history of hypertension is highly prevalent in HF-pEF. We varied parameters associated with hypothesized HF-pEF mechanisms over a wide range, alone and in combination. Cardiac changes included increased myocardial stiffness (representing fibrosis), decreased myocardial contractility (representing impaired cardiac bioenergetics), and impaired LV relaxation. Vascular changes included increased arterial stiffness and increased arterial resistance. HF-pEF was defined as a state with elevated LV end diastolic pressure (LVEDP), increased interstitial fluid volume (IFV), and normal ejection fraction (EF). As expected, hypertension and LV hypertrophy alone were not sufficient to increase LV EDP or IFV. Our simulations predicted that increasing LV stiffness or decreasing LV contractility tended to increase LVEDP and IFV, while changing both stiffness and contractility together magnified their effects. However, substantial changes in these parameters also suppressed EF into the HF-rEF range. A range of parameter values was identified that elevated LVEDP and IFV while keeping EF above 50%. In addition, inducing delayed ventricular relaxation had minimal effect on LVEDP or EF, but did elevate mean pulmonary venous pressure. On the vascular side, decreases in systemic or pulmonary vascular compliance had minimal effects on LVEDP or EF, but increased IFV. In summary, increased LV stiffness and mild decreases in LV contractility, on top of existing hypertension and hypertrophy, are predicted to contribute to the shift toward elevated preload and volume retention characteristic of heart failure, without suppressing ejection fraction. Decreased vascular compliance may exacerbate fluid overload.