Evaluation of an Acute Animal Model of Heart Failure with Preserved Ejection Fraction (HFpEF) and Simulation with Consideration of the Pulmonary Baroreceptor Reflex

Abstract

Heart failure with preserved ejection fraction (HFpEF) patients suffer from high filling pressures and pulmonary congestion. Despite the disease severity and prevalence, there are currently no approved devices to treat this condition, and pharmacologic therapies have limited efficacy. Hence, there is a large unmet need for new treatments that can directly address the underlying disease mechanisms. Current animal models do not mimic the disease state, so a novel, acute animal model was examined in this study. Single-day terminal studies were performed in anesthetized healthy ovine (n=5). A balloon was placed in the left atrium and inflated with saline to restrict left ventricular filling to induce hemodynamic changes commonly seen in HFpEF then deflated while cardiovascular hemodynamic parameters were collected. Pulmonary capillary wedge pressure (PCWP) was of most interest in this study because it is a primary change that occurs in HFpEF patients. Surprisingly, even at full restriction from inflation of the balloon, a significant increase of PCWP was not observed. These findings led us to investigate a type of regulatory mechanism that compensated for the occlusion. A minimal closed loop model (MCLM) of the cardiovascular system was used to simulate hemodynamic parameter trends in three different conditions: no regulation, systemic regulation, and systemic and pulmonary regulation. To mimic the animal model design, pulmonary resistance was varied to mimic the expected restriction caused by the left atrial balloon. Specifically, the pulmonary arterial baroreceptor reflex (PBR) was modeled as the source of pulmonary regulation. The results of the MCLM showed that the condition of pulmonary regulation most closely matched the trends observed in the animal studies. With the results from both the animal studies and the MCLM, there a few modifications that could greatly improve the animal study design and protocol. The primary recommendation is to remove the PBR from denervation of the pulmonary artery to allow for those changes to occur in the hemodynamic parameters of interest for the HFpEF disease state. Thus, we believe that these findings have led to a better understanding of the fundamental mechanisms of HFpEF.