Predicting cardiac and renal responses to sacubitril/valsartan with a mathematical model of heart failure with preserved ejection fraction

Heart failure (HF) with preserved ejection fraction (HFpEF) now accounts for most cases of HF. The majority of patients with HFpEF have hypertension (HTN) and chronic kidney disease (CKD), which increase their risk of cardiovascular (CV) morbidity and mortality and further complicates the management of these patients. Recently, clinical trials investigating sacubitril/valsartan, a dual angiotensin receptor blocker (ARB) and neprilysin inhibitor (ARNI), demonstrated greater lowering of blood pressure (BP) and N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) in patients with HFpEF as compared with ARB alone. However, effects on CV morbidity or mortality have not been convincing in the ARNI clinical trials thus far, and the responses to ARNI when specific HFpEF comorbidities are present, such as CKD, are not well-defined. To examine the detailed physiological responses that occur in the heart and kidney during ARNI therapy in HFpEF, we used the large mathematical model of physiology, HumMod. As compared with the 36-wk responses to ARB treatment, the simulation predicted greater reductions in cardiac pressures, left ventricular wall stress and mass, BP, and NT-proBNP levels with ARNI treatment, similar to the results from PARAMOUNT and PARAGON-HF trials. Our model predicted that ARNI increased incidence of glomerular HTN, albuminuria, and nephron damage, despite improved glomerular filtration rate and greater decreases in cardiac mass and BP, irrespective of salt intake, warranting further attention for endpoint selection in future clinical studies of these therapies. This physiological model offers a new promising approach to guide future clinical decision making for ARNI therapy in HFpEF.<b>NEW & NOTEWORTHY</b> This analysis addresses current unknowns in the treatment of HFpEF: whether ARNI is appropriate for ejection fractions >60%, the role of renal dysfunction during ARNI treatment, and responses to high salt. These predictions indicate that the superior lowering of systemic BP and cardiopulmonary pressures from ARNI may mitigate the detrimental effects from increasing glomerular pressure but may not be the case for patient populations with high salt intakes, impaired renal autoregulation, or glomerular hyperfiltration.