Abstract
Congestive heart failure is characterized by suppressed cardiac output and arterial filling pressure, leading to renal retention of salt and water, contributing to further volume overload. Mathematical modeling provides a means to investigate the integrated function and dysfunction of heart and kidney in heart failure. This study updates our previously reported integrated model of cardiac and renal functions to account for the fluid exchange between the blood and interstitium across the capillary membrane, allowing the simulation of edema. A state of heart failure with reduced ejection fraction (HF-rEF) was then produced by altering cardiac parameters reflecting cardiac injury and cardiovascular disease, including heart contractility, myocyte hypertrophy, arterial stiffness, and systemic resistance. After matching baseline characteristics of the SOLVD clinical study, parameters governing rates of cardiac remodeling were calibrated to describe the progression of cardiac hemodynamic variables observed over one year in the placebo arm of the SOLVD clinical study. The model was then validated by reproducing improvements in cardiac function in the enalapril arm of SOLVD. The model was then applied to prospectively predict the response to the sodium-glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin, which has been shown to reduce heart failure events in HF-rEF patients in the recent DAPAHF clinical trial by incompletely understood mechanisms. The simulations predict that dapagliflozin slows cardiac remodeling by reducing preload on the heart, and relieves congestion by clearing interstitial fluid without excessively reducing blood volume. This provides a quantitative mechanistic explanation for the observed benefits of SGLT2i in HF-rEF. The model also provides a tool for further investigation of heart failure drug therapies.
Highlights
Chronic heart failure (HF) is a condition in which the heart is incapable of preserving a sufficient cardiac output (CO) to reach the metabolic requirements of peripheral organs [1]
HF with reduced ejection fraction (HF-rEF) is associated with reduced cardiac contractility along with cardiac dilatation, usually subsequent to myocardial infarction or other ischemic injuries
After matching an HF-rEF virtual patient to the baseline hemodynamic characteristics in the SOLVD clinical trial [42], the model was able to describe the rightward progression of the P-V loop in the placebo arm, as well as the leftward shift in the enalapril arm, providing validation that the model adequately describes the progression of cardiac remodeling in response to hemodynamic overload in HF, as well as improvements with renally acting therapies
Summary
Chronic heart failure (HF) is a condition in which the heart is incapable of preserving a sufficient cardiac output (CO) to reach the metabolic requirements of peripheral organs [1]. HF with reduced ejection fraction (HF-rEF) is characterized by a left ventricle ejection fraction (LVEF) less than 40%, suppressed CO, elevated cardiac filling pressure, and progressive eccentric remodeling of the heart. Excessive volume retention increases both preload and afterload on the heart, causing detrimental cardiac remodeling. Excessive preload leads to elevated venous pressure and the development of peripheral edema and pulmonary congestion [7,8]. These factors contribute to the progressive worsening of HF over time, usually with repeated and costly hospitalizations [9]
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