Mathematical modeling of left ventricle hypertrophy and dilatation in response to volume overload in heart failure: a coupled renal‐cardiac model

Abstract

It is well‐established that the heart remodels in response to changes in mechanical loads, and mathematical modeling of cardiac function and remodeling is an advanced field. However, volume regulation is a critical component in the pathogenesis, progression, and management of congestive heart failure, and few existing models account for the interaction between cardiac function and volume regulation by the kidney and neurohumoral signaling. A primary failure in cardiac function is compounded by volume retention as the heart and kidney work together to try to maintain organ perfusion. Eccentric hypertrophy occurs in response to volume overload, as increases in ventricular filling pressure elevate stress and stretch experienced in myocytes during diastole is believed to cause the series replication of sarcomeres and chamber enlargement. In this study, we utilized a coupled model of cardiac mechanics [1] and renal function, volume regulation, and the renin‐angiotensin‐aldosterone system[2]. We previously expanded the model to include mechanisms of cardiac hypertrophy and wall thickening in response to pressure overload – a self‐limiting process. We have now also incorporated a mechanism for left ventricle dilatation in response to volume overload, a progressive process. Specifically, myocyte length is modeled as a function of end‐diastolic myocyte stress, a relationship governed by a time constant. The model reflects the expected behavior of heart failure patients: reduced ejection fraction and increased left ventricle end diastolic volume, stress, and pressure. After inducing “heart failure” by reducing cardiac contractility, we used temporal pressure‐volume data from heart failure patients in the SOLVD study to ensure that the model accurately reflects the structural and hemodynamic changes characteristic of heart failure. We also used published data to establish an empirical relationship between left ventricle End Diastolic Stress and n‐Type Brain Natriuretic Peptide (NT‐pro BNP). We then validated the model by simulating and showing agreement with changes in the pressure‐volume loop in response to enalapril treatment in SOLVD, and NT‐proBNP at baseline and after treatment with valsartan in the VALHEFT[4] trial. This model improve our understanding of the hemodynamic interactions between renal and cardiac function and volume homeostasis in disease, and is a step toward in silico evaluation of new therapeutic mechanisms.Support or Funding InformationThis work was funded by collaborative grant from Pfizer Worldwide Research & Development and Merck & Co., Inc.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.