Cardiac and renal function interactions in heart failure with reduced ejection fraction: A mathematical modeling analysis

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. Recently, the DAPAHF and EMPA-REG clinical trials showed that the Sodium-Glucose Cotransporter-2 Inhibitor (SGLT2i) class of drugs are beneficial in reducing the heart failure with reduced ejection fraction (HFrEF) hospitalization and lowering the risk of PLOS COMPUTATIONAL BIOLOGY

Predicted Cardiac Hemodynamic Consequences of the Renal Actions of SGLT2i in the DAPA‐HF Study Population: A Mathematical Modeling Analysis

“…This study used a previously published cardiorenal model 17 that links a renal physiological model 19,20 and a cardiac hemodynamic model. 21 The major functional modules and mechanisms of the mathematical model are shown schematically in Figure 1.…”

“…Briefly, the cardiac portion of the model describes the dynamics of the cardiac cycle (Figure 1A), adaptation of myocytes and remodeling of the left ventricle in response to changes in mechanical loading (Figure 1B), and cardiovascular hemodynamics (Figure 1C). 17 The renal and volume homeostasis portion of the model describes blood flow and pressure through the renal vasculature (Figure 1D); renal filtration, reabsorption, and excretion of sodium, water, and glucose (Figure 1F); wholebody fluid/electrolyte distribution (Figure 1E); and key neurohormonal and intrinsic feedback mechanisms (Figure 1G). The renal and cardiac functions were coupled through mean arterial pressure (MAP), venous pressure, and blood volume.…”

“…Overview of DAPA-HF Simulation Procedure Figure 2 summarizes the process used to simulate the DAPA-HF clinical study. First, building on our previously described simulation of a representative HF-rEF virtual patient, 17 we sampled a subset of model parameters, given in Table 1 and described later, over a range of values with a uniform distribution. The ranges for the parameters were calibrated to ensure that the distribution of the simulated baseline characteristics for variables of interest (LVEF, MAP, NT-proBNP, eGFR, hematocrit, and glucose) covered the range of values observed in DAPA-HF.…”

“…[31][32][33] We have previously described the modeled mechanisms of action of the ACEi enalapril and SGLT2i dapagliflozin in our earlier publications. 17,19,20,22 A detailed description of the simulation of ACEi and SGLT2i is given in the Supplemental Information.…”

“…We have previously used a mathematical model of cardiorenal function to quantify the effects of SGLT2is on renal hemodynamics and fluid status (blood volume and IFV) consequent to its natriuretic and diuretic effects. 17 We have also used this model to reproduce states of HF-rEF, and have shown that the model reproduces the progressive cardiac remodeling in HF-rEF over 1 year, as well as slowing of progression with an angiotensin-converting enzyme inhibitor (ACEi), as observed in the Studies of Left Ventricular Dysfunction. 18 Because this model integrates cardiac and renal function, it allows prediction of the cardiac hemodynamic and remodeling consequences of primarily renally acting drugs like SGLT2is.…”