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

Area of Science:

• Cardiovascular Physiology
• Computational Biology
• Pharmacology

Background:

• Congestive heart failure (CHF) involves reduced cardiac output and fluid retention, worsening with kidney dysfunction.
• Mathematical modeling offers a way to study the complex interplay between heart and kidney in CHF.
• Previous models lacked detailed fluid exchange dynamics, limiting simulation of edema.

Purpose of the Study:

• To update an integrated cardiac and renal model to simulate edema formation in heart failure with reduced ejection fraction (HF-rEF).
• To validate the model using data from the SOLVD clinical study.
• To prospectively predict the effects of SGLT2 inhibitors, like dapagliflozin, on HF-rEF.

Main Methods:

• An integrated mathematical model of cardiac and renal functions was enhanced to include fluid exchange across capillary membranes.
• HF-rEF was simulated by adjusting cardiac parameters reflecting injury and disease.
• Model parameters were calibrated using the SOLVD placebo arm and validated with the enalapril arm.

Main Results:

• The updated model successfully simulated edema formation.
• Model calibration matched hemodynamic changes in the SOLVD placebo arm over one year.
• The model reproduced improvements seen in the SOLVD enalapril arm.

Conclusions:

• The model predicts dapagliflozin slows cardiac remodeling by reducing preload and clears interstitial fluid without significant volume loss.
• This provides a mechanistic explanation for SGLT2 inhibitor benefits in HF-rEF.
• The model serves as a valuable tool for investigating novel heart failure therapies.