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Abstract
Heart Failure (HF) is clinically defined as when the heart fails to pump out an adequate amount of blood at normal filling pressures to satisfy the physiological needs of the body. Ejection fraction (EF) is the fraction of blood volume in the heart at the end of the relaxing phase of the ventricles, that is ejected out of the left ventricle (LV) during the contracting phase of the ventricles. Ejection fraction, which is normally 60%-70%, is a key measure of heart function and is often used to classify heart failure. Based on EF, heart failure can be broadly classified into two types: Heart Failure with Reduced Ejection Fraction (HFrEF) where EF is <40% and Heart Failure with Preserved Ejection Fraction (HFpEF) where EF is > 50%. Evidence-based treatments such as vasodilators (angiotensin-converting-enzyme-inhibitors, angiotensin-receptor-blockers, etc.), beta-blockers, and diuretics are often used to treat HFrEF patients. Recent clinical trials which investigated the effects of Sodium Glucose Co-Transporter II (SGLT2) -inhibitors (Empagliflozin, Dapagliflozin, etc.) in HFrEF patients, have shown beneficial outcomes in the improvement of HF hospitalization and mortality rate. However, the cardio-protective mechanisms of SGLT2-inhibitors on cardiac and renal hemodynamics, are still unknown and of varied interests.
In contrast to HFrEF, therapeutic interventions in long-term outcomes for HFpEF patients have proven elusive because of its heterogeneous phenotype and poorly or incompletely understood mechanisms. Furthermore, the failure of the same therapeutic interventions in HFpEF, that have proven to be beneficial in HFrEF, have added to the perplexity. Although, recent clinical trials which investigated the effects of SGLT2-inhibitors in HFpEF patients have shown beneficial outcomes in reducing HF hospitalization, it was unable to improve mortality rate.
These indicate that there are fundamental differences in pathophysiologic phenotypes between HFpEF and HFrEF, which contribute to the differential responses to the same treatments. Quantitative systems modeling can be a powerful tool to understand the relationship between organ function and dysfunction. Therefore, we sought to investigate these key questions regarding the differentiating phenotypes in the pathophysiology of heart failure and its potential therapeutics in virtual HFrEF and HFpEF patients, through quantitative systems modeling.