Predicted Cardiac Functional Responses to Renal Actions of SGLT2i in the DAPACARD Trial Population: A Mathematical Modeling Analysis

Yu, Hongtao; Basu, Sanchita; Tang, Weifeng; Penland, Robert C.; Greasley, Peter J.; Oscarsson, Jan; Boulton, David W.; Hallow, K. Melissa

doi:10.1002/jcph.1987

Cited by 2 publications

(1 citation statement)

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“…The effects of changes in preload and afterload on cardiac remodeling over time can then be simulated through growth and remodeling laws that link myocardial loading to changes in myocyte diameter/length, and subsequently to LV wall thickness and chamber volume [39]. The model has been validated by reproducing clinical trials in LV hypertrophy [39] and HFrEF patients [44][45][46].…”

Section: Introductionmentioning

confidence: 99%

Understanding heterogeneous mechanisms of heart failure with preserved ejection fraction through cardiorenal mathematical modeling

Basu,

Yu,

Murrow

et al. 2023

PLoS Comput Biol

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In contrast to heart failure (HF) with reduced ejection fraction (HFrEF), effective interventions for HF with preserved ejection fraction (HFpEF) have proven elusive, in part because it is a heterogeneous syndrome with incompletely understood pathophysiology. This study utilized mathematical modeling to evaluate mechanisms distinguishing HFpEF and HFrEF. HF was defined as a state of chronically elevated left ventricle end diastolic pressure (LVEDP > 20mmHg). First, using a previously developed cardiorenal model, sensitivities of LVEDP to potential contributing mechanisms of HFpEF, including increased myocardial, arterial, or venous stiffness, slowed ventricular relaxation, reduced LV contractility, hypertension, or reduced venous capacitance, were evaluated. Elevated LV stiffness was identified as the most sensitive factor. Large LV stiffness increases alone, or milder increases combined with either decreased LV contractility, increased arterial stiffness, or hypertension, could increase LVEDP into the HF range without reducing EF. We then evaluated effects of these mechanisms on mechanical signals of cardiac outward remodeling, and tested the ability to maintain stable EF (as opposed to progressive EF decline) under two remodeling assumptions: LV passive stress-driven vs. strain-driven remodeling. While elevated LV stiffness increased LVEDP and LV wall stress, it mitigated wall strain rise for a given LVEDP. This suggests that if LV strain drives outward remodeling, a stiffer myocardium will experience less strain and less outward dilatation when additional factors such as impaired contractility, hypertension, or arterial stiffening exacerbate LVEDP, allowing EF to remain normal even at high filling pressures. Thus, HFpEF heterogeneity may result from a range of different pathologic mechanisms occurring in an already stiffened myocardium. Together, these simulations further support LV stiffening as a critical mechanism contributing to elevated cardiac filling pressures; support LV passive strain as the outward dilatation signal; offer an explanation for HFpEF heterogeneity; and provide a mechanistic explanation distinguishing between HFpEF and HFrEF.

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