Abstract
Cardiosphere-derived cells (CDCs) and the nonsteroidal aldosterone antagonist finerenone can each reduce myocardial fibrosis and have emerged as potential therapeutics for heart failure with preserved ejection fraction (HFpEF). Although these interventions can improve diastolic properties, their direct effects on left ventricular (LV) chamber stiffness have not been established. Accordingly, we examined their effect in swine with increased LV chamber stiffness and fibrosis from repetitive pressure overload (RPO). Swine (n = 19) were subjected to daily (1 h) episodes of RPO for 2 wk using phenylephrine to transiently elevate left ventricular end-diastolic volume (LVEDP) to ∼30 mmHg. After 2 wk, RPO was discontinued, and animals received intracoronary saline (n = 6), allogeneic CDCs (30 × 10(6), n = 7), or oral finerenone (20 mg/day; n = 6) and were followed for 4 wk. LV end-diastolic pressure and end-diastolic volume index were measured at normal and elevated preload to assess LV chamber stiffness (ΔLVEDP/ΔLVEDVi), and postmortem picrosirius red staining was performed to quantify interstitial fibrosis. Four weeks after cessation of RPO, saline-treated swine demonstrated sustained increases in LV chamber stiffness (1.7 ± 0.3 mmHg/mL/m(2) vs. 0.6 ± 0.1 mmHg/mL/m(2) in controls, P < 0.01). This was associated with increased fibrosis (8.5 ± 0.7% vs. 6.7 ± 0.4% in controls, P < 0.05) that decreased after treatment with CDCs (6.1 ± 0.5%, P < 0.05) and finerenone (5.4 ± 0.6%, P < 0.05). Despite these antifibrotic effects, LV chamber stiffness remained elevated after both agents (CDCs: 1.9 ± 0.4 mmHg/mL/m(2); finerenone: 1.4 ± 0.3 mmHg/mL/m(2), both P < 0.05 vs. normal controls). Although both CDCs and finerenone reduced fibrosis, these changes were not associated with reductions in LV chamber stiffness. Additional mechanisms likely underlie increased LV chamber stiffness in this model, which may have relevance to the therapeutic impact of these interventions on diastolic function in HFpEF.NEW & NOTEWORTHY Swine with increased left ventricular (LV) chamber stiffness and fibrosis from 2 wk of repetitive pressure overload demonstrated discordant effects following two disparate antifibrotic interventions. A single infusion of intracoronary allogeneic cardiosphere-derived cells and 4 wk of oral finerenone each effectively reduced myocardial interstitial fibrosis. Despite reversal of fibrosis, LV chamber stiffness did not improve with either intervention, suggesting that myocyte-dependent mechanisms may play an important role in diastolic dysfunction from intermittent hemodynamic overload.