Reductions in Myocardial Interstitial Fibrosis are Dissociated From LV Chamber Stiffness in Swine with Repetitive Pressure Overload

<b>Background:</b> Cardiosphere-derived cells (CDCs) and the non-steroidal aldosterone antagonist finerenone can each reduce myocardial fibrosis and have emerged as potential therapeutics for HFpEF. While these interventions can improve diastolic properties, their direct effects on 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). <b>Methods:</b> Swine (n=19) were subjected to daily (1-hour) episodes of RPO for 2-weeks using phenylephrine to transiently elevate LVEDP to ~30mmHg. After 2-weeks, RPO was discontinued and animals received intracoronary saline (n=6), allogeneic CDCs (30x106, n=7) or oral finerenone (20mg/day; n=6) and were followed for 4-weeks. LV end-diastolic pressure and end-diastolic volume index were measured at normal and elevated preload to assess LV chamber stiffness (ΔLVEDP/ΔLVEDVi) and post-mortem picrosirius red staining was performed to quantify interstitial fibrosis. <b>Results:</b> Four-weeks after cessation of RPO, saline-treated swine demonstrated sustained increases in LV chamber stiffness (1.7±0.3mmHg/mL/m² vs. 0.6±0.1mmHg/mL/m² 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 anti-fibrotic effects, LV chamber stiffness remained elevated after both agents (CDCs: 1.9±0.4mmHg/mL/m²; finerenone: 1.4±0.3mmHg/mL/m², both p<0.05 vs. normal controls). <b>Conclusion:</b> 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.