The anti-fibrotic effects of novel heart failure pharmacotherapies in advanced heart failure patients.

BACKGROUND AND PURPOSE: Novel heart failure (HF) pharmacotherapies, including angiotensin receptor-neprilysin inhibitor (ARNI) and sodium-glucose cotransporter 2 inhibitors (SGLT2is), may confer cardiovascular benefits by attenuating myocardial fibrosis. However, direct evidence from human failing myocardial samples is limited. Thus, we assessed the associations of ARNI and SGLT2i therapies with fibrosis on myocardial samples from advanced HF patients undergoing heart transplantation (HTX).

EXPERIMENTAL APPROACH: Ninety-three patients receiving stable combined HF pharmacotherapy (uninterrupted use of β-blockers, mineralocorticoid receptor antagonists, angiotensin-converting enzyme inhibitors or ARNI, and optionally SGLT2is) without the need for pharmacological or mechanical circulatory support for at least three months pre-HTX, were enrolled. Standardized regions of the left ventricular anterior wall from explanted hearts were analysed. The primary outcome was the percentage of interstitial myocardial fibrosis area measured via histology. The expression of pro-fibrotic and pathological remodelling markers was quantified with qRT-PCR.

KEY

RESULTS

Both ARNI and SGLT2i therapies were associated with reduced interstitial collagen accumulation in adjusted analyses. None of the tested clinical parameters (sex, age, serum creatinine, presence of hypertension or diabetes) interacted with the effects of ARNI or SGLT2i on fibrosis. Additionally, no interaction was observed between ARNI and SGLT2i use regarding collagen content. Among the examined genes, ARNI was linked to a decreased beta-to-alpha myosin heavy chain expression ratio, while in SGLT2i-treated patients, reduced mRNA levels of matrix metalloproteinase 9 (MMP9) and tissue inhibitor of metalloproteinases 2 (TIMP2) were observed in adjusted models.

CONCLUSIONS AND IMPLICATIONS: ARNI and SGLT2i therapies might exert anti-fibrotic effects in advanced HF.