The antifibrotic effect of novel heart failure pharmacotherapies in myocardial samples of patients undergoing heart transplantation

Abstract Background The addition of the novel angiotensin receptor-neprilysin inhibitors (ARNI) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) to heart failure (HF) therapy improve cardiovascular survival. Preclinical and indirect evidence suggests that ARNI and SGLT2i may have antifibrotic and antiremodeling effects; however, whether these mechanisms contribute to their superior survival benefits remains uncertain. Purpose This study aimed to evaluate the antifibrotic and antiremodeling effects of ARNI and SGLT2i therapies in myocardial samples from advanced HF patients undergoing heart transplantation (HTX). Methods Myocardial biobank samples from the anterior left ventricle of 93 HF patients who underwent HTX were analyzed. All patients had received beta-blockers, mineralocorticoid receptor antagonists, and either angiotensin-converting enzyme inhibitors (ACEi) or ARNI, with optional SGLT2i, for at least three months before HTX. Patients with anterior ischemia, mechanical or pharmacological circulatory support, or systemic inflammatory/fibrotic diseases were excluded. The primary outcome was the interstitial myocardial fibrosis area assessed via histology. Additionally, fibrosis and remodeling marker gene expressions (collagen types 1 and 3, MMP2, MMP9, TIMP1, TIMP2, NPPA, NPPB, MYH6, and MYH7) were quantified using qRT-PCR. The additional antifibrotic effects of ARNI compared to ACEi, and the potential added benefits of SGLT2i, were evaluated using multivariable linear and beta-regression models, adjusting for clinical confounders. Results Median (IQR) interstitial myocardial fibrosis area was 7.4 (5.4-9.4) % in the samples. ARNI (P=0.048) and SGLT2i (P=0.005) therapies were independently associated with reduced myocardial fibrosis. Nine clinical parameters significantly influenced fibrosis in univariate models, while sex, time since HTX, implantable cardioverter defibrillator use, and serum creatinine remained independent determinants in the multivariable beta-regression analysis. In univariate linear regression, all fibrosis marker genes were affected by ARNI and SGLT2i. However, multivariable analysis confirmed independent effects of SGLT2i on MMP9 (P=0.049) and TIMP2 (P=0.031) and the effect of ARNI on MYH7/MYH6 ratio (P=0.022). Time since HTX, sex, body mass index, and atrial fibrillation were also independent regulators of fibrosis marker gene expression. Conclusions ARNI and SGLT2i therapies may exert antifibrotic effects independently of other clinical factors in myocardial samples from advanced HF patients undergoing HTX.