The effect of ARNI and SGLT2i therapies on the inflammasome pathway in myocardial heart transplantation biobank samples
D Nagy, Z S Onodi, A Kovacs, T Balint, Z Horvath, D Ivanics, L Meszaros, A Olah, A A Sayour, B A Barta, P Ferdinandy, B Merkely, T Radovits, Z Varga, M RuppertAbstract
Introduction
Angiotensin receptor–neprilysin inhibitors (ARNI) and sodium–glucose cotransporter 2 inhibitors (SGLT2i) have markedly improved cardiovascular survival in a wide spectrum of HF populations. Beyond their hemodynamic and metabolic effects, experimental studies suggest that these therapies may attenuate adverse myocardial remodeling through the inhibition of myocardial fibrosis and inflammatory signaling pathways, including the inflammasome cascade. However, human evidence remains scarce regarding this postulation.
Purpose
Therefore, we aimed to investigate the association of ARNI and SGLT2i therapies with myocardial fibrosis and the activity of the inflammasome pathway in left ventricular myocardial samples from patients with advanced HF undergoing heart transplantation (HTX).
Methods
Myocardial biobank samples from 93 advanced HF patients who underwent HTX were included. All patients received optimal guideline-directed HF therapy, including beta-blockers and mineralocorticoid receptor antagonists, combined with either angiotensin converting enzyme inhibitor (ACEi) or ARNI treatment, and optionatern blot. The examined inflammasome-related targets included absent in melanoma 2, caspase-1, Gasdermin D, nuclear factor kappa-light-chain-enhancer of activated B cells, and stimulator of interferon genes. Multivariable linear and beta regression models were constructed to adjust the measured outcomes for relevant clinical covariates.
Results
Both ARNI and SGLT2i therapies were associated with a significantly reduced extent of interstitial myocardial fibrosis in univariate analyses, and these associations remained independent after multivariable adjustment. In patients treated with SGLT2i, lower myocardial mRNA expression levels of matrix metalloproteinase 9 (MMP9) and tissue inhibitor of metalloproteinases 2 (TIMP2) were observed in the adjusted models, suggesting a potential modulation of extracellular matrix turnover. In contrast, neither ARNI nor SGLT2i therapies were associated with significant changes in the myocardial gene or protein expressions oflly SGLT2i therapy, for at least 3 months prior HTX. During HTX, left ventricular myocardial tissue was harvested from the explanted hearts. Interstitial myocardial fibrosis was quantified by histological analysis. In parallel, myocardial mRNA expression of fibrosis-related markers and inflammasome pathway proteins was measured using qRT-PCR and Wes the investigated inflammasome pathway components.
Conclusions
In myocardial samples of patients with advanced HF undergoing HTX, ARNI and SGLT2i therapies are independently associated with reduced myocardial fibrosis. However, no significant relationship could be demonstrated between these treatments and myocardial inflammasome pathway gene expression, indicating that the clinical benefits of these drugs may be mediated predominantly through antifibrotic rather than direct anti-inflammasome effects in end-stage human HF.