PhD Scientific Days 2025

Poster Session II. - J: Theoretical and Translational Medicine

The Effect of Novel Heart Failure Pharmacotherapies on Myocardial Inflammation and Fibrosis in Myocardial Samples of Advanced Heart Failure Patients Undergoing Heart Transplantation.

Name of the presenter

Nagy Dávid

Institute/workplace of the presenter

Department of Experimental Cardiology and Surgical Techniques, Heart and Vascular Center, Semmelweis University

Authors

Dávid Nagy¹, Zsófia Onódi², Andrea Kovács², Tímea Bálint¹, Attila Oláh¹, Alex Ali Sayour¹, Bálint András Barta¹, Péter Ferdinandy², Béla Merkely³, Tamás Radovits¹, Zoltán Varga², Mihály Ruppert¹

1: Department of Experimental Cardiology and Surgical Techniques, Heart and Vascular Center, Semmelweis University
2: Department of Pharmacology and Pharmacotherapy, Semmelweis University
3: Heart and Vascular Center of Semmelweis University

Text of the abstract

Introduction: Novel heart failure (HF) pharmacotherapies such as angiotensin receptor-neprilysin inhibitors (ARNI) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve HF survival. Behind this clinical benefit, the inhibition of myocardial inflammation (such as the inflammasome pathway) and fibrosis are postulated based on previous experimental results, but human evidence in this area remain limited.
Aims: We aimed to measure the antifibrotic action and the inhibition of the inflammasome pathway by ARNI and SGLT2i therapies in myocardial biobank samples of advanced HF patients undergoing heart transplantation (HTX).
Methods: 93 advanced HF patients who received either ARNI or angiotensin converting enzyme inhibitor (ACEi) treatment along with optional SGLT2i therapy and optimal HF medical therapy (including a beta-blocker and mineralocorticoid receptor antagonist) for at least 3 months prior to HTX were enrolled in our analysis. Left ventricular myocardial samples from the explanted hearts of these patients were harvested during HTX. The myocardial mRNA expression of fibrotic markers and inflammasome pathway proteins were assessed by qRT-PCR. Interstitial fibrosis area was measured by histological analysis. The measured outcomes were adjusted to other clinical parameters in multivariable linear- or beta regression models.
Result: Both ARNI and SGLT2i therapies were independently associated with reduced interstitial myocardial fibrosis in univariate and multivariable regression models as well. In SGLT2i-treated patients, reduced mRNA levels of matrix metalloproteinase 9 (MMP9) and tissue inhibitor of metalloproteinases 2 (TIMP2) were observed in adjusted models. However, neither ARNI, nor SGLT2i therapies were associated with significant changes in the examined inflammasome protein genes (absent in melanoma 2, caspase-1, Gasdermin D, nuclear factor kappa-light-chain-enhancer of activated B cells, stimulator of interferon genes).
Conclusion: ARNI and SGLT2i therapies are associated with reduced myocardial fibrosis in myocardial samples of advanced HF patients, but no significant associations can be observed with the myocardial gene expression of inflammasome pathway proteins.
Funding: EKÖP-2024-18. (D.N.) STARTING 150923 (M.R.), BO/00619/22/ (M.R.), ADVANCED 150829 (T.R.), K134939 (T.R.), RRF-2.3.1-21-2022-00003, TKP2021-EGA-23, TKP2021-NVA-15