PhD Scientific Days 2025

Poster Session I. - T: Cardiovascular Medicine and Research

Age-Associated Cardiac Dysfunction in a Mouse Model of HFpEF

Name of the presenter

ALHADDAD AYHAM

Institute/workplace of the presenter

Department of Pharmacology and Pharmacotherapy, Semmelweis University

Authors

Ayham R Alhaddad^1,2,3, Márk E Jakab^1,2,3, Zsombor I Hegedűs^1,2,3, Zoltán Márton Köhler1^1,2,3, Péter Ferdinandy^2,3, Zoltán V. Varga^1,2,3

1: HCEMM-SU Cardiometabolic Immunology Research Group, Budapest
2: Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
3: Center for Pharmacology and Drug Research & Development, Semmelweis University, Budapest, Hungary

Text of the abstract

Background: Heart failure with preserved ejection fraction (HFpEF) is responsible for more than half of all heart failure cases and is increasingly prevalent, particularly with aging. In addition to cardiac remodeling, fibrosis, and systemic inflammation seen in HFpEF, recent studies suggest an important role of bone marrow in cardiac-related inflammatory and immune responses. However, the underlying mechanisms driving these changes, especially with age, are still not well understood.
Aims: Thus, we aim to investigate the immunomodulatory changes in the heart and bone marrow in relation to age, providing insights into their contribution to HFpEF.
Methods: Ten-week-old male C57Bl/6J mice were randomized to receive control diet (CON) or high-fat diet (HFD) + L-NAME for 17 weeks (n=10). Cardiac function was assessed by echocardiography. Metabolic status was studied by glucose tests and physical activity via voluntary running wheels. At termination, organs were collected for histological examination, molecular analysis (PCR, Western blot) and RNA sequencing. To study the effect of aging, we compared the findings with 17-month-old mice subjected to the same protocol.
Results: Our results confirmed the development of cardio-metabolic co-morbidities in young, treated mice, with significantly higher body weight, insulin resistance, and lower running distances. Echocardiographic evaluations supported the development of HFpEF phenotype in treated young mice. Structural changes showed significantly higher LV mass, LVRI, and LVAWd. However, despite the preserved ejection fraction, minimal diastolic dysfunction (E/E′ and E/A) was observed. In contrast, treated aged mice showed elevated E/E′ with preserved EF, and signs of cardiac hypertrophy, compared to control animals, consistent with advanced diastolic dysfunction in HFpEF. Histological analysis revealed significant cardiomyocyte fibrosis in treated mice, with aged mice exhibiting more fibrosis than young ones.
Conclusion: This study demonstrated age-dependent differences in an animal model of HFpEF. The results confirmed HFpEF phenotypes in both age groups; however, older mice showed more severe structural and functional diastolic changes. Moving forward, we aim to investigate the underlying mechanisms, particularly the role of bone marrow-derived immune and inflammatory pathways, in age-related HFpEF development.