https://doi.org/10.1007/s00392-025-02625-4
1Deutsches Herzzentrum der Charité Department of Cardiology, Angiology and Intensive Care Medicine Berlin, Deutschland; 2Charité - Universitätsmedizin Berlin Klinik für Kardiologie, Angiologie und Intensivmedizin Berlin, Deutschland; 3Deutsches Herzzentrum der Charité Klinik für Kardiologie, Angiologie und Intensivmedizin , Campus Benjamin-Franklin Berlin, Deutschland; 4Charité - Universitätsmedizin Berlin CC 11: Med. Klinik für Kardiologie Berlin, Deutschland; 5Charité - Universitätsmedizin Berlin CC11: Med. Klinik m.S. Kardiologie Berlin, Deutschland
Background:
Heart failure with preserved ejection fraction (HFpEF) is phenotypically characterized by the accumulation over time of cardiovascular risk factors including metabolic syndrome, diabetes and hypertension, eventually leading to endothelial dysfunction. Interestingly, a maladaptive role of miR-483-3p was suggested in endothelial dysfunction as it was found overexpressed in M2 macrophages and endothelial cells of type 2 diabetic patients. However, the role of miR-483-3p in cardio-metabolic HFpEF is unknown.
Purpose:
In this study, a multifactorial porcine model of HFpEF was established to investigate the expression of miR-483-3p during the course of disease development.
Methods:
Adult female Göttingen minipigs (n=6) were subcutaneously implanted drug eluting chips to continuously release deoxycorticosterone acetate (DOCA, 50mg/Kg bw) for 60 days. From that day, the animals were fed a diet high in cholesterol, fat, fructose, and salt over 5 months. Every 4 weeks until sacrifice, the following assessments were performed under sedation: tail-cuff blood pressure, echocardiography, blood, and plasma sampling. At week 20, measurement of the pulmonary capillary wedge pressure (PCWP) was performed with the animals acutely instrumented closed-chest with a Swan Ganz catheter, while invasive hemodynamic assessment was conducted with a LV conductance catheter. Additionally, coronary microvascular function was invasively assessed as coronary flow reserve (CFR). Two (n=2) adult female Göttingen minipigs, without DOCA and fed a standard diet, were used as controls and underwent the same investigations of the HFpEF animals.
Results:
Animals developed a metabolic syndrome, including obesity, dyslipidaemia and glucose intolerance. The echocardiographic examination showed a preserved LV EF throughout the study while demonstrating cardiac remodelling with LV concentric hypertrophy as relative wall thickness (RWT) increased from a Week 0 value of 0.43 to 0.52 at Week 20, while the control animals showed an unaltered value of 0.53 during the 5-months protocol. At week 20, HFpEF animals were hypertensive (SBP: 181.33±12.59 mmHg; DBP: 133.17±9.44 mmHg; mAOP: 148.33±9.82 mmHg), showed a PCWP of 20±6.6 mmHg, and a compromised CFR (1.37±0.06 vs 2.10±0.01). LV PV-loop assessment revealed increased end-systolic pressure (114.28±9.11 vs 80 mmHg), end-diastolic pressure (18.28±5.95 vs 9.75 mmHg). Of importance, the expression profile of miR-483-3p showed a steady increase over the time course of disease, reaching a plateau at week 12 (fold change increase ~1000 compared to baseline).
Conclusion:
A clinically relevant model of cardio-metabolic HFpEF, comprising the main risk factors of the disease, has been successfully established. The expression profile of miR-483-3p is in line with the alterations occurring over the course of the pathology, making it a candidate target for future therapies.