A multifactorial porcine model of cardio-metabolic HFpEF highlights miR-483-3p as a promising target therapy

Abstract Abstract A multifactorial porcine model of cardio-metabolic HFpEF highlights miR-483-3p as a promising target therapy. Background Heart failure with preserved ejection fraction (HFpEF) is associated with risk factors such as metabolic syndrome, diabetes, and hypertension, ultimately leading to endothelial dysfunction. Recent findings suggest a maladaptive role for miR-483-3p in endothelial cells and M2 macrophages in type 2 diabetes, but its role in HFpEF remains unclear. Purpose This study aimed to establish a multifactorial porcine model of cardio-metabolic HFpEF and investigate the expression of miR-483-3p during disease progression. Methods Adult female Göttingen minipigs (n=9) received subcutaneous drug-eluting implants releasing DOCA (50 mg/kg BW) for 60 days and were fed a high-fat, high-fructose, high-cholesterol, high-salt diet for 20 weeks. Assessments were performed every 4 weeks, including blood pressure, echocardiography, blood sampling, and at Week 20, invasive hemodynamic measurements (PCWP, LV conductance catheter), and coronary flow reserve (CFR). Six (n=6) adult female Göttingen minipigs, without DOCA and fed a standard diet, were used as controls and underwent the same investigations as the HFpEF animals. Results Animals developed a metabolic syndrome, including obesity, dyslipidaemia and glucose intolerance. Although the LVEF remained preserved throughout the study by echocardiography, cardiac remodeling was evident. This manifested as concentric LV hypertrophy, since the relative wall thickness (RWT) increased from 0.47 ± 0.11 (Week 0) to 0.73 ± 0.19 (Week 20). The control animals maintained their value of 0.49 ± 0.11. At Week 20, HFpEF animals were hypertensive (SBP: 182,8 ± 20,4mmHg vs. 114,1 ± 9,1mmHg; DBP: 127,3 ± 9,06mmHg vs. 63,0 ± 18,04mmHg; mAOP: 134,0 ± 18,02mmHg vs. 76,5 ± 10,8mmHg), showed a PCWP of 17,2±5,4mmHg and a compromised CFR (1.26±0.15 vs 2.10±0.3). LV PV-loop assessment revealed increased end-diastolic pressure (20.16±7.35 vs 9.96 ± 2.0 mmHg), as well as stroke work (5197 ± 1191J vs. 3299 ± 816J) and potential energy (1193 ± 217J vs. 722,5 ± 187.5J). Notably, the expression profile of miR-483-3p showed a continuous increase throughout the disease progression, reaching a plateau at week 12 with an approximately 1000-fold increase compared to baseline in M2 macrophages. In circulating plasma, miR-483-3p expression, normalized to the housekeeping gene miR-16-5p, was elevated up to 8-fold in the HFpEF group at weeks 12, 16, and 20 compared to the control group. Conclusion This study successfully establishes a clinically relevant porcine model of cardio-metabolic HFpEF. The progressive upregulation of miR-483-3p correlates with disease severity, supporting its potential as a therapeutic target in HFpEF.