Background: Heart failure with preserved ejection fraction (HFpEF) is characterized by the accumulation of cardiovascular risk factors including metabolic syndrome, diabetes, and hypertension, eventually leading to endothelial dysfunction. A maladaptive role of miR-483-3p has been linked to endothelial dysfunction, as it is overexpressed in M2 macrophages and endothelial cells of type 2 diabetic patients. However, its role in cardio-metabolic HFpEF remains unclear.
Purpose: This study established a multifactorial porcine model of HFpEF to investigate miR-483-3p expression during disease progression.
Methods: Adult female Göttingen minipigs (n=9) were implanted with drug-eluting chips releasing deoxycorticosterone acetate (DOCA, 50 mg/kg bw) for 60 days and got fed a diet high in cholesterol, fat, fructose and salt for 20 weeks. Every 4 weeks, under sedation, blood pressure, echocardiography, and blood sampling were performed. At Week 20, pulmonary capillary wedge pressure (PCWP) was measured with the animals acutely instrumented closed-chest via Swan-Ganz catheterization, while invasive hemodynamic assessment was conducted with a LV conductance catheter. Coronary microvascular function was assessed via coronary flow reserve (CFR). Control animals (n=6) received a standard diet and underwent the same evaluations.
Results: HFpEF animals developed metabolic syndrome including obesity, dyslipidemia, and glucose intolerance. Echocardiography showed preserved LVEF but demonstrated cardiac remodeling with LV concentric hypertrophy, as relative wall thickness (RWT) is increasing from 0.47 ± 0.11 at baseline to 0.73 ± 0.19 at Week 20 (controls: 0.49 ± 0.11). At Week 20, HFpEF animals were hypertensive (SBP 182.8 ± 20.4 mmHg vs 114.1 ± 9.1 mmHg; DBP 127.3 ± 9.1 mmHg vs 63.0 ± 18.0 mmHg; mAOP: 134,0 ± 18,02mmHg vs. 76,5 ± 10,8mmHg), showed elevated PCWP (17.2 ± 5.4 mmHg) and reduced CFR (1.26 ± 0.15 vs 2.10 ± 0.3). LV pressure-volume analysis revealed higher end-diastolic pressure (20.2 ± 7.4 mmHg vs 10.0 ± 2.0 mmHg), stroke work (5197 ± 1191 J vs 3299 ± 816 J), and potential energy (1193 ± 217 J vs 722 ± 188 J). MiR-483-3p expression continuously increased during disease progression, plateauing at Week 12 with ~1000-fold elevation in M2 macrophages compared to baseline. In plasma, miR-483-3p normalized to miR-16-5p was up to 8-fold higher in HFpEF pigs at Weeks 12 to 20 compared to controls.
Conclusion: A clinically relevant cardio-metabolic HFpEF model incorporating key risk factors was successfully established. The progressive rise of miR-483-3p parallels disease development, identifying it as a potential biomarker and therapeutic target.
