Key result
DOCA plus cardiometabolic diet in minipigs induces HFpEF and elevates plasma miR-483-3p ~8-fold.
Why the study?
A maladaptive role of miR-483-3p was suggested in endothelial dysfunction among type 2 diabetic patients, but its role and expression during the development of cardio-metabolic HFpEF were unknown.
Does induction of cardio-metabolic HFpEF via DOCA and a high-cholesterol, fat, fructose, and salt diet alter the expression of miR-483-3p and hemodynamic parameters in adult female Göttingen minipigs?
Does induction of cardio-metabolic HFpEF via DOCA and a high-cholesterol, fat, fructose, and salt diet alter the expression of miR-483-3p and hemodynamic parameters in adult female Göttingen minipigs?
In a multifactorial porcine model of cardio-metabolic HFpEF, miR-483-3p expression markedly increased in M2 macrophages and plasma in parallel with disease progression, highlighting it as a candidate therapeutic target.
miR-483-3p upregulation tracks HFpEF progression in minipigs; hypothesis-generating for therapeutic targeting, requires human validation.
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=9) were subcutaneously implanted drug eluting chips to continuously release deoxycorticosterone acetate (DOCA, 50mg/Kg) 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 tail-cuff blood pressure, echocardiography, blood, and plasma sampling were performed. At week 20, measurement of the pulmonary capillary wedge pressure (PCWP) was performed 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). Six (n=6) adult female Göttingen minipigs, without DOCA and fed a standard diet, underwent the same investigations as the HFpEF animals. Results Animals developed a metabolic syndrome. The echocardiographic examination showed a preserved LVEF throughout the study while demonstrating cardiac remodelling with LV concentric hypertrophy as relative wall thickness (RWT) increased from a Week 0 (0.47 ± 0,11) to Week 20 (0.73 ± 0,19), while the control animals showed an unaltered value of 0.49 ± 0,11. At week 20, HFpEF animals were hypertensive (mAOP: 134,0 ± 18,02mmHg vs. 76,5 ± 10,8mmHg), showed a PCWP of 17,2±5,4mmHg, and a compromised Coronary Flow Reserve (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 compared to the control group. 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.
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Kohlat et al. (2026) studied Cardio-metabolic heart failure with preserved ejection fraction (HFpEF) (n=15). Subcutaneous deoxycorticosterone acetate (DOCA) implant plus a diet high in cholesterol, fat, fructose, and salt vs. Standard diet without DOCA was evaluated on Expression of miR-483-3p and development of cardio-metabolic HFpEF phenotype. DOCA and a high-fat/fructose/salt diet in minipigs induced HFpEF with reduced coronary flow reserve (1.26 vs 2.10) and elevated plasma miR-483-3p up to 8-fold versus controls.
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