A multifactorial porcine model of cardio-metabolic HFpEF highlights miR-483-3p as a promising target therapy
K Kohlat, F P Lo Muzio, S Baer, J Oetvoes, N Kraenkel, A AlognaAbstract
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.EchocardiographyGraphical Abstract