Administration of apo A-I (Milano) nanoparticles reverses pathological remodelling, cardiac dysfunction, and heart failure in a murine model of HFpEF associated with hypertension

Abstract

Therapeutic interventions with proven efficacy in heart failure with reduced ejection fraction (HFrEF) have been unsuccessful in heart failure with preserved ejection fraction (HFpEF). The modifiable risk factor with the greatest impact on the development of HFpEF is hypertension. The objectives of this study were to establish a murine model of HFpEF associated with hypertension and to evaluate the effect of apo A-IMilano nanoparticles (MDCO-216) on established HFpEF in this model. Subcutaneous infusion of angiotensin II in combination with 1% NaCl in the drinking water was started at the age of 12 weeks in male C57BL/6 N mice and continued for the entire duration of the experiment. Treatment with MDCO-216 partially reversed established cardiac hypertrophy, cardiomyocyte hypertrophy, capillary rarefaction, and perivascular fibrosis in this model. Pressure-volume loop analysis was consistent with HFpEF in hypertension mice as evidenced by the preserved ejection fraction and a significant reduction of cardiac output (7.78 ± 0.56 ml/min versus 10.5 ± 0.7 ml/min; p < 0.01) and of the peak filling rate (p < 0.05). MDCO-216 completely reversed cardiac dysfunction and abolished heart failure as evidenced by the normal lung weight and normal biomarkers of heart failure. In conclusion, apo A-IMilano nanoparticles constitute an effective treatment for established hypertension-associated HFpEF.

HDL Composition, Heart Failure, and Its Comorbidities

“…Mishra et al (222) reported that MDCO-216 attenuated cardiac hypertrophy, increased capillary density, and decreased interstitial fibrosis in murine models. In a subsequent study, Mishra et al showed similar results of MDCO-216 in murine models of hypertension-associated cardiac hypertrophy (170). Aboumsallem et al have demonstrated that MDCO-216 improves systolic and diastolic dysfunction, reduces myocardial fibrosis, and enhances myocardial vascularity in mice with HF (221).…”

“…HDL can protect against myocardial fibrosis through inhibition of the pro-fibrotic transforming growth factor-β1 (TGF-β1), which induces collagen production and deposition in the myocardium of murine models ( 169 , 170 ). In a study on aortic endothelial cells in vitro , HDL reduced TGF-β1-induced endothelial-mesenchymal transition and attenuated fibrosis of the vascular wall in response to various insults ( 171 ).…”

High-Density Lipoprotein-Targeted Therapies for Heart Failure

“…Intervention studies with HDL-targeted therapies in four different models of pre-existing heart failure (HFrEF after transverse aortic constriction [ 122 ], heart failure in a model of diabetic cardiomyopathy [ 123 ], two HFpEF models [ 59 , 124 ]) show that the impact of HDL-targeted interventions on cardiac structure and function is highly reproducible, indicating broad robustness of the effects. HDL-targeted interventions in these animal models result in a reversal of pathological cardiac hypertrophy with regression of myocardial fibrosis and of capillary rarefaction, in a powerful improvement of systolic and of diastolic cardiac function, and in a reversal of heart failure.…”

“…This point is, for example, illustrated by the fact that direct effects on contractility may be accompanied by indirect effects on myocardial fibrosis since mechanical cues affect myofibroblast differentiation [ 55 , 118 , 119 ]. Several recent studies in mouse models of non-ischemic heart failure have shown that HDLs may prevent heart failure development or induce reversal of existing heart failure, whereas dysfunctional HDLs may worsen heart failure development [ 59 , 120 , 121 , 122 , 123 , 124 ]. In all studies supporting this claim, there is a complete absence of coronary atherosclerosis, which implies that the effects of HDLs on cardiac structure and function and on heart failure are secondary to the direct effects of HDLs in the myocardium or secondary to its systemic anti-inflammatory and antioxidative properties or its effects on circulating cells.…”

“…The efficacy of MDCO-216 treatment was also demonstrated in a mouse model of hypertension-associated HFpEF [ 124 ]. To induce hypertension and HFpEF, subcutaneous infusion of angiotensin II in combination with 1% NaCl in the drinking water was started at the age of 12 weeks in male C57BL/6N mice and was maintained for the entire duration of the experiment.…”