Reconstituted HDL (Milano) Treatment Efficaciously Reverses Heart Failure with Preserved Ejection Fraction in Mice

Abstract

Heart failure with preserved ejection fraction (HFpEF) represents a major unmet therapeutic need. This study investigated whether feeding coconut oil (CC diet) for 26 weeks in female C57BL/6N mice induces HFpEF and evaluated the effect of reconstituted high-density lipoprotein (HDL)Milano (MDCO-216) administration on established HFpEF. Eight intraperitoneal injections of MDCO-216 (100 mg/kg protein concentration) or of an equivalent volume of control buffer were executed with a 48-h interval starting at 26 weeks after the initiation of the diet. Feeding the CC diet for 26 weeks induced pathological left ventricular hypertrophy characterized by a 17.1% (p < 0.0001) lower myocardial capillary density and markedly (p < 0.0001) increased interstitial fibrosis compared to standard chow (SC) diet mice. Parameters of systolic and diastolic function were significantly impaired in CC diet mice resulting in a reduced stroke volume, decreased cardiac output, and impaired ventriculo-arterial coupling. However, ejection fraction was preserved. Administration of MDCO-216 in CC diet mice reduced cardiac hypertrophy, increased capillary density (p < 0.01), and reduced interstitial fibrosis (p < 0.01). MDCO-216 treatment completely normalized cardiac function, lowered myocardial acetyl-coenzyme A carboxylase levels, and decreased myocardial transforming growth factor-β1 in CC diet mice. In conclusion, the CC diet induced HFpEF. Reconstituted HDLMilano reversed pathological remodeling and functional cardiac abnormalities.

Advances in HDL: Much More than Lipid Transporters

“…MDCO-216 has been tested in healthy volunteers and patients with stable CAD, showing modulation of lipid parameters and an increase of cholesterol efflux with no adverse effects [129,130]. More recently, MDCO-216 has also reported, at an experimental level, to revert heart failure progression in Type 2 diabetic mice as well as restore cardiac function [154], lower myocardial acetyl-coenzyme A carboxylase levels, and decrease myocardial transforming growth factor-β1 [155]. CSL112, a reconstituted, infusible, plasma-derived ApoA-I structure, is another promising HDL-mimetic.…”

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

“…HDL also has anti-fibrotic effects. HDL decreases transforming growth factor-ß1-induced collagen accumulation 53 and reduces transforming growth factor-ß1 in the myocardium 24 . Furthermore, HDL has been demonstrated to decrease endothelial-mesenchymal transition in aortic endothelial cells in vitro induced by transforming growth factor-ß1 54 .…”

“…Apo A-i Milano nanoparticles. MDCO-216 is a 1:1 by weight complex of dimeric apo A-I Milano produced by recombinant DNA technology and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine 24 and was supplied by The Medicines Company (Parsipanny, NJ, USA) as a solution in buffer containing mannitol 43.6 mM, sucrose 181 mM, NaH 2 PO 4 •2H 2 O 3.46 mM, and 8.43 mM Na 2 HPO 4 •7H 2 O. Non-denaturing polyacrylamide gradient-gel electrophoresis has previously demonstrated that these nanoparticles are characterised by an apparent diameter of 8 nm and that no free apoA-I Milano was observed 61 .…”

“…Invasive hemodynamic measurements were performed before sacrifice following anaesthesia induced by intraperitoneal administration of 1.2 g/ kg urethane (Sigma). Measurements were performed using Millar's Mikro-Tip ultra-miniature pressure-volume (PV) loop catheter PVR-1035 (1.0 French polyimide catheter), the MPVS Ultra Single Segment pressure-volume unit, and a PowerLab 16/35 data acquisition system (ADInstruments Ltd, Oxford, United Kingdom) as described before 24 .…”

“…Previous studies from our lab provide powerful evidence that high-density lipoproteins (HDL) exert direct effects on the myocardium that are entirely independent of any effect on the epicardial coronary arteries [21][22][23][24][25] . Apolipoprotein (apo) A-I is the main apolipoprotein of HDL.…”