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

1
Centre for Molecular and Vascular Biology, Department of Cardiovascular Sciences, Catholic University of Leuven, 3000 Leuven, Belgium
2
The Medicines Company (Schweiz), CH-8001 GmbH Zürich, Switzerland
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2018, 19(11), 3399; https://doi.org/10.3390/ijms19113399
Received: 18 September 2018 / Revised: 22 October 2018 / Accepted: 27 October 2018 / Published: 30 October 2018
(This article belongs to the Special Issue Cholesterol and Lipoprotein Metabolism)
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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. View Full-Text
Keywords: Reconstituted HDL; cardiac hypertrophy; coconut oil; heart failure; HFpEF; cardiac function; exercise capacity; lactate; acetyl-coenzyme A carboxylase; transforming growth factor-β1 Reconstituted HDL; cardiac hypertrophy; coconut oil; heart failure; HFpEF; cardiac function; exercise capacity; lactate; acetyl-coenzyme A carboxylase; transforming growth factor-β1
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Mishra, M.; Muthuramu, I.; Aboumsallem, J.P.; Kempen, H.; De Geest, B. Reconstituted HDL (Milano) Treatment Efficaciously Reverses Heart Failure with Preserved Ejection Fraction in Mice. Int. J. Mol. Sci. 2018, 19, 3399.

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