Successful treatment of established heart failure in mice with recombinant HDL (Milano)

Aboumsallem, Joseph Pierre; Mishra, Mudit; Amin, Ruhul; Muthuramu, Ilayaraja; Kempen, H.J.M.; Geest, Bart De

doi:10.1111/bph.14463

Cited by 26 publications

(30 citation statements)

References 61 publications

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“…Administration of MDCO-216 in SC diet mice or in CC diet mice had no effect on HDL cholesterol levels 24 h after the last injection. Murine apo A-I levels were decreased following MDCO-216 administration, which has previously also been observed following MDCO-216 administration injection in another murine model [ 23 ] and after apo A-I Milano gene transfer in mice [ 31 ]. Furthermore, HDL cholesterol in scavenger receptor class B, type I (SR-BI) deficient mice are prominently increased [ 18 ].…”

Section: Discussionsupporting

confidence: 63%

“…Moreover, HDL has been demonstrated to reduce TGF-β1-induced collagen deposition in murine fibroblasts [ 35 ] and to decrease TGF-β1-induced endothelial-mesenchymal transition in aortic endothelial cells in vitro [ 36 ]. Regression of myocardial fibrosis after administration of MDCO-216 has previously also been observed in mice with pressure overload [ 23 ].…”

Section: Discussionmentioning

confidence: 90%

“…The clinical safety of MDCO-216 has been established in several studies [ 19 , 20 , 21 , 22 ]. We have recently demonstrated that intervention with MDCO-216 reverses established pathological remodeling induced by pressure overload and constitutes a successful treatment for heart failure in mice with pressure overload [ 23 ]. Since pressure overload induced by transverse aortic constriction (TAC) leads to cardiac dilatation and HFrEF [ 24 ], the question remains whether this HDL-targeted intervention may be effective in HFpEF.…”

Section: Introductionmentioning

confidence: 99%

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

Mishra

Muthuramu

Aboumsallem

et al. 2018

IJMS

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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.

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Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

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

Mishra

Muthuramu

Aboumsallem

et al. 2018

IJMS

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“…While these findings were related to an animal model preceding fully established HF, in a follow up study the same investigators used a more targeted approach, i.e. that of infusing recombinant AIM phospholipid particles in mice with established HF [136]. Mice underwent TAC or sham operations at 14 weeks of age, and 8 weeks later were randomised to HDL therapy (5 i.p.…”

Section: Hdl Therapy For Heart Failurementioning

confidence: 99%

HDL therapy today: from atherosclerosis, to stent compatibility to heart failure

et al. 2019

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Epidemiologically, high-density lipoprotein (HDL) cholesterol levels have been inversely associated to cardiovascular (CV) events, although a Mendelian Randomisation Study had failed to establish a clear causal role. Numerous atheroprotective mechanisms have been attributed to HDL, the main being the ability to promote cholesterol efflux from arterial walls; anti-inflammatory effects related to HDL ligands such as S1P (sphingosine-1-phosphate), resolvins and others have been recently identified. Experimental studies and early clinical investigations have indicated the potential of HDL to slow progression or induce regression of atherosclerosis. More recently, the availability of different HDL formulations, with different phospholipid moieties, has allowed to test other indications for HDL therapy. Positive reports have come from studies on coronary stent biocompatibility, where the use of HDL from different sources reduced arterial cell proliferation and thrombogenicity. The observation that low HDL-C levels may be associated with an enhanced risk of heart failure (HF) has also suggested that HDL therapy may be applied to this condition. HDL infusions or apoA-I gene transfer were able to reverse heart abnormalities, reduce diastolic resistance and improve cardiac metabolism. HDL therapy may be effective not only in atherosclerosis, but also in other conditions, of relevant impact on human health. KEY MESSAGES High-density lipoproteins have as a major activity that of removing excess cholesterol from tissues (particularly arteries). Knowledge on the activity of high-density lipoproteins on health have however significantly widened. HDL-therapy may help to improve stent biocompatibility and to reduce peripheral arterial resistance in heart failure.

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“…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.…”

mentioning

confidence: 99%

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

Mishra

Muthuramu

Kempen³

et al. 2020

Sci Rep

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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.

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Successful treatment of established heart failure in mice with recombinant HDL (Milano)

Abstract: MDCO-216 improves diastolic function, induces regression of interstitial fibrosis and normalizes lung weight in mice with established heart failure. Recombinant HDL may emerge as a treatment modality in heart failure.

Cited by 26 publications

References 61 publications

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

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

HDL therapy today: from atherosclerosis, to stent compatibility to heart failure

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

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