High-Density Lipoprotein-Targeted Therapies for Heart Failure

Abstract

The main and common constituents of high-density lipoproteins (HDLs) are apolipoprotein A-I, cholesterol, and phospholipids. Biochemical heterogeneity of HDL particles is based on the variable presence of one or more representatives of at least 180 proteins, 200 lipid species, and 20 micro RNAs. HDLs are circulating multimolecular platforms that perform divergent functions whereby the potential of HDL-targeted interventions for treatment of heart failure can be postulated based on its pleiotropic effects. Several murine studies have shown that HDLs exert effects on the myocardium, which are completely independent of any impact on coronary arteries. Overall, HDL-targeted therapies exert a direct positive lusitropic effect on the myocardium, inhibit the development of cardiac hypertrophy, suppress interstitial and perivascular myocardial fibrosis, increase capillary density in the myocardium, and prevent the occurrence of heart failure. In four distinct murine models, HDL-targeted interventions were shown to be a successful treatment for both pre-existing heart failure with reduced ejection fraction (HFrEF) and pre-existing heart failure with preserved ejection fraction (HFrEF). Until now, the effect of HDL-targeted interventions has not been evaluated in randomized clinical trials in heart failure patients. As HFpEF represents an important unmet therapeutic need, this is likely the preferred therapeutic domain for clinical translation.

Current Understanding of the Immunomodulatory Activities of High-Density Lipoproteins

“…Importantly, apart from the aforementioned mimetic peptides, administration of apoA-I Milano nanoparticles has gained much attention for treating heart failure and coronary artery disease [ 303 , 304 , 305 ]. Briefly, apoA-I Milano is an apoA-I mutant resulting from an arginine 173 to cysteine mutation [ 306 , 307 ], leading to a higher life expectancy in heterozygotes and a lower atherosclerosis rate [ 304 ]. MDCO-216 is a form of reconstituted HDLs consisting of purified recombinant dimer apoA-I Milano complexed with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine [ 308 ].…”

Role of Oxidative Stress in Heart Failure: Insights from Gene Transfer Studies

“…The causal role of oxidative stress in heart failure is also supported by gene transfer studies of the three primary antioxidant enzymes (SODs, catalase, and glutathione peroxidase), of thioredoxin, and of heme oxygenase-1. Finally, multiple gene transfer prevention and intervention studies have demonstrated that gene therapy directed at the correction of metabolic risk factors resulted in a marked reduction of systemic oxidative stress and oxidative stress in the myocardium [63,64]. This correction of metabolic risk factors also resulted in improved cardiac function and prevention or reversal of pathological remodeling and heart failure [63,64].…”

“…Finally, multiple gene transfer prevention and intervention studies have demonstrated that gene therapy directed at the correction of metabolic risk factors resulted in a marked reduction of systemic oxidative stress and oxidative stress in the myocardium [63,64]. This correction of metabolic risk factors also resulted in improved cardiac function and prevention or reversal of pathological remodeling and heart failure [63,64]. The broad robustness of the strong link between reduction of oxidative stress and prevention and treatment of heart failure suggests that reduction of oxidative stress is an important mediator of the observed effects of metabolic gene therapy on cardiac structure and function.…”

“…Several metabolic risk factors are associated with prominent systemic oxidative stress [59][60][61][62] and are also linked with an increased risk of heart failure. Multiple gene transfer prevention and intervention studies have demonstrated that cardiac function is improved and heart failure prevented or reversed following gene therapy directed at correction of these metabolic risk factors [63,64]. Gene therapy directed at correction of metabolic risk factors also resulted in a marked reduction of systemic oxidative stress and of oxidative stress in the myocardium [63,64].…”

“…Multiple gene transfer prevention and intervention studies have demonstrated that cardiac function is improved and heart failure prevented or reversed following gene therapy directed at correction of these metabolic risk factors [63,64]. Gene therapy directed at correction of metabolic risk factors also resulted in a marked reduction of systemic oxidative stress and of oxidative stress in the myocardium [63,64]. These studies do not prove an obligatory causeand-effect relationship between the decrease of oxidative stress and cardiac phenotype.…”