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.
Highlights
Inhibition of the renin‐angiotensin‐aldosterone system and ß‐receptor blockade improve survival and reduce hospitalization in patients with heart failure with reduced ejection fraction (HFrEF) [136]. In contrast to these advances in the treatment of HFrEF, no therapy has been found to be of clinical benefit in patients with heart failure with preserved ejection fraction (HFpEF)
High‐Density Lipoproteins (HDLs)‐targeted therapies for heart failure have never been evaluated in patients with heart failure
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
Summary
Heart failure is a clinical syndrome distinguished by characteristic symptoms (e.g., shortness of breath, ankle swelling, and fatigue) that may be accompanied by clinical signs (e.g., elevated jugular venous pressure, pulmonary crackles, and peripheral edema) [1]. The high‐density lipoprotein (HDL)‐targeted interventions for heart failure discussed in this review are considered for heart failure secondary to myocardial pathology. Transendothelial transport of HDLs to the interstitium occurs via transcytosis [13] These direct effects should be considered in light of existing knowledge on the cellular composition of the myocardium. Based on immunohistochemical analysis of human cardiac tissue, Pinto et al [18] demonstrated that 31% of nuclei in the human heart correspond to cardiomyocytes (α‐actinin 2 positive cells), 54% to endothelial cells (CD31 positive cells), 3% to leukocytes (CD45 positive cells), and the remaining to resident mesenchymal cells including fibroblasts. The impact of these properties of HDLs on the heart may be secondary to the local presence of HDLs in the myocardium or may reflect systemic effects of HDLs in non‐cardiac tissues or on circulating cells
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