High-density lipoprotein-targeted therapies for heart failure with preserved ejection fraction

The distribution of ejection fraction in patients admitted for acutely decompensated heart failure is bimodal. A distinction is made between heart failure with reduced ejection fraction (HFrEF) (ejection fraction ≤ 40%) and heart failure with preserved ejection fraction (HFpEF) (ejection fraction ≥ 50%). This distinction reflects different pathophysiological mechanisms that ultimately are responsible for left ventricular chamber dilatation in HFrEF and a normal or near-normal left ventricular chamber size in HFpEF. Ventricular remodelling induced by age, hypertension, and in some cases diabetes mellitus may generate a slowly progressive substrate upon which HFpEF develops whereas accelerated and larger-scale myocyte loss and/or dysfunction is required for development of HFrEF. Most randomized clinical trials in patients with heart failure have been restricted to HFrEF patients since ejection fraction was a major inclusion criterion in these studies. Inhibition of the renin-angiotensin-aldosterone system and ß-receptor blockade improve survival and decrease hospitalizations in patients with HFrEF. In contrast to these advances in the treatment of HFrEF, no therapy has been found to have clinical benefit in patients with HFpEF and the mortality in patients with HFpEF has remained unchanged. HFpEF represents a major unmet therapeutic need. In this thesis, overwhelming evidence is presented that reconstituted HDLMilano is an effective treatment for HFpEF induced by feeding a 0.2% cholesterol 10% coconut oil diet in female C57BL/6N mice and for HFpEF associated with hypertension in male C57BL/6N mice.status: publishe