Lipoprotein-targeted therapies for lipotoxic heart disease

Overwhelming epidemiological evidence shows that diabetes mellitus is independently associated with heart failure incidence, with the risk being increased by more than twofold in men and by more than fivefold in women. The most prevalent phenotype of heart failure in patients with obesity and diabetes mellitus is heart failure with preserved ejection fraction (HFpEF) (ejection fraction ≥50%)2. Inflammation has been proposed to be the primary pathophysiological driver of HFpEF, whereas cardiomyocyte loss and stretch are the principal drivers of heart failure with reduced ejection fraction (HFrEF) (ejection fraction ≤40%). Diabetic cardiomyopathy was first described in 1972 and is characterized by the existence of ventricular dysfunction in the absence of other cardiac risk factors, such as coronary artery disease, hypertension, and significant valvular disease, in individuals with diabetes mellitus. In this PhD thesis, hard evidence is provided that cholesterol lowering gene therapy prevents HFpEF in a model of high sugar-high fat (HSHF) diet-induced diabetic cardiomyopathy. Furthermore, infusion of reconstituted HDLMilano reverses established heart failure in mice with HSHF diet-induced diabetic cardiomyopathy.