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

Background And Purpose: The pleiotropic properties of HDL may exert beneficial effects on the myocardium. The effect of recombinant HDL on established heart failure was evaluated in C57BL/6 mice.

Experimental Approach: Mice were subjected to transverse aortic constriction (TAC) or sham operation at the age of 14 weeks. Eight weeks later, TAC and sham mice were each randomized into three different groups. Reference groups were killed at day 56 after the operation for baseline analysis. Five i.p. injections of recombinant HDL (MDCO-216), 100 mg·kg , or an equivalent volume of control buffer were administered with a 48 h interval starting at day 56. Endpoint analyses in the control buffer groups and in the MDCO-216 groups were executed at day 65.

Key Results: Lung weight in MDCO-216 TAC mice was 25.3% lower than in reference TAC mice and 27.9% lower than in control buffer TAC mice and was similar in MDCO-216 sham mice. MDCO-216 significantly decreased interstitial fibrosis and increased relative vascularity compared to reference TAC mice and control buffer TAC mice. The peak rate of isovolumetric relaxation in MDCO-216 TAC mice was 30.4 and 36.3% higher than in reference TAC mice and control buffer TAC mice respectively. Nitro-oxidative stress and myocardial apoptosis were significantly reduced in MDCO-216 TAC mice compared to control buffer TAC mice.

Conclusions And Implications: 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.