Abstract 23: Immunosuppression with FTY720 Reverses Cardiac Dysfunction to Prevent Chronic Heart Failure in Mice that Survive Diet-induced Myocardial Infarction
We recently reported that immunosuppression with FTY720 improves cardiac function and extends longevity in the HypoE/SR-BI-/- mouse model of diet-induced coronary atherosclerosis and myocardial infarction (MI). In this study we tested whether FTY720 could also reverse cardiac dysfunction in mice that survive MI and subsequently develop chronic heart failure (CHF). HypoE/SR-BI-/- mice were bred to Mx1-Cre mice and offspring were fed a high fat diet (HFD) for 21 days to provoke hyperlipidemia, coronary atherosclerosis and recurrent MIs. HypoE/SR-BI-/-Mx1-Cre mice were subsequently given oral FTY720 in drinking water or not. Hyperlipidemia was permanently reversed by inducible Cre-mediated gene repair of the HypoE allele (also known as the Apoeh/h allele) that rapidly restores normal apoE expression in all tissues and by switching mice to a normal chow diet. In cohorts of mice that survived this period of HFD, left ventricular (LV) function was monitored using serial echocardiography for up to 15 weeks. In untreated mice, LV performance progressively deteriorated. Although FTY720 treatment did not initially prevent a decline of heart function among HypoE/SR-BI-/-Mx1-Cre mice six weeks after Cre-mediated gene repair, it almost completely restored normal LV function in these mice by 15 weeks after cessation of HFD. Reversal of heart failure did not result from reduced atherosclerosis as the burden of both aortic and coronary atherosclerosis increased to similar levels in both groups of mice. Rather, FTY720 caused systemic immunosuppression as assessed by reduced numbers of circulating T and B lymphocytes. In the heart, FTY720 led to reduced expression of MMP-2 along with the expression of genes involved in Type I innate inflammation that we have recently demonstrated as major contributors to heart failure. Our data demonstrate the benefit of immunosuppression with FTY720 post MI to prevent progressive pathological remodeling of the heart, which leads to CHF.
Author Disclosures: F. Luk: None. R.Y. Kim: None. K. Li: None. D. Ching: None. S. Joshi: None. N. Honbo: None. I. Imhof: None. B. Zhu: None. D. Lovett: None. J.S. Karliner: None. R.L. Raffai: None.
- © 2015 by American Heart Association, Inc.