Nonalcoholic fatty liver disease worsens cardiac repair after myocardial infarction

Abstract Background There is a strong epidemiological link between nonalcoholic fatty liver disease (NAFLD) and ischemic heart disease such as myocardial infarction (MI). Yet, a causal relationship between liver injury and post-MI cardiac repair remains to be established. Purpose NAFLD impairs post-MI myocardial repair processes. In particular, we hypothesized that the pathological liver could transmit deleterious signals shaping the inflammatory reaction in the infarcted milieu. Methods To characterize post-MI cardiac function and remodeling in three mouse models of liver damage mimicking different stages of NAFLD without cardiovascular (CV) risk factors : i) choline-deficient, L-amino-acid-defined, high fat diet (CDA-HFD) causing severe non-alcoholic steatohepatitis; ii) NEMOLPC-KO mice deficient for NF-κB in liver parenchymal cells, exhibiting liver inflammation and fibrosis, but mild steatosis; and ATGLLPC-KO animals deficient for Adipose Triglyceride Lipase in liver parenchymal cells displaying strong steatosis. Results In our three experimental models, liver damages were characterized by inflammation, steatosis and fibrosis but were not associated with metabolic syndrome. More interestingly, left ventricular ejection fraction were reduced by 1.2-fold, 1.3-fold and 1.3-fold in CDA-HFD, NEMOLPC-KO and ATGLLPC-KO male and female mice, respectively when compared to their respective controls, at 35 days post-MI (n=12-25 per group). NAFLD-induced cardiac dysfunction was not associated with worsen cardiac remodeling as infarct size, fibrosis and vascular density were not significantly affected. On the same note, flow cytometry experiments, at 7- and 14-days post-MI, showed no changes in the number or type of inflammatory cells, particularly that of cardiac resident macrophages, in CDAHFD, ATGLLPC-KO and NEMOLPC-KO mice. We next hypothesized that reduced left ventricular function could be induced by altered cardiomyocyte contractility. To corroborate this hypothesis, we isolated cardiomyocytes from hearts of infarcted mice with or without NAFLD and assessed cell contractility using IonOptix technology. Our preliminary results, in the CDAHFD model, showed that there was a reduction in contraction amplitude, defining by the ratio of the difference in sarcomere length during contraction/relaxation to the sarcomere length at the time of relaxation. The speed of contraction and relaxation were also decreased in CDAHFD mice compared with control animals. Conclusions NAFLD favors cardiac dysfunction post-MI. We now aim to identify molecular and cellular entities participating to such pathogenic dialogue between the dysfunctional liver and the infarcted heart.