AASLD Washington DC October 2017:
Abdul Oseini1, Stefano Toldo5, Mulugeta Seneshaw1, Divya P. Kumar1, Prasanna K. Santhekadur1, Hae-Ki Min1, Eleonora Mezzaroma5, Pierre Bedossa2, A. Gabriele Mauro5, Federico Quaini3, Caterina Frati3, Angela Falco3, Srinivas Koduru4, Bubu A. Banini1, Faridoddin Mirshahi1, Antonio Abbate5, Oliver Rider6, Mohammad Siddiqui1, Arun J. Sanyal1;
1Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA; 2Hospital Beaujon, Clichy, France; 3University of Parma, Parma, Italy; 4Gene Arrays, Entity of Vedic Research, Inc, New York, NY; 5Division of Cardiology, Virginia Commonwealth University, Richmond, VA;6Division of Cardiology, Oxford University, John Radcliffe Hospital, Oxford, United Kingdom
BACKGROUND: There is a paucity of data on the physiological, pathological and molecular basis of myocardial dysfunction in NASH. The Diet-induced animal model of NAFLD (DIAMOND) develops fatty liver, NASH and bridging fibrosis after 4, 16 and 36 weeks respectively, on western diet (WD). HYPOTHESIS: NASH-associated cardiomyopathy (NAC) is driven by pathways similar to those seen in NASH. AIMS: (1) To determine if the DIAMOND model reproduces the myocardial dysfunction seen in humans with NASH; (2) To determine the histological, cell signaling and transcriptomic drivers of cardiac physiological changes. METHODS: DIAMOND mice were fed chow diet (CD) or WD for 8, 16-24, or 48-52 weeks (n=6-8/ group). Trans-thoracic echocardiography was performed and related to cardiac MRI in humans with NASH. H&E, Sirius Red stains and electron microscopy (EM) were performed. Molecular analysis (PCR/Western blot) of pathways related to NASH pathogenesis, and unbiased analysis (RNA Seq) to evaluate the transcriptome were performed. RESULTS: Physiological Changes: In WD-fed vs CD-fed mice, diastolic dysfunction (increased isovolumetric relaxation time) occurred by 8 wks (NAFL) and persisted up to 52 wks (NASH with bridging fibrosis). Systolic dysfunction (decreased LV fractional shortening) occurred by 8 wks, corrected, and worsened again at 52 wks. Progressive worsening of myocardial performance index and RV systolic function was noted over time in WD-fed mice. This was similar to humans with NASH. Histology: Increasing myocardial fibrosis was seen from week 24 (NASH with fibrosis) onwards, with EM showing disruption of Z line, myofibrillar disorganization, mitochondrial abnormalities, gap junction internalization and fibrosis and microthrombi with megakaryocytes. Cell Signaling: At 24 wks, WD-fed (vs CD) mice had no differences in lipid metabolism, but showed significant increase (p< 0.05) in markers of oxidative stress (superoxide dismutase, NADPH oxidase, NRF2), endoplasmic reticulum stress (ATF4, GRP78, CHOP), inflam- masome activation (NLRP3, ASC, Caspase 1), inflammation (pJNK, NFKB, pERK), and fibrosis (Collagen I and III, MMP13 and α-SMA). Transcriptome: Cell cycle and apoptosis pathways were activated by 8 wks with epigenetic changes (Histone 1 -linked networks). At 24 wks, myofibrillar protein synthetic pathways increased with cytoskeletal remodeling proteins, followed by increased fibrogenic and angiogenic signaling and metabolic reprogramming after 36 wks CONCLUSIONS: There are several similarities between the pathogenesis of NAC and NASH, providing potential targets for combined therapeutics in the management of these two important disease processes.
Disclosures:Arun J. Sanyal – Advisory Committees or Review Panels: Bristol Myers, Gilead, Genfit, Abbott, Ikaria, Pfizer, Novartis, Virology Education, Intercept, Sanofi; Consulting: Salix, Immuron, Exhalenz, Nimbus, Genentech, Echosens, Takeda, Merck, Enanta, Zafgen, JD Pharma, Islet Sciences, ardelyx; Grant/Research Support: Salix, Genentech, Intercept, Ikaria, Takeda, GalMed, Novartis, Gilead, Tobira; Independent Contractor: UpToDate, Elsevier; Management Position: Sanyal Biotechnology; Stock Shareholder: Exhalenz, Hemoshear, Akarna, tiziana, Genfit
The following people have nothing to disclose: Abdul Oseini, Stefano Toldo, Mulugeta Seneshaw, Divya P. Kumar, Prasanna K. Santhekadur, Hae-Ki Min, Eleonora Mezzaroma, Pierre Bedossa, A. Gabriele Mauro, Federico Quaini, Caterina Frati, Angela Falco, Bubu A. Banini, Faridoddin Mirshahi, Oliver Rider, Mohammad Siddiqui