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Non-alcoholic fatty liver disease is associated with QTc lengthening in the general population [Meeting Abstract]

Banini, B; Issa, D; Seneshaw, M; Siddiqui, M; Oseini, A; Mirshahi, F; Dessie, S; Puri, P; Aneni, E; Blaha, M; Budoff, M; Rifai, M A; Szklo, M; Nasir, K; Sanyal, A J
Background and aims: Cardiovascular disease is the leading cause of mortality in the general population. Prolonged heart rate corrected QT (QTc)interval is a risk factor for cardiac death. We aimed to determine: (1)if underlying non-alcoholic fatty liver disease (NAFLD), a common disease in the population, is associated with QTc length and (2)if the histological severity of NAFLD is associated with more severe QTc prolongation. Method(s): Two cohorts were studied: (1)The Multi-Ethnic Study of Atherosclerosis (MESA), a population-based prospective cohort study of 6814 adult men and women free of cardiovascular disease at enrollment, and (2)A biopsy-proven non-cirrhotic NAFLD cohort (n = 52)and age/gender matched non-NAFLD controls (n = 67)at Virginia Commonwealth University (VCU). NAFLD was identified by a Liver to spleen attenuation ratio (L/S)>1 on CT scan. Severity of NAFLD in the general population was graded as: no NAFLD (Hounsfield Units (HU)>= 55), mild NAFLD (HU 40-54)and moderate to severe NAFLD (HU < 40). Liver histology was scored by Non-alcoholic steatohepatitis Clinical Research Network (NASH CRN)criteria. Patients with alcohol consumption >2 units/day, viral hepatitis, cardiac arrhythmias, or patients taking antiarrhythmic medications or systemic steroids were excluded from the analyses. QTc was determined by Bazett formula using electrocardiograms performed at the time of initial enrollment. Data are presented as mean +/- standard deviation (SD). The odds ratio (OR)with confidence interval (CI)of having a clinically significant QTc prolongation in NAFLD vs non-NAFLD individuals was determined. Result(s): (1)MESA cohort: A subset of 3892 individuals met eligibility criteria; 666 individuals (17%)had NAFLD. Those with NAFLD had longer QTc than those without NAFLD (424 +/- 22.7 ms vs 418 +/- 21.2 ms; p < 0.0001). There was a step-wise increase in the mean QTc interval in association with NAFLD severity (p < 0.0001 for trend). Moreover, NAFLD was associated with higher likelihood of clinically significant QTc prolongation of >450 ms in men (OR 2.24; 95% CI 1.4 to 3.6)and >460 ms in women (OR 1.8; 95% CI 1.2 to 2.7)(2)VCU cohort: Mean QTc for grade 1, 2 and 3 steatosis was 422 +/- 7 ms, 435 +/- 8 ms, and 466 +/- 19 ms, respectively; p < 0.03. Aside from steatosis, other histological features of NASH, NAFLD activity score and fibrosis stage were not significantly related to QTc. Conclusion(s): The presence and severity of hepatic steatosis is associated with lengthening of the QTc interval.
EMBASE:2001821066
ISSN: 0168-8278
CID: 3905542

The impact of obeticholic acid (OCA) on atherogenic lipoproteins in nonalcoholic steatohepatitis [Meeting Abstract]

Sanyal, A J; Van, Natta M L; Yamada, G; Connelly, M A; Siddiqui, M; Wattacheril, J; Neuschwander-Tetri, B A; Chalasani, N P; Kowdley, K V; Diehl, A M; Contos, M J; Behling, C A
Small dense LDL (sdLDL) is more atherogenic than large LDL particles. NASH is associated with increased cholesterol synthesis and sdLDL. OCA improves the histological severity of NASH but increases LDL-C. The impact of OCA on LDL particle size and the mechanisms involved remain to be defined. Aims: To determine the impact of OCA and histological response on LDL particles. Methods: Samples from subjects enrolled in the FLINT trial of OCA (n=99) and placebo (n=99) on whom baseline and end of treatment (EOT) biopsies were available were analyzed. Lipoprotein analysis was performed using NMR. Results: At entry, both treatment groups were comparable with respect to total cholesterol, LDL-C, triglyceride-rich particles (VLDL) and VLDL and LDL particle size distribution. 12 weeks after randomization, LDL-C increased significantly with OCA vs placebo (+25 vs-6 mg/dL, p<0.0001) and then trended downwards until EOT. There was a highly significant decrease in large VLDL particles with OCA vs placebo (-3 vs 0 nmol/L, p=0.0008) and medium VLDL (-3 vs +2 nmol/L, p=0.04), which trended upwards and were no longer significant at EOT. This was accompanied by a corresponding increase in small VLDL with OCA vs placebo (+13 vs-6 nmol/L, p<0.001) at 12 weeks. Changes in triglyceride and cholesterol concentration in triglyceride-rich lipoproteins were similar at 12 weeks with OCA vs placebo (-1 vs-1 mg/dL, p=0.97) and at EOT (-3 vs-3 mg/dL, p=0.87). ApoB, a marker of VLDL secretion, increased (week 12) with OCA vs placebo (+16 vs-4 mg/dL, p<0.0001). At 12 weeks, a decrease in VLDL size, a function of VLDL triglyceride, was accompanied by an increase in large LDL with OCA vs placebo (105 vs-7 nmol/L, p<0.0001) and non-significant change in sdLDL-C (+94 vs-40 nmol/L, p=0.10). The levels of sdLDL-C remained similar across treatment groups throughout the trial. In the placebo arm, histological response (vs nonresponse) was associated with greater mean change from VLDL cholesterol (-3.6 vs 0.4 nmol/L, p<0.08), LDL-C (-16 vs-3 mg/dL, p<0.04), large LDL (-89 vs 8 nmol/L p<0.02). In the OCA arm, histological response (>NAS>2) was associated with the following changes: LDL particles (-62 vs 184 nmol/L, p<0.06), LDL-C (17.4 vs 34 mg/dL, p<0.02), sdLDL (18 vs 139 nmol/L, p< 0.09). None of the lipoproteins changed significantly with resolution of NASH in either arm. Conclusions: The data are compatible with the hypothesis that OCA decreases VLDL size resulting in LDL less susceptible to lipases and thus larger in size. Improvement in disease activity was associated with lower LDL-C in both arms underscoring the relevance of cholesterol in NASH
EMBASE:618936608
ISSN: 1527-3350
CID: 2778722

The physiological, pathological and molecular basis of nonalcoholic steatohepatitis associated cardiomyopathy [Meeting Abstract]

Oseini, A; Toldo, S; Seneshaw, M; Kumar, D P; Santhekadur, P K; Min, H -K; Mezzaroma, E; Bedossa, P; Mauro, A G; Quaini, F; Frati, C; Falco, A; Koduru, S; Banini, B A; Mirshahi, F; Abbate, A; Rider, O; Siddiqui, M; Sanyal, A J
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. HandE, 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), inflammasome activation (NLRP3, ASC, Caspase 1), inflammation (pJNK, NFkappaB, pERK), and fibrosis (Collagen I and III, MMP13 and <-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
EMBASE:618936278
ISSN: 1527-3350
CID: 2778762

Randomised clinical study: GR-MD-02, a galectin-3 inhibitor, vs. placebo in patients having non-alcoholic steatohepatitis with advanced fibrosis

Harrison, S A; Marri, S R; Chalasani, N; Kohli, R; Aronstein, W; Thompson, G A; Irish, W; Miles, M V; Xanthakos, S A; Lawitz, E; Noureddin, M; Schiano, T D; Siddiqui, M; Sanyal, A; Neuschwander-Tetri, B A; Traber, P G
BACKGROUND: Non-alcoholic steatohepatitis (NASH) and resultant liver fibrosis is a major health problem without approved pharmacotherapy. Pre-clinical results of GR-MD-02, a galectin-3 inhibitor, suggested potential efficacy in NASH with advanced fibrosis/cirrhosis and prompted initiation of a clinical development programme in NASH with advanced fibrosis. AIM: To evaluate the safety, pharmacokinetics and exploratory pharmacodynamic markers of GR-MD-02 in subjects having NASH with bridging fibrosis. METHODS: The GT-020 study was a first-in-human, sequential dose-ranging, placebo controlled, double-blinded study with the primary objective to assess the safety, tolerability and dose limiting toxicity of GR-MD-02, in subjects with biopsy-proven NASH with advanced fibrosis (Brunt stage 3). The secondary objectives were to characterise first-dose and multiple-dose pharmacokinetic profiles and to evaluate changes in potential serum biomarkers and liver stiffness as assessed by FibroScan. RESULTS: GR-MD-02 single and three weekly repeated of 2, 4 and 8 mg/kg revealed no meaningful clinical differences in treatment emergent adverse events, vital signs, electrocardiographic findings or laboratory tests. Pharmokinetic parameters showed a dose-dependent relationship with evidence of drug accumulation following 8 mg/kg (~twofold). CONCLUSIONS: GR-MD-02 doses were in the upper range of the targeted therapeutic dose determined from pre-clinical data and were safe and well tolerated with evidence of a pharmacodynamic effect. These results provide support for a Phase 2 development programme in advanced fibrosis due to NASH.
PMID: 27778367
ISSN: 1365-2036
CID: 2678662