Abstract 246: Rescuing an Acquired Cardiac Retinoic Acid Deficiency Prevents Hypertrophy and Sudden Cardiac Death in a Pressure Overload/Chronic Catecholamine Model of Hypertrophy and Heart Failure

Abstract

Introduction: Recently, we have investigated a pressure-overload/chronic catecholamine guinea pig model (ACi) of cardiac hypertrophy (HYP) and HF with the unique features of acquired long QT syndrome and sudden cardiac death (SCD) by quantitative global-scale proteomics using isobaric tags for relative and absolute quantitation. Hypothesis: By compiling proteins altered significantly both compensated HYP and HF, it may be possible to identify novel early contributors to pressure overload- induced HF pathogenesis. Results: Pathway mapping of proteins differentially regulated in HYP that were also changed in HF (p<0.05 in both HYP and HF) revealed altered “retinoate biosynthesis” (p<0.01) and “RAR Activation” (p<0.05), suggesting that guinea pig HYP &HF might be related to impaired Vitamin A metabolism, specifically, to a deficit in the bioactive metabolite, all-trans retinoic acid. Causal Regulator Analysis indicated that coordinate regulation of ATRA-responsive proteins was unlikely to have occurred by chance (p=1.88x10 -11 ) and that the ATRA program was downregulated (z-score<-1.2). ATRA deficit would attenuate transcriptional programs that control fatty acid oxidation, excitation/contraction-coupling, contraction, and antioxidant defense - all of which were decreased in heart failure. Metabolomic profiling by mass spectrometry showed that ATRA, alone among the resident cardiac retinoids, was downregulated in HYP and HF (Down 32% & 33% respectively p<0.05). Secondly, the specific agonist of RXR signaling, 9-cis RA, is not present in adult guinea pig hearts. Proteome and transcriptome data indicate that the ATRA deficit stems from downregulation of retinaldehyde dehydrogenase 1 (RALDH1) by 23% in HYP and 39% in HF (p<0.01 each). Treatment with ATRA (2mg/kg/day) mitigated heart weight/tibia length (ACi: 0.71 , ACi + ATRA: 0.57; p<0.01), improved fractional shortening (27.4% vs 37.5%, p<0.01) and ejection fraction (50.4% vs. 64.8%, p<0.01). Preliminary studies indicate that ATRA treatment also reduces the incidence of sudden cardiac death (55% vs 15% (p<0.01)) in the guinea pig ACi model. Conclusion: The data support a causal role for ATRA deficiency in the pathogenesis of pressure overload-induced HF and susceptibility to SCD.