S11 * ALCOHOL AND THE HEART * S11.1 * CLINICAL OVERVIEW OF ALCOHOL EFFECTS ON THE HEART

Abstract

Alcohol consumption is associated with positive beneficial and negative toxic effects on the heart and cardiovascular system. Moderate alcohol consumption has been linked to beneficial effects on arterial atherogenesis and thrombus formation, with increase of HDL cholesterol, endothelial vasorelaxation, reduced platelet aggregation and fibrinogen. The French paradox of relatively low cardiovascular mortality despite high saturated fat intake has sparked research of chronic red wine consumption. Alcoholic heart disease caused by high consumption includes arrhythmias, especially atrial fibrillation and holiday heart syndrome, increased hypertension with LV hypertrophy, heart failure and cardiomyopathy (CMP). Consumption of >90 g/day over 5 years has been associated with development of alcoholic CMP. Alcoholic CMP is accompanied by apoptosis of cardiac myocytes, but importantly shows improved outcome in absolute alcohol abstinence. In chronic alcohol abuse even without overt cardiac disease, we recently reported increased cardiac NT-proBNP plasma levels, decreasing after withdrawal, reflecting early negative cardiac effects. Interestingly, even in patients with previous cardiovascular ischemic events, up to moderate alcohol consumption has been shown to decrease secondary mortality. Overall, alcohol has controversial J-curve dose effects on the heart and cardiovascular system. # S11.2 QUANTITATIVE PROTEOMIC ANALYSIS OF ALCOHOLIC CARDIOMYOPATHY {#article-title-2} Chronic heavy alcohol consumption is responsible for the development of alcoholic cardiomyopathy (ACM), a dilated cardiomyopathy which at early stages may be reversed after withdrawal from alcohol consumption. If untreated, ACM leads often to heart failure. Mitochondrial dysfunction, reduced cardiac contractility, left ventricular (LV) dilation and reduction in LV ejection fraction have been shown to be involved in the pathobiology of ACM. However, there are no biomarkers characteristic of ACM that could be used for early diagnosis. For the discovery of proteomic biomarkers, we developed an animal model of ACM of rats fed long-term a Lieber DeCarli liquid diet and isocalorically fed paired controls. Hearts pre-screened by echocardiography and hemodynamics for cardiac dysfunction were used for protein fractionation, digestion, peptides separation by strong cation ion exchange liquid chromatography (LC) and detection by mass spectrometry (MS) using a Fourier Transform Ion Cyclotron Resonance instrument. Comparison of LC-MS/MS spectra from rats with ACM and paired controls provided over 300 differentially expressed proteins. Quantitative analysis of the datasets by Elucidator software identified 32 downregulated proteins with P  < 0.05 that were visualized on IPA pathway maps and DAVID canonical pathways into three pathways: oxidative phosphorylation, ribosome and glutathione. Human heart samples of transplantation quality from heavy alcohol drinkers with or without ACM, and non-alcoholic controls were obtained from the University of Barcelona Hospital Clinic, and processed by the same proteomic methodology as rat samples. Analysis on the datasets identified 117 differentially expressed proteins among the three sample groups, with significant changes in 31 proteins belonging to the oxidative phosphorylation chain, cardiac muscle and citrate cycle pathways. In the oxidative phosphorylation chain, alcohol affected predominantly proteins of the mitochondrial Complex I and III in alcoholics without ACM, which progressed to include proteins of Complex IV and V in alcoholics with clinical symptoms of ACM. Overall, the label-free proteomic and pathway analyses of rat and human heart samples provided potential targets to aid in the early diagnosis of ACM. # S11.3 MOLECULAR MECHANISM OF ALCOHOL-INDUCED CARDIAC DAMAGE {#article-title-3} One-third of alcohol abusers manifest decreased cardiac contractility and muscle strength termed, respectively, alcoholic cardiomyopathy and myopathy. In fact, the most common cause of cardiomyopathy with congestive heart failure is chronic alcoholism. However, the pathogenesis of these conditions still remains obscure. Studies on human alcoholics and animal models have demonstrated that chronic ethanol causes structural and functional derangements of mitochondria. Impairments of mitochondrial bioenergetics and the apoptosis-regulating function of mitochondria are considered to be central for the increased cell death in both alcoholic heart and liver disease. Emerging research indicates the interdependence between the factors that regulate mitochondrial morphology and function. Here, we have studied the effect of chronic alcohol exposure on mitochondrial dynamics in cardiac cells using organelle-targeted fluorescent proteins. Since chronic ethanol treatment results in oxidative stress, not only in liver, but also in heart, we have also investigated the effect of reactive oxygen species (ROS) on mitochondrial fusion–fission and motility. Our studies provide evidence that both chronic alcohol exposure and ROS result in a decrease in mitochondrial motility and fusion activity. ROS produced by a subset of mitochondria resulted in rapid and spatially confined motility inhibition. Although both alcohol and ROS promote mitochondrial permeability transition pore (PTP) opening and the ensuing swelling can contribute to suppression of mitochondrial dynamics, inhibition of motility by ROS was also observed in the presence of cyclosporine A, a drug that inhibits PTP opening. These data indicate that mitochondrial dynamics is suppressed during chronic alcohol exposure, and this may be mediated by increased ROS production through some PTP-dependent and -independent pathways.