Oxidative Stress in Alcoholic Cardiomyopathy

描述(由申请人提供)： 酗酒是U S最大的公共卫生问题之一虽然酗酒可导致心肌功能障碍，患病率相对较高，但早期疾病状态通常在临床上未被认识到，由于当心功能障碍的程度变得明显时，患者很少出现充血性心力衰竭的症状，因此该病总是导致心脏严重增大(扩张型心肌病)，通常被描述为酒精所致的心肌病或酒精性心肌病实验数据普遍支持酒精是这种疾病发展的唯一病因的观点。然而，越来越多的证据表明，无论病因如何，心肌病都直接或间接地与心脏氧化应激增加有关，这是一种常见的最终途径。由于硒和维生素缺乏在酗酒者中很常见，可能是由于营养不良和/或吸收不良所致，因此假设酒精性心肌病是由于长期酗酒而导致的，在涉及硒和维生素E的营养缺乏的背景下，由于硒和维生素E是重要的抗氧化剂，涉及这两种抗氧化剂的缺乏状态将导致抗氧化防御能力的下降。众所周知，饮酒与自由基产生的增加有关。在这两种特殊的营养缺乏状态下，由此导致的抗氧化防御能力的下降可能不足以猝灭/消除因高酒精摄入而产生的自由基。由此导致的氧化应激增加可能损害心脏等各种器官，导致心脏收缩功能障碍，临床表现为充血性心力衰竭。因此，本研究旨在通过长期给予大鼠高剂量酒精和缺乏硒和/或维生素E的饮食来证实这一假说，当超声心动图检查显示血压-体积电导下降时，将进行压力-体积电导和组织学研究。在喂养40周后，将进行心肌病心脏的生化和分子研究，以了解心脏功能和心室扩大情况。其中包括测定4-羟基-2-壬烯醛，这是一种主要的脂质过氧化产物和生物标志物。为了研究细胞凋亡是否由于氧化应激增加而增加，连续两次测量细胞凋亡指数和caspase3释放将首先在连续超声心动图检测到肥大时进行，并随着酒精性心肌病的发展再次进行。这项研究的结果不仅将提供有关酒精性心肌病发病机制的独特信息，还可能产生一种新的酒精性心肌病模型，适用于未来的研究，以评估治疗方案，如补充硒、维生素E、酒精的特定抗代谢产物、特定的抗脂质过氧化抑制剂或特定的抗细胞凋亡药物，以防止酒精性心肌病的发展，以及逆转更为普遍但经常未确诊的酒精性心肌病阶段。

DESCRIPTION (provided by applicant): Alcoholism is one of the top public health problems in the U S Although alcohol abuse can cause cardiac muscle dysfunction with a relatively high prevalence, the early disease states usually go unrecognized clinically, since patients seldom experience any symptom of congestive heart failure When the extent of cardiac dysfunction becomes clinically evident, the disease has invariably resulted in a severely enlarged heart (dilated cardiomyopathy) commonly described as alcohol-induced heart muscle disease or alcoholic cardiomyopathy Experimental data generally supports the notion that alcohol is the sole causative agent in the development of this disease. However, there is a growing body of evidence to suggest that cardiomyopathy, regardless of etiology, is directly or indirectly related to an increased oxidative stress to the heart as a common final pathway. Since selenium and vitamin deficiencies are common among alcoholics, possibly as a result of malnutrition and/or malabsorption, it is hypothesized that alcoholic cardiomyopathy is caused by long-term alcohol abuse in the setting of nutritional deficiency involving both selenium and vitamin E. Since selenium and vitamin E are important anti-oxidants, a deficiency state involving these two anti-oxidants will result in a decrease in anti-oxidant defense. Alcohol consumption is well recognized to be associated with an increase in free radical production. Under these two specific nutritional deficiency states, the resultant decrease in anti-oxidant defense may not be adequate in quenching/removing the free radicals generated from high alcohol intake. This resultant increase in oxidative stress may damage various organs such as the heart leading to cardiac contractile dysfunction manifested clinically as congestive heart failure. Therefore, the present study is designed to confirm such hypothesis by feeding rats long-term high-dose alcohol and diets deficient in selenium and/or vitamin E. Pressure-volume conductance and histological studies will be performed when echocardiographic study indicates a decrease. Biochemical and molecular studies of the cardiomyopathic heart will then be performed in cardiac function and ventricular enlargement after 40 weeks of feeding. They include measuring 4-hydroxy-2-nonenal, a major product and biomarker of lipid peroxidation. To investigate if increased apoptosis occurs as a result of increased oxidative stress, two consecutive measurements of apoptotic index and caspase 3 release will be conducted first when hypertrophy is detected from serial echocardiography and again with the development of alcoholic cardiomyopathy. The results obtained from this study will not only provide unique information regarding the pathogenetic mechanism involved in the development of alcoholic cardiomyopathy, but may also yield a new model of alcoholic cardiomyopathy suitable for future studies to evaluate therapeutic options such as selenium-, vitamin E supplementation, specific anti-metabolites of alcohol, specific anti-lipid peroxidation inhibitor or specific anti-apoptosis agent for preventing the development of alcoholic cardiomyopathy as well as reversing the far more prevalent yet frequently undiagnosed stage of alcoholic cardiomyopathy.