Oxidative Stress in Alcoholic Cardiomyopathy

描述（由申请人提供）： 酒精中毒是美国最严重的公共卫生问题之一。尽管酒精滥用可导致心肌功能障碍，发病率相对较高，但由于患者很少出现充血性心力衰竭的症状，因此临床上通常无法识别早期疾病状态。这种病总是导致心脏严重肥大（扩张型心肌病）通常被描述为酒精-诱发的心肌疾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致病因素的观点。 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与心脏的氧化应激增加有关，这是一种常见的最终途径。 由于硒和维生素缺乏症在酗酒者中很常见，可能是营养不良和/或吸收不良的结果，因此假设酒精性心肌病是由长期酒精滥用引起的，营养缺乏症包括硒和维生素E。 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的降低。 酒精消费被公认与自由基产生的增加有关。 在这两种特定的营养缺乏状态下，由此产生的抗氧化防御能力的降低可能不足以淬灭/消除由大量酒精摄入产生的自由基。 这种氧化应激的结果增加可能损害各种器官，例如心脏，导致心脏收缩功能障碍，临床上表现为充血性心力衰竭。因此，本研究旨在通过给大鼠长期高剂量酒精和缺乏硒和/或维生素E的饮食来证实这一假设。 当超声心动图研究表明降低时，将进行压力-容积传导和组织学研究。 在喂养40周后，将对心肌病心脏的心脏功能和心室扩大进行生化和分子研究。 它们包括测量4-羟基-2-壬烯醛，这是脂质过氧化的主要产物和生物标志物。 为了研究氧化应激增加是否会导致细胞凋亡增加，首先在连续超声心动图检测到肥大时进行两次连续的细胞凋亡指数和半胱天冬酶3释放测量，然后在酒精性心肌病发生时再次进行测量。 从这项研究中获得的结果不仅将提供关于酒精性心肌病发展中涉及的发病机制的独特信息，而且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，以评估治疗选择，如硒，维生素E补充剂，酒精的特异性抗代谢物，特异性抗脂质过氧化抑制剂或特异性抗细胞凋亡剂，用于预防酒精性心肌病的发展以及逆转酒精性心肌病的更普遍但经常未诊断的阶段。

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.