Oxidative Stress in Alcoholic Cardiomyopathy

描述（由申请人提供）： 酗酒是美国最重要的公共卫生问题之一。 尽管酗酒可导致心肌功能障碍，且患病率相对较高，但早期疾病状态通常在临床上未被识别，因为患者很少出现任何充血性心力衰竭症状。 当心脏功能障碍的程度在临床上变得明显时，该疾病总是会导致心脏严重扩大（扩张性心肌病），通常被称为酒精性心肌病或酒精性心肌病。 实验数据通常支持酒精是唯一的治疗方法。这种疾病发展的病原体。 然而，越来越多的证据表明，无论病因如何，心肌病都与心脏氧化应激增加直接或间接相关，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，可能是营养不良和/或吸收不良的结果，因此推测酒精性心肌病是由于长期酗酒而导致硒和维生素E营养缺乏所致。由于硒和维生素E是重要的抗氧化剂，这两种抗氧化剂的缺乏状态将导致抗氧化防御能力下降。 众所周知，饮酒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下降可能不足以淬灭/消除因大量饮酒而产生的自由基。 由此产生的氧化应激增加可能会损害多种器官，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饮酒和缺乏硒和/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压力-容积电导下降时，将进行压力-容积电导和组织学研究。 然后，在喂养 40 周后，将对心肌病心脏进行心脏功能和心室扩大的生化和分子研究。 其中包括测量 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导致细胞凋亡增加，当连续超声心动图检测到肥厚时，首先对细胞凋亡指数和 caspase 3 释放进行两次连续测量，并在酒精性心肌病发生时再次测量。 这项研究获得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，而且还可能产生一种新的酒精性心肌病模型，适合未来的研究，以评估治疗方案，例如补充硒、维生素E、特异性抗酒精代谢物、特异性抗脂质过氧化抑制剂或特异性抗凋亡剂，以预防酒精性心肌病的发展，并扭转更为普遍但经常未被诊断的阶段。酒精性心肌病。

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.