Aging, Insulin Resistance, and Dilated Cardiomyopathy

描述（由申请人提供）：充血性心力衰竭是老年人发病率和死亡率的主要原因，尽管解释这种倾向增强的机制尚不清楚。至于年龄相关的心血管功能障碍倾向是由于衰老本身还是心血管危险因素的累积，仍然存在争议。特别是，衰老与内脏脂肪的增加密切相关，内脏脂肪的增加与年龄相关的胰岛素抵抗的发病机制有关。是否年龄相关的胰岛素抵抗有助于心肌损伤后心功能障碍的进展还没有系统的探讨。胰岛素细胞活动的改变是生理性胰岛素抵抗的基础，可能对衰竭的心脏有重大影响。受损的心肌逐渐依赖葡萄糖作为首选的代谢底物。这种偏好取决于生成高能磷酸盐时葡萄糖的氧化效率。由于脂肪酸的氧化能力受到脂肪酸运输和氧化关键调控组分的一系列分子开关的限制，这种偏好成为一种要求。我们已经确定扩张型心肌病的晚期失代偿阶段与心肌胰岛素抵抗的发展有关，这限制了心肌葡萄糖的摄取和氧化。这些生理特征与心肌细胞胰岛素信号异常有关，不同于在其他胰岛素抵抗状态下骨骼肌和脂肪组织中观察到的异常。总之，衰老和心力衰竭具有胰岛素抵抗的共同病理生理特征。在解释老年人心力衰竭发病率和严重程度的增加时，这些影响是相加的还是协同的，仍有待确定。我们将确定年龄是否与有意识的起搏诱导扩张型心肌病狗的心力衰竭加速进展有关。我们将定义在扩张型心肌病的演变过程中，胰岛素抵抗在衰老心肌中的生理和细胞作用。最后，我们将确定是否克服心肌胰岛素抵抗在老化和心力衰竭将防止扩张型心肌病的进展。

DESCRIPTION (provided by applicant): Congestive heart failure is a leading cause of morbidity and mortality in the elderly, although the mechanisms to explain the enhanced proclivity are poorly understood. It remains debatable as to whether the age-associated propensity to cardiovascular dysfunction is attributable to aging per se or the accumulation of cardiovascular risk factors that accrue over time. In particular, aging has been closely associated with the development of increased visceral adiposity that has been implicated in the pathogenesis of age associated insulin resistance. Whether age associated insulin resistance contributes to the progression of cardiac dysfunction following myocardial injury has not been explored systematically. The altered cellular actions of insulin that underlie physiological insulin resistance may have significant consequences to the failing heart. The injured myocardium develops an evolving dependence on glucose as its preferred metabolic substrate. The preference is dependent upon the efficiencies of oxidation of glucose in the generation of high-energy phosphates. This preference becomes a requirement as the ability to oxidized fat acids is limited through a series of molecular switches in key regulatory components of fatty acid transport and oxidation. We have determined that advanced, decompensated stages of dilated cardiomyopathy are associated with the development of myocardial insulin resistance, which limits myocardial glucose uptake and oxidation. These physiological features are associated with cellular insulin signaling abnormalities in the myocardium that are distinct from those observed in skeletal muscle and adipose tissue in other insulin resistant states. Together, aging and heart failure share the common pathophysiological features of insulin resistance. Whether the effects are additive or synergistic in explaining the increased incidence and severity of heart failure in the elderly remains to be determined. We will determine if aging is associated with accelerated progression of heart failure in conscious dogs with pacing induced dilated cardiomyopathy. We will define the physiological and cellular effects of insulin resistance in the senescent myocardium during the evolution of dilated cardiomyopathy. Finally, we will determine if overcoming myocardial insulin resistance in the aging and failing heart will prevent the progression of dilated cardiomyopathy.