Aging, Insulin Resistance, and Dilated Cardiomyopathy

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 解释这种增强倾向的机制还知之甚少。至于是否会出现这种情况，还有待商榷 与年龄相关的心血管功能障碍的倾向可归因于年龄本身或 随着时间的推移而累积的心血管危险因素。特别是，老龄化一直在密切地 与内脏肥胖症的发展有关，内脏肥胖症与 年龄相关性胰岛素抵抗的发病机制。年龄相关的胰岛素抵抗是否有助于 心肌损伤后心功能不全的进展尚未有系统的研究。 作为生理性胰岛素抵抗基础的胰岛素细胞活动的改变可能具有重要意义 给衰竭的心脏带来的后果。受损的心肌对葡萄糖的依赖逐渐发展为 它的首选代谢底物。这种偏好取决于葡萄糖氧化的效率。 在高能磷酸盐的产生中。这种偏好成为一种要求，因为有能力 氧化脂肪酸通过脂肪酸关键调节成分中的一系列分子开关而受到限制 运输和氧化。我们已经确定晚期失代偿的扩张期 心肌病与心肌胰岛素抵抗的发展有关，这限制了 心肌葡萄糖摄取和氧化。这些生理特征与细胞胰岛素有关。 心肌中的信号异常，不同于在骨骼肌和 其他胰岛素抵抗状态下的脂肪组织。 总而言之，衰老和心力衰竭具有胰岛素抵抗的共同病理生理特征。 在解释心脏发病率和严重程度的增加方面，这些影响是相加的还是协同的 老年人的失败仍有待确定。我们将确定衰老是否与加速相关 起搏诱导的扩张型心肌病清醒犬的心力衰竭进展。我们将定义 胰岛素抵抗在衰老心肌演变过程中的生理和细胞效应 扩张型心肌病。最后，我们将确定是否在衰老过程中克服心肌胰岛素抵抗 心力衰竭将阻止扩张型心肌病的进展。

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.