Aging, Insulin Resistance, and Dilated Cardiomyopathy

衰老、胰岛素抵抗和扩张型心肌病

• 批准号: 7477691
• 负责人: Richard P Shannon
• 金额: $ 32.93万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-15 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7477691
• 关键词: 2,4-thiazolidinedione; Accounting; Acids; Acute; Adipose tissue; Admission activity; Affect; Age; Aging; American; Amides; Appendix; Attenuated; Body fat; Body mass index; Canis familiaris; Cardiac; Cardiomyopathies; Cardiovascular system; Clinical; Condition; Congestive Heart Failure; Conscious; Continuous Infusion; Coronary; Data; Dependence; Development; Dilated Cardiomyopathy; Distal; Elderly; Esterified Fatty Acids; Euglycemic Clamping; Evolution; Excess Mortality; Family; Fatty acid glycerol esters; Functional disorder; Generations; Glucose; Glucose Clamp; Heart; Heart failure; Hospitals; Hour; Incidence; Infusion procedures; Injury; Insulin; Insulin Resistance; Laboratories; Life; Mediating; Metabolic; Modeling; Molecular; Morbidity - disease rate; Myocardial; Myocardium; Nature; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Obesity; Outcome; PTEN gene; Pathogenesis; Performance; Peroxisome Proliferator-Activated Receptors; Pharmacological Treatment; Phosphoric Monoester Hydrolases; Phosphorylation; Physiological; Play; Predisposition; Property; Residual state; Risk; Role; Series; Serine; Severities; Signal Transduction; Site; Skeletal Muscle; Societies; Staging; Standards of Weights and Measures; Testing; Therapeutic; Thiazolidinediones; Thinking; Time; Tumor Suppressor Proteins; Ventricular Dysfunction; Visceral; age effect; age related; aged; base; cardiovascular risk factor; cohort; demographics; deprivation; design; fatty acid transport; glucagon-like peptide 1; glucose uptake; hemodynamics; improved; injured; inorganic phosphate; instrument; insulin sensitivity; insulin signaling; integrin-linked kinase; member; mortality; oxidation; preference; prevent; proglucagon; programs; receptor; recombinant peptide; response; senescence; uptake

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.

充血性心力衰竭是老年人发病和死亡率的主要原因，尽管 解释增强的倾向的机制知之甚少。关于是否是否有争议 与年龄相关的心血管功能障碍的倾向归因于衰老本身或 随着时间的推移会产生的心血管危险因素的积累。特别是，衰老密切 与增加内脏肥胖的发展有关，这与 年龄相关胰岛素抵抗的发病机理。与年龄相关的胰岛素抵抗是否有助于 心肌损伤后心脏功能障碍的进展尚未系统地探索。 胰岛素的细胞作用改变了生理胰岛素耐药性基础的细胞作用可能具有显着 对失败的心脏的后果。受伤的心肌会形成对葡萄糖的不断发展的依赖 它首选的代谢底物。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 通过一系列脂肪酸的关键调节成分中的一系列分子开关限制了氧化的脂肪酸。 运输和氧化。我们已经确定了扩张的高级，代偿阶段 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 心肌中的信号异常与骨骼肌和 其他胰岛素耐药态中的脂肪组织。 衰老和心力衰竭共享胰岛素抵抗的常见病理生理特征。 效果是在解释心脏发病率增加和严重性方面的添加剂还是协同作用 老年人失败尚待确定。我们将确定衰老是否与加速有关 有意识的狗的心力衰竭进展会引起诱发的扩张心肌病。我们将定义 胰岛素抵抗在进化过程中的生理和细胞作用 扩张的心肌病。最后，我们将确定是否克服衰老中的心肌胰岛素抵抗 心脏衰竭将阻止扩张的心肌病的进展。

项目成果

Chronic glucagon-like peptide-1 infusion sustains left ventricular systolic function and prolongs survival in the spontaneously hypertensive, heart failure-prone rat.

• DOI: 10.1161/circheartfailure.108.766402
• 发表时间: 2008-09
• 期刊: Circulation. Heart failure
• 作者: Poornima I;Brown SB;Bhashyam S;Parikh P;Bolukoglu H;Shannon RP
• 通讯作者: Shannon RP

GLP-1 (7-36) amide restores myocardial insulin sensitivity and prevents the progression of heart failure in senescent beagles.

• DOI: 10.1186/s12933-014-0115-x
• 发表时间: 2014-07-31
• 期刊: Cardiovascular diabetology
• 影响因子: 9.3
• 作者: Chen M;Angeli FS;Shen YT;Shannon RP
• 通讯作者: Shannon RP

The effects of combined versus selective adrenergic blockade on left ventricular and systemic hemodynamics, myocardial substrate preference, and regional perfusion in conscious dogs with dilated cardiomyopathy.

联合与选择性肾上腺素能阻滞对患有扩张型心肌病的清醒犬的左心室和全身血流动力学、心肌底物偏好和局部灌注的影响。

• DOI: 10.1016/j.jacc.2005.11.082
• 发表时间: 2006
• 期刊: Journal of the American College of Cardiology
• 影响因子: 24
• 作者: Nikolaidis,LazarosA;Poornima,Indu;Parikh,Pratik;Magovern,Megan;Shen,You-Tang;Shannon,RichardP
• 通讯作者: Shannon,RichardP