The Impact on Diabetes on Left Ventricular Remodeling

糖尿病对左心室重构的影响

• 批准号: 6893059
• 负责人: JOHN C CHATHAM
• 金额: $ 49.79万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6893059
• 关键词: allopurinol; angiotensin II; apoptosis; cardiovascular disorder chemotherapy; cardiovascular disorder epidemiology; cardiovascular disorder risk; chemoprevention; free radical oxygen; heart contraction; heart failure; heart function; hemodynamics; hyperglycemia; insulin sensitivity /resistance; laboratory rat; magnetic resonance imaging; medical complication; muscle cells; myocardial infarction; nonhuman therapy evaluation; noninsulin dependent diabetes mellitus; shear stress; ventricular hypertrophy

Following myocardial infarction (MI) both the incidence of heart failure and mortality rates are approximately two-fold higher in patients with diabetes compared to those without diabetes. This increased risk for heart failure and mortality appears to be refractory to currently available treatments. The overall hypothesis of this proposal is that diabetes leads to myocyte specific changes mediated by hyperglycemia, ANG II and ROS, which prevent myocyte hypertrophy and stimulate apoptotic pathways. Therefore, an increase in hemodynamic stress combined with diabetes leads to greater myocyte loss and impaired hypertrophic response resulting in adverse LV remodeling and accelerating the progression of contractile dysfunction and heart failure. Our preliminary data suggests that hyperglycemia and diabetes alters cardiomyocyte signaling pathways involved in the regulation of myocyte growth and apoptosis. This is supported by our observation of increased LV dysfunction and replacement fibrosis in following volume overload in Type-2 diabetic rats. Consequently, the aims of this proposal are 1) Show that the progression of cardiac dysfunction in diabetic patients will be worse than in non-diabetic subjects following transmural myocardial infarction and evaluate whether AT1 RB and allopurinol slow the progression of LV remodeling and dysfunction in diabetic patient; 2) Determine impact of diabetes and insulin resistance on the time course of LV hypertrophy, function and myocyte apoptosis in rats following the and evaluate effect of RAS blockade and xanthine oxidase inhibition are more effective in slowing the progression of LV remodeling; 3) Determine impact of in vivo insulin resistance and Type-2 diabetes on the response of isolated adult cardiomyocytes to hypertrophic and apoptotic stimuli. In Aim 1 we will use state of the art MRI methods coupled with serum markers of collagen turnover and oxidative stress. In Aims 2 and 3 we will use the Zucker diabetic fatty rat that exhibits many of the characteristics of human Type-2 diabetes to assess, for the first time, the effects of diabetes on LV remodeling at all levels from in vivo cardiac function, through to intra myocellular signaling pathways in isolated cells. This combination of clinical and basic science studies into the impact of diabetes on LV remodeling will enable us to identify novel treatment strategies designed to close the gap in outcomes between diabetic and non-diabetic patients with heart disease.

与没有糖尿病患者相比，糖尿病患者心力衰竭的发生率和死亡率的发生率均高两倍。心力衰竭和死亡率的风险增加似乎是对当前可用治疗的难治性。该提议的总体假设是糖尿病会导致高血糖，ANG II和ROS介导的肌细胞特异性变化，从而预防肌细胞肥大并刺激凋亡途径。因此，血流动力应激的增加与 糖尿病会导致肌细胞损失更大，肥厚性反应受损，导致LV重塑不良，并加速收缩功能障碍和心力衰竭的进展。我们的初步数据表明，高血糖和糖尿病会改变涉及肌细胞生长和凋亡调节的心肌细胞信号通路。在2型糖尿病大鼠中，我们观察到LV功能障碍增加和替换纤维化的增加，这支持了这一点。因此，该提议的目的是1）表明 糖尿病患者心脏功能障碍的进展将比透壁心肌梗死后的非糖尿病受试者差，并评估糖尿病患者LV重塑和功能障碍的AT1 RB和别嘌呤醇是否会减慢。 2）确定糖尿病和胰岛素抵抗对大鼠的LV肥大，功能和心肌细胞凋亡的影响，遵循RAS封锁和Xananthine氧化酶抑制的作用，在减慢LV重塑的进展方面更有效； 3）确定 体内胰岛素抵抗和2型糖尿病对分离的成年心肌细胞对肥厚和凋亡刺激的反应的影响。在AIM 1中，我们将使用最先进的MRI方法以及胶原蛋白转换和氧化应激的血清标记。在目标2和3中，我们将使用Zucker糖尿病脂肪大鼠，该脂肪大鼠表现出许多人类2型糖尿病的特征，以首次评估糖尿病对体内心脏功能中各级LV重塑的影响，从 细胞。临床和基础科学研究对糖尿病对LV重塑的影响的这种结合将使我们能够确定旨在缩小糖尿病患者和非糖尿病患者患有心脏病的糖尿病患者之间差距的新型治疗策略。