Cardiac Autonomic Neuropathy and Myocardial Dysfunction in Type 1 Diabetes

1 型糖尿病患者的心脏自主神经病变和心肌功能障碍

• 批准号: 7864523
• 负责人: RODICA BUSUI (POP-BUSUI)
• 金额: $ 47.22万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7864523
• 关键词: Acetates; Acute; Biological Markers; Biomechanics; Blood Glucose; Blood Pressure Monitors; Cardiac; Cardiomyopathies; Cardiovascular Diseases; Caring; Catecholamines; Cell Respiration; Chronic; Clinical Research; Clinical Trials; Complications of Diabetes Mellitus; Coronary Arteriosclerosis; Data; Development; Diabetes Mellitus; Diabetic Angiopathies; Disease; Event; Fiber; Fingerprint; Functional disorder; Future; General Population; Glucose; Goals; Heart; Heart failure; Hour; Hyperglycemia; Hypertension; Hypoglycemia; Impairment; Injury; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Lead; Left ventricular structure; Longitudinal Studies; Magnetic Resonance Imaging; Mass Fragmentography; Measures; Mediating; Metabolic; Metabolism; Motion; Myocardial; Myocardial Ischemia; Myocardial dysfunction; Natural History; Nerve; Nerve Fibers; Outcome Measure; Oxidative Stress; Pathway interactions; Patients; Pattern; Poly(ADP-ribose) Polymerases; Positron-Emission Tomography; Prevalence; Recruitment Activity; Reporting; Risk Factors; Secondary to; Stream; Testing; Therapeutic; Time; Tissues; Torsion; Toxic effect; Ventricular; Work; autonomic neuropathy; base; cardiovascular disorder risk; cardiovascular risk factor; cohort; density; design; diabetic; glycemic control; heart rate variability; meta-hydroxyephedrine; minimally invasive; mortality; patient population; prevent; prospective; public health relevance; standard of care

DESCRIPTION (provided by applicant): In type 1 diabetes (T1DM), left ventricle (LV) dysfunction often precedes or occurs in the absence of coronary artery disease or hypertension. This suggests that diabetes has direct effects on the heart, which can contribute to the development of cardiomyopathy and LV dysfunction through other mechanisms including: microvascular disease, myocardial metabolism and energetic impairment, autonomic neuropathy and oxidative stress. Cardiac autonomic neuropathy (CAN) is associated with an increased prevalence of silent myocardial ischemia, and is an independent predictor of increased cardiac mortality. Sympathetic imbalance associated with CAN may critically influence myocardial glucose utilization and contribute to LV contractile abnormalities and functional deficits. We have previously shown that CAN is associated with diastolic dysfunction in patients with T1DM. Recently, magnetic resonance imaging (MRI) myocardial tagging has been used to demonstrate increased LV torsion in T1DM patients, a measure providing sensitive information on early LV tissue deformation. Our preliminary studies indicated that increased torsion correlates with markers of CAN. Recent evidence also suggests that glycemic variability may influence the risk of cardiovascular complications, possibly through a mechanism mediated by activation of oxidative stress. We have previously found that oxidative stress was highest in CAN subjects, and we hypothesize that this could be secondary to increased glycemic excursions. Based on these data, our hypothesis is that, in T1DM, sympathetic activation induced by acute glycemic fluctuations, in concert with activation of oxidative stress, promotes alterations in myocardial oxidative metabolism and efficiency via catecholamine toxicity. Subsequently, the development of increased LV torsion and strain, diastolic dysfunction, and cardiomyopathy increase the risk of cardiovascular events. We propose to test these hypotheses in a prospective clinical study with two specific aims. Aim 1 will determine the association between sympathetic activation and cardiac metabolic and functional deficits in subjects with T1DM free of coronary artery disease. The manifestations of sympathetic activation will be determined by positron emission tomography (PET) with [11C]meta-hydroxyephedrine ([11C]HED), heart rate variability, and 24-hour blood pressure monitoring in patients with T1DM (5-10 years' diabetes duration). These will be correlated with changes in cardiac oxidative metabolism and efficiency determined by [11C]acetate PET and with LV torsion and strain assessed by cardiac MRI with tagging. Aim 2 will explore the natural history of myocardial dysfunction in T1DM and will identify predictive biomarkers and potential pathways involved in the development of these deficits. Subjects with T1DM recruited in Aim 1 will be followed prospectively for 3 years, while adhering to the current standard of care for T1DM, and re-assessed utilizing the outcome measures described in Aim 1. We will correlate changes in sympathetic function, LV torsion, and efficiency with the magnitude of glycemic excursions and down-stream biomarkers proposed to contribute to the development of small fiber dysfunction and microvascular disease: oxidative stress fingerprints as assessed by gas- chromatography/mass spectrometry, real-time qRT-PCR, poly(ADP-ribose) polymerase activation and deficits of intraepidermal nerve fiber density (IENFD). We will also determine whether these minimally invasive surrogate measures can identify subjects susceptible to the development of sympathetic and cardiac deficits. These studies will help elucidate mechanisms of myocardial dysfunction in T1DM with ultimate goal of designing future studies implementing therapeutic strategies aimed at preventing increased cardiovascular risk in patients with T1DM. PUBLIC HEALTH RELEVANCE: It was shown that the injury to heart nerves in diabetes, called cardiac autonomic neuropathy (CAN), is an independent predictor of cardiovascular disease (CVD) mortality, which is up to 4 fold more in patients with diabetes than the general population. Heart failure contributes to CVD and in type 1 diabetes (T1DM) it may occur in the absence of significant ischemic heart disease. This proposal will test if, in T1DM, wide blood glucose fluctuations lead to diabetic CAN and to impaired heart contractile patterns and will evaluate the natural history of heart failure and enhanced CVD risk in patients with T1DM in the current standard of diabetes care. These studies also seek to characterize minimally invasive and sensitive biomarkers that may predict the development and progression of these deficits in T1DM. Identifying the impact of acute and wide glucose fluctuations in T1DM, and their relationship with CAN and cardiovascular risk, could help clinicians better determine the safe premises for intensifying insulin therapy in this patient population.

描述（由申请人提供）：在1型糖尿病（T1DM）中，左心室（LV）功能障碍通常在没有冠状动脉疾病或高血压的情况下发生或发生。这表明糖尿病对心脏有直接的影响，这可以通过其他机制，包括：微血管疾病，心肌代谢和能量障碍，自主神经性神经病和氧化应激，从而有助于心肌病和LV功能障碍。心脏自主神经病（CAN）与静音心肌缺血的患病率增加有关，并且是心脏死亡率增加的独立预测指标。与之相关的交感神经失衡可能会严重影响心肌葡萄糖利用，并导致LV收缩异常和功能缺陷。我们以前已经表明，T1DM患者的舒张功能障碍与舒张功能障碍有关。最近，磁共振成像（MRI）心肌标记已被用来证明T1DM患者的LV扭转增加，这项措施提供了有关早期LV组织变形的敏感信息。我们的初步研究表明，增加的扭转与罐子的标记相关。最近的证据还表明，血糖变异性可能会通过激活氧化应激介导的机制影响心血管并发症的风险。我们以前已经发现，氧化应激在罐头受试者中​​最高，我们假设这可能是血糖偏离增加的继发性。基于这些数据，我们的假设是，在T1DM中，急性血糖波动引起的交感神经激活与氧化应激的激活一致，可促进心肌氧化代谢和通过儿茶酚胺毒性的效率的改变。随后，左旋扭转和应变，舒张功能障碍和心肌病的发展增加了心血管事件的风险。我们建议在具有两个具体目标的前瞻性临床研究中检验这些假设。 AIM 1将确定无冠状动脉疾病的T1DM受试者的交感神经激活与心脏代谢和功能缺陷之间的关联。交感神经激活的表现将通过具有[11C]元羟基麻黄碱（[[11C] HED），心率变异性和24小时血压监测的T1DM患者（5-10岁糖尿病持续时间）的正电子发射断层扫描（PET）确定。这些将与[11C]乙酸PET确定的心脏氧化代谢和效率的变化以及与心脏MRI评估的LV扭转和菌株相关。 AIM 2将探索T1DM中心肌功能障碍的自然史，并将确定这些缺陷发展所涉及的预测性生物标志物和潜在途径。在AIM 1中招募的T1DM的受试者将前瞻性遵循3年，同时遵守当前的T1DM护理标准，并利用AIM 1中描述的结果指标进行重新评估。我们将相关联的效果，lv扭转和效率与较小的促进型的促进性促进的促进型和促进的人的效率的变化相关。微血管疾病：通过气相色谱/质谱法评估的氧化应激指纹，实时QRT-PCR，聚（ADP-核糖）聚合酶激活和epi性神经纤维密度（IENFD）的缺陷。我们还将确定这些微创替代措施是否可以识别出易受交感神经和心脏不足发展的受试者。这些研究将有助于阐明T1DM中心肌功能障碍的机制，最终目的是设计实施旨在防止T1DM患者心血管风险增加的治疗策略的未来研究。 公共卫生相关性：表明糖尿病中心脏神经的损伤称为心脏自主神经病（CAN），是心血管疾病（CVD）死亡率的独立预测指标，糖尿病患者的心血管疾病（CVD）死亡率比一般人群高4倍。心力衰竭有助于CVD，在1型糖尿病（T1DM）中，它可能在没有明显缺血性心脏病的情况下发生。该提案将测试在T1DM中，是否会导致糖尿病性易感性波动会导致心脏收缩模式损害，并评估当前糖尿病护理标准中T1DM患者心力衰竭的自然病史和CVD风险增强。这些研究还试图表征微创和敏感的生物标志物，这些标志物可以预测T1DM中这些缺陷的发展和进展。确定急性和广泛的葡萄糖波动在T1DM中的影响，以及它们与CAN和心血管风险的关系，可以帮助临床医生更好地确定该患者人群中胰岛素治疗的安全前提。