Cardiac Autonomic Neuropathy and Myocardial Dysfunction in Type 1 Diabetes

描述(由申请人提供)：在1型糖尿病(T1 DM)中，左心室(LV)功能障碍通常先于或发生在没有冠状动脉疾病或高血压的情况下。这表明糖尿病对心脏有直接影响，可通过其他机制促进心肌病和左心功能不全的发展，包括：微血管疾病、心肌代谢和能量障碍、自主神经病变和氧化应激。心脏自主神经病变(CAN)与无症状心肌缺血的发生率增加有关，是心脏死亡率增加的独立预测因素。与CAN相关的交感失衡可能严重影响心肌葡萄糖的利用，并导致左心室收缩异常和功能缺陷。我们先前已经证明，在T1 DM患者中，CaN与舒张期功能障碍有关。最近，核磁共振成像(MRI)心肌标记术被用来显示T1 DM患者左室扭转增加，这一指标提供了早期左室组织变形的敏感信息。我们的初步研究表明，扭转增加与CAN的标志物相关。最近的证据还表明，血糖变异性可能影响心血管并发症的风险，可能是通过氧化应激激活所介导的机制。我们之前已经发现，氧化应激在CAN受试者中最高，我们假设这可能是血糖升高的次要原因。基于这些数据，我们的假设是，在T1 DM患者中，急性血糖波动引起的交感神经激活与氧化应激激活相结合，通过儿茶酚胺毒性促进心肌氧化代谢和效率的改变。随后，左心室扭转和应变增加、舒张期功能障碍和心肌病的发生增加了心血管事件的风险。我们建议在一项有两个特定目标的前瞻性临床研究中检验这些假设。目的1将确定交感神经激活与无冠状动脉病变的T1 DM患者的心脏代谢和功能缺陷之间的关系。交感神经激活的表现将通过[11C]间羟基麻黄碱([11C]HED)正电子发射断层扫描(PET)、心率变异性和T1 DM患者(糖尿病病程5-10年)的24小时血压监测来确定。这将与[11C]醋酸酯PET测定的心脏氧化代谢和效率的变化相关，与心脏MRI标记评估的左心室扭转和应变相关。目的2将探索T1 DM患者心肌功能障碍的自然历史，并将确定预测生物标记物和参与这些功能障碍发展的潜在途径。在AIM 1招募的T1 DM受试者将被前瞻性跟踪3年，同时坚持目前的T1 DM护理标准，并使用AIM 1中描述的结果测量方法重新评估。我们将交感功能、左心室扭转和效率的变化与血糖漂移的幅度和下游生物标记物相关联，这些生物标记物被认为有助于小纤维功能障碍和微血管疾病的发展：通过气相色谱/质谱仪、实时qRT-PCR、聚(ADP-核糖)聚合酶激活和表皮内神经纤维密度缺陷(IENFD)来评估氧化应激指纹。我们还将确定这些微创替代措施是否能够识别易患交感神经和心脏缺陷的受试者。这些研究将有助于阐明T1 DM患者心肌功能障碍的机制，最终目标是设计未来的研究，实施旨在预防T1 DM患者心血管风险增加的治疗策略。 公共卫生相关性：研究表明，糖尿病对心脏神经的损害，称为心脏自主神经病变(CAN)，是心血管疾病(CVD)死亡率的独立预测因子，糖尿病患者的死亡率是普通人群的4倍。心力衰竭会导致心血管疾病，在1型糖尿病(T1 DM)中，如果没有明显的缺血性心脏病，就可能发生心力衰竭。这项建议将测试在T1 DM患者中，广泛的血糖波动是否会导致糖尿病和心脏收缩模式受损，并将在当前的糖尿病护理标准下评估T1 DM患者心力衰竭的自然病史和心血管风险增加。这些研究还试图表征微创和敏感的生物标记物，这些标记物可能预测T1 DM这些缺陷的发展和进展。确定T1 DM患者急性和广泛血糖波动的影响，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在这一患者群体中加强胰岛素治疗的安全前提。

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.