Early myocardial remodeling and progressive kidney function decline in type 1 diabetes

1 型糖尿病的早期心肌重塑和进行性肾功能下降

• 批准号: 10371705
• 负责人: Alessandro Doria
• 金额: $ 82.17万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-24 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10371705
• 关键词: Address; Age; Albuminuria; Atherosclerosis; Blood Glucose; Blood Pressure; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Diseases; Cholesterol; Cicatrix; Clinic; Coronary Arteriosclerosis; Data; Development; Diabetes Mellitus; Diabetic Nephropathy; Disease; Disease Pathway; Early identification; End stage renal failure; Etiology; Event; Fiber; Fibrosis; Fostering; Functional disorder; Gadolinium; Goals; Hand; Health; Heart Atrium; Heart failure; Hypertrophy; Impairment; Individual; Insulin-Dependent Diabetes Mellitus; Intervention; Left Ventricular Ejection Fraction; Left Ventricular Mass; Link; Magnetic Resonance; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Morbidity - disease rate; Myocardial; Myocardium; Nature; Participant; Patients; Persons; Play; Population; Positioning Attribute; Process; Recording of previous events; Renal function; Risk; Risk Factors; Role; Serum Proteins; Severities; Smoking; Sudden Death; Systole; Tumor Necrosis Factor Receptor; Ventricular Remodeling; X-Ray Computed Tomography; base; cardiovascular disorder risk; cardiovascular risk factor; coronary artery calcium; diabetic; diabetic cardiomyopathy; experience; extracellular; functional decline; heart function; heart imaging; high risk; imaging biomarker; indexing; innovation; insight; interstitial; mortality; multiplex assay; non-diabetic; novel; novel strategies; novel therapeutics; preservation; prevent; protein metabolite; response; tool

SUMMARY A large proportion of the excess CVD morbidity and mortality experienced by individuals with T1D occur in conjunction with diabetic kidney disease (DKD), which is associated with a striking increase in the risk of coronary artery disease (CAD) and heart failure. The latter is frequently due to the development of diabetic cardiomyopathy – a diabetes-specific alteration of the myocardium. The etiologic links between DKD and cardiomyopathy are not clear, but preliminary data from our group suggest a pivotal role of the kidney function decline component of DKD rather than albuminuria. Specifically, using an MRI-derived marker of cardiomyocyte size, we have observed that patients with T1D who are losing kidney function but still have preserved GFR have subclinical signs of myocardial remodeling, as indicated by a larger cardiomyocyte size and a reduction of myocardial fiber shortening during systole as compared to T1D patients with stable kidney function. The overall goal of this collaborative proposal, which is in response to RFA-HL-21-014, is to take advantage of the latest developments in cardiac imaging and biomarker platforms to characterize the cardiac involvement in patients with T1D and DKD, focusing on the initial events in the development of diabetic cardiomyopathy. “GFR Decliners” (GFR loss in the previous 3-6 years ≥3 ml/min/year, n=100) and “GFR Non- Decliners” (n=100) with T1D and CKD stage 1-3A, along with Non-diabetic controls (n=100) of similar age and CKD stage, will undergo a gadolinium-enhanced cardiac magnetic resonance (CMR) and a gated cardiac CT scan to quantify coronary artery calcium (CAC). Through these studies, we will address the following Specific Aims: 1. To evaluate the presence and severity of myocardial remodeling among T1D patients and assess its relationship with early progressive kidney function decline. Cardiomyocyte size (τic) and interstitial fibrosis (measured as extracellular volume [ECV]) will be quantified by CMR and compared among GFR Decliners, GFR Non-Decliners, and Non-Diabetic subjects, and also related to albuminuria and presence and severity of CAD. 2. To assess the relative contribution of cardiomyocyte hypertrophy and interstitial fibrosis to impaired cardiac function among T1D patients. Indices of cardiac function and myocardial strain will be derived from the CMR data and evaluated for their association with cardiomyocyte size (τic) and interstitial fibrosis (ECV), in relation to the severity of concomitant CAD. 3. To gain insights into the disease processes involved in the etiology of myocardial remodeling and assess whether these overlap with those involved in the progressive kidney function decline. In targeted studies, we will focus on serum proteins implicated in heart failure or previously associated with increased risk of GFR loss. In untargeted studies, we will leverage the latest developments in multiplexed assays to evaluate serum protein profiles in a systematic fashion. With the information generated by this study on hand, we will be optimally positioned to develop new strategies and possibly new drugs to prevent CVD in T1D.

概括 T1D 患者的 CVD 发病率和死亡率过高大部分发生在 与糖尿病肾病 (DKD) 结合，糖尿病肾病与患糖尿病的风险显着增加有关 冠状动脉疾病（CAD）和心力衰竭。后者通常是由于糖尿病的发展 心肌病——糖尿病特异性的心肌改变。 DKD 与 DKD 之间的病因学联系 心肌病尚不清楚，但我们小组的初步数据表明肾功能起着关键作用 DKD 的下降成分而不是蛋白尿。具体来说，使用 MRI 衍生的标记 心肌细胞大小，我们观察到正在丧失肾功能但仍具有肾功能的 T1D 患者 保留的 GFR 具有心肌重塑的亚临床迹象，如较大的心肌细胞所示 与 T1D 患者相比，收缩期心肌纤维的尺寸和缩短减少 肾功能稳定。该协作提案的总体目标是对 RFA-HL-21-014 的回应， 是利用心脏成像和生物标志物平台的最新发展来表征 T1D 和 DKD 患者的心脏受累，重点关注糖尿病发展的初始事件 心肌病。 “GFR 下降者”（过去 3-6 年 GFR 下降≥3 ml/min/年，n=100）和“GFR 非- 患有 T1D 和 CKD 1-3A 期的下降者”(n=100)，以及年龄相近的非糖尿病对照组 (n=100) CKD 阶段，将接受钆增强心脏磁共振 (CMR) 和门控心脏 CT 扫描以量化冠状动脉钙（CAC）。通过这些研究，我们将解决以下具体问题 目的： 1. 评估 T1D 患者心肌重构的存在及其严重程度 评估其与早期进行性肾功能衰退的关系。心肌细胞大小 (τic) 和 间质纤维化（以细胞外体积 [ECV] 测量）将通过 CMR 进行量化，并在 GFR 下降、GFR 非下降和非糖尿病受试者，也与白蛋白尿和存在相关 和 CAD 的严重程度。 2. 评估心肌细胞肥大和间质的相对贡献 T1D 患者的纤维化导致心脏功能受损。心功能和心肌应变指数 将源自 CMR 数据并评估其与心肌细胞大小 (τic) 的关联以及 间质纤维化 (ECV)，与伴随 CAD 的严重程度相关。 3.深入了解疾病 参与心肌重塑病因学的过程并评估这些过程是否与心肌重塑重叠 那些参与进行性肾功能衰退的人。在有针对性的研究中，我们将重点关注血清 与心力衰竭有关或之前与 GFR 损失风险增加相关的蛋白质。在无针对性的 研究中，我们将利用多重检测的最新进展来评估血清蛋白谱 系统化的时尚。有了本研究产生的信息，我们将能够最佳地定位 开发新策略和可能的新药物来预防 1 型糖尿病中的 CVD。