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: 10544058
• 负责人: Alessandro Doria
• 金额: $ 78.76万
• 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/10544058
• 关键词: Acceleration; Address; Age; Albuminuria; Atherosclerosis; Biological Markers; Blood Glucose; Blood Pressure; Calcium; 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; Ischemia; 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; cardiovascular disorder risk; cardiovascular risk factor; coronary artery calcium; diabetic; diabetic cardiomyopathy; experience; extracellular; functional decline; heart function; heart imaging; high risk; improved; indexing; innovation; insight; interstitial; mortality; multiplex assay; non-diabetic; novel; novel strategies; novel therapeutics; preservation; prevent; 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发生的个人经历的过量CVD发病率和死亡率很大一部分 与糖尿病肾脏疾病（DKD）的结合，这与罢工的增加有关 冠状动脉疾病（CAD）和心力衰竭。后者经常是由于糖尿病的发展 心肌病 - 心肌的特定糖尿病改变。 DKD和 心肌病不清楚，但是我们组的初步数据表明肾功能的角色 DKD而不是蛋白尿的衰落组成部分。具体而言，使用MRI源性标记 心肌细胞的大小，我们观察到患有肾功能但仍具有的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 稳定的肾功能。这项合作提议的总体目标是回应RFA-HL-21-014 是利用心脏成像和生物标志物平台中的最新发展来表征 心脏参与T1D和DKD患者，重点是糖尿病发展的初始事件 心肌病。 “ GFR Decliners”（前3-6岁的GFR损失≥3ml/min/lem/Year，n = 100）和“ GFR非 - T1D和CKD阶段1-3A的偏斜器”（n = 100），以及类似年龄的非糖尿病对照（n = 100）和 CKD阶段，将经历gadolinium增强的心脏磁共振（CMR）和门控心脏CT 扫描以量化冠状动脉钙（CAC）。通过这些研究，我们将解决以下特定 目的：1。评估T1D患者中心肌重塑的存在和严重程度 评估其与早期渐进肾功能下降的关系。心肌细胞大小（τIC）和 CMR将量化间质纤维化（以细胞外体积[ECV]测量），并比较 GFR删除者，GFR非脱节者和非糖尿病主体，也与蛋白尿和存在有关 和CAD的严重程度。 2。评估心肌肥大和间质的相对贡献 T1D患者的纤维化会损害心脏功能。心脏功能和心肌菌株的指标 将从CMR数据中得出，并评估其与心肌大小（τIC）和 间质纤维化（ECV），与伴随CAD的严重程度有关。 3。洞悉该疾病 心肌重塑和评估的病因涉及的过程是否与 那些参与进行性肾脏功能下降的人。在有针对性的研究中，我们将专注于串行 在心力衰竭中实施的蛋白质或以前与GFR损失风险增加有关。在未定位的情况下 研究，我们将利用多重测定中的最新发展来评估A中的血清蛋白谱 系统的时尚。借助本研究产生的信息，我们将最佳地定位 制定新的策略和可能的新药物，以防止T1D中的CVD。