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.

总结