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

摘要 患有T1D的人经历的心血管疾病发病率和死亡率过高的很大一部分发生在 与糖尿病肾病(DKD)有关，这与患糖尿病的风险显著增加有关 冠心病(CAD)和心力衰竭。后者往往是由于糖尿病的发展所致。 心肌病--一种糖尿病特有的心肌改变。DKD和DKD的病因学联系 心肌病尚不清楚，但来自我们小组的初步数据表明，肾脏功能起着关键作用 DKD的下降成分，而不是蛋白尿。具体地说，使用MRI衍生的标记物 心肌细胞大小，我们观察到T1D患者正在失去肾功能，但仍有 保存的GFR有心肌重构的亚临床迹象，如较大的心肌细胞所示 与T1D患者相比，T1D患者在收缩期间心肌纤维缩短的大小和减少 肾功能稳定。这项合作提案的总体目标是响应RFA-HL-21-014， 是利用心脏成像和生物标记物平台的最新发展来表征 T1D和DKD患者的心脏受累：关注糖尿病发展过程中的初始事件 心肌病。“肾小球滤过率下降”(过去3-6年≥肾小球滤过率损失3毫升/分钟/年，n=100)和“肾小球滤过率非 T1D和CKD阶段1-3A的衰退者(n=100)，以及年龄和年龄相似的非糖尿病对照组(n=100)。 CKD期，将接受Gd增强心脏磁共振(CMR)和门控心脏CT 扫描以量化冠状动脉钙化(CAC)。通过这些研究，我们将解决以下具体问题 目的：1.评价T1D患者心肌重构的存在及严重程度。 评估其与早期进行性肾功能下降的关系。心肌细胞大小(τic)和 间质纤维化(以细胞外体积[ECV]衡量)将通过CMR进行量化，并在 肾小球滤过率下降、肾小球滤过率不下降和非糖尿病受试者，也与蛋白尿和存在有关 和冠脉病变严重程度。2.评价心肌细胞肥大和间质的相对贡献 肝纤维化导致T1D患者心功能受损。心功能和心肌应变指数 将从cmr数据中得出，并评估它们与心肌细胞大小(τic)和 间质纤维化(ECV)与合并冠心病的严重程度有关。3.深入了解这种疾病 参与心肌重构病因学的过程，并评估这些过程是否与 参与进行性肾功能减退的患者。在有针对性的研究中，我们将重点关注血清 与心力衰竭有关的蛋白质或以前与GFR丢失风险增加相关的蛋白质。在无目标的情况下 研究中，我们将利用多重分析的最新发展来评估血清蛋白质谱 有系统的时尚。有了这项研究产生的信息，我们将处于最佳位置 开发新的策略和可能的新药来预防T1D的心血管疾病。

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.