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

总结 T1 D个体经历的大部分过量CVD发病率和死亡率发生在 与糖尿病肾病（DKD）相关，这与糖尿病风险的显著增加有关。 冠状动脉疾病（CAD）和心力衰竭。后者往往是由于糖尿病的发展， 心肌病-心肌的糖尿病特异性改变。DKD与 心肌病的发病机制尚不清楚，但我们小组的初步数据表明，肾功能在其中起着关键作用。 DKD下降而不是蛋白尿。具体地，使用MRI衍生的标记物， 心肌细胞大小，我们观察到T1 D患者失去肾功能，但仍然有 保留的GFR具有心肌重塑的亚临床体征，如较大的心肌细胞所示。 与T1 D患者相比， 肾功能稳定本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志物平台的最新发展， T1 D和DKD患者的心脏受累，重点关注糖尿病发展中的初始事件 心肌病“GFR下降者”（过去3-6年GFR下降≥3 ml/min/年，n=100）和“GFR非下降者”（过去3-6年GFR下降≥3 ml/min/年，n=100） T1 D和CKD 1-3A期的“下降者”（n=100），沿着相似年龄的非糖尿病对照（n=100）， CKD分期，将接受钆增强心脏磁共振（CMR）和门控心脏CT 扫描以定量冠状动脉钙（CAC）。通过这些研究，我们将解决以下具体问题： 目的：1.评价T1 D患者中心肌重塑的存在和严重程度， 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（测量为细胞外体积[ECV]）将通过CMR定量，并在 GFR下降者、GFR未下降者和非糖尿病受试者，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性心肌炎的相对作用， 纤维化与T1 D患者心脏功能受损的关系。心功能和心肌应变指标 将从CMR数据中得出，并评价其与心肌细胞大小（τic）的相关性， 间质纤维化（ECV），与伴随CAD的严重程度相关。3.为了深入了解这种疾病 参与心肌重塑的病因学过程，并评估这些过程是否与 参与进行性肾功能下降的患者。在靶向研究中，我们将重点关注血清 与心力衰竭有关或先前与GFR丧失风险增加相关的蛋白质。在非目标 研究，我们将利用最新的发展，在多重测定，以评估血清蛋白质谱， 系统的方式。有了这项研究所产生的信息，我们将处于最佳地位， 开发新的策略和可能的新药来预防T1 D的CVD。

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.