Lipid Biomarkers for Diabetic Heart Disease

描述(申请人提供)：糖尿病与严重的心血管并发症有关，包括动脉粥样硬化性冠状动脉疾病和心肌功能障碍，即使没有潜在的冠状动脉疾病，一种称为糖尿病心肌病(DCM)的疾病。来自动物模型和人类受试者的研究数据提供的证据表明，心肌脂代谢的改变是扩张型心肌病发病机制的核心，早期可能没有症状，但可以进展为症状性心力衰竭。识别新的疾病标志物以促进早期检测和干预的能力受到现有人类全身和心肌脂代谢测量不足的限制。在我们的初步研究中，我们通过使用敏感的基于质谱学的代谢组学来解决这个问题，以确定两种血浆超长链神经酰胺，Cer(22：0)和Cer(24：0)，它们与肥胖和2型糖尿病患者的无症状收缩功能障碍高度相关。细胞生物学和小鼠模型研究表明，这些物种起源于异位脂质积累和先天免疫信号通路激活的独特交集。我们假设血浆Cer(22：0)和Cer(24：0)反映了全身性脂质代谢的变化，可作为DCM的新生物标志物。超声心动图可以无创地诊断心功能不全，而Cer(22：0)和Cer(24：0)跟踪异位脂质堆积的病理生理后果，因此有可能预测个体处于危险之中，加深我们对疾病机制的理解，并确定新的治疗靶点。我们组建了一个多学科团队来扩展这些发现，方法包括：1)开发一种强大的高通量临床检测方法来检测Cer(22：0)和Cer(24：0)；2)在两组现有的人类受试者中验证并推广这些发现；3)在DCM的相关小鼠模型中探索超长链神经酰胺和心功能之间的机制联系；以及4)确定人类2型糖尿病患者血脂暴露、血浆神经酰胺和心功能之间关系的因果方向。我们的方法有可能定义一种可用于跟踪干预成功的病理生理学相关脂质暴露的综合测量，将表型与目标人群中目前未得到充分治疗的可修改风险因素(血脂异常)联系起来的数据，以及可用于预防临床明显发病率和死亡率的未来疾病风险的标记物。

DESCRIPTION (provided by applicant): Diabetes is associated with serious cardiovascular complications that include atherosclerotic coronary artery disease and myocardial dysfunction even in the absence of underlying coronary artery disease, a disorder termed diabetic cardiomyopathy (DCM). Data from studies of animal models and human subjects provide evidence that alterations in myocardial lipid metabolism is central to the pathogenesis of DCM, which early on can be asymptomatic, but which can progress to symptomatic heart failure. The ability to identify new disease markers to facilitate early detection and intervention is limited b inadequacies of existing measures of systemic and myocardial lipid metabolism in humans. In our Preliminary Studies, we have addressed this problem by using sensitive mass spectrometry-based metabolomics to identify two plasma very long-chain ceramides, Cer(22:0) and Cer(24:0), that are highly correlated with asymptomatic systolic dysfunction in obese and type 2 diabetic humans. Cell biological and mouse model studies suggest these species arise from the unique intersection of ectopic lipid accumulation and activation of innate immune signaling pathways. We hypothesize that plasma Cer(22:0) and Cer(24:0) reflect systemic alterations in lipid metabolism that can be exploited as novel biomarkers for DCM. While the diagnosis of cardiac dysfunction can be readily made noninvasively by echocardiogram, Cer(22:0) and Cer(24:0) track with pathophysiological consequences of ectopic lipid accumulation and thus have potential to predict individuals at risk, to further our understanding of disease mechanism, and to identify new treatment targets. We have assembled a multidisciplinary team to extend these findings by 1) Developing a robust high-throughput clinical assay for Cer(22:0) and Cer(24:0); 2) Validating and extending these findings in two existing cohorts of human subjects; 3) Exploring the mechanistic links between very long-chain ceramides and cardiac dysfunction in relevant mouse models of DCM; and 4) Defining the direction of causality in the relationships among lipid exposure, plasma ceramides, and cardiac function in humans with type 2 diabetes. Our approach has the potential to define an integrated measure of pathophysiologically relevant lipid exposure that can be used to track intervention success, data linking phenotype to a modifiable risk factor that is currently undertreated in the target population (dyslipidemia), and marker for future disease risk that can be acted upon to prevent clinically apparent morbidity and mortality.