Lipid Biomarkers for Diabetic Heart Disease

描述（由申请人提供）：糖尿病与严重的心血管并发症相关，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，也称为糖尿病性心肌病（DCM）。来自动物模型和人类受试者的研究数据表明，心肌脂质代谢的改变是DCM发病机制的核心，DCM早期可能无症状，但可发展为症状性心力衰竭。识别新的疾病标志物以促进早期发现和干预的能力受到现有人类全身和心肌脂质代谢措施不足的限制。在我们的初步研究中，我们通过使用基于灵敏质谱的代谢组学来鉴定两种血浆非常长链神经酰胺，Cer（22:0）和Cer(24:0)，这两种神经酰胺与肥胖和2型糖尿病患者的无症状收缩功能障碍高度相关，从而解决了这个问题。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）反映了脂质代谢的系统性改变，可以作为DCM的新生物标志物。虽然心功能障碍的诊断可以很容易地通过无创超声心动图进行，但Cer（22:0）和Cer（24:0）与异位脂质积累的病理生理后果密切相关，因此有可能预测高危个体，进一步了解疾病机制，并确定新的治疗靶点。我们已经组建了一个多学科团队来扩展这些发现：1)开发一种强大的高通量临床检测Cer（22:0）和Cer(24:0)；2)在两个现有的人类受试者队列中验证和扩展这些发现；3)探讨超长链神经酰胺与DCM相关小鼠心功能障碍的机制联系；4)确定2型糖尿病患者脂质暴露、血浆神经酰胺和心功能之间因果关系的方向。我们的方法有可能定义一种病理生理相关脂质暴露的综合测量方法，可用于跟踪干预成功，将表型与目前在目标人群中未得到充分治疗的可改变风险因素（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标记。

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.