Role of liver fat and fibrosis in human CVD risk phenotypes.

肝脏脂肪和纤维化在人类心血管疾病风险表型中的作用。

• 批准号: 10461067
• 负责人: ROHIT LOOMBA
• 金额: $ 56.54万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-21 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10461067
• 关键词: Adult; Biological Markers; Biological Specimen Banks; Biopsy; Cardiovascular Diseases; Cardiovascular system; Cholesterol Homeostasis; Clinical; Clinical Data; Clinical Research; Cohort Studies; Collaborations; Data; Data Set; Databases; Development; Disease; Enrollment; Epitopes; Fatty acid glycerol esters; Fibrosis; Framingham Heart Study; Goals; Gold; Grain; Hepatic; Hepatic Fibrogenesis; Histologic; Human; Imaging Techniques; Imaging technology; Individual; Investigation; Knowledge; Liver; Liver Fibrosis; Magnetic Resonance; Magnetic Resonance Elastography; Magnetic Resonance Imaging; Measurement; Measures; Metabolic syndrome; Noise; Outcome; Participant; Pathogenicity; Patients; Persons; Phenotype; Pilot Projects; Population; Process; Protons; Research; Research Personnel; Resources; Risk; Risk Assessment; Risk Factors; Role; Sampling Errors; Site; Suggestion; Surrogate Markers; Testing; United States; Validation; attenuation; biobank; cardiovascular disorder risk; cardiovascular risk factor; circulating biomarkers; clinical practice; cohort; coronary artery calcification; coronary calcium scoring; cost; density; diabetic; diagnosis standard; elastography; end stage liver disease; epidemiology study; high risk; imaging biomarker; imaging modality; lipid biosynthesis; liver biopsy; liver imaging; liver transplantation; mortality; multidisciplinary; non-alcoholic fatty liver; non-alcoholic fatty liver disease; non-invasive imaging; nonalcoholic steatohepatitis; novel; oxidation; potential biomarker; prospective; risk stratification; screening; study population; therapeutic target; ultrasound; validation studies; vibration

PROJECT SUMMARY Project 4. Role of liver fat and fibrosis in human CVD risk phenotypes Cardiovascular disease (CVD) is the leading cause of mortality among individuals with nonalcoholic fatty liver (NAFLD). NAFLD afflicts 80 million persons in the United States and is projected to become the main cause of end-stage liver disease and liver transplantation within the next 10 years. NAFLD, and especially its progressive form NASH, is associated with an increase in CVD risk, independent of common CVD risk factors. The pathophysiological mechanisms that contribute to the clinical association between NAFLD and CVD remain only partially understood. There are limited data regarding the potential role of liver fat or liver fibrosis content in their association with CVD risk in NAFLD. The central objective of Project 4 is to fill this gap in knowledge by prospectively assessing the cardiovascular risk (CVR) phenotype (low risk versus high risk) by non-invasively quantifying liver fat and fibrosis content in participants with and without NAFLD. CVR phenotypes will be assessed using a well-accepted and validated CVD risk score: Framingham Risk Score and Coronary Artery Calcium score. Our group has developed and clinically validated two advanced magnetic resonance imaging (MRI) modalities for non-invasive assessment of liver fat and fibrosis: MRI Proton Density Fat Fraction (MRI- PDFF) and MR Elastography (MRE). To validate findings in the UCSD cohort, we will collaborate with investigators of the Framingham Heart Study (FHS) (Drs Ramachandran and Long) using Controlled Attenuation Parameter (CAP) and Vibration Controlled Elastography (VCTE) assessments for liver phenotyping. Project 4 will also explore several pathogenic mechanisms that may be shared by CVD and NASH. It will also serve as the central hub for translational human validation of mechanistic studies conducted in Projects 1, 2, and 3 and provide access to a prospectively collected biospecimens from patients enrolled at UCSD. To achieve our goal, our specific aims are: Aim 1: Development and validation of imaging biomarkers for CVD risk in the NAFLD population. Test the hypotheses that liver fat content and fibrosis, as assessed by MRI-PDFF and MRE, respectively, each are independently associated with increased CVD risk phenotypes in NAFLD in the UCSD cohort. Validate these associations in the Framingham Heart Study (FHS). Aim 2: Investigation of common mechanisms underlying CVD and NAFLD. Test hypotheses that NAFLD and CVD share increased de novo lipogenesis, hepatic fibrogenesis, or abnormal hepatic cholesterol metabolism as common underlying mechanisms. Aim 3: Test hypothesis that OSE biomarkers can differentiate NAFLD and CVD risk in a population of NAFLD patients. In collaboration with Project 3, we will test the hypothesis that OSE biomarkers associate with liver fat, fibrosis, and/or CVD risk phenotypes in a population of NAFLD patients.

项目摘要 项目4。肝脂肪和纤维化在人CVD风险表型中的作用 心血管疾病（CVD）是非酒精性脂肪肝个体死亡率的主要原因 （NAFLD）。 NAFLD在美国遭受了8000万人的折磨，预计将成为 未来10年内终末期肝病和肝移植。 NAFLD，尤其是它的进步 NASH表格与CVD风险的增加有关，与普通CVD风险因素无关。这 有助于NAFLD和CVD之间临床关联的病理生理机制仅仍然存在 部分理解。关于肝脏脂肪或肝纤维化含量在其中的潜在作用的数据有限 NAFLD中与CVD风险的关联。项目4的核心目标是通过 前瞻性评估非侵入性的心血管风险（CVR）表型（低风险与高风险） 量化有或没有NAFLD的参与者中的肝脂肪和纤维化含量。 CVR表型将是 使用经过良好接受且经过验证的CVD风险评分评估：弗雷明汉风险评分和冠状动脉动脉 钙评分。我们的小组已经开发并在临床上验证了两个高级磁共振成像 （MRI）非侵入性评估肝脂肪和纤维化的方式：MRI质子密度级分（MRI- PDFF）和MR弹性图（MRE）。为了验证UCSD队列中的发现，我们将与 Framingham心脏研究（FHS）的研究人员（Ramachandran博士和Long）使用受控衰减 参数（CAP）和振动控制的弹性学（VCTE）评估肝脏表型。项目4 还将探索CVD和NASH可能共享的几种致病机制。它也将作为 在项目1、2和3进行的机械研究的转化验证的中央枢纽和 提供从UCSD招收的患者获得前瞻性收集的生物测量的访问权限。为了实现我们的目标， 我们的具体目的是： 目标1：对NAFLD人群中CVD风险的成像生物标志物的开发和验证。测试 由MRI-PDFF和MRE评估的假设，即肝脏脂肪含量和纤维化的假设是 与UCSD队列中NAFLD中CVD风险表型的增加有关。验证这些 Framingham心脏研究（FHS）的关联。 目的2：调查CVD和NAFLD的共同机制。测试假设NAFLD 和CVD共享增加的脂肪生成，肝纤维发生或异常肝胆固醇代谢 作为常见的基本机制。 目标3：检验假设，即OSE生物标志物可以区分NAFLD和CVD风险 NAFLD患者。通过与项目3合作，我们将检验以下假设，即OSE生物标志物与 NAFLD患者人群中的肝脂肪，纤维化和/或CVD风险表型。