Causal mechanisms in adolescent arterial stiffness

青少年动脉硬化的因果机制

基本信息

批准号：
10006029
负责人：
Justin P.V. Zachariah
金额：
$ 40.11万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10006029
关键词：
Adolescence Adolescent Adult Advanced Glycosylation End Products Affect Age Aging Antihypertensive Agents Biological Biological Markers Blood Pressure Blood Vessels Body Weight Changes Body Weight decreased Calories Cardiovascular Diseases Carnitine Child Childhood Cholesterol Coupled Cross-Sectional Studies Data Diastolic blood pressure Diet Modification Double-Blind Method Dyslipidemias Effectiveness Ethnic Origin Etiology Event Exercise Fatty Acids Fibrosis Framingham Heart Study Future Genes Genetic Risk Guidelines Heart Diseases Hemodialysis Hypertension Incidence Insulin Resistance International Life Cycle Stages Life Style Life Style Modification Link Lipids Longitudinal cohort Measures Mediating Modeling Modification Obesity Observational Study Oral Outcome Pharmacotherapy Physiologic pulse Placebos Plasma Proteins Pulse Pressure Race Randomized Randomized Controlled Trials Research Design Risk Risk Factors Role Serum Signal Transduction Single Nucleotide Polymorphism Therapeutic Clinical Trial Time Triglycerides Variant Weight Youth acylcarnitine adverse event monitoring arm arterial remodeling arterial stiffness blood pressure reduction carbohydrate metabolism carnitine supplementation fatty acid metabolism fatty acid oxidation genetic variant glucose metabolism good diet hemodynamics high risk improved lipid metabolism long chain fatty acid metabolome metabolomics oxidation prevent sex young adult

项目摘要

Aortic stiffness measured in adolescence or adulthood determines current hypertension, predicts future incidence of hypertension, and future cardiovascular disease (CVD) events International hypertension guidelines list severe aortic stiffness as grounds to intensify anti-hypertensive pharmacotherapy. Mechanisms of arterial stiffness beyond aging and obesity warrant further elucidation. In our preliminary data from adolescents attending weight-loss summer camps arterial stiffness improvement was not associated with weight change but was with change in circulating carnitine. Carnitine influences fatty acid oxidation and carbohydrate metabolism. Carnitine could therefore link to arterial stiffness through insulin resistance which in turn affects cellular tone, vascular fibrosis, modification of lipids or glucose metabolism, and/or advanced glycation end products. This proposal leverages 2 instrumental variable study designs to infer a causal relation between carnitine and arterial stiffness. First, in 166 adolescents at risk of arterial stiffening due to high serum TGs, we will conduct a mechanistic, double blinded, RCT for the effect of 6 months of oral carnitine supplementation (CS+, n=83) versus placebo (CS-, n=83) on aortic stiffness measured as carotid femoral pulse wave velocity (CFPWV); serum fatty acid oxidation biomarkers by metabolomics analysis; insulin resistance as homeostatic model assessment of insulin resistance (HOMA-IR); and trigylcerides (TG). Aim 1 is to compare CS+ versus CS- on change in arterial stiffness and monitor adverse events. The hypothesis CS+ is associated with lower arterial stiffening, and CS+ effect is not modified by sex or race/ethnicity. Aim 2 is to compare the effect of CS+ versus CS- on fatty acid metabolism, insulin resistance, and lipids. The hypothesis is that CS+ alters long chain fatty acid beta oxidation, measured as lower long chain acylcarnitines, which in turn improves (HOMA-IR), and in turn decreases TG levels. This causal chain will be disentangled for direct versus indirect effects on CFWPV change. Second, naturally randomly assorted carnitine SNPs noted above will be used to characterize the relationship of carnitine to arterial stiffness and stratify the effectiveness of CS+.Aim 3a is to obtain the direct effect of carnitine on arterial stiffness using Mendelian randomization of SNPs associated with serum carnitine as instrumental variables with the hypothesis these variant SNPs are associated with lower arterial stiffness, supporting a causal inference. Aim 3b is to identify effect modification of CS+ vs CS- on arterial stiffness by examining if a carnitine genetic risk score will modify the effect of CS+ on change in arterial stiffness. This proposal with 2 instrumental variable projects would evaluate a causal role for carnitine in arterial stiffness at a point when the life course trajectory to hypertension can be modified. The study will also investigate the role of carnitine in insulin resistance and dyslipidemia at this same age, which may serve as grounds for future therapeutic clinical trials. Discovering genetically mediated causes of arterial stiffness or other outcomes may facilitate targeting of future therapies on susceptible youth before atherosclerotic changes are irreversible.

在青春期或成年期测量的主动脉僵硬度决定当前的高血压，预测未来高血压的发病率和未来心血管疾病 (CVD) 事件国际高血压指南列出严重的主动脉僵硬作为加强抗高血压药物治疗的理由。动脉的机制衰老和肥胖之外的僵硬值得进一步阐明。根据我们来自参加的青少年的初步数据减肥夏令营动脉僵硬度的改善与体重变化无关，但与循环肉碱的变化。肉碱影响脂肪酸氧化和碳水化合物代谢。肉碱因此，可能通过胰岛素抵抗与动脉僵硬度联系起来，进而影响细胞张力、血管纤维化、脂质或葡萄糖代谢的改变和/或晚期糖基化终产物。这个提议利用 2 个工具变量研究设计来推断肉碱和动脉僵硬度之间的因果关系。首先，我们将对 166 名因高血清 TG 而面临动脉硬化风险的青少年进行机械性、双针对 6 个月口服肉碱补充剂（CS+，n=83）与安慰剂（CS-， n=83) 以颈动脉股动脉脉搏波速度 (CFPWV) 测量的主动脉僵硬度；血清脂肪酸氧化通过代谢组学分析确定生物标志物；胰岛素抵抗作为胰岛素抵抗的稳态模型评估（HOMA-IR）；和甘油三酯（TG）。目标 1 是比较 CS+ 与 CS- 的动脉硬度变化和监测不良事件。假设 CS+ 与较低的动脉硬化相关，但 CS+ 效应并不存在因性别或种族/民族而改变。目标 2 是比较 CS+ 与 CS- 对脂肪酸代谢的影响，胰岛素抵抗和血脂。假设 CS+ 改变了长链脂肪酸 β 氧化，经测量作为较低的长链酰基肉碱，这反过来又提高了 (HOMA-IR)，进而降低了 TG 水平。这 CFWPV 变化的直接影响与间接影响的因果链将被理清。其次，自然而然上述随机分类的肉碱 SNP 将用于表征肉碱与动脉的关系僵硬度并对 CS+ 的有效性进行分层。目标 3a 是获得肉碱对动脉僵硬度的直接影响使用与血清肉碱相关的 SNP 的孟德尔随机化作为工具变量假设这些变异的 SNP 与较低的动脉硬度相关，支持因果推论。目的 3b 是通过检查肉碱遗传风险是否存在来确定 CS+ 与 CS- 的修改对动脉僵硬度的影响评分将修改 CS+ 对动脉僵硬度变化的影响。该提案有 2 个工具变量项目将评估生命历程轨迹达到时肉碱对动脉僵化的因果作用高血压是可以改变的。该研究还将调查肉碱在胰岛素抵抗和胰岛素抵抗中的作用在同一年龄出现血脂异常，这可以作为未来治疗性临床试验的基础。发现动脉硬化或其他结果的遗传介导原因可能有助于未来治疗的目标在动脉粥样硬化变化不可逆转之前易受影响的青少年。