Causal mechanisms in adolescent arterial stiffness

青少年动脉硬化的因果机制

• 批准号: 9802825
• 负责人: Justin P.V. Zachariah
• 金额: $ 40.05万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 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/9802825
• 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

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得的主动脉僵硬决定了当前的高血压，可预测未来 高血压的发病率和未来的心血管疾病（CVD）事件国际高血压指南 列出严重的主动脉僵硬度作为加强抗高血压药物疗法的理由。动脉机制 超出衰老和肥胖的僵硬需要进一步阐明。在我们参加的青少年的初步数据中 减肥夏令营动脉僵硬的改善与体重的变化无关，但与 变化循环肉碱。肉碱会影响脂肪酸氧化和碳水化合物代谢。肉碱 因此，可以通过胰岛素抵抗与动脉刚度联系，从而影响细胞张力，血管 纤维化，脂质或葡萄糖代谢的修饰和/或晚期糖基化最终产物。这个建议 利用2仪器可变研究设计，以推断肉碱和动脉刚度之间的因果关系。 首先，在166名青少年中，由于高血清TG而有动脉僵硬的风险，我们将进行机械，双重 盲目的RCT对6个月的口服肉碱补充（CS+，n = 83）的影响（CS-，， n = 83）在主动脉刚度上以颈动脉股脉冲波速度（CFPWV）测量；血清脂肪酸氧化 代谢组学分析生物标志物；胰岛素抵抗作为胰岛素抵抗的稳态模型评估 （homa-ir）;和甘油酯（TG）。目标1是比较CS+与CS-有关动脉刚度的变化和 监视不良事件。假设CS+与较低的动脉僵硬有关，而CS+效应不是 通过性别或种族/种族修改。 AIM 2是比较CS+与CS-对脂肪酸代谢的影响， 胰岛素抵抗和脂质。假设是CS+改变了长链脂肪酸β氧化，测量 随着较低的长链酰基肉碱的依次改善（HOMA-IR），进而降低TG水平。这 因果链将被解散，以直接与间接影响CFWPV变化的影响。第二，自然 上面指出的随机各种肉碱SNP将用于表征肉碱与动脉的关系 刚度和分层CS+.AIM 3A的有效性是获得肉碱对动脉刚度的直接影响 使用Mendelian随机化与血清肉碱相关的SNP作为仪器变量 假设这些变体SNP与较低的动脉刚度有关，支持因果推断。目的 3B是通过检查肉碱遗传风险来确定CS+ VS CS-对动脉刚度的影响的影响 得分将改变CS+对动脉刚度变化的影响。该提案具有2个仪器变量 项目将评估肉碱在动脉僵硬中的因果作用 高血压可以修改。该研究还将研究肉碱在胰岛素抵抗中的作用， 同一年龄的血脂异常，这可能是未来治疗临床试验的理由。发现 基因介导的动脉僵硬或其他结局的原因可能有助于对未来的疗法靶向 动脉粥样硬化变化之前的敏感青年是不可逆转的。