Causal mechanisms in adolescent arterial stiffness

在青春期或成年期测量的主动脉僵硬度确定当前的高血压，预测未来 高血压发病率和未来心血管疾病（CVD）事件国际高血压指南 将严重的主动脉僵硬列为加强抗高血压药物治疗的理由。动脉机制 老化后的僵硬和肥胖需要进一步阐明。在我们对青少年的初步数据中， 减肥夏令营动脉僵硬度的改善与体重变化无关， 循环肉毒碱的变化。肉毒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相关，胰岛素抵抗反过来影响细胞张力、血管张力和血管张力。 纤维化、脂质或葡萄糖代谢的改变和/或晚期糖基化终产物。这项建议 利用2个工具变量研究设计来推断肉毒碱和动脉僵硬度之间的因果关系。 首先，在166名因高血清TG而有动脉硬化风险的青少年中，我们将进行一项机械性、双重 盲法随机对照试验，观察6个月口服肉毒碱补充剂（CS+，n = 83）与安慰剂（CS-， n = 83）对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 通过代谢组学分析的生物标志物;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）。目的1是比较CS+与CS-在动脉僵硬度变化方面的差异， 监测不良事件。假设CS+与下动脉硬化相关，而CS+效应不相关 按性别或种族/民族修改。目的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CS+改变长链脂肪酸β氧化，测量 作为较低的长链酰基肉毒碱，这反过来又改善（HOMA-IR），并反过来降低TG水平。这 因果链将被解开的直接与间接影响CFWPV的变化。第二，自然 上述随机分类的肉毒碱SNP将用于表征肉毒碱与动脉粥样硬化的关系。 目的3a是获得肉毒碱对动脉僵硬度的直接影响 使用与血清肉毒碱相关的SNPs的孟德尔随机化作为工具变量， 假设这些变异SNP与较低的动脉硬度相关，支持因果推断。目的 3b是通过检查是否存在肉毒碱遗传风险来确定CS+与CS-对动脉硬度的影响修饰 评分将修改CS+对动脉硬度变化的影响。该提案包含2个工具变量 项目将评估肉毒碱在动脉僵硬度中的因果作用， 高血压可以改变。这项研究还将调查肉毒碱在胰岛素抵抗中的作用， 在这个相同的年龄，这可能是未来的治疗性临床试验的基础。发现 基因介导的动脉僵硬或其他结果的原因可能有助于未来的治疗目标， 易感青年前动脉粥样硬化的变化是不可逆转的。

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.