Causal Mechanisms in Adolescent Arterial Stiffness
Keywords
Abstract
Description
Aortic stiffness measured in adolescence or adulthood determines current hypertension, predicts future incidence of hypertension, and future atherosclerotic cardiovascular disease (ASCVD) 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 triglycerides(TG), we will conduct a mechanistic, double blinded, randomized controlled trial 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 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 CFPWV change. Second, naturally randomly assorted carnitine single nucleotide polymorphisms (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.
Dates
| Last Verified: | 01/31/2020 |
| First Submitted: | 10/10/2019 |
| Estimated Enrollment Submitted: | 10/13/2019 |
| First Posted: | 10/15/2019 |
| Last Update Submitted: | 02/19/2020 |
| Last Update Posted: | 02/23/2020 |
| Actual Study Start Date: | 01/31/2020 |
| Estimated Primary Completion Date: | 05/29/2024 |
| Estimated Study Completion Date: | 08/29/2024 |
Condition or disease
Intervention/treatment
Dietary Supplement: Carnitine supplementation (CS+)
Dietary Supplement: Placebo (CS-)
Phase
Arm Groups
| Arm | Intervention/treatment |
|---|---|
| Experimental: Carnitine supplementation (CS+) Carnitine supplementation in liquid form, sugar free. | Dietary Supplement: Carnitine supplementation (CS+) Oral carnitine supplementation |
| Placebo Comparator: Placebo (CS-) Placebo comparator liquid similar in appearance and taste to CS+. | Dietary Supplement: Placebo (CS-) Placebo |
Eligibility Criteria
| Ages Eligible for Study | 13 Years To 13 Years |
| Sexes Eligible for Study | All |
| Accepts Healthy Volunteers | Yes |
| Criteria | Inclusion Criteria: 1. 13-19 year old adolescents 2. males and females 3. all ethnicities and races 4. fasting serum triglyceride levels over 130 and less than 500 mg/dL 5. fasting low density lipoprotein cholesterol (LDL-C) less than 160mg/dL. Exclusion Criteria: 1. known seizure disorder 2. renal failure patients requiring renal replacement therapy like dialysis or renal transplant 3. diabetes mellitus type 1 or 2 4. congenital heart disease requiring surgical or catheterization intervention 5. current pregnancy or planned pregnancy during the active study participation 6. incarceration/institutionalized/wards of the state 7. known metabolic disorders that require carnitine therapy 8. nonadherence to study protocol during run-in phase defined as possessing 25% more than the expected remainder of placebo supplement pro-rated to the day of assessment |
Outcome
Primary Outcome Measures
1. Change in Carotid Femoral Pulse Wave Velocity [6 months]
Secondary Outcome Measures
1. Change in Fasting Triglyceride [6 months]
2. Change in Insulin Resistance [6 month]
