Causal Mechanisms in Adolescent Arterial Stiffness

  • STATUS
    Recruiting
  • End date
    Aug 30, 2024
  • participants needed
    166
  • sponsor
    Baylor College of Medicine
Updated on 23 February 2022
fasting
heart disease
low density lipoprotein
LDL Cholesterol
protein supplement
cholesterol level
lipoprotein cholesterol
hdl cholesterol
serum triglycerides

Summary

Hardening of the blood vessels, called arterial stiffness, is a risk factor for future heart disease and its causes are unclear. The proposed study will 1) randomly assign adolescents at high risk of stiffening blood vessels to take a protein supplement called carnitine and study its effects on arterial stiffening and 2) study carnitine related genes for their effect on arterial stiffening. The study will definitively establish a role for carnitine action as a cause of stiffening blood vessels and signal a way to treat or prevent stiffening.

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 CSon 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.

Details
Condition Lipid Disorder, Dyslipidemias, Aortic Stiffness, Insulin Resistance Syndrome, Metabolic Syndrome, Pediatric Obesity
Treatment CS+, CS-
Clinical Study IdentifierNCT04128969
SponsorBaylor College of Medicine
Last Modified on23 February 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

13-19 year old adolescents
males and females
all ethnicities and races
fasting serum triglyceride levels over 130 and less than 500 mg/dL
fasting low density lipoprotein cholesterol (LDL-C) less than 160mg/dL

Exclusion Criteria

known seizure disorder
renal failure patients requiring renal replacement therapy like dialysis or renal transplant
diabetes mellitus type 1 or 2
congenital heart disease requiring surgical or catheterization intervention
current pregnancy or planned pregnancy during the active study participation
incarceration/institutionalized/wards of the state
known metabolic disorders that require carnitine therapy
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
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