Causal Mechanisms in Adolescent Arterial Stiffness

Metabolic Syndrome Clinical Trial

Official title:

Causal Mechanisms in Adolescent Arterial Stiffness

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04128969
• Other study ID #: H-45557
• Secondary ID: R01HL148217
• Status: Recruiting
• Phase: Phase 2
• Start date: February 1, 2020
• Est. completion date: August 30, 2025

Study information

• Verified date: May 2024
• Source: Baylor College of Medicine
• Contact: Sandra Pena, CCRP
• Phone: 832-826-2806
• Email: sypena[@]texaschildrens.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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 90 youth 11-21 years old 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=45) versus placebo (CS-, n=45) 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 90
• Est. completion date: August 30, 2025
• Est. primary completion date: May 30, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 11 Years to 21 Years

Eligibility

Inclusion Criteria:

1. 11-21 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

Related Conditions & MeSH terms

• Aortic Stiffness
• Dyslipidemias
• Insulin Resistance
• Insulin Resistance Syndrome
• Lipid Disorder
• Lipid Metabolism Disorders
• Metabolic Syndrome
• Pediatric Obesity
• Syndrome

Intervention

Dietary Supplement:
• CS+
Oral carnitine supplementation
• CS-
Placebo

Locations

Country	Name	City	State
United States	Texas Children's Hospital	Houston	Texas

Sponsors (2)

Lead Sponsor	Collaborator
Baylor College of Medicine	National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Carotid Femoral Pulse Wave Velocity	Carotid Femoral Pulse Wave Velocity will be measured noninvasively using applanation tonometry.	6 months
Secondary	Change in Fasting Triglyceride	Fasting serum triglycerides to be measured using conventional techniques.	6 months
Secondary	Change in Insulin Resistance	Insulin resistance will be assessed using fasting serum glucose and fasting serum insulin to calculate homeostatic model assessment of insulin resistance.	6 month