Carnitine for the Treatment of Atherosclerosis.

Primary Question: Does L-carnitine (L-C) therapy slows down and/or regress atherosclerosis, as measured by total plaque volume (TPV) assessed by 3-dimensional (3D) carotid ultrasound in patients with metabolic syndrome? We hypothesize that L-C will regress atherosclerotic plaque formation.

To assess our primary outcome of L-C induced atherosclerosis regression, we anticipate a significant percent (%) difference in carotid total plaque volume (TPV) over six months of L-C treatment, compared to placebo. For our secondary outcome, we expect to show that L-C therapy compared to placebo, induces a reduction in the proportion of small-sized LDL and an increase in large LDL particles. As small dense LDL particles are more atherogenic than large buoyant ones, this would suggest a mechanism contributing to the atherosclerosis reduction induced by L-C therapy.

Study Population: Patients, followed in our clinics for cardiovascular disease (CVD) prevention, fulfilling diagnosis criteria for metabolic syndrome (MetS) will be recruited. Eligibility will require a 2 step process as described.

Inclusion criteria

STEP 1: Initial screening; BP, weight and fasting blood samples will be obtained.

• Men and women, >18 years, meeting the criteria for clinical diagnosis of MetS, according to the International Diabetes Federation (IDF) harmonized definition, where any 3 of the 5 following risk factors cut points constitutes a diagnosis of MetS:

• Elevated waist circumference: Population- and country-specific definitions; Health Canada recommends males 102 cm and women 88cm.
• Elevated triglycerides: 150 mg/dL (1.7 mmol/L).
• Reduced HDL: 40 mg/dL (1.0 mmol/L) in males; 50 mg/dL (1.3 mmol/L) in females or treated.
• Elevated BP: Systolic 130 and/or diastolic 85 mm Hg or treated.
• Elevated fasting glucose: 100 mg/dL (5.6 mmol/L), or HbA1c ≥6.2%, or treated.
• Willing to provide informed consent. STEP 2: Baseline plaque volume ≥50 mm3 by 3D US, to ensure sufficient detectable plaque. This will be measured after consent (at Step 1), but prior to randomization/enrolment (Step 2).

Exclusion criteria

• Individuals who have had a change in statin and/or diabetes medication therapy or dosing in the last three months;
• Who are actively having an unstable arrhythmia, angina or heart attack (untreated and/or unstable patients): symptomatic heart failure (NYHA 2 or greater); renal failure (GFR <50 mL/min/1.73m2);
• Known severe abnormal blood biochemistries: Na <100 or >150 mmol/L, K <2 or >5 mmol/L, Total Serum Ca >3 mmol/L;
• Known severe liver disease: AST >100 U/L, ALT >80 U/L, or a diagnosis of cirrhosis (Child Pugh Class A to C);
• Known severe anemia: HgB <70 g/L;
• Have endocrine disorders, e.g. Cushing's disease, hyper- or hypo-thyroidism;
• Any condition expected to limit survival to less than six (6) months (ex. malignant tumor);
• A condition limiting adherence to study procedure (i.e. alcoholism, drug addiction, known poor adherence, severe mental disorder);
• Concomitant treatment with: anticonvulsants; L-C or derivatives; Acenocoumarol (Sintrom) and Warfarin (Coumadin) anticoagulants and vitamin K antagonists; >1g fish oil; and/or thyroid treatment;
• A seizure disorder or at risk of seizure (CNS mass or medications that lower seizure threshold); receiving treatments for cancer or HIV infection (secondary L-C deficiency);
• Currently pregnant or breastfeeding;
• A history of allergy or intolerance to L-C or derivatives;
• Vegetarians (do not eat animal flesh) due to potential for altered L-C metabolism;
• Patients who have had a carotid surgery (ie. endarterectomy (CEA) or stent) or who are scheduled to receive carotid surgery during the trial.