Myocardial Function & FFA Metabolism in HIV Metabolic Syndrome

Not Applicable

Completed

• Conditions: HIV Infections; Cardiovascular Disease; Insulin Resistance; HIV Lipodystrophy; The Metabolic Syndrome
• Interventions: Behavioral: Exercise Training; Drug: Pioglitazone

• Registration Number: NCT00656851
• Lead Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Brief Summary

We hypothesize that the hearts of HIV+ people with The Metabolic Syndrome use and oxidize fats and sugars inappropriately, and that this may impair the heart's ability to pump blood. We hypothesize that exercise training or pioglitazone (Actos) will improve fat and sugar metabolism in the hearts of HIV+ people with The Metabolic Syndrome. This study will advance our understanding of cardiovascular disease in HIV+ people, and will test the efficacy of exercise training and pioglitazone for improving insulin resistance, heart metabolism and heart function in this at risk population.

Detailed Description

We hypothesize that myocardial free fatty acid and glucose utilization and oxidation rates are dysregulated in HIV+ people with The Metabolic Syndrome in comparison to HIV+ people without The Metabolic Syndrome, and in comparison to HIV-seronegative people with and without The Metabolic Syndrome. We hypothesize that dysregulated myocardial fatty acid and glucose metabolism is associated with impaired heart function (diastolic dysfunction) in HIV+ people with The Metabolic Syndrome. We will use myocardial positron emission tomography, radioactive isotope tracers of palmitate and glucose, and echocardiography to evaluate myocardial metabolism and function. HIV+ people with The Metabolic Syndrome will receive 16wks of exercise training or pioglitazone (Actos), and we will evaluate their potential beneficial effects on myocardial metabolism and function.

Study Timeline

• Study Start: 2005-09
• Study First Submitted: 2008-04-10
• Study First Submitted QC: 2008-04-10
• Study First Posted: 2008-04-11
• Primary Completion: 2009-08
• Study Completion: 2010-08
• Results First Submitted: 2013-04-30
• Results First Submitted QC: 2013-07-16
• Status Verified: 2013-08
• Last Update Submitted: 2013-08-19
• Results First Posted: 2013-08-20
• Last Update Posted: 2013-08-28

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 24

Inclusion Criteria

All participants both with and without metabolic syndrome:

1. 28-50 years old.
2. Plasma HIV RNA less than 5,000 copies/mL for previous 3 months OR CD4 count greater than 100 cells/µL for previous 3 months.
3. Stable for at least the past 3 months on any HAART regimen.
4. "Normal" blood chemistries for at least 1 month prior to enrollment: platelet count >50,000/mm3, absolute neutrophil count >750/mm3, liver transaminases <2.5x the upper limit of normal (ULN), creatinine <1.3x ULN, albumin >30g/L, creatine kinase <5.9x ULN.

Menstruating women must have a negative urine beta-HCG pregnancy test within 14 days prior to study. To control for potential metabolic effects of alterations in female hormones during the menstrual cycle, all menstruating women will be studied during the follicular phase (serum 17beta-estradiol <165 pg/mL).

Exclusion Criteria

1. Frank obesity (BMI >35kg/m2).
2. Chronic hepatitis B infection (HB surface antigen positive). Active hepatitis C infection (detectable Hep C RNA). Those who have cleared hepatitis B or C infection are eligible.
3. Diabetes [fasting glucose >125 mg/dL, or fasting insulin >45 µU/mL, or 2-hr glucose >200mg/dL].
4. Medications or agents that regulate glucose metabolism (e.g., insulin-sensitizers, insulin-secretagogues). Lipid lowering agents that regulate lipid metabolism (i.e. fibrate, statin).
5. Gestational diabetes, pregnancy, or nursing mothers.
6. Serum triglycerides ≥ 500 mg/dL.
7. Hypogonadism [total testosterone <200ng/dL (men) or <15ng/dL (women)]; thyroid disorder [TSH <0.2 or >12µIU/mL]; hypercortisolemia [morning cortisol >22µg/dL]. Replacement testosterone or thyroid hormones to normalize abnormal levels is acceptable, as long as treatment and blood levels have been stable for at least 3 months.
8. Use of human growth hormone (hGH) or GH-secretagogues (GH-releasing hormone-peptides) within the previous 3 months.
9. History of serious cardiovascular disease; MI, angina pectoris, heart failure, congenital heart disease, coronary artery disease, coronary artery bypass graft, stroke. Bundle branch block is exclusionary because it limits the interpretability of the resting/exercise ECG. Cardiovascular or physical contraindications to maximal exercise testing on a cycle ergometer.
10. Uncontrolled hypertension (>140/90 mmHg). Certain antihypertensive medications will be permitted (diuretics, ACE inhibitors) as long as the medication, dose, and blood pressure have been stable for at least 3 months.
11. Well-trained athletes (defined as >3 exercise training exposures/week; >30min regimented exercise/exposure maintained for at least the prior 4 weeks).
12. History of or active substance abuse (eg, alcoholism, cocaine, heroin, crack, methamphetamine, phencyclidine).
13. Active secondary infection. Any significant change in chronic suppressive therapy for an opportunistic infection during 1 month prior to enrollment.
14. New serious systemic infection during the 3 weeks prior to enrollment.
15. History of hyperlactatemia or lactic acidosis, esp. with rapid weight loss.
16. Debilitating-painful myopathy or neuropathy that requires 'assistance' to conduct normal activities of daily living (dressing, hygiene, preparing meals, operating a vehicle). These might affect peripheral substrate metabolism.
17. Chronic renal insufficiency/failure or other comorbid conditions (eg. cancer, COPD) that alter metabolism.
18. Pancreatitis, celiac disease, or cirrhosis.
19. Inadequate macronutrient or energy intake, or malabsorptive disorder.
20. Dementia or any condition that would prevent voluntary informed consent or compliance.
21. Other compounds or blinded investigational new drugs that might affect metabolism or confound data interpretation (eg. RU486, interleukin therapy, or cytokine-receptor antagonist).
22. Oral glucocorticoid or corticosteroid use within previous 3 months.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Exercise Training	Exercise Training	Cardiorespiratory and resistance exercise training 3days/wk for 16 weeks
Pioglitazone	Pioglitazone	Pioglitazone (Actos, 30mg/day for 16 weeks)

Primary Outcome Measures

Name	Time	Method
Myocardial Glucose Utilization Rate	Weeks 0 and 16	Radio-tracer (11C-glucose) and positron emission tomography quantification of myocardial glucose utilization rate. The rate at which glucose exits the blood, enters the muscle cells in the left ventricle, and is metabolized (ATP generation, glycolysis, glycogenolysis, or lactate production). Total glucose utilization rate in the left ventricle of the heart.
Myocardial Glucose Utilization Rate Per Unit Insulin	Weeks 0 and 16	Radio-tracer (11C-glucose) and positron emission tomography quantification of myocardial glucose utilization rate per unit of plasma insulin. Total glucose utilization rate in the left ventricle of the heart expressed per unit of the circulating plasma insulin concentration.
Myocardial Fatty Acid Utilization Rate	Weeks 0 and 16	Radio-tracer (11C-palmitate) and positron emission tomography quantification of myocardial fatty acid utilization rate. The rate at which palmitate exits the blood, enters the muscle cells in the left ventricle, and is metabolized (oxidation, re-esterification).
Myocardial Fatty Acid Oxidation Rate	Weeks 0 and 16	Radio-tracer (11C-palmitate) and positron emission tomography quantification of myocardial fatty acid oxidation rate.
Myocardial Fatty Acid Esterification	Weeks 0 and 16	Radio-tracer (11C-palmitate) and positron emission tomography quantification of myocardial fatty acid esterification as a % of total fatty acid extraction

Secondary Outcome Measures

Name	Time	Method
Myocardial Contractile Function During Diastole	Weeks 0 and 16	Echocardiographic quantification of (E/A) early to late diastolic filling velocity. Aria transfer blood to the ventricles in 2 steps: 1. blood collected in the atria falls into the ventricles when the atrioventricular valves opens. In the left heart, the velocity at which the blood moves during this initial action is called the early or "E" filling velocity.; 2. residual blood in the atria, is emptied during diastole by atrial contraction. The velocity of the blood during atrial contraction is the "A" (for atrial) filling velocity. These are expressed as a ratio (E/A). If A exceeds E velocity (ratio \<1.0) this is a clinical marker of diastolic dysfunction. This can occur when the left ventricular wall becomes so stiff as to impair proper filling, which can lead to diastolic heart failure.
Myocardial Contractile Function During Systole	Weeks 0 and 16	Echocardiographic quantification of E' wall velocity during systole averaged at the lateral wall and septum
Fasting Lipids and Lipoproteins	Week 0 and 16	fasting serum triglycerides, LDL-, and HDL-cholesterol concentrations
Fasting Glucose Insulin and HOMA	Week 0 and 16	fasting plasma glucose, insulin concentrations and HOMA-insulin resistance

Trial Locations

Locations (1)

Washington University School of Medicine; 🇺🇸 St. Louis, Missouri, United States