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Myocardial Function & FFA Metabolism in HIV Metabolic Syndrome (WU197)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Kevin Yarasheski, Washington University School of Medicine
ClinicalTrials.gov Identifier:
NCT00656851
First received: April 10, 2008
Last updated: August 19, 2013
Last verified: August 2013
History of Changes
  Purpose

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.


Condition Intervention
HIV Infections
Cardiovascular Disease
Insulin Resistance
HIV Lipodystrophy
The Metabolic Syndrome
 Drug: Pioglitazone
Behavioral: Exercise Training

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Diagnostic
Official Title: Myocardial Function, Free Fatty Acid and Glucose Metabolism in HIV Metabolic Syndrome

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):

Primary Outcome Measures:
  • Myocardial Glucose Utilization Rate [ Time Frame: Weeks 0 and 16 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Weeks 0 and 16 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Weeks 0 and 16 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Weeks 0 and 16 ] [ Designated as safety issue: No ]
    Radio-tracer (11C-palmitate) and positron emission tomography quantification of myocardial fatty acid oxidation rate.

  • Myocardial Fatty Acid Esterification [ Time Frame: Weeks 0 and 16 ] [ Designated as safety issue: No ]
    Radio-tracer (11C-palmitate) and positron emission tomography quantification of myocardial fatty acid esterification as a % of total fatty acid extraction


Secondary Outcome Measures:
  • Myocardial Contractile Function During Diastole [ Time Frame: Weeks 0 and 16 ] [ Designated as safety issue: No ]

    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 [ Time Frame: Weeks 0 and 16 ] [ Designated as safety issue: No ]
    Echocardiographic quantification of E' wall velocity during systole averaged at the lateral wall and septum

  • Fasting Lipids and Lipoproteins [ Time Frame: Week 0 and 16 ] [ Designated as safety issue: Yes ]
    fasting serum triglycerides, LDL-, and HDL-cholesterol concentrations

  • Fasting Glucose Insulin and HOMA [ Time Frame: Week 0 and 16 ] [ Designated as safety issue: Yes ]
    fasting plasma glucose, insulin concentrations and HOMA-insulin resistance
Enrollment: 24
Study Start Date: September 2005
Study Completion Date: August 2010
Primary Completion Date: August 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Pioglitazone
Pioglitazone (Actos, 30mg/day for 16 weeks)
 Drug: Pioglitazone
30mg/day for 16 weeks
Other Name: Actos
Active Comparator: Exercise Training
Cardiorespiratory and resistance exercise training 3days/wk for 16 weeks
 Behavioral: Exercise Training
Cardiorespiratory and resistance exercise training 3days/wk for 16 weeks
Other Names:
  • Physical activity
  • Aerobic exercise
  • Weight lifting exercise

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.

  Eligibility
Ages Eligible for Study:   28 Years to 50 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00656851

Locations
United States, Missouri
Washington University School of Medicine
St. Louis, Missouri, United States, 63110
Sponsors and Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
Principal Investigator: Kevin Yarasheski, PhD Washington University School of Medicine
  More Information

Publications:

Responsible Party: Kevin Yarasheski, Professor of Medicine, Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT00656851     History of Changes
Other Study ID Numbers: DK59531 (completed), HRPO 05-0976
Study First Received: April 10, 2008
Results First Received: April 30, 2013
Last Updated: August 19, 2013
Health Authority: United States: Federal Government

Keywords provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):
HIV/AIDS
Heart disease
Diabetes
Cardiovascular disease risk
 Dyslipidemia
Visceral adiposity
treatment experienced

Additional relevant MeSH terms:
Cardiovascular Diseases
Insulin Resistance
Metabolic Syndrome X
Syndrome
Disease
Glucose Metabolism Disorders
Hyperinsulinism
 Metabolic Diseases
Pathologic Processes
Pioglitazone
Hypoglycemic Agents
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on February 27, 2015