Fat Gain and Cardiovascular Disease Mechanisms

Understanding the mechanisms of obesity-induced hypertension is important both for prevention and therapy. Studies of patients with established obesity have provided valuable information on pathophysiologic links between obesity and both blood pressure and cardiovascular risk. However, these studies are necessarily limited by the heterogeneity of obesity-associated disease so that the relative contribution of obesity or hypertension or other co-existing diseases to specific regulatory abnormalities is often not clear. Clarification of whether any abnormalities associated with increased cardiovascular risk were present before or after the development of obesity has also been problematic.

We therefore propose a series of novel studies directed at establishing the effects of increased body fat in otherwise healthy individuals. We will determine the distribution patterns of increased body fat and how both increased body fat and fat distribution relate to changes in blood pressure, and in neural, endothelial and inflammatory mechanisms which have been implicated in the development and progression of cardiac and vascular disease.

We will study non-obese subjects with and without a family history of hypertension. These subjects will undergo an eight-week program of overfeeding with the objective of inducing a 4 kg fat gain. We will determine the nature of fat distribution in these individuals after the fat gain program and subsequently after an eight-week period of weight loss and restoration of normal body weight. Measurements will be compared to those obtained in a matched control group with and without a family history of hypertension, who will continue their normal diets. We will test the following hypotheses:

• Individuals with a family history of hypertension will gain more visceral fat and upper body subcutaneous fat and will have greater blood pressure increases with overfeeding- compared with those without such a family history.
• For all overfed subjects, increases in blood pressure and insulin resistance with fat gain will be most marked in those individuals with a predominantly upper body and visceral fat accumulation.
• Upper body and visceral fat gain will also be associated with greater impairment in cardiovascular function, higher nocturnal blood pressures and an increased likelihood of sleep disordered breathing.

Study Overview

• Status: Completed
• Conditions: Sleep Apnea Syndromes; Hypertension; Obesity
• Intervention / Treatment: Dietary supplement: 1000 extra calories

• Study Type: Interventional
• Enrollment (Actual): 69
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• We will enroll up to 180 subject in order to fulfill screening requirements and have complete studies in 120 total (60 with and 60 without family history hypertension).
• Gender: Male and female.
• Ages: 18 to 40 (inclusive).

Exclusion Criteria:

• Body-mass index > 33 kg/m2
• Tobacco smoking or chewing
• Shift worker
• Any diseases
• Any prescription medications (except, oral contraceptives are permitted)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; Subjects who are randomized to overfeed will visit with the General Clinical Research Center dieticians as often as necessary to gain 2 kg of fat (about 4 kg overall) over a period of 8 weeks.	Dietary supplement: 1000 extra calories; Each subject received 1000 kcal/d in addition to weight maintenance requirements. The diet composition throughout the study was 40% carbohydrate, 40% fat, and 20% protein.
No Intervention: 2; Subjects who are randomized to non-overfeeding will continue with their normal diet and activity levels for a period of 8 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Individuals with a family history of hypertension will gain more visceral fat and upper body subcutaneous fat and will have greater blood pressure increases with overfeeding- compared with those without such a family history.	conclude the 180 patients recruited

Secondary Outcome Measures

Outcome Measure	Time Frame
* For all overfed subjects, increases in blood pressure and insulin resistance with fat gain will be most marked in those individuals with a predominantly upper body and visceral fat accumulation.	after recruiting at least 70 patients
Upper body and visceral fat gain will also be associated with greater impairment in cardiovascular function, higher nocturnal blood pressures and an increased likelihood of sleep disordered breathing	Recruit at least 70 subjects
Increased weight gain, particularly in the upper body and visceral regions, will be accompanied by enhanced production of inflammatory mediators linked to cardiovascular risk, including adhesion molecules and C-reactive protein.	Recruit at least 70 patients
These changes will resolve with subsequent loss of weight at the end of the overfeeding program and restoration of normal body fat and fat distribution.	Recruit at least 70 patients

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: National Institutes of Health (NIH)

Publications and helpful links

General Publications

• Romero-Corral A, Sert-Kuniyoshi FH, Sierra-Johnson J, Orban M, Gami A, Davison D, Singh P, Pusalavidyasagar S, Huyber C, Votruba S, Lopez-Jimenez F, Jensen MD, Somers VK. Modest visceral fat gain causes endothelial dysfunction in healthy humans. J Am Coll Cardiol. 2010 Aug 17;56(8):662-6. doi: 10.1016/j.jacc.2010.03.063.

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start: December 1, 2005
• Primary Completion (Actual): December 1, 2012
• Study Completion (Actual): December 1, 2012

Study Registration Dates

• First Submitted: January 7, 2008
• First Submitted That Met QC Criteria: January 7, 2008
• First Posted (Estimate): January 9, 2008

Study Record Updates

• Last Update Posted (Estimate): November 3, 2013
• Last Update Submitted That Met QC Criteria: November 1, 2013
• Last Verified: November 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Respiratory Tract Diseases; Apnea; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Sleep Apnea Syndromes; Cardiovascular Diseases
• Other Study ID Numbers: 652-03; NIH HL-073211