FFA-Induced Hypertension and Endothelial Dysfunction

NCT ID: NCT00589888

Last Updated: 2018-10-16

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 13 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-08-31
• Study Completion Date: 2008-08-31

Brief Summary

The study is a prospective open label study to examine the effects of oral and intravenous fat load on blood pressure, endothelial function, sympathetic activity, and oxidative stress in obese healthy subjects. Subjects will receive either 8-hour of intravenous or oral fat loads in either low or high doses or normal saline in random order. Blood samples are drawn and vitals are measured before and after the infusions. Endothelial function and plasma glucose and lipid levels are measured to study the effects.

Detailed Description

Insulin resistance has been implicated as the central mechanism in the development of several cardiovascular risk factors including hypertension, diabetes, lipid disorders, and coagulation disorders. Recent evidence suggests that increased levels of a circulation fat (free fatty acids or FFAs) are a leading candidate causing insulin resistance. Our preliminary studies in indicate that, in addition to insulin resistance, the infusion of Intralipid and heparin to increase FFAs resulted in a significant rise in systolic and diastolic blood pressure, impaired endothelial (vascular) function, and increased inflammatory markers in obese African Americans with and without diabetes. The effects of FFA on insulin action are well established; however, the blood pressure and vascular effects of FFAs infusion in obese subjects have not been fully investigated. We hypothesize that observed changes in blood pressure are the result of acute endothelial dysfunction, and/or increased activation of the autonomic nervous system. No previous studies have attempted to determine a dose response effect of increasing FFA on blood pressure. In addition, it is not know if increased FFAs by repeated oral fat load results in similar blood pressure than intravenous lipid infusion. Accordingly, we propose: 1) a systematic evaluation of the effects of increasing FFA levels on blood pressure and endothelial (vascular) function, and 2) determine the effects of comparable increases in FFA concentration via intravenous infusion of Intralipid or by repeated oral fat load on blood pressure, insulin resistance and endothelial dysfunction in obese subjects.

A group of obese normotensive subjects will be admitted to the Grady Clinical Research Center or to the Outpatient Research Unit in the Grady Diabetes Clinic on five occasions. In four of these admissions, research subjects will receive an 8-hour intravenous infusion, in random order, of increasing Intralipid concentration (10 ml, 20 ml, 40 ml per hour) or normal saline (40 ml per hour). During the final admission, research subjects will receive an oral liquid fat diet every 2 hours for 8-hours. The effect of increased FFAs on blood pressure and endothelial (vascular) function via intravenous infusion and via oral fat load therapy will be assessed.

Conditions

Endothelial Dysfunction; Hypertension

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: OTHER
• Blinding Strategy: NONE

Study Groups

Intralipid 20%@ 20cc/hour

Intralipid 20% IV infusion at 20cc/hour

Group Type: ACTIVE_COMPARATOR

Intralipid 20% @ 20cc/hour

Intervention Type: DRUG

In this arm subjects received Intralipid 20% Intravenous IV continuous infusion at 20cc/hour for 8 hours. The 20% intralipid solution is a long-chain triglyceride emulsion composed of 50% polyunsaturated fatty acids, 26% monounsaturated fatty acids, and 19% saturated fatty acids. During the intralipid infusion studies, subjects remained fasting

Intralipid 20% @ 40cc/hour

Intralipid 20% IV infusion at 40cc/hour

Group Type: ACTIVE_COMPARATOR

Intralipid 20%@ 40cc/hour

Intervention Type: DRUG

In this arm subjects received Intralipid 20% IV continuous infusion at 40cc/hour for 8 hours. In this arm subjects will receive Intralipid 20% Intravenous IV continuous infusion at 20cc/hour for 8 hours. The 20% intralipid solution is a long-chain triglyceride emulsion composed of 50% polyunsaturated fatty acids, 26% monounsaturated fatty acids, and 19% saturated fatty acids. During the intralipid infusion studies, subjects remained fasting.

Normal Saline infusion @ 40cc/hour

Normal Saline continuous IV infusion at 40cc/hour for 8 hours

Group Type: PLACEBO_COMPARATOR

Normal Saline

Intervention Type: DRUG

In this arm subjects received 0.9% Normal Saline continuous IV infusion at 40/cc for 8 hours.

32-gram oral fat load

32-gram oral fat load once

Group Type: ACTIVE_COMPARATOR

32-gram oral fat load

Intervention Type: DIETARY_SUPPLEMENT

In this arm subjects received oral liquid fat load prepared by the General Clinical Research Center (GCRC) at baseline and every 2 hours for 6 hours. Participants received fat with Free Fatty Acids (FFA) composed of 33% polyunsaturated fatty acids, 34% monounsaturated fatty acids, and 22% saturated fatty acids. The oral fat load in either low or high dose was given in four equally divided doses at 0, 2, 4, and 6 h.

64-gram oral fat load

64-gram oral fat load once

Group Type: ACTIVE_COMPARATOR

64-gram oral fat load

Intervention Type: DIETARY_SUPPLEMENT

In this arm subjects received 60-gram oral fat load intake at baseline and every 2 hours for 6 hours prepared by the General Clinical Research Center (GCRC). Participants received fat with Free Fatty Acids (FFA) composed of 33% polyunsaturated fatty acids, 34% monounsaturated fatty acids, and 22% saturated fatty acids. The oral fat load in either low or high dose was given in four equally divided doses at 0, 2, 4, and 6 h.

Interventions

Intralipid 20% @ 20cc/hour

In this arm subjects received Intralipid 20% Intravenous IV continuous infusion at 20cc/hour for 8 hours. The 20% intralipid solution is a long-chain triglyceride emulsion composed of 50% polyunsaturated fatty acids, 26% monounsaturated fatty acids, and 19% saturated fatty acids. During the intralipid infusion studies, subjects remained fasting

Intervention Type: DRUG

Intralipid 20%@ 40cc/hour

In this arm subjects received Intralipid 20% IV continuous infusion at 40cc/hour for 8 hours. In this arm subjects will receive Intralipid 20% Intravenous IV continuous infusion at 20cc/hour for 8 hours. The 20% intralipid solution is a long-chain triglyceride emulsion composed of 50% polyunsaturated fatty acids, 26% monounsaturated fatty acids, and 19% saturated fatty acids. During the intralipid infusion studies, subjects remained fasting.

Intervention Type: DRUG

Normal Saline

In this arm subjects received 0.9% Normal Saline continuous IV infusion at 40/cc for 8 hours.

Intervention Type: DRUG

32-gram oral fat load

In this arm subjects received oral liquid fat load prepared by the General Clinical Research Center (GCRC) at baseline and every 2 hours for 6 hours. Participants received fat with Free Fatty Acids (FFA) composed of 33% polyunsaturated fatty acids, 34% monounsaturated fatty acids, and 22% saturated fatty acids. The oral fat load in either low or high dose was given in four equally divided doses at 0, 2, 4, and 6 h.

Intervention Type: DIETARY_SUPPLEMENT

64-gram oral fat load

In this arm subjects received 60-gram oral fat load intake at baseline and every 2 hours for 6 hours prepared by the General Clinical Research Center (GCRC). Participants received fat with Free Fatty Acids (FFA) composed of 33% polyunsaturated fatty acids, 34% monounsaturated fatty acids, and 22% saturated fatty acids. The oral fat load in either low or high dose was given in four equally divided doses at 0, 2, 4, and 6 h.

Intervention Type: DIETARY_SUPPLEMENT

Other Intervention Names

20% i.v. fat emulsion; 20% i.v. fat emulsion; 0.9% Sodium Chloride

Eligibility Criteria

Inclusion Criteria

• Males or females between the ages of 18 and 65 years.
• Definition: obese = BMI ≥ 30 kg/m2
• Blood pressure < 140/80 mm Hg and no prior history of hypertension

Exclusion Criteria

• History of hypertension or previous history of antihypertensive drug therapy.
• Current tobacco use
• Fasting triglyceride levels > 250 mg/dL during the stabilization period.
• Liver disease (ALT 2.5x > upper limit of normal), or other significant medical or surgical illness, including myocardial ischemia, congestive heart failure, liver failure, and infectious processes.
• Serum creatinine ≥1.5 mg/dL for males, or ≥ 1.4 mg/dL for females.
• History of drug or alcohol abuse within the last 5 years.
• Mental condition rendering the subject unable to understand the nature, scope, and possible consequences of the study.
• Female subjects are pregnant or breast feeding at time of enrollment into the study.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

American Heart Association

OTHER

Sponsor Role: collaborator

Emory University

OTHER

Sponsor Role: lead

Responsible Party

Guillermo Umpierrez, MD

Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Guillermo Umpierrez, MD

Role: PRINCIPAL_INVESTIGATOR

Emory University SOM/GCRC

Locations

Grady Memorial Hospital

Atlanta, Georgia, United States

Countries

United States

References

Gosmanov AR, Smiley DD, Robalino G, Siquiera J, Khan B, Le NA, Patel RS, Quyyumi AA, Peng L, Kitabchi AE, Umpierrez GE. Effects of oral and intravenous fat load on blood pressure, endothelial function, sympathetic activity, and oxidative stress in obese healthy subjects. Am J Physiol Endocrinol Metab. 2010 Dec;299(6):E953-8. doi: 10.1152/ajpendo.00469.2010. Epub 2010 Oct 5.

Reference Type: RESULT

PMID: 20923960 (View on PubMed)

Other Identifiers

IRB 668-2006

Identifier Type: OTHER

Identifier Source: secondary_id

IRB00041116

Identifier Type: -

Identifier Source: org_study_id