- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00115583
The Contribution of Endothelin to Vasomotor Function in Diseased Coronary Arteries
The Contribution of Endothelin to Vasoreactivity in Atherosclerotic Coronary Arteries
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
There are many substances that influence the diameter of the coronary artery and a number of these are actually released by the lining of the coronary arteries (referred to as the endothelium). Over the past 15 years, our laboratory has been instrumental in establishing the role of endothelium-released relaxing factors which relax (open) the coronary arteries. We are now focussing our attention on factors which constrict the coronary artery, in particular a substance called endothelin-1 (ET-1). This potent constrictor substance has been found to accumulate at coronary artery sites which may produce unstable angina (ie the culprit lesion or stenosis). Hence ET-1 may produce localized constriction of a coronary stenosis thereby further narrowing the remaining lumen and cutting off blood flow to the heart muscle and thus leading to unstable angina.
If ET-1 is important in the development of unstable angina, then medications which inhibit the effects of ET-1 should improve the condition. To achieve a blockade of ET-1, inhibitors of the two receptors (ET-A and ET-B) responsible for ET-1's action must be administered. Animal and human studies have demonstrated that a blockade of the ET-A receptor by the new antagonist, BQ-123, inhibits most of the ET-1 induced constrictor response. BQ-123 has been safely administered systemically by intravenous infusion and locally in the human forearm where it produces dilation of the forearm arteries. It has not been previously administered into human coronary arteries.
Consented patients whose routine diagnostic angiogram shows suitable anatomy (i.e., normal angiogram for the control group, or one/two vessel coronary artery disease with an identifiable culprit stenosis) will have placement of a coronary artery angiographic catheter. Placement of this catheter does not require an additional puncture of an artery (already performed in the routine diagnostic angiogram).
The angiographic catheter allows visualization of the internal diameter of the coronary arteries by the injection of a radiographic contrast with the image being recorded on a cine film. Specialized imaging machines will measure the diameter of the vessel.
Through the angiographic catheter, an infusion catheter (by which the drugs can be administered) and a coronary Doppler flow wire are placed in the coronary artery. The latter instrument is a well-established tool for measuring coronary blood flow.
After establishing baseline values for heart rate, blood pressure, culprit stenosis internal diameter and coronary blood flow, the following sequential intracoronary infusions will be undertaken:
- Infusion of the endothelin antagonist, BQ-123, over a 60 minute period. This inhibitor requires up to 60 minutes exerting a full effect;
- Adenosine bolus injection, to assess the vasodilation capacity of the small coronary arteries; and
- Nitroglycerin bolus injection, to assess the maximal vasodilation capacity of the large coronary arteries.
At 5, 15, 30, 45, and 60 minutes of endothelin antagonist infusion, and immediately after the bolus injections, the above parameters will be reassessed. It is anticipated that this research protocol will be completed within 90 minutes.
Following the research protocol, the patient will undergo appropriate coronary intervention as dictated by the clinical situation. If coronary atherectomy is required for clinical indications, then the specimen extracted by this procedure will be sent for specific analysis of endothelin-1 content. A correlation between the amount of endothelin at the culprit stenosis and the response to the endothelin antagonist can then be examined. In cardiac transplant recipients, endomyocardial biopsies are also routinely obtained for clinical purposes at the time of catheterization. One of these specimens will be used for ET-1 immunoreactivity analysis. A total of 2 teaspoons of blood will be taken and frozen for analysis.
Study Type
Enrollment
Phase
- Not Applicable
Contacts and Locations
Study Locations
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Massachusetts
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Boston, Massachusetts, United States, 02115
- Brigham and Womens Hospital
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
Adult men and women between the ages of 18 to 75 years will be enrolled and categorized into one of 4 groups. The categories are defined below:
- Control patients characterized by chest pain and angiographically normal coronary arteries.
- Chronic stable angina patients who describe a history of exertional chest pain which is unchanged in frequency over the preceding month, and who have at least a 70% stenosis in a coronary artery.
- Unstable angina patients who describe chest pain at rest or with minimal exertion over the preceding 2 weeks, and who have an identifiable culprit stenosis in a coronary artery.
- Cardiac transplant recipients who are undergoing routine annual surveillance cardiac catheterization.
Exclusion Criteria:
Patients with the following will be excluded from the study:
- Angiographic exclusion criteria: *Left main coronary artery disease or severe triple vessel disease; *Unstable angina without any identifiable culprit lesion.
- Severe left ventricular dysfunction (ejection fraction < 40%) or clinical cardiac failure.
- Nitroglycerin required in the preceding 4 hours prior to the investigation.
- Severe renal, hepatic or hematologic abnormalities.
- Inability to obtain written informed consent.
Study Plan
How is the study designed?
Design Details
- Allocation: NON_RANDOMIZED
- Interventional Model: CROSSOVER
- Masking: NONE
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
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Change in minimum luminal diameter from baseline assessed by Quantitative Angiography
|
Coronary Flow Reserve (max/basal CBFV) assessed by coronary Doppler Wire
|
Correlation between the change in culprit epicardial artery stenosis MLD and atherectomy specimen ET-1 content assessed by immunochemistry
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Peter A Ganz, MD, Brigham and Women's Hospital
Study record dates
Study Major Dates
Study Start
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ESTIMATE)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Heart Diseases
- Cardiovascular Diseases
- Vascular Diseases
- Arteriosclerosis
- Arterial Occlusive Diseases
- Coronary Disease
- Coronary Artery Disease
- Myocardial Ischemia
- Atherosclerosis
- Molecular Mechanisms of Pharmacological Action
- Antihypertensive Agents
- Endothelin Receptor Antagonists
- cyclo(Trp-Asp-Pro-Val-Leu)
Other Study ID Numbers
- 1999-P-003104
- P01HL048743 (NIH)
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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