|
|
Home
Search
Study Topics
Glossary
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
||||||||||||||||||||||||||||||||||||
| Sponsors and Collaborators: |
Department of Veterans Affairs Medical University of South Carolina |
|---|---|
| Information provided by: | Department of Veterans Affairs |
| ClinicalTrials.gov Identifier: | NCT00744211 |
Purpose
Aim 1: The purpose of this study is to test the hypothesis that the release of endothelin (ET) (protein), is directly involved in the induction/activation of MMPs (cardiac enzymes). MMPs released during and following Coronary Artery Bypass Grafting may result in different heart abnormalities after surgery. It is hoped that by measuring this protein and these enzymes, new protective treatments for the heart during surgery will be discovered, which could improve the safety of heart surgery for all patients. It is important that you understand why the research is being done and what it will involve. Please take time to read the following information carefully and discuss it with your family, friends and your doctor if you wish. Please ask questions if anything is unclear or if you would like further information. Take time to decide whether or not you wish to take part.
Advanced age is a recognized risk of cardiac surgical procedures, such as coronary artery bypass grafting (CABG).
Since you are having coronary artery bypass grafting surgery, your heart will be connected to a perfusion pump that acts as your heart to pump blood throughout your body during the surgical procedure. After surgery, your heart cells may not work correctly which may cause an increase in the risk of death or sickness. The cause of this is most likely by events happening inside you heart cells and mechanisms outside your heart cells. The changes in structure and function around and in the heart cells have been observed in the stopping and starting of blood during heart surgery and appear to be caused by the start up of proteins around heart cells called matrix metalloproteinases (MMPs). Earlier results from our laboratory and others have provided evidence that increased MMPs and their naturally occurring inhibitors, tissue inhibitors of metalloproteinase (TIMPs), which stop MMPs are released in patients having a heart attack or stopping of the heart and coronary artery bypass grafting. Past studies have shown that changes will occur outside your heart and vascular system, as well as in other tissues due to age and MMP expression.
Endothelin is a protein that is made in a number of cell types within the cardiovascular system. Endothelin has properties that cause arteries to tighten and decrease blood flow after surgery that can have direct negative effects, i.e. an increase blood pressure. Clinical studies have reported that high endothelin levels in the early post-cardiopulmonary bypass (post-CPB) period can be associated with problems after surgery.
Aim 2: A.The purpose of this study is to demonstrate that Sitaxsentan Sodium, which is an endothelin inhibitor is administered through the vein and reduces the activation of MMPs, which are cardiac enzymes that cause different heart abnormalities following surgery.
Advanced age is a recognized risk of cardiac surgical procedures, such as coronary artery bypass grafting (CABG).
Since you are having coronary artery bypass grafting surgery, your heart will be connected to a perfusion pump that acts as your heart to pump blood throughout your body during the surgical procedure. After surgery, your heart cells may not work correctly which may cause an increase in the risk of death or sickness. The cause of this is most likely by events happening inside you heart cells and mechanisms outside your heart cells. The changes in structure and function around and in the heart cells have been observed in the stopping and starting of blood during heart surgery and appear to be caused by the start up of proteins around heart cells called matrix metalloproteinases (MMPs). Earlier results from our laboratory and others have provided evidence that increased MMPs and their naturally occurring inhibitors, tissue inhibitors of metalloproteinase (TIMPs), which stop MMPs are released in patients having a heart attack or stopping of the heart and coronary artery bypass grafting. Past studies have shown that changes will occur outside your heart and vascular system, as well as in other tissues due to age and MMP expression.
Endothelin is a protein that is made in a number of cell types within the cardiovascular system. Endothelin has properties that cause arteries to tighten and decrease blood flow after surgery that can have direct negative effects, i.e. an increase blood pressure. Clinical studies have reported that high endothelin levels in the early post-cardiopulmonary bypass (post-CPB) period can be associated with problems after surgery.
Sitaxsentan sodium (pronounced "sy-TAX-sen-tan", and called sitaxsentan) is an endothelin receptor blocker, which prevents the negative effects caused by endothelin. Sitaxsentan is an experimental medication and has not been approved by the FDA (Food and Drug Administration) for the purpose mentioned.
| Condition |
|---|
|
Heart Disease |
| Study Type: | Observational |
| Study Design: | Cohort, Prospective |
| Official Title: | Proteolytic Enzyme Induction Within the Human Myocardial Interstitium |
| Estimated Enrollment: | 1 |
| Study Start Date: | July 2008 |
| Estimated Study Completion Date: | June 2012 |
| Estimated Primary Completion Date: | June 2012 (Final data collection date for primary outcome measure) |
| Groups/Cohorts |
|---|
|
1
Ralph H. Johnson VA Medical Center
|
|
2
Medical University of South Carolina
|
Problem to Be Investigated. Transient left ventricular (LV) dysfunction can occur following cardiac surgery requiring cardiopulmonary bypass/cardioplegic arrest (CPB) and contribute to a complex post-operative course.1-6 One factor that contributes to LV myocardial dysfunction is the ischemia/reperfusion (I/R) attendant to CPB.
Myocardial contractile performance is predicated upon transduction of myocyte shortening into an overall muscle contraction. The extracellular matrix (ECM) plays a critical role in this process by providing coordination and connection of individually contracting myocytes which is then translated into an efficient muscle contraction.7-12 Acute changes within the ECM have been demonstrated with I/R, which in turn would affect myocardial contractile function.13-18 Specifically with I/R, increased release of ECM proteolytic enzymes, the matrix metalloproteinases (MMPs).15-19 Moreover, we have demonstrated increased release of MMPs in patients following CPB.17 The ECM is also an important reservoir for bioactive molecules and signaling proteins.
Neurohormonal activation, a common occurrence with I/R and CPB, evokes the release of potent bioactive peptides such as endothelin-1 (ET).20-25 Our laboratory and others have demonstrated that ET receptor activation (primarily the ET-A subtype) following I/R or CPB contributes to myocardial dysfunction.20,21,23,26-28 Importantly, ET-A receptor activation can induce the release of MMPs.29-33 Thus, while it is likely that a number of upstream signaling pathways contribute to MMP induction/activation with I/R, basic research has provided a link between ET receptor activation and MMP induction. This laboratory is now poised to establish that this mechanistic relation is operative in patients. Hypothesis. The central hypothesis of this project is that ET is released into the ECM in patients following cardioplegic arrest and reperfusion (I/R), which in turn stimulates the ET-A receptor and evokes MMP induction/activation. Specific Aims. Through a validated microdialysis approach,18,24,34,35 we can directly quantify myocardial interstitial ET and MMP activity in patients during cardiac surgery. We recently demonstrated that infusion of a selective ET-A receptor antagonist can be deployed in patients undergoing cardiac surgery.37 Finally, we have developed high sensitivity methods to measure MMP profiles in patients.17,19 Through these approaches, this project will address the following: (1) Demonstrate that in patients requiring CPB and reperfusion that a direct temporal relationship exists between myocardial interstitial ET release and MMP activation. Baseline and intra-operative myocardial interstitial ET levels and specific MMP activity (microdialysis/specific MMP fluorogenic substrates)18,24,34,35 will be measured in patients before, during and after CPB in order to establish direct relationships between ET release and specific MMP activation. (2) Demonstrate that selective ET-A receptor inhibition instituted at the time of reperfusion, reduces intra-operative myocardial interstitial MMP activation. Using the validated microdialysis approach and a selective infusible ET-A antagonist established by this laboratory,17,37 the direct inter-relationship between ET-A receptor activation to local myocardial MMP induction/activation can be established in humans. (3) Demonstrate that ET-A receptor activation which occurs early following I/R induces a cytokine signaling cascade which contributes to persistent MMP release. Our preliminary results and past studies have demonstrated a link between ET-A receptor activation and cytokine release such as tumor necrosis factor (TNF).13,14,30,38,39 Since TNF can in and of itself cause MMP induction, then a significant feed-forward mechanism may be in place which causes persistent MMP release in patients following CPB. This will be directly addressed in the present study through serially profiling plasma collected from subjects aim #1 and 2 for ET, TNF and MMPs using a high sensitivity multiplex approach.40,41 Thus, biomarkers for ET/TNF receptor activation can be related to MMP release during the entire post-operative course.
The findings from this clinical research investigation will establish for the first time, upstream signaling mechanisms which trigger a proteolytic cascade contributing to myocardial dysfunction within the human myocardium. These findings will identify potential therapeutic targets and set the stage for larger, outcomes based studies.
Eligibility| Ages Eligible for Study: | 18 Years to 80 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
| Sampling Method: | Probability Sample |
Women and Men
Inclusion Criteria:
Exclusion Criteria:
Contacts and Locations| Contact: John M Mulcahy, BA | (846) 876-5010 | mulcahy@musc.edu |
| Contact: Heather Smith, BS | (843) 792-8941 | smithhea@musc.edu |
| United States, South Carolina | |
| Ralph H Johnson VA Medical Center, Charleston | Recruiting |
| Charleston, South Carolina, United States, 29401-5799 | |
| Contact: John M Mulcahy, BA 846-876-5010 mulcahy@musc.edu | |
| Contact: Heather Smith, BS (843) 792-8941 smithhea@musc.edu | |
| Principal Investigator: Francis Spinale, MD PhD | |
| Principal Investigator: | Francis Spinale, MD PhD | Ralph H Johnson VA Medical Center, Charleston |
More Information
| Responsible Party: | Department of Veterans Affairs ( Spinale, Francis - Principal Investigator ) |
| Study ID Numbers: | SURG-001-07F |
| Study First Received: | August 27, 2008 |
| Last Updated: | July 6, 2009 |
| ClinicalTrials.gov Identifier: | NCT00744211 History of Changes |
| Health Authority: | United States: Federal Government |
|
Heart Diseases |
|
Heart Diseases Cardiovascular Diseases |
