Trial record 5 of 21 for:    coronary artery bypass grafting OR coronary bypass surgery | Open Studies | NIH, U.S. Fed

Proteolytic Enzyme Induction Within the Human Myocardial Interstitium

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2013 by Department of Veterans Affairs
Sponsor:
Collaborator:
Medical University of South Carolina
Information provided by (Responsible Party):
Department of Veterans Affairs
ClinicalTrials.gov Identifier:
NCT00744211
First received: August 27, 2008
Last updated: March 7, 2013
Last verified: March 2013
  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 your 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: 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 your 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: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Proteolytic Enzyme Induction Within the Human Myocardial Interstitium

Resource links provided by NLM:


Further study details as provided by Department of Veterans Affairs:

Primary Outcome Measures:
  • Changes in Interstitial Metalloproteinase Activity From Pre-Bypass Levels [ Time Frame: 2 hours ] [ Designated as safety issue: No ]

Biospecimen Retention:   Samples Without DNA

Myocardial interstitial fluid


Estimated Enrollment: 30
Study Start Date: July 2008
Estimated Study Completion Date: June 2013
Estimated Primary Completion Date: June 2013 (Final data collection date for primary outcome measure)
Groups/Cohorts
Group 1
Ralph H. Johnson VA Medical Center
Group 2
Medical University of South Carolina

Detailed Description:

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
Study Population

Women and Men

Criteria

Inclusion Criteria:

  • 18 and 80 years of age
  • Body mass index <40 kg/m2
  • Left ventricular ejection fraction > 30%
  • This study will assess elective coronary artery bypass surgery patients
  • If diabetic, be under proper control, (fasting glucose <350 mg/dL or recent hemoglobin A1c [HgbA1c] <12%) and with no change in glycemic control medications within the past 6 months.
  • Female of child bearing potential with a negative pregnancy test, or post-menopausal for at least 2 years
  • The patient is an appropriate study candidate as determined by the Investigator on the basis of medical history and physical examination

Exclusion Criteria:

  • Previous stroke or thrombo-embolic event in the 3 months prior to study entry
  • Off pump surgery is planned
  • A previous myocardial infarction within the last 7 days, characterized by a clearly defined ST segment elevation (STEMI) or a clinically significant and persistent increase in cardiac enzymes (such as troponin) that is accompanied by clear wall motion abnormalities
  • Documented coagulopathy
  • Hepatic dysfunction as defined by aspartate transaminase (AST) or alanine transaminase (ALT) 1.5 times the upper limit of normal
  • Chronic renal insufficiency as defined by a creatinine >2.5mg/dL or the patient required dialysis
  • Undergoing HIV therapy that affects the enzyme p450 system
  • Psychiatric or other disorders that compromise the ability to obtain informed consent
  • Patient is pregnant or breastfeeding
  • Is taking cyclosporine A, because of drug interaction with sitaxsentan
  • Severe left ventricular hypertrophy
  • Other significant cardiac disease
  • Participation in any investigational device or drug clinical study within 30 days prior to study entry
  • Active Malignancy
  • Chronic inflammatory disease
  • Redo Operation
  • Severe chronic obstructive pulmonary disease (FEV1<60% predicted)
  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: NCT00744211

Contacts
Contact: An O Van Laer, MS (843) 876-5010 An.VanLaer@va.gov
Contact: Michael R Zile, MD (843) 792-6866 zilem@musc.edu

Locations
United States, South Carolina
Ralph H Johnson VA Medical Center, Charleston Recruiting
Charleston, South Carolina, United States, 29401-5799
Contact: An O Van Laer, MS    843-876-5010    An.VanLaer@va.gov   
Contact: Michael R Zile, MD    (843) 792-6866    zilem@musc.edu   
Principal Investigator: Francis Spinale, MD PhD         
Sponsors and Collaborators
Medical University of South Carolina
Investigators
Principal Investigator: Francis Spinale, MD PhD Ralph H Johnson VA Medical Center, Charleston
  More Information

No publications provided

Responsible Party: Department of Veterans Affairs
ClinicalTrials.gov Identifier: NCT00744211     History of Changes
Other Study ID Numbers: SURG-001-07F
Study First Received: August 27, 2008
Last Updated: March 7, 2013
Health Authority: United States: Federal Government

Additional relevant MeSH terms:
Heart Diseases
Cardiovascular Diseases

ClinicalTrials.gov processed this record on July 24, 2014