Haptoglobin Polymorphism as a Determinant of Adverse Outcome After Cardiac Surgery in Diabetic Patients

Coronary Artery Disease Clinical Trial

Official title:

Haptoglobin Polymorphism as a Determinant of Adverse Outcome After Cardiac Surgery in Diabetic Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02771808
• Other study ID #: 14691
• Status: Completed
• Phase: Phase 0
• First received: September 17, 2010
• Last updated: May 12, 2016
• Start date: September 2010
• Est. completion date: May 2015

Study information

• Verified date: May 2016
• Source: University of Virginia
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Observational

Clinical Trial Summary

Specific aim 1a will test the hypothesis that diabetic patients with 2-2 haptoglobin genotype have higher indices of postoperative myocardial injury (creatine kinase MB isoenzyme , Troponin I ) and renal injury (as indicated by elevated creatinine, cytostatin C and glomerular filtration rate). Of note, significantly elevated levels (>5 times the upper normal limit) of creatine kinase MB isoenzyme and troponins postoperatively have been associated with postoperative myocardial ischemia/infarction and are a predictor of short-term and long-term mortality after cardiac surgery.

Specific aim 1b will evaluate preoperative and postoperative indices of oxidative stress (such as isoprostane f2 alpha and malondialdehyde) and will evaluate whether patients with type 2-2 haptoglobin express increased oxidative stress. The investigators will also try to correlate whether patients with increased oxidative stress are those with elevated indices of myocardial and/or renal injury Specific aim 1c will try to evaluate whether patients with type 2-2 haptoglobin also have increased levels of inflammatory indices (C-reactive protein,[interleukin] IL-1, IL-2, IL-6, TNF[tumor necrosis factor]) and try to correlate the findings with postoperative myocardial and or renal injury.

The incidence of atrial fibrillation after coronary artery bypass graft ranges from 19% to 27%. The investigators will also look at any correlation of the type 2-2 haptoglobin and the incidence of post-operative atrial fibrillation.

Description:

Diabetes mellitus is a major risk factor for postoperative morbidity and mortality after cardiac surgery, mainly because of accelerated atherosclerosis and target-organ injury that predispose these patients to increased incidence of postoperative morbidity (such as but not limited to, postoperative adverse cardiac events, renal injury or stroke) and mortality.

Over the past several years haptoglobin has been identified as a risk factor that predicts the development of cardiovascular complications in diabetics. There are 3 major haplotypes of haptoglobin: 1-1; 1-2 and 2-2. Several studies have demonstrated that diabetic individuals with the 2-2 genotype have up to 5 fold increased risk to develop cardiovascular complications as compared to diabetic patients with a non-2-2 haptoglobin genotype. There is no data in the literature that evaluated whether the haptoglobin 2-2 genotype is a risk factor for increased postoperative morbidity and/or mortality after cardiac surgery in patients with DM.

Therefore, the aims of the study are to evaluate whether diabetic patients with the 2-2 genotype are at increased risk for postoperative morbidity and/or mortality after cardiac surgery.

Preliminary studies in diabetic patients demonstrated that those with haptoglobin 2-2 genotype are at increased risk for cardiovascular complications of diabetes. Moreover, these patients were found to have increased in-hospital mortality after acute MI compared to diabetic individuals that do not have the 2-2 genotype, and they also suffer from increased incidence of post catheterization stent thrombosis compared to diabetics that do not have the 2-2 genotype

Recruitment information / eligibility

• Status: Completed
• Enrollment: 83
• Est. completion date: May 2015
• Est. primary completion date: May 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 18 years of age and older

• Scheduled for an elective cardiac surgery on pump

• Diabetic -type I or type II

• Informed consent

Exclusion Criteria:

• Patients with chronic hemolytic disorders;

• Patients with hemoglobinopathies

• Enrollment in another interventional clinical trial

Study Design

Observational Model: Case-Only, Time Perspective: Prospective

Related Conditions & MeSH terms

• Coronary Artery Disease
• Coronary Disease
• Myocardial Ischemia

Intervention

Other:
• biomarker samples
biomarker samples for haptoglobin genotype (RT-PCR) and phenotype (hemoglobin electrophoresis) general markers for oxidative stress (isoprostane f2 alpha, malondialdehyde) markers of inflammation (CRP, IL-1, 2, 6, 10 and TNF) markers of cardiac injury (CPK, troponins and BNP) markers of kidney injury (cystatin C, creatinine, GFR)

Locations

Country	Name	City	State
United States	University of Virginia Health System	Charlottesville	Virginia

Sponsors (2)

Lead Sponsor	Collaborator
University of Virginia	International Anesthesia Research Society (IARS)

Country where clinical trial is conducted

United States, 

References & Publications (23)

Adabag AS, Rector T, Mithani S, Harmala J, Ward HB, Kelly RF, Nguyen JT, McFalls EO, Bloomfield HE. Prognostic significance of elevated cardiac troponin I after heart surgery. Ann Thorac Surg. 2007 May;83(5):1744-50. — View Citation

Asleh R, Guetta J, Kalet-Litman S, Miller-Lotan R, Levy AP. Haptoglobin genotype- and diabetes-dependent differences in iron-mediated oxidative stress in vitro and in vivo. Circ Res. 2005 Mar 4;96(4):435-41. Epub 2005 Jan 20. — View Citation

Bahar I, Akgul A, Ozatik MA, Vural KM, Demirbag AE, Boran M, Tasdemir O. Acute renal failure following open heart surgery: risk factors and prognosis. Perfusion. 2005 Oct;20(6):317-22. — View Citation

Brown JR, Cochran RP, Leavitt BJ, Dacey LJ, Ross CS, MacKenzie TA, Kunzelman KS, Kramer RS, Hernandez F Jr, Helm RE, Westbrook BM, Dunton RF, Malenka DJ, O'Connor GT; Northern New England Cardiovascular Disease Study Group. Multivariable prediction of renal insufficiency developing after cardiac surgery. Circulation. 2007 Sep 11;116(11 Suppl):I139-43. — View Citation

Bucerius J, Gummert JF, Walther T, Doll N, Falk V, Onnasch JF, Barten MJ, Mohr FW. Impact of diabetes mellitus on cardiac surgery outcome. Thorac Cardiovasc Surg. 2003 Feb;51(1):11-6. Erratum in: Thorac Cardiovasc Surg. 2003 Apr;51(2):113. — View Citation

Carson JL, Scholz PM, Chen AY, Peterson ED, Gold J, Schneider SH. Diabetes mellitus increases short-term mortality and morbidity in patients undergoing coronary artery bypass graft surgery. J Am Coll Cardiol. 2002 Aug 7;40(3):418-23. — View Citation

Cuthbertson BH, Croal BL, Rae D, Gibson PH, McNeilly JD, Jeffrey RR, Smith WC, Prescott GJ, Buchan KG, El-Shafei H, Gibson GA, Hillis GS. N-terminal pro-B-type natriuretic peptide levels and early outcome after cardiac surgery: a prospective cohort study. Br J Anaesth. 2009 Nov;103(5):647-53. doi: 10.1093/bja/aep234. Epub 2009 Aug 27. — View Citation

Donahoe SM, Stewart GC, McCabe CH, Mohanavelu S, Murphy SA, Cannon CP, Antman EM. Diabetes and mortality following acute coronary syndromes. JAMA. 2007 Aug 15;298(7):765-75. — View Citation

Fox AA, Shernan SK, Collard CD, Liu KY, Aranki SF, DeSantis SM, Jarolim P, Body SC. Preoperative B-type natriuretic peptide is as independent predictor of ventricular dysfunction and mortality after primary coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2008 Aug;136(2):452-61. doi: 10.1016/j.jtcvs.2007.12.036. — View Citation

Greenson N, Macoviak J, Krishnaswamy P, Morrisey R, James C, Clopton P, Fitzgerald R, Maisel AS. Usefulness of cardiac troponin I in patients undergoing open heart surgery. Am Heart J. 2001 Mar;141(3):447-55. — View Citation

Guetta J, Strauss M, Levy NS, Fahoum L, Levy AP. Haptoglobin genotype modulates the balance of Th1/Th2 cytokines produced by macrophages exposed to free hemoglobin. Atherosclerosis. 2007 Mar;191(1):48-53. Epub 2006 Jul 3. — View Citation

Levy AP, Hochberg I, Jablonski K, Resnick HE, Lee ET, Best L, Howard BV; Strong Heart Study. Haptoglobin phenotype is an independent risk factor for cardiovascular disease in individuals with diabetes: The Strong Heart Study. J Am Coll Cardiol. 2002 Dec 4;40(11):1984-90. — View Citation

McGuinness J, Bouchier-Hayes D, Redmond JM. Understanding the inflammatory response to cardiac surgery. Surgeon. 2008 Jun;6(3):162-71. Review. — View Citation

Moreno PR, Fuster V. New aspects in the pathogenesis of diabetic atherothrombosis. J Am Coll Cardiol. 2004 Dec 21;44(12):2293-300. Review. — View Citation

Muehlschlegel JD, Perry TE, Liu KY, Nascimben L, Fox AA, Collard CD, Avery EG, Aranki SF, D'Ambra MN, Shernan SK, Body SC; CABG Genomics Investigators. Troponin is superior to electrocardiogram and creatinine kinase MB for predicting clinically significant myocardial injury after coronary artery bypass grafting. Eur Heart J. 2009 Jul;30(13):1574-83. doi: 10.1093/eurheartj/ehp134. Epub 2009 Apr 30. — View Citation

Orhan G, Yapici N, Yuksel M, Sargin M, Senay S, Yalçin AS, Aykaç Z, Aka SA. Effects of N-acetylcysteine on myocardial ischemia-reperfusion injury in bypass surgery. Heart Vessels. 2006 Jan;21(1):42-7. — View Citation

Paparella D, Cappabianca G, Visicchio G, Galeone A, Marzovillo A, Gallo N, Memmola C, Schinosa Lde L. Cardiac troponin I release after coronary artery bypass grafting operation: effects on operative and midterm survival. Ann Thorac Surg. 2005 Nov;80(5):1758-64. — View Citation

Paparella D, Yau TM, Young E. Cardiopulmonary bypass induced inflammation: pathophysiology and treatment. An update. Eur J Cardiothorac Surg. 2002 Feb;21(2):232-44. Review. — View Citation

Ramsay J, Shernan S, Fitch J, Finnegan P, Todaro T, Filloon T, Nussmeier NA. Increased creatine kinase MB level predicts postoperative mortality after cardiac surgery independent of new Q waves. J Thorac Cardiovasc Surg. 2005 Feb;129(2):300-6. — View Citation

Roguin A, Koch W, Kastrati A, Aronson D, Schomig A, Levy AP. Haptoglobin genotype is predictive of major adverse cardiac events in the 1-year period after percutaneous transluminal coronary angioplasty in individuals with diabetes. Diabetes Care. 2003 Sep;26(9):2628-31. — View Citation

Suleiman M, Aronson D, Asleh R, Kapeliovich MR, Roguin A, Meisel SR, Shochat M, Sulieman A, Reisner SA, Markiewicz W, Hammerman H, Lotan R, Levy NS, Levy AP. Haptoglobin polymorphism predicts 30-day mortality and heart failure in patients with diabetes and acute myocardial infarction. Diabetes. 2005 Sep;54(9):2802-6. — View Citation

Thourani VH, Weintraub WS, Stein B, Gebhart SS, Craver JM, Jones EL, Guyton RA. Influence of diabetes mellitus on early and late outcome after coronary artery bypass grafting. Ann Thorac Surg. 1999 Apr;67(4):1045-52. — View Citation

Warren OJ, Smith AJ, Alexiou C, Rogers PL, Jawad N, Vincent C, Darzi AW, Athanasiou T. The inflammatory response to cardiopulmonary bypass: part 1--mechanisms of pathogenesis. J Cardiothorac Vasc Anesth. 2009 Apr;23(2):223-31. doi: 10.1053/j.jvca.2008.08.007. Epub 2008 Oct 19. Review. — View Citation

* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	number of participants with myocardial injury	number of participants with general markers for myocardial injury	24 hours post CPB	No
Secondary	number of participants with renal injury	number of participants with markers of kidney injury (cystatin C, creatinine, GFR)	24 hrs post CPB	No
Secondary	number of participants with incidence of new onset atrial fibrillation	incidence of new onset atrial fibrillation will be recorded	day 15	No