The RAS, Fibrinolysis and Cardiopulmonary Bypass

Each year over a million patients worldwide undergo cardiac surgery requiring cardiopulmonary bypass (CPB).1 CPB is associated with significant morbidity including hemodynamic instability, the transfusion of allogenic blood products, and inflammation. Blood product transfusion increases mortality after cardiac surgery. Enhanced fibrinolysis contributes to increased blood product transfusion requirements in the perioperative period. CPB activates the kallikrein-kinin system (KKS), leading to increased bradykinin concentrations. Bradykinin, acting through its B2 receptor, stimulates the release of nitric oxide, inflammatory cytokines and tissue-type plasminogen activator (t-PA). Based on data indicating that angiotensin-converting enzyme (ACE) inhibitors reduce mortality in patients with coronary artery disease, many patients undergoing CPB are taking ACE inhibitors. While interruption of the renin-angiotensin system (RAS) reduces inflammation in response to CPB, ACE inhibitors also potentiate the effects of bradykinin and may augment B2-mediated change in fibrinolytic balance and inflammation. In contrast, angiotensin II type 1 receptor antagonism does not potentiate bradykinin and does not inhibit bradykinin metabolism. Studies in animals suggest that bradykinin receptor antagonism inhibits reperfusion-induced increases in vascular permeability and neutrophil recruitment.A randomized, placebo controlled clinical trial of a bradykinin B2 receptor antagonist demonstrated some effect on survival in patients with systemic inflammatory response syndrome and gram-negative sepsis. In addition, we and others have shown bradykinin B2 receptor antagonism reduces vascular t-PA release during ACE inhibition. The current proposal derives from data from our laboratory and others elucidating the role of the KKS in the inflammatory, hypotensive and fibrinolytic response to CPB. Specifically, we have found that CPB activates the KKS and that ACE inhibition and smoking further increases bradykinin concentrations. During CPB, bradykinin concentrations correlate inversely with mean arterial pressure and directly with t-PA. Moreover, we have found that bradykinin receptor antagonism attenuates protamine-related hypotension following CPB. The current proposal tests the central hypothesis that the fibrinolytic and inflammatory response to cardiopulmonary bypass differ during angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor antagonism.

Coronary Artery Disease, Angiotensin Converting Enzyme, Angiotensin Receptor Blockers, Cardiopulmonary Bypass, Fibrinolysis, Inflammation

Angiotensin Converting Enzyme, Angiotensin Receptor Blockers, Cardiopulmonary Bypass, Fibrinolysis, Inflammation

To compare the effects of angiotensin II type I (AT1) receptor antagonism or angiotensin-converting enzyme (ACE) inhibition versus placebo on the fibrinolytic responses to cardiopulmonary bypass (CPB) as measured by t-PA antigen response

To compare the effects of AT1 receptor antagonism or ACE inhibition versus placebo on the fibrinolytic responses to CPB as measured by PAI-1 response

To compare the effects of AT1 receptor antagonism or ACE inhibition versus placebo on the inflammatory response to CPB as measured by IL-6

To compare the effects of AT1 receptor antagonism or ACE inhibition versus placebo on the inflammatory response to CPB as measured by IL-8

To compare the effects of AT1 receptor antagonism or ACE inhibition versus placebo on the inflammatory response to CPB as measured by the IL-10 response

The percentage of patients that were taken back to the operating room for re-exploration because of bleeding

New onset atrial fibrillation based on electrocardiogram (ECG) rhythm strips with a duration longer than 10 seconds

Acute kidney injury (AKI) was defined according to Acute Kidney Injury Network (AKIN) criteria,specifically any increase in subject serum creatinine concentration of 50% or 0.3 mg/dL (26.5 umol/L) within 72 hours of surgery.

Inclusion Criteria: Inclusion Criteria Subjects, 18 to 80 years of age, scheduled for elective cardiac surgery requiring CPB For female subjects, the following conditions must be met: postmenopausal for at least 1 year, or status-post surgical sterilization, or if of childbearing potential, utilizing adequate birth control and willing to undergo urine beta-hcg testing prior to drug treatment and on every study day Exclusion Criteria: Left ventricle ejection fraction less than 30% History of ACE inhibitor-induced angioedema Hypotension (systolic blood pressure <100 mmHg and evidence of hypoperfusion) Hyperkalemia (baseline potassium >5.0 mEq/L) Inability to discontinue current ACE inhibitor or AT1 receptor antagonist. Emergency surgery Impaired renal function (serum creatinine >1.6 mg/dl) Pregnancy Breast-feeding Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult History of alcohol or drug abuse Treatment with any investigational drug in the 1 month preceding the study Mental conditions rendering the subject unable to understand the nature, scope and possible consequences of the study Inability to comply with the protocol, e.g. uncooperative attitude and unlikelihood of completing the study

Billings FT 4th, Balaguer JM, C Y, Wright P, Petracek MR, Byrne JG, Brown NJ, Pretorius M. Comparative effects of angiotensin receptor blockade and ACE inhibition on the fibrinolytic and inflammatory responses to cardiopulmonary bypass. Clin Pharmacol Ther. 2012 Jun;91(6):1065-73. doi: 10.1038/clpt.2011.356.

Gamboa JL, Pretorius M, Sprinkel KC, Brown NJ, Ikizler TA. Angiotensin converting enzyme inhibition increases ADMA concentration in patients on maintenance hemodialysis--a randomized cross-over study. BMC Nephrol. 2015 Oct 22;16:167. doi: 10.1186/s12882-015-0162-x.