Angiotensin-Converting Enzyme Inhibition Alters the Fibrinolytic Response to Cardiopulmonary Bypass

Abstract

Background-Increased plasminogen activator inhibitor-1 (PAI-1) concentrations after coronary artery bypass grafting (CABG) are associated with increased risk of vein graft occlusion. Because angiotensin II stimulates PAI-1 expression, we tested the hypothesis that preoperative angiotensin-converting enzyme (ACE) inhibition decreases PAI-1 expression after CABG. Methods and Results-We measured the effects of cardiopulmonary bypass (CPB) on PAI-1 antigen and tissue-type plasminogen activator (tPA) antigen and activity in 31 patients taking an ACE inhibitor (ACEI) who were randomized to continue ACEI until the morning of surgery (ACEI group, nϭ19) or to discontinue it 48 hours before surgery (No-ACEI group, nϭ12). Arterial blood samples were taken at baseline before CPB, twice during CPB, after separation from CPB, and on postoperative day 1 (POD1). CPB caused an early decrease in PAI-1 antigen, followed by an increase in PAI-1 antigen on POD1 (PϽ0.001 for effect of time). ACE inhibition attenuated the increase in PAI-1 antigen such that both PAI-1 antigen on POD1 (Pϭ0.013) and the change in PAI-1 antigen from baseline to POD1 (Pϭ0.009) were higher in the No-ACEI group (from 17.0Ϯ5.0 to 48.7Ϯ8.8 ng/mL) versus the ACEI group (from 19.9Ϯ3.4 to 33.1Ϯ6.2 ng/mL). There was no significant difference between the 2 groups in intraoperative tPA activity (Pϭ0.259); however, the increase in tPA activity was significantly greater in the ACEI group than in the No-ACEI group (Pϭ0.030). Conclusions-Preoperative

Plasminogen Activator Inhibitor-1 as a Predictor of Postoperative Atrial Fibrillation After Cardiopulmonary Bypass

“…19 PAI-1 antigen concentrations transiently decrease during CPB and then begin to rise by separation from CPB, peaking on postoperative day 1. 9,20 On the other hand, we found that preoperative PAI-1 concentrations predicted postoperative AF suggesting that the underlying inflammatory and profibrotic state rather than the acute inflammatory response, may determine risk of this event. Moreover, the selection of the postprotamine time point enabled us to assay blood when many biomarkers are starting to rise, but early enough to direct future preventive strategies.…”

“…30,31 In a study of patients treated preoperatively with an ACE inhibitor and randomized to continue or discontinue ACE inhibition, continued ACE inhibition decreased plasma PAI-1 antigen concentrations after CPB. 20 …”

Angiotensin-converting enzyme inhibition or mineralocorticoid receptor blockade do not affect prevalence of atrial fibrillation in patients undergoing cardiac surgery*

“…(31) In two small randomized trials in chronic ACE inhibitor users, postoperative PAI-1 concentrations were lower in patients continued on ACE inhibitor therapy compared to in patients whose ACE inhibitor was stopped prior to cardiac surgery. (13, 32) MR antagonists also reduce inflammatory cytokines and PAI-1 in normotensive or hypertensive subjects. (33, 34) In the present clinical trial, we observed the previously reported association between the inflammatory response to cardiac surgery and postoperative AF.…”

“…ACE inhibitors attenuate the inflammatory response to cardiac surgery and specifically reduce plasma concentrations of inflammatory biomarkers associated with the development of postoperative AF. (12, 13) Conversely, ACE inhibitor withdrawal is associated with postoperative AF. (3) Nevertheless, many physicians withhold ACE inhibitors in the perioperative period due to concerns about perioperative hypotension and impaired kidney function.…”

Targeted Treatments for Restenosis and Vein Graft Disease

“…This change may be due to improving endothelial cell function, PAI-1 antigen attenuation (thus reducing thrombosis), or due to a decrease in matrix metalloproteinase production and matrix remodelling (thus limiting SMC migration) and SMC proliferation [225].…”