Effect of rosuvastatin pretreatment on myocardial damage after coronary surgery: a randomized trial. Effects of simvastatin on systemic inflammatory responses after cardiopulmonary bypass. Reduced P-selectin in hearts pretreated with fluvastatin: a novel benefit for patients undergoing open heart surgery. Atorvastatin increases the number of endothelial progenitor cells after cardiac surgery: a randomized control study. Effect of preoperative atorvastatin therapy on atrial fibrillation following off-pump coronary artery bypass grafting. Effects of atorvastatin on systemic inflammatory response after coronary bypass surgery. The effects of atorvastatin on the occurrence of postoperative atrial fibrillation after off-pump coronary artery bypass grafting surgery. Can statins reduce the inflammatory response to cardiopulmonary bypass? A clinical study. Pravastatin immunomodulates IL-6 and C-reactive protein, but not IL-1 and TNF-alpha, in cardio-pulmonary bypass. Randomized trial of atorvastatin for reduction of postoperative atrial fibrillation in patients undergoing cardiac surgery: results of the ARMYDA-3 (Atorvastatin for Reduction of MYocardial Dysrhythmia After cardiac surgery) study.
Myocardial disease without evidence of myocardial infarction is a frequent complication after cardiac surgery during cardiopulmonary bypass. Statins might be protective, but their efficacy has not been established in randomized trials.
                Two hundred patients undergoing coronary surgery were enrolled. They were randomized to rosuvastatin (20 mg/d, n = 100) or placebo (n = 100) starting 1 week before the operation. Troponin I, myoglobin, creatine kinase-MB mass, and high-sensitivity C-reactive protein were used as markers of myocardial injury, and their values were determined at baseline and at regular intervals after the operation. Electrocardiography and echocardiography were performed before and after the operation.
                Myocardial disease was diagnosed when troponin I, myoglobin, and creatine kinase-MB mass values were above the upper normal limit without evidence of electrocardiographic changes, echocardiographic changes, or both. The percentages of marker level increase indicative of myocardial disease were determined in the placebo versus statin groups and were as follows: troponin I, 35% versus 65% (P < .0001); myoglobin, 39% versus 72% (P < .0001); creatine kinase-MB mass, 22% versus 40% (P = .0002). Peak postoperative values of troponin I (0.16 +/- 0.15 vs 0.32 +/- 0.26 ng/mL, P = .0008), myoglobin (72.25 +/- 25 vs 98.31 +/- 31 ng/mL, P < .0001), and creatine kinase-MB mass (3.9 +/- 3.3 vs 9.3 +/- 8.1 ng/mL, P < .0001) were significantly higher in the placebo group. High-sensitivity C-reactive protein values were increased in 58% of pretreated versus 88% of the control patients (15.4 +/- 2.5 vs 17.2 +/- 3.4 mg/L, P < .0001). In high-risk patients myocardial disease was observed more frequently but significantly less in statin-pretreated patients.
                Statin pretreatment reduces myocardial damage after coronary surgery and could improve both short- and long-term results. Cardiopulmonary bypass is associated with a complex systemic inflammatory response and the extent of their increase has been correlated with the development of postoperative complications. Recent studies suggest that treatment with statins is associated with a significant and marked decrease in inflammation-associated variables such as cytokines. Therefore, we investigated the effects of preoperative simvastatin treatment on systemic inflammatory response and perioperative morbidity after cardiopulmonary bypass.
                A prospective, randomized study, was designed. Forty-four subjects undergoing elective coronary artery bypass grafting who fulfilled the inclusion criteria were randomized to treatment with simvastatin (20 mg/day, group A, N. 22) or control (group B, N. 22) before surgery. Plasma levels of interleukins (IL-6, IL-8, TNF-alpha), and systemic inflammatory response score (SIRS) were measured during the surgical intervention and over the following 48 postoperative hours. Cytokine levels were measured by enzyme-linked assays from plasma samples obtained at specific time points pre- and post-operation.
                In both groups the serum levels of the proinflammatory cytokines (IL-6, IL-8, TNF-alpha), and leukocytes, and the SIRS score increased significantly over the baseline, though no significant differences were observed between the two groups. The preoperative and postoperative course did not differ between both groups.
                In patients undergoing coronary artery bypass grafting with cardiopulmonary bypass, the administration of simvastatin doses not produce any changes in the inflammatory response as measured by the levels of IL-6, IL-8, TNF-alpha and SIRS score, nor does it reduce the complications after cardiac surgery. P-selectin is an adhesion molecule that plays a role in the pathogenesis of atherosclerosis. The aim of this study was to assess whether or not the treatment with fluvastatin for 3 weeks preoperatively would reduce the levels of circulating P-selectin in patients with coronary heart disease undergoing coronary artery bypass grafting surgery (CABG).
                Forty-six patients referred to CABG operation were included in the study. The patients were randomized into two groups (1:1): one treated with fluvastatin (80 mg/day, fluvastatin group, n = 23), and the other one treated with placebo (placebo group, n = 23) for three weeks before surgery. All patients underwent CABG using CPB. Blood samples were collected at baseline (the day before surgery), before and after aortic cross-clamping (ACC), at postoperative 0 h (the end of surgical intervention), and at 4, 12, and 24 hours postoperatively. Concentrations of soluble P-selectin (sP-selectin) were analyzed.
                The sP-selectin values measured in the fluvastatin group were significantly lower than the values measured in the placebo group. There was less use of intraoperative inotropic agents in the fluvastatin group ( P < 0.015) and the difference in the length of ICU and hospital stay showed a significantly shorter stay for the fluvastatin group.
                Pretreatment with fluvastatin seemed to reduce P-selectin levels compared to patients given placebo, and hence, we think that pretreatment with a statin, fluvastatin in our study, might reduce the perioperative cardiac injury caused by cardiopulmonary bypass-induced inflammatory changes. We believe that routine preoperative use of fluvastatin should be carefully considered. Endothelial progenitor cells (EPCs) are a subtype of hematopoietic stem cells, which contribute to the repair of injured endothelium. Treatment with atorvastatin has been shown to increase EPC count in patients with coronary artery disease. Therefore, we investigated whether atorvastatin augments the number of EPCs after cardiopulmonary bypass (CPB) surgery. We conducted a randomized double-blind, placebo-controlled, 2-way crossover trial in 50 patients undergoing elective coronary surgery. Patients received either 3-week treatment with atorvastatin or placebo. EPCs were quantitated by flow cytometric phenotyping on blood samples. Levels of interleukin, IL-6 and IL-8; tumor necrosis factor alpha; SDF-1alpha; granulocyte colony-stimulating factor; and vascular endothelial growth factor were determined at recruitment, preoperatively, post-CPB, and 6, 12, and 24 hours postoperatively. The atorvastatin group showed a significantly higher amount of EPCs both pre- and postoperatively compared with the placebo, with a >4-fold increase compared with the baseline values. CPB induced an increase in all cytokines, but the levels of proinflammatory cytokines were significantly lower in the atorvastatin group (P < 0.05). Statin did not affect levels of SDF-1alpha, granulocyte colony-stimulating factor, and vascular endothelial growth factor. However, no correlation was found between plasma levels of any cytokine and number of EPCs, with the exception of SDF-1alpha. Pretreatment with atorvastatin significantly increases the amount of EPCs after CPB, by a mechanism independent of plasma levels of cytokines and cholesterol. Atrial fibrillation (AF) after coronary artery bypass grafting (CABG) is still the most common postoperative arrhythmic complication. Previous studies report that patients undergoing preoperative statin therapy had a lower incidence of postoperative AF. This study aimed to assess the effect of preoperative atorvastatin therapy on preventing AF following off-pump CABG in a randomized, controlled trial.
                The 140 consecutive patients undergoing elective off-pump CABG, without a history of AF or previous statin treatment, were enrolled and randomly assigned to a statin (atorvastatin 20 mg/day, n=71) or a control group (placebo, n=69) starting 7 days preoperatively. The primary endpoint was the occurrence of postoperative AF; secondary endpoints were major adverse in-hospital cardiac and cerebrovascular events and identification of variables predicting postoperative AF. Atorvastatin significantly reduced the incidence of postoperative AF and the postoperative peak C-reactive protein (CRP) level vs placebo (14% vs 34%, P=0.009; 126.5 +/-22.3 vs 145.2 +/-31.6 mg/L, P<0.0001). Logistic regression analysis showed preoperative atorvastatin treatment was an independent factor associated with a significant reduction in postoperative AF (odds ratio (OR) 0.219, P=0.005), whereas a high postoperative CRP level was associated with increased risk (OR 2.011, P=0.013).
                Administration of atorvastatin 20 mg/day, initiated 1 week before elective off-pump CABG and continued in the postoperative period, significantly decreases postoperative AF. Systemic inflammatory response occurs frequently after coronary artery bypass surgery, and it is strongly correlated with the risk of postoperative morbidity and mortality. Recent studies demonstrate that treatment with statin is associated with a significant and marked decrease in inflammation-associated variables such as the C-reactive protein, cytokines, and adhesion molecules. Therefore, we investigated the effects of preoperative atorvastatin treatment on systemic inflammatory response and perioperative morbidity after cardiopulmonary bypass.
                Double-blinded, placebo-controlled, randomized study.
                University hospital.
                Forty patients were randomized to treatment with atorvastatin (20 mg/day, group A, n=20) or placebo (group B, n=20) 3 wks before surgery.
                Three-week treatment by atorvastatin 20 mg/day.
                Postoperative serum levels of both interleukin-6 and interleukin-8 increased significantly over baseline, but the peak levels observed 4 hrs postoperatively were significantly lower in the atorvastatin group. In the same fashion, CD11b expression on neutrophils was significantly lower in the statin group at 4 and 24 hrs postoperatively. Finally, neutrophil-endothelial adhesion was significantly reduced in the statin patients compared with controls. The operation time, blood loss, need for inotropic support, intubation time, and length of intensive care unit or hospital stay did not differ significantly between the two groups. The systemic inflammatory response syndrome score on postoperative days 1 and 2 was comparable in both groups.
                Pretreatment with atorvastatin significantly reduces cytokine release and neutrophil adhesion to the venous endothelium in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass. Atrial fibrillation (AF) after coronary artery bypass graft (CABG) surgery is still the most common arrhythmic complication. This study evaluated whether pretreatment with atorvastatin protects against AF after off-pump CABG.
                One hundred twenty-four patients without a history of AF or previous statin use, who were scheduled to undergo elective off-pump CABG, were enrolled. Patients were randomized to control group (n = 62) or to atorvastatin group (n = 62) who were administered atorvastatin 20 mg/d for 3 days before the surgery. Primary outcome was the incidence of postoperative AF. Secondary outcomes were major adverse cardiac and cerebrovascular events, persistent AF at 1 month, and identification of the markers to predict inhospital postoperative AF.
                The incidence of AF was significantly lower in the atorvastatin group than in the control group (13% vs 27%, P = .04). The incidence of major adverse cardiac and cerebrovascular events and persistent AF at 1 month was similar in comparisons between the groups. Postoperative peak N-terminal pro-brain natriuretic peptide levels were significantly higher in the patients with AF (P = .03). Multivariate analysis identified pretreatment with atorvastatin as an independent factor associated with a significant reduction in postoperative AF (odds ratio 0.34, P = .04). Higher postoperative peak N-terminus pro-B-type natriuretic peptide levels were associated with the development of postoperative AF (odds ratio 1.02 per 100 pg/mL, P = .03).
                Pretreatment with atorvastatin significantly reduced the occurrence of postoperative AF after off-pump CABG. In addition to lowering lipid levels, statins might reduce leukocyte-endothelial cell interactions. Therefore, we assessed whether this effect could limit the inflammatory response to cardiopulmonary bypass (CPB) in cardiac surgical patients.
                Twenty patients undergoing valve or coronary operations with tepid (34 degrees C) CPB were randomized to receive an oral dose of atorvastatin (40 mg the evening before and 40 mg the morning of surgery) or to serve as controls. Pre- and post-CPB blood samples were assayed for neutrophil CD11b surface adhesion molecule and oxidative burst. Plasma levels of interleukins 6 and 8, P-selectin, soluble intercellular adhesion molecule-1, and lactoferrin were measured by enzyme-linked immunosorbent assay (ELISA). In addition, right atrial biopsies were taken before and at the end of CPB, and processed for the expression of the transcription nuclear factor-kappa B (NF-kappaB).
                The two groups did not differ with regard to pre- and intraoperative data. Except for P-selectin, postbypass values of all markers significantly increased over baseline values, but atorvastatin therapy failed to attenuate the magnitude of this increase. In the two groups, the expression of NF-kappaB significantly (p = 0.004) increased over baseline without group effect. Postoperative clinical outcomes did not differ either between the two groups.
                These data show that acute preoperative statin therapy fails to limit the inflammatory response to CPB; however, the data also document a major upregulation of NF-kappaB during cardiac operations, thereby providing a sound rationale for interventions targeted at inactivating this key component of the inflammatory cascade. While statins are increasingly used in cardiopulmonary bypass (CPB), the anti-inflammatory effects of individual statins, within the context of various treatment regimes, need further examination. The present study evaluates the anti-inflammatory effectiveness of the short-term, preoperative and intensive postoperative use of pravastatin in CPB.
                Forty three patients undergoing CPB were enrolled in a randomized, prospective clinical study. One group (n = 21), received pravastatin, the other (n = 22) did not. Patients in the pravastatin group received one dose of 40 mg per day for nine days, starting 48 hours before CPB, with an additional dose of 40 mg one hour after surgery. Plasma levels of selected inflammatory mediators were measured at baseline and tracked systematically.
                Pravastatin reduced postoperative interleukin-6 (IL-6) levels significantly at 24 and 48 hours, and at seven days. Mean +/- SD values, for treated versus untreated patients were: at 24 hours, 159.5 +/- 58.5 versus 251.2 +/- 53.0 pg/mL (p < 0.001); at 48 hours, 81.9 +/- 31.5 versus 194.2 +/- 56.3 pg/mL (p < 0.001); and at seven days, 16.4 +/- 7.2 versus 30.8 +/- 12.6 (p < 0.001). C-reactive protein (CRP) decreased significantly on the seventh postoperative day, when plasma levels were 3.6 +/- 1.1 in the treated patients versus 8.2 +/- 2.1 mg/dL in the controls (p < 0.001). No changes in plasma IL-1 and TNF-alpha were found during entire study.
                Pravastatin induced a precocious modulation of IL-6 expression and a later reduction of plasma CRP levels. Pravastatin;s effects on the expression of these pivotal inflammatory mediators strongly support its well-timed use in CPB. Atrial fibrillation (AF) after cardiac surgery is associated with increased risk of complications, length of stay, and cost of care. Observational evidence suggests that patients who have undergone previous statin therapy have a lower incidence of postoperative AF. We tested this observation in a randomized, controlled trial.
                Two hundred patients undergoing elective cardiac surgery with cardiopulmonary bypass, without previous statin treatment or history of AF, were enrolled. Patients were randomized to atorvastatin (40 mg/d, n=101) or placebo (n=99) starting 7 days before operation. The primary end point was incidence of postoperative AF; secondary end points were length of stay, 30-day major adverse cardiac and cerebrovascular events, and postoperative C-reactive protein (CRP) variations. Atorvastatin significantly reduced the incidence of AF versus placebo (35% versus 57%, P=0.003). Accordingly, length of stay was longer in the placebo versus atorvastatin arm (6.9+/-1.4 versus 6.3+/-1.2 days, P=0.001). Peak CRP levels were lower in patients without AF (P=0.01), irrespective of randomization assignment. Multivariable analysis showed that atorvastatin treatment conferred a 61% reduction in risk of AF (odds ratio 0.39, 95% confidence interval 0.18 to 0.85, P=0.017), whereas high postoperative CRP levels were associated with increased risk (odds ratio 2.0, 95% confidence interval 1.2 to 7.0, P=0.01). The incidence of major adverse cardiac and cerebrovascular events at 30 days was similar in the 2 arms.
                Treatment with atorvastatin 40 mg/d, initiated 7 days before surgery, significantly reduces the incidence of postoperative AF after elective cardiac surgery with cardiopulmonary bypass and shortens hospital stay. These results may influence practice patterns with regard to adjuvant pharmacological therapy before cardiac surgery.