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Reviews

Applications of statins in cardiothoracic surgery: more than just lipid-lowering

Department of Clinical Biochemistry (Vascular Disease Prevention Clinics) and Academic Department of Surgery, Royal Free Hospital, Pond Street, London NW3 2QG, UK

Received 10 October 2007; received in revised form 12 December 2007; accepted 12 December 2007.

^_* Corresponding author. Tel.: +44 20 7830 2258; fax: +44 20 7830 2235. (Email: paraskevask{at}hotmail.com).

	Abstract

Top Abstract 1. Introduction 2. Literature search methods 3. Literature search results 4. Conclusions References

 
Statins exert several actions in cardiothoracic surgical procedures besides lipid-lowering. In patients undergoing coronary artery bypass grafting (CABG), statins improve bypass graft patency, perioperative as well as long-term mortality rates. In addition, statins reduce the number of postoperative complications and clinical events, revascularization rates and postoperative hospital stay (as well as associated costs). Furthermore, they are protective against de novo atrial fibrillation and renal dysfunction following CABG. In cardiac transplantation, statins decrease cardiac allograft vasculopathy and cardiac rejection rates. They are also associated with a significant reduction in mortality rates in cardiac transplant patients. According to the results of a meta-analysis, statins are associated with one life saved for every 8.5 heart transplant recipients treated for 1 year. Alternatively, routine statin treatment in cardiac transplant patients might have the potential to save 471 lives each year among the 4000 heart transplantation operations performed worldwide. The results from several studies suggest that statins may also play a role in heart valve surgery, lung transplantation, pulmonary resection and thoracic aortic aneurysm repair. Statin use is safe and cost-effective. Despite the multiple beneficial effects of statin therapy, there is evidence suggesting that a large percentage of cardiothoracic surgical patients are suboptimally treated with respect to statins. Risk management in these patients should be improved to reduce cardiovascular morbidity and mortality rates.

Key Words: Statins • Coronary artery bypass grafting • Cardiac transplantation • Valve surgery • Cardiac surgery • Thoracic aortic aneurysm

	1. Introduction

Top Abstract 1. Introduction 2. Literature search methods 3. Literature search results 4. Conclusions References

 
In the last few years, there is accumulating evidence that statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) exert several non-lipid related actions [1–8]. Statins have an established role in primary and secondary prevention of cardiovascular events [9–14]. Besides this, however, a number of studies suggest that statins exert pleiotropic actions in patients undergoing percutaneous or open surgical procedures [15–21].

Statins are safe drugs with very few adverse effects described; their most frequent side-effects (liver failure and rhabdomyolysis) occur at a rate of only one case per 1,000,000 person–years [22,23].

This review discusses the multiple beneficial effects of statins in cardiothoracic surgery.

	2. Literature search methods

Top Abstract 1. Introduction 2. Literature search methods 3. Literature search results 4. Conclusions References

 
A literature search was performed in Medline using the following mesh headings: ‘statins’, ‘coronary artery bypass grafting’, ‘cardiac transplantation’, ‘cardiac surgery’, ‘valve surgery’, ‘lung transplantation’, ‘thoracic surgery’ and ‘thoracic aortic aneurysms’. Additional studies from the reference lists of the gathered reports were also considered.

	3. Literature search results

Top Abstract 1. Introduction 2. Literature search methods 3. Literature search results 4. Conclusions References

 
Statins appear to exert several beneficial, non-lipid related actions in many cardiothoracic surgical operations, namely coronary artery bypass grafting (CABG), valve surgery, heart and lung transplantation, pulmonary lobectomy/pneumonectomy and thoracic aortic aneurysm surgery. Current evidence suggests that a large percentage of cardiothoracic surgical patients are undertreated with respect to statins. This has considerable implications for perioperative, as well as long-term morbidity and mortality rates.

The effects of statins on cardiothoracic surgical procedures are briefly presented.

3.1 Statins and CABG
Early studies showed that atherosclerosis frequently develops in saphenous vein coronary bypass grafts leading to occlusion rates as high as 40% at 10–12 years following CABG surgery [24,25]. An observational study following up 1041 post-CABG patients for 20 years showed that one in five patients underwent repeat CABG and another 7% had percutaneous transluminal coronary angioplasty during this time period [26]. These progressive atherosclerotic obstructive changes are especially common in patients with hyperlipidemia [27–30]. The key role of managing hyperlipidemia in these patients was demonstrated in the post-CABG trial [31]. Compared with moderate lipid-lowering treatment with lovastatin (target low-density lipoprotein cholesterol (LDL-C): 132–136 mg/dl), aggressive lovastatin treatment aiming at target LDL-C levels <100 mg/dl resulted in a reduced percentage of grafts per patient with angiographically detected atherosclerosis progression after a mean follow-up of 4.3 years (39% vs 27%, respectively; p < 0.001). Similar results were reported regarding the mean percentage of grafts per patient with occlusion or new lesions (Table 1 ) [31]. The post-CABG trial was designed to have adequate power to detect treatment-related differences in angiographic characteristics but not in clinical events. As a result, a reduction in the number of clinical events was not seen [31]. Nevertheless, a 29% lower rate of revascularization procedures was observed in the aggressive compared with the moderate treatment group (p = 0.03) [31].

Following the post-CABG trial, several other studies on patients undergoing CABG showed that statin treatment is beneficial in these patients with respect to the incidence of postoperative adverse cardiovascular outcomes (unstable angina, MI, arrhythmia, stroke and cardiac death) (Table 1). The possible mechanisms through which statins exert their beneficial actions in CABG are reviewed elsewhere [33–35]. Briefly, these include reduction of inflammation and oxidative stress, improvement of vascular endothelial function and management of postoperative hyperlipidemia/dyslipidemia [33–35]. Lipid-lowering in post-CABG patients is crucial; hyperlipidemia is responsible for the development of atherosclerotic changes in vein grafts eventually leading to graft occlusion [34,35].

Preoperative statin therapy in CABG patients improves postoperative myocardial perfusion of bypassed areas [36]. It also significantly reduces cytokine release (such as interleukin (IL)-6 [37–39] and IL-8 [37]) and neutrophil adhesion to the venous endothelium via a nitric oxide-mediated mechanism. Preoperative statin treatment is also associated with improved perioperative mortality rates [40–43] and reduced risk of postoperative thrombocytosis and thrombotic complications [44]. Postoperative thrombocytosis occurs in 20–30% of the patients undergoing CABG and it is associated with an increase in late thrombotic complications [45]. Furthermore, pre-CABG statin use is associated with a 33% reduction in the odds of developing a postoperative infection and a 20% reduction in the odds of requiring a prolonged postprocedural hospitalization [46]. Another beneficial action of statins in CABG patients is stroke prevention, which is one of the most serious complications of this procedure [47]; a recent prospective study showed that, compared with non-use, statin treatment for at least 4 weeks prior to surgery was significantly and independently associated with a lower risk of perioperative cerebrovascular events (odds ratio (OR) 0.26; 95% confidence interval (CI) 0.06–086; p = 0.027) [47].

Acute renal failure occurs in 1–5% of the patients following CABG surgery [48–50]. It is associated with mortality rates as high as 60% [48,49] and substantial increases in the lengths of intensive care and hospital stay [48–50]. A large, multi-center trial including 19,625 patients undergoing isolated CABG surgery showed that patients with preoperative non-dialysis-dependent renal dysfunction had significantly higher in-hospital mortality (adjusted OR 3.0; p < 0.001), stroke (adjusted OR 2.0; p = 0.33), atrial arrhythmia (adjusted OR 1.5, p = 0.003), prolonged ventilation (adjusted OR 2.1; p < 0.001), postoperative hospital stay >6 days (adjusted OR 2.6; p < 0.001) and follow-up mortality rates (adjusted OR 2.7; p < 0.001) [51]. A retrospective cohort study including 1802 CABG patients suggested that preoperative statin therapy might be renoprotective in patients undergoing CABG [52]. By multivariate analysis, preoperative statin use was associated with an almost 50% lower incidence of new postoperative renal insufficiency (OR 0.54, 95% CI 0.18–0.82; p = 0.047) [52].

Statins exert several beneficial actions on saphenous venous bypass graft patency rates. A 4-year prospective study with a median follow-up of 32 months (mean: 38.54 ± 0.54 months) investigated predictors of symptom recurrence (recurrent angina, MI and congestive heart failure) and adverse cardiac events (MI, coronary reintervention and any cardiac-related mortality including sudden cardiac death) in 591 patients undergoing CABG [53]. Following the procedure, statins were used in 391 patients (66.1%). Postoperative statin use was associated with both decreased symptom recurrence (hazard ratio (HR) 0.157, 95% CI 0.075–0.330; p < 0.0001) and adverse cardiac events (HR 0.178, 95% CI 0.076–0.418; p < 0.0001)) [53]. Similar results were also reported in other studies [31,54–58]; statins improve endothelial cell function and inhibit smooth muscle cell proliferation in human saphenous veins thus effectively decreasing progression of atherosclerosis in the vein grafts used in CABG [31,54–58].

An interesting study evaluated the predictive role of preoperative C-reactive protein (CRP) levels in the long-term outcome of 843 patients undergoing CABG [59]. Among operative survivors (753 patients with low CRP (<1.0 mg/dl) and 87 with high CRP (1.0 mg/dl)), patients in the low CRP group had significantly better 12-year overall survival rate (74.1% vs 63.0%; p = 0.004) and survival freedom from fatal cardiac events (86.7% vs 78.1%; p = 0.008). In multivariate analysis, CRP 1.0 mg/dl was an independent predictor of late all-cause mortality (risk ratio 1.60, 95% CI 1.09–2.35; p = 0.017) [59]. These results were verified by an independent group [60]; high preprocedural CRP levels were associated with an almost 6-fold increase in 9-month mortality rates in 108 patients with left main coronary artery stenosis treated with CABG (HR 5.86, 95% CI 1.71–20.03; p = 0.005) [60]. Statins effectively reduce circulating CRP levels [61–63]. Therefore, their use may be associated with a beneficial effect on long-term survival rates in post-CABG patients.

Statins are also protective against de novo atrial fibrillation developing following CABG [64–67]. Post-CABG atrial fibrillation is a frequent complication occurring in approximately one third of male patients and 40% of female patients [68]. International guidelines on the management of atrial fibrillation after cardiac and thoracic surgery were recently reported [69]. Two earlier meta-analyses showed that angiotensin-converting enzyme inhibitors and angiotensin receptor blockers effectively prevent the development of new onset atrial fibrillation in patients with cardiovascular diseases [70,71]. Nevertheless, a cohort evaluation study showed that preoperative use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers was associated with a non-significant 29% reduction in postoperative atrial fibrillation (adjusted OR 0.71, 95% CI 0.42–1.20, p = 0.20) [72]. Therefore, their use for the management of post-CABG atrial fibrillation has limitations. Two studies showed that de novo atrial fibrillation following CABG is associated with several inflammation-associated parameters and inflammatory cytokines [73,74]. It was thus hypothesized that statins, by reducing postoperative inflammatory response, could be beneficial for these patients [73]. It remains to be determined whether statin treatment should play a role in the therapeutic approach of these patients.

An important issue that is often neglected is continuation of preoperative statin therapy following CABG surgery. It was recently demonstrated that post-CABG discontinuation of statin therapy in patients who were on statins preoperatively is associated with an increase in late (>4 days postoperatively) cardiac and all-cause mortality compared with continuous statin use following the procedure (2.64% vs 0.60%, respectively; adjusted OR 2.64; 95% CI 1.32–5.26; p < 0.01) [40]. This correlation was seen even when controlling for the postoperative discontinuation of other medications (e.g. aspirin, beta-blocker, or angiotensin-converting enzyme inhibitors) [40]. Discontinuation of statin therapy after surgery was also independently associated with a significant increase in late cardiac mortality compared with continuous postoperative statin use (1.91% vs 0.45%, respectively; adjusted OR 2.95; 95% CI 1.31–6.66; p < 0.01) [40]. It is, therefore, crucial not to discontinue statin therapy postoperatively in these patients.

A different opinion has also been reported. In a single-center retrospective study, 1706 patients undergoing isolated CABG or CABG combined with heart valve surgery were classified according to preoperative statin use (1075 statins users vs 631 non-users) [75]. An analysis according to preoperative statin use showed that, compared with non-users, statin users were more likely to undergo non-urgent in-house surgery (54.2% vs 70.8%, respectively; p = 0.0001) and have an ejection fraction <40% (23.0% vs 14.8%, respectively; p = 0.0001). The end-points of interest analyzed were in-hospital mortality, intra- or postoperative intra-aortic balloon pump use, perioperative MI, stroke, prolonged (>24 h) ventilation and a composite outcome defined as a combination of 2 or more of the above. The results of this analysis showed that preoperative statin use was not associated with a reduction of in-hospital mortality (OR 1.0, 95% CI 0.6–1.5, p = 0.85), the composite outcome (OR 1.1, 95% CI 0.8–1.4, p = 0.69) or any of the outcomes of interest [75]. Until now, these results have not been verified by other independent studies.

3.2 Statins and valve surgery
It was suggested that statins might reduce the progression of calcific aortic valve stenosis [76–79]. According to one theory, aortic stenosis is the product of an active inflammatory process, which shares many similarities with atherosclerosis (e.g. lipoprotein accumulation) [76,80,81]. An additional finding supporting this theory is that aortic stenosis progresses faster in patients with hypercholesterolemia [78]. As statins are indicated both in the management of hypercholesterolemia [82,83] and atherosclerosis [84,85], it is possible that these agents comprise an effective way to retard the progression of aortic stenosis.

Statins have also been reported to reduce aortic valve calcium accumulation [86,87], as well as the progression of biologic prosthetic aortic valve degeneration [88,89]. The explanation for these results was provided by a retrospective cohort study; by stepwise multiple regression analysis, it was shown that hypercholesterolemia was an independent predictor for bioprosthetic aortic or mitral valve calcification (p = 0.02) [90]. These effects hold considerable implications both in the conservative and the surgical management of patients with aortic valve stenosis. The extent of aortic valve calcification is a strong predictor of aortic valve stenosis [87]. Thus, by retarding this process, the rates of progression of aortic valve stenosis are reduced. Furthermore, an effect of statins on the progression of biologic prosthetic aortic valve degeneration [88,89] could potentially influence the type of aortic valve prosthesis selected in patients requiring aortic valve replacement.

It was proposed that statins might have a role in the management of patients with congenital bicuspid aortic valve malformations [90]. These patients are at a higher risk of developing aortic stenosis, aortic root dilation, aortic regurgitation, aortic aneurysm, aortic dissection and infective endocarditis. This is done via two different mechanisms: (i) by reducing the progression of aortic stenosis and aortic valve calcification [76–79,88,89]; and (ii) by limiting aortic dilatation through inhibition of matrix metalloproteinases (MMPs) [91–93] and improvement of endothelial function [94,95].

Whether statin therapy has an effect on long-term morbidity and mortality rates following valve surgery has not been investigated so far. A recent systematic review including 28 studies and a total of 106,660 patients did not identify statin non-use as a predictor of early or late mortality following aortic valve replacement [96]. Nevertheless, statins may improve some of the predictors of mortality identified, such as renal dysfunction [97,98] and coronary artery disease [11–13,99,100]. Thus, it could be hypothesized that statins potentially influence mortality rates following valve surgery in an indirect way.

Two prospective, randomized, multi center, double-blind, placebo-controlled trials, the Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER) Trial in Canada [101] and the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) Study in Europe [102] are currently under way. The ASTRONOMER trial aims to determine the effect of rosuvastatin 40 mg/day versus placebo on the rate of cardiac death and aortic valve replacement in patients with mild to moderate aortic stenosis. The results of this trial, which will be available at the end of 2008, will clarify the role of statin therapy in the management of aortic stenosis [101]. The SEAS Study investigates the effect of lipid-lowering with a combination of ezetimibe 10 mg/day and simvastatin 40 mg/day in patients with asymptomatic aortic stenosis with peak transvalvular jet velocity 2.5–4.0 m/s. The results of the SEAS Study will help determine the prognostic value of aggressive lipid-lowering treatment in patients with asymptomatic aortic stenosis [102].

3.3 Statins and cardiac transplantation
Transplant coronary artery disease (cardiac allograft vasculopathy) remains the leading cause of death or retransplantation in cardiac transplant recipients up to 5 years post-transplant, accounting for nearly 30% of deaths [103,104]. It is characterized by a diffuse proliferative vasculopathy limited to the allograft coronary arteries and is associated with the development of MI, ventricular failure, malignant arrhythmias and sudden death [103–106]. Besides antiproliferative and immunosuppressive agents (such as ciclosporin, sirolimus and everolimus), routine statin use in heart transplant patients for the management of cardiac allograft vasculopathy has been advocated [107,108].

Early in vitro studies with HMG-CoA reductase inhibitors showed that these agents suppress natural killer cells [109,110]. Interpretation of this finding suggested an immunomodulatory role for statins in the management of acute rejection and coronary vasculopathy [111]. These preliminary results were also verified in animals; statins were shown to affect coronary vasculopathy by a mechanism independent of cholesterol lowering [112,113].

Based on the positive results of in vitro and animal studies, a similar effect on human cardiac transplantations was hypothesized. An early, randomized, placebo-controlled trial showed that, compared with placebo, 12-month treatment with pravastatin 40 mg/day was associated with improved 1-year survival rates, as well as reduced incidence of coronary vasculopathy and cardiac rejection rates [114]. Additionally, there was significantly lower natural killer cell cytotoxicity in the pravastatin compared with the placebo group (9.8% vs 22% specific lysis, respectively; p = 0.014) [114]. The results of several other trials support a role for statins in cardiac transplantation (Table 2 ).

Several in vitro and animal reports have implicated MMPs in the pathogenesis of coronary vasculopathy and acute and chronic cardiac allograft rejection [129–132]. Statins effectively suppress production of MMPs in several tissues and organs [92,133–135]. Through their effect on MMPs, statins may reduce coronary vasculopathy and cardiac rejection rates.

An important issue in heart transplantation is the extent of coronary atherosclerosis of the donor heart [136]. Statins have been reported to cause regression of coronary atherosclerosis [137,138]. A recent animal study also showed that statins attenuate transplant-associated coronary arterial intima hyperplasia and arteriosclerosis in a murine model of cardiac transplantation [139]. Moreover, statin therapy initiated early after heart transplantation leads to better short- and long-term survival rates and a significantly lower incidence of transplant vasculopathy without impairment of organ function or severe adverse effects [140–144]. An economic analysis showed that statin therapy after heart transplantation offers a significant survival benefit and a lower incidence of graft vessel disease in a cost-effective way [145]. These findings hold implications for an important role of statin therapy in heart transplantation.

Another important issue is post-transplant hyperlipidemia/dyslipidemia [146]. The risk of developing hyperlipidemia/dyslipidemia following orthotopic heart transplantation is estimated to range between 50% and 80% [147,148]. The association between hyperlipidemia/dyslipidemia and the development of coronary allograft vasculopathy is well established [148–150]. Statins successfully reduce post-transplant hyperlipidemia/dyslipidemia, coronary allograft vasculopathy and mortality rates in both pediatric [151–154] and adult heart transplant patients [140,141,144,155–160]. The results from randomized trials suggest that the optimal time for initiation of statin therapy is early (<3 years) after cardiac transplantation [140,141,144,155–160]. A possible explanation for this finding is that the immunomodulatory effects of statins are most important in the early post-transplant period perhaps preventing endothelial dysfunction and the cascade that leads to allograft vasculopathy [156–158].

A meta-analysis of the effect of statin therapy initiated within 3 months after cardiac transplantation in patients aged >18 years followed up for 1 year showed that statin use was associated with a significant reduction in mortality in cardiac transplant patients (relative risk 0.31; 95% CI 0.13–0.7; p = 0.006) [142]. It was demonstrated that statins are associated with one life saved for every 8.5 heart transplant recipients treated for 1 year. A different interpretation of the results showed that routine statin treatment in cardiac transplant patients might have the potential to save 471 lives each year among the 4000 heart transplantation operations performed worldwide [142]. Besides being effective and safe [141,142,144,151–163], statin use in cardiac transplant patients is also cost-effective [145]. Despite this, there is evidence suggesting that hyperlipidemias/dyslipidemias are suboptimally managed in many cardiac transplant patients [155].

Future trials are expected to define the exact role of statin therapy in heart transplantation. Encouraging results emerged recently from a cardiac transplantation animal model [164]; soluble IL-1 type-2 receptor gene transfer was demonstrated to attenuate cardiac allograft rejection in a rat model [164]. The authors concluded that IL-1 inhibition might prove useful as an adjuvant therapy in heart transplantation [164]. Statins were shown to be potent inhibitors of several members of the IL family in heart transplantation [63,124] and CABG studies [38–40]. Therefore, a role for these agents in cardiac transplantation should be expected.

3.4 Statins and lung transplantation
The results from preliminary studies suggest that statins play an important role in lung transplantation. Pravastatin was shown to prolong graft survival in an allogeneic rat model of orthotopic lung transplantation [165]. It was supported that the mechanism via which statins exert their beneficial effect may involve inhibition of major histocompatibility complex (MHC) class II molecules [165].

A retrospective study consisting of 200 consecutive patients who survived >30 days after pulmonary transplantation compared the effects of statin use versus non-use on lung transplantation (39 statin users vs 161 non-users) [166]. Compared with controls, statin users had a lower incidence of acute rejection rates, as defined by acute cellular rejection established from lung biopsies (25.6% vs 15.1%, respectively; p < 0.01). Furthermore, patients on statins had lower incidence of chronic (1 year) rejection as determined by signs of obliterative bronchiolitis in lung biopsy (37% vs 0%, respectively; p < 0.01) and improved 6-year survival rates (91% vs 54%, respectively; p = 0.002). A limitation of this retrospective study is that there was no randomization; statins were prescribed to lung transplant recipients solely for the treatment of hypercholesterolemia (>240 mg/dl) refractory to dietary modification [166]. As a result, the results produced are liable to inherent limitations and/or unrecognised biases. A prospective observational study on 64 patients (37 elective cardiac and 27 vascular surgery patients of whom 68% and 44%, respectively had received prior statin therapy) did not reveal significant differences caused by statins in the pulmonary capillary permeability of these patients [167]. Preoperative statin therapy neither had an adverse effect on mildly increased pulmonary capillary permeability nor did it ameliorate increased capillary permeability [167].

Following lung transplantation, lung ischemia–reperfusion injury occurs which is associated with an increase in vascular permeability and manifests itself clinically as pulmonary edema [168]. During the early phase of the ischemia–reperfusion injury, there is increased free radical production, which is secondary to increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in alveolar macrophages [168–170]. Statins were shown to inhibit NADPH oxidase in vitro resulting in decreased production of reactive oxygen intermediates [169,170]. An animal study verified the positive results of in vitro studies [171]; statin pretreatment prior to induction of experimental lung ischemia–reperfusion injury lead to a reduction in lung vascular permeability by 71% (p = 0.001). It was concluded that statin pretreatment of lung transplant recipients to ameliorate reperfusion injury appears to be a promising novel protective strategy [171].

The results of these preliminary studies need to be verified in prospective randomized trials before solid conclusions are drawn regarding the efficacy of statin treatment in lung transplantation.

3.5 Statins and thoracic aortic aneurysms
It was shown that oxidative stress plays a pivotal role in the pathogenesis of thoracic aortic aneurysms [91]. More specifically, the generation of reactive oxygen species was demonstrated to be markedly increased in the aneurysmal aorta compared with non-aneurysmal controls [91]. Reactive oxygen species activate MMPs [172]. An imbalance between MMPs and their inhibitors is crucial in the remodelling of the aortic wall and the pathogenesis of AAAs [173–176]. Activation of MMPs contributes to destructive remodelling of the aortic wall and the development of thoracic aortic aneurysms [91]. As earlier mentioned, statins effectively suppress production of MMPs [133–135]. It can, therefore, be assumed that these agents may reduce expansion rates of thoracic aortic aneurysms. A beneficial effect of statins on abdominal aortic aneurysms has already been described [177]; statins were demonstrated to reduce abdominal aortic aneurysm growth rates in both animal [93,178] and human studies [179,180].

Future trials may also show an effect of statin treatment on long-term morbidity and mortality rates in patients undergoing thoracic aortic aneurysm repair. In a long-term (4.7 years) follow-up study of patients who had undergone successful abdominal aortic aneurysm surgery it was demonstrated that, compared with non-users, statin users had significantly reduced all-cause (50% vs 18%; or 178 of 356 vs 27 of 154 patients, respectively; p < 0.001) and cardiovascular (34% vs 11%; or 122 of 356 vs 17 of 154 patients; p < 0.001) mortality rates [181]. After adjusting for clinical risk factors and beta-blocker use, the association between statin use and reduced all-cause (HR 0.4, 95% CI 0.3–0.6; p < 0.001) and cardiovascular (HR = 0.3, 95% CI 0.2–0.6; p < 0.001) mortality persisted [181]. Statins also reduce cardiac events in patients undergoing non-cardiac vascular surgery [182,183] and improve perioperative morbidity and mortality rates in these patients [184]. Up to now, there have not been any similar reports on patients undergoing thoracic aortic aneurysm repair. Nevertheless, extrapolating from the results of the above studies [181–184], similar effects for statins on thoracic aortic aneurysms should be expected.

3.6 Statins and thoracic surgery
Postoperative atrial fibrillation/flutter (and, generally, atrial arrhythmias) are seen in more than one in five elderly patients undergoing non-cardiac thoracic surgery [185]. These incidents are associated with a prolonged hospitalization and increased associated costs [185]. Consequently, the establishment of measures to decrease the incidence of postoperative atrial arrhythmias following non-cardiac thoracic surgery holds implications for better patient management, decreased morbidity and mortality rates and reduction of the length (and cost) of hospital stay.

A total of 131 patients scheduled to undergo pulmonary lobectomy (n = 117), pneumonectomy (n = 5) or esophagectomy (n = 9) were enrolled in a prospective study investigating the role of preoperative statin therapy in the management of atrial fibrillation following non-cardiac thoracic surgery [186]. The occurrence of atrial fibrillation in statin users was significantly lower compared with non-users (4 of 28 vs 27 of 93 patients, or 11% vs 29%, respectively, p = 0.025). After stepwise logistic regression, statin use was associated with a >three-fold decrease in the odds of developing atrial fibrillation (OR 0.26, 95% CI 0.08–0.82; p = 0.022). The protective effect of statins was independent of CRP levels [186]. Interpretation of these results showed that levels of CRP and inflammatory markers (e.g. IL–6) were not accurate predictors of the postoperative occurrence of atrial fibrillation [186].

Additionally, oxidative stress is prominent during pulmonary lobectomy [187]. The degree of oxidative stress generated is associated with the duration of the procedure (p < 0.001) [187]. Moreover, severe oxidative stress is an independent predictor of postoperative cardiopulmonary complications, namely acute respiratory failure, cardiac arrhythmias and pulmonary hypertension (for all, p < 0.05) [187]. Statins reduce oxidative stress via several mechanisms [188–191]. In addition to direct antioxidant effects, statins reduce circulating oxidized LDL particles and inhibit their uptake by macrophages. Furthermore, they inhibit oxidant enzymes activity (such as that of reduced NADPH oxidase and myeloperoxidase) and up-regulate the activity of antioxidant enzymes (such as catalase and paraoxonase). They also reduce endothelial dysfunction mainly by their ability to enhance endothelial nitric oxide bioavailability, which is achieved by several mechanisms [188–191]. It should be expected that the net result will be reduction of oxidative stress and, consequently, postoperative complications.

3.7 Evidence for patient undertreatment with respect to statins
Several studies have demonstrated that a considerable proportion of cardiovascular patients are undertreated with respect to statins [192–198]. As a result of the suboptimal statin treatment in this high-risk population, cardiovascular event and mortality rates remain high [192–198]. This also applies to CABG surgery patients. A recent study showed that approximately 25% of patients referred for elective CABG are not on statin treatment [199]; even among statin users, the majority of patients were prescribed very low dosages, which were not adequate to achieve LDL–C targets [199]. Several other studies have shown that one in two patients do not receive statin therapy at discharge following CABG surgery [200–202]. Risk management in these patients should be improved as it has been demonstrated that even a modest increase in statin prescribing rates could lead to substantial reduction of cardiovascular events and improvement of morbidity and mortality rates [198].

Statins are well-tolerated agents with few adverse effects [22,23,203]. In patients receiving chronic statin treatment, regular monitoring of liver function tests is advised. Detection of an abnormal elevation of liver enzymes is an indication that the statin dose should be decreased [22,23,203]. If the plasma hepatic enzyme levels remain elevated despite adaptation of the prescribed dose, it may be necessary to stop the statin treatment [22,23,203].

	4. Conclusions

Top Abstract 1. Introduction 2. Literature search methods 3. Literature search results 4. Conclusions References

 
Statins should become an essential component of the therapeutic approach of cardiothoracic surgical patients. In CABG patients, statins improve bypass graft patency rates, perioperative and long-term mortality rates and reduce revascularization rates, the number of postoperative complications and hospital stay. All patients undergoing CABG should receive statins before surgical intervention; most patients undergoing elective procedures should aim for target LDL-C <100 mg/dl, whereas high-risk cases should aim for LDL-C levels <70 mg/dl [204].

In addition to these effects, statins decrease cardiac allograft vasculopathy and cardiac rejection rates in cardiac transplant patients. Although no definite conclusions can be drawn yet, current evidence implies that statin therapy is beneficial in patients undergoing heart valve surgery, lung transplantation, pulmonary resection and thoracic aortic aneurysm repair.

Cardiothoracic surgical patients are undertreated with respect to statins. As a result, cardiovascular event and mortality rates remain high. Improvement of statin prescription rates in this high-risk group would have important consequences on cardiovascular morbidity and mortality rates.

	References

Top Abstract 1. Introduction 2. Literature search methods 3. Literature search results 4. Conclusions References

 

1. Wierzbicki AS, Poston R, Ferro A. The lipid and non-lipid effects of statins. Pharmacol Ther 2003;99:95-112.[CrossRef][Medline]
2. Calabro P, Yeh ET. The pleiotropic effects of statins. Curr Opin Cardiol 2005;20:541-546.[CrossRef][Medline]
3. Almuti K, Rimawi R, Spevack D, Ostfeld RJ. Effects of statins beyond lipid-lowering: potential for clinical benefits. Int J Cardiol 2006;109:7-15.[CrossRef][Medline]
4. Alegret M, Silvestre JS. Pleiotropic effects of statins and related pharmacological experimental approaches. Methods Find Exp Clin Pharmacol 2006;28:627-656.[CrossRef][Medline]
5. Paraskevas KI, Tzovaras AA, Briana DD, Mikhailidis DP. Emerging indications for statins: a pluripotent family of agents with several potential applications. Curr Pharm Des 2007;13:3622-3636.[CrossRef][Medline]
6. Liao JK. Effects of statins on 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition beyond low-density lipoprotein cholesterol. Am J Cardiol 2005;96:24F-33F.[Medline]
7. Davignon J. Beneficial cardiovascular pleiotropic effects of statins. Circulation 2004;109:II39-II43.
8. Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol 2005;45:89-118.[CrossRef][Medline]
9. Collins R, Armitage J, Parish S, Sleigh P, Peto R, Heart Protection Study Collaborative Group MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003;361:2005-2016.[CrossRef][Medline]
10. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998;279:1615-1622.[Abstract/Free Full Text]
11. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383–9.
12. Clearfield M. Statins and the primary prevention of cardiovascular events. Curr Atheroscler Rep 2006;8:390-396.[CrossRef][Medline]
13. Briel M, Nordmann AJ, Bucher HC. Statin therapy for prevention and treatment of acute and chronic cardiovascular disease: update on recent trials and metaanalyses. Curr Opin Lipidol 2005;16:601-605.[Medline]
14. Ferdinard KC. Primary prevention trials: lessons learned about treating high-risk patients with dyslipidemia without known cardiovascular disease. Curr Med Res Opin 2005;21:1091-1097.[CrossRef][Medline]
15. Paraskevas KI, Athyros VG, Briana DD, Kakafika AI, Karagiannis A, Mikhailidis DP. Statins exert multiple beneficial effects on patients undergoing percutaneous revascularization procedures. Curr Drug Targets 2007;8:942-951.[CrossRef][Medline]
16. Biccard BM, Sear JW, Foex P. Statin therapy: a potentially useful peri-operative intervention in patients with cardiovascular disease. Anaesthesia 2005;60:1106-1114.[CrossRef][Medline]
17. Hindler K, Shaw AD, Samuels J, Fulton S, Collard CD, Riedel B. Improved postoperative outcomes associated with preoperative statin therapy. Anesthesiology 2006;105:1260-1272.[CrossRef][Medline]
18. Karthikeyan G, Bhargava B. Managing patients undergoing non-cardiac surgery: need to shift emphasis from risk stratification to risk modification. Heart 2006;92:17-20.[Abstract/Free Full Text]
19. Passamonti E, Pirelli S. Reducing risk of cardiovascular events in noncardiac surgery. Expert Opin Pharmacother 2005;6:1507-1515.[CrossRef][Medline]
20. Schouten O, Bax JJ, Dunkelgrun M, Feringa HH, van Urk H, Poldermans D. Statins for the prevention of perioperative cardiovascular complications in vascular surgery. J Vasc Surg 2006;44:419-424.[CrossRef][Medline]
21. Dunkelgrun M, Schouten O, Feringa HH, Vidakovic R, Poldermans D. Beneficial effects of statins on perioperative cardiovascular outcome. Curr Opin Anaesthesiol 2006;19:418-422.[Medline]
22. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low-density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 2003;326:1423-1427.[Abstract/Free Full Text]
23. Choudhry NK, Avorn J. Over-the-counter statins. Ann Intern Med 2005;142:910-913.[Abstract/Free Full Text]
24. Campeau L, Enjalbert M, Lesperance J, Vaislic C, Grondin CM, Bourassa MG. Atherosclerosis and late closure of aortocoronary saphenous vein grafts: sequential angiographic studies at 2 weeks, 1 year, 5–7 years, and 10–12 years after surgery. Circulation 1983;68:II1-II7.[Medline]
25. Barboriak JJ, Batayias GE, Pintar K, Korns ME. Pathological changes in surgically removed aortocoronary vein grafts. Ann Thorac Surg 1976;21:524-527.[Abstract]
26. van Domburg RT, Foley DP, Breeman A, van Herwerden LA, Serruys PW. Coronary artery bypass graft surgery and percutaneous transluminal coronary angioplasty. Twenty-year clinical outcome. Eur Heart J 2002;23:543-549.[Abstract/Free Full Text]
27. Campeau L, Enjalbert M, Lesperance J, Bourassa MG, Kwiterovich Jr. P, Wacholder S, Sniderman A. The relation of risk factors to the development of atherosclerosis in saphenous-vein bypass grafts and the progression of disease in the native circulation. A study 10 years after aortocoronary bypass surgery. N Engl J Med 1984;311:1329-1332.[Abstract]
28. Lie JT, Lawrie GM, Morris Jr. GC. Aortocoronary bypass saphenous vein graft atherosclerosis. Anatomic study of 99 vein grafts from normal and hyperlipoproteinemic patients up to 75 months postoperatively. Am J Cardiol 1977;40:906-914.[CrossRef][Medline]
29. Palac RT, Meadows WR, Hwang MH, Loeb HS, Pifarre R, Gunnar RM. Risk factors related to progressive narrowing in aortocoronary vein grafts studied 1 and 5 years after surgery. Circulation 1982;66:I40-I44.[Medline]
30. Neitzel GF, Barboriak JJ, Pintar K, Qureshi I. Atherosclerosis in aortocoronary bypass grafts. Morphologic study and risk factor analysis 6–12 years after surgery. Arteriosclerosis 1986;6:594-600.[Abstract]
31. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. The Post Coronary Artery Bypass Graft Trial Investigators. N Engl J Med 1997;336:153–62.
32. Knatterud GL, Rosenberg Y, Campeau L, Geller NL, Hunninghake DB, Forman SA, Forrester JS, Gobel GL, Herd JA, Hickey A, Hoogwerf BJ, Terrin ML, White C. Long-term effects of clinical outcomes of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation in the post coronary artery bypass graft trial. Post CABG Investigators. Circulation 2000;102:157-165.[Abstract/Free Full Text]
33. Merla R, Daher IN, Ye Y, Uretsky BF, Birnbaum Y. Pretreatment with statins may reduce cardiovascular morbidity and mortality after elective surgery and percutaneous coronary intervention: clinical evidence and possible underlying mechanisms. Am Heart J 2007;154:391-402.[CrossRef][Medline]
34. Werba JP, Tremoli E, Massironi P, Camera M, Cannata A, Alamanni F, Biglioli P, Parolari A. Statins in coronary bypass surgery: rationale and clinical use. Ann Thorac Surg 2003;76:2132-2140.[Abstract/Free Full Text]
35. Lazar HL. Role of statin therapy in the coronary bypass patient. Ann Thorac Surg 2004;78:730-740.[Abstract/Free Full Text]
36. Dotani MI, Morise AP, Haque R, Jain AC, Gupta N, Gibson CM. Association between short-term simvastatin therapy before coronary artery bypass grafting and postoperative myocardial blood flow as assessed by positron emission tomography. Am J Cardiol 2003;91:1107-1109.[CrossRef][Medline]
37. Chello M, Patti G, Candura D, Mastrobuoni S, Di Sciascio G, Agro F, Carassiti M, Covino E. Effects of atorvastatin on systemic inflammatory response after coronary bypass surgery. Crit Care Med 2006;34:660-667.[CrossRef][Medline]
38. Brull DJ, Sanders J, Rumley A, Lowe GD, Humphries SE, Montgomery HE. Statin therapy and the acute inflammatory response after coronary artery bypass grafting. Am J Cardiol 2001;88:431-433.[CrossRef][Medline]
39. Liakopoulos OJ, Dorge H, Schmitto JD, Nagorsnik U, Grabedunkel J, Schoendube FA. Effects of preoperative statin therapy on cytokines after cardiac surgery. Thorac Cardiovasc Surg 2006;54:250-254.[CrossRef][Medline]
40. Collard CD, Body SC, Shernan SK, Wang S, Mangano DT, Multicenter Study of Perioperative Ischemia (MCSPI) Research Group, Inc. Ischemia Research and Education Foundation (IREF) Investigators Preoperative statin therapy is associated with reduced cardiac mortality after coronary artery bypass graft surgery. J Thorac Cardiovasc Surg 2006;132:392-400.[Abstract/Free Full Text]
41. Dotani MI, Elnicki DM, Jain AC, Gibson CM. Effect of preoperative statin therapy and cardiac outcomes after coronary artery bypass grafting. Am J Cardiol 2000;86:1128-1130.[CrossRef][Medline]
42. Pan W, Pintar T, Anton J, Lee VV, Vaughn WK, Collard CD. Statins are associated with a reduced incidence of perioperative mortality after coronary artery bypass graft surgery. Circulation 2004;110:II45-II49.[Medline]
43. Pascual DA, Arribas JM, Tornel PL, Marin F, Oliver C, Ahumada M, Gomez-Plana J, Martinez P, Arcas R, Valdes M. Preoperative statin therapy and troponin T predict early complications of coronary artery surgery. Ann Thorac Surg 2006;81:78-83.[Abstract/Free Full Text]
44. Christenson JT. Preoperative lipid-control with simvastatin reduces the risk of postoperative thrombocytosis and thrombotic complications following CABG. Eur J Cardiothorac Surg 1999;15:394-399.[Abstract/Free Full Text]
45. Christenson JT, Gras PA, Grosclaude A, Simonet F, Schmuziger M. Reactive thrombocytosis following coronary artery bypass surgery: a possible link to a lipid dysfunction. J Cardiovasc Surg (Torino) 1996;37:491-498.[Medline]
46. Coleman CI, Lucek DM, Hammond J, White CM. Preoperative statins and infectious complications following cardiac surgery. Curr Med Res Opin 2007;23:1783-1790.[CrossRef][Medline]
47. Aboyans V, Labrousse L, Lacroix P, Guilloux J, Sekkal S, Le Guyader A, Cornu E, Laskar M. Predictive factors of stroke in patients undergoing coronary bypass grafting: statins are protective. Eur J Cardiothorac Surg 2006;30:300-304.[Abstract/Free Full Text]
48. Mangano CM, Diamondstone LS, Ramsay JG, Aggarwal A, Herskowitz A, Mangano DT, The Multicenter Study of Perioperative Ischemia Research Group Renal dysfunction after myocardial revascularization: risk factors, adverse outcomes, and hospital resource utilization. Ann Intern Med 1998;128:194-203.[Abstract/Free Full Text]
49. Chertow GM, Lazarus JM, Christiansen CL, Cook EF, Hammermeister KE, Grover F, Daley J. Preoperative renal risk stratification. Circulation 1997;95:878-884.[Abstract/Free Full Text]
50. Conlon PJ, Stafford-Smith M, White WD, Newman MF, King S, Winn MP, Landolfo K. Acute renal failure following cardiac surgery. Nephrol Dial Transplant 1999;14:1158-1162.[Abstract/Free Full Text]
51. Devbhandari MP, Duncan AJ, Grayson AD, Fabri BM, Keenana DJ, Bridgewater B, Jones MT, Au J. North West Quality Improvement Programme in Cardiac Interventions. Effect of risk-adjusted, non-dialysis-dependent renal dysfunction on mortality and morbidity following coronary artery bypass surgery: a multi-centre study. Eur J Cardiothorac Surg 2006;29:964-970.[Abstract/Free Full Text]
52. Tabata M, Khalpey Z, Pirundini PA, Byrne ML, Cohn LH, Rawn JD. Renoprotective effect of preoperative statins in coronary artery bypass grafting. Am J Cardiol 2007;100:442-444.[CrossRef][Medline]
53. Gurbuz AT, Zia AA, Cui H, Sasmazel A, Ates G, Aytac A. Predictors of mid-term symptom recurrence, adverse cardiac events and mortality in 591 unselected off-pump coronary artery bypass graft patients. J Card Surg 2006;21:28-34.[CrossRef][Medline]
54. Yang Z, Kozai T, van der Loo B, Viswambharan H, Lachat M, Turina MI, Malinski T, Luscher TF. HMG-CoA reductase inhibition improves endothelial cell function and inhibits smooth muscle cell proliferation in human saphenous veins. J Am Coll Cardiol 2000;36:1691-1697.[Abstract/Free Full Text]
55. Momin A, Melikian N, Wheatcroft SB, Grieve D, John LC, El Gamel A, Marrinan MT, Desai JB, Driver C, Sherwood R, Shah AM, Kearney MT. The association between saphenous vein endothelial function, systemic atherosclerosis, and statin therapy in patients undergoing coronary artery bypass surgery. J Thorac Cardiovasc Surg 2007;134:335-341.[Abstract/Free Full Text]
56. Chello M, Spadaccio C, Anselmi A, Patti G, Lusini M, Di Sciascio G, Covino E. Simvastatin reduces CD40 expression in an experimental model of early arterialization of saphenous vein graft. J Surg Res 2006;136:302-308.[CrossRef][Medline]
57. Christenson JT. Preoperative lipid control with simvastatin protects coronary artery bypass grafts from obstructive disease. Am J Cardiol 2001;88:896-899.[CrossRef][Medline]
58. Deglise S, Martin D, Probst H, Saucy F, Hayoz D, Waeber G, Nicod P, Ris HB, Corpataux JM, Haefliger JA. Increased connexin43 expression in human saphenous veins in culture is associated with intimal hyperplasia. J Vasc Surg 2005;41:1043-1052.[CrossRef][Medline]
59. Kangasniemi OP, Biancari F, Luukkonen J, Vuorisalo S, Satta J, Pokela R, Juvonen T. Preoperative C-reactive protein is predictive of long-term outcome after coronary artery bypass surgery. Eur J Cardiothorac Surg 2006;29:983-985.[Abstract/Free Full Text]
60. Palmerini T, Marzocchi A, Marrozzini C, Reggiani LB, Savini C, Marinelli G, Di Bartolomeo R, Branzi A. Preoperative C-reactive protein levels predict 9-month mortality after coronary artery bypass grafting surgery for the treatment of left main coronary artery stenosis. Eur J Cardiothorac Surg 2007;31:685-690.[Abstract/Free Full Text]
61. Field KM. Effect of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on high-sensitivity C-reactive protein levels. Pharmacotherapy 2005;25:1365-1377.[CrossRef][Medline]
62. Prasad K. C-reactive protein (CRP)-lowering agents. Cardiovasc Drug Rev 2006;24:33-50.[CrossRef][Medline]
63. Holm T, Andreassen AK, Ueland T, Kjekshus J, Froland SS, Kjekshus E, Simonsen S, Aukrust P, Gullestad L. Effect of pravastatin on plasma markers of inflammation and peripheral endothelial function in male heart transplant recipients. Am J Cardiol 2001;87:815-818.[CrossRef][Medline]
64. Marin F, Pascual DA, Roldan V, Arribas JM, Ahumada M, Tornel PL, Oliver C, Gomez-Plana J, Lip GY, Valdes M. Statins and postoperative risk of atrial fibrillation following coronary artery bypass grafting. Am J Cardiol 2006;97:55-60.[CrossRef][Medline]
65. Patti G, Chello M, Candura D, Pasceri V, D’Ambrosio A, Covino E, Di Sciascio G. 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. Circulation 2006;114:1455-1461.[Abstract/Free Full Text]
66. Mariscalco G, Lorusso R, Klersy C, Ferrarese S, Tozzi M, Vanoli D, Domenico BV, Sala A. Observational study on the beneficial effect of preoperative statins in reducing atrial fibrillation after coronary surgery. Ann Thorac Surg 2007;84:1158-1164.[Abstract/Free Full Text]
67. Shantsila E, Watson T, Lip GY. Atrial fibrillation post-cardiac surgery: changing perspectives. Curr Med Res Opin 2006;22:1437-1441.[CrossRef][Medline]
68. Basaran M, Selimoglu O, Ozcan H, Ogus H, Kafali E, Ozcelebi C, Ogus TN. Being an elderly woman: is it a risk factor for morbidity after coronary artery bypass surgery?. Eur J Cardiothorac Surg 2007;32:58-64.[Abstract/Free Full Text]
69. Dunning J, Treasure T, Versteegh M, Nashef SA. EACTS Audit and Guidelines Committee. Guidelines on the prevention and management of de novo atrial fibrillation after cardiac and thoracic surgery. Eur J Cardiothorac Surg 2006;30:852-872.[Free Full Text]
70. Madrid AH, Peng J, Zamora J, Marin I, Bernal E, Escobar C, Munos-Tinoco C, Rebollo JM, Moro C. The role of angiotensin receptor blockers and/or angiotensin converting enzyme inhibitors in the prevention of atrial fibrillation in patients with cardiovascular diseases: meta-analysis of randomized controlled clinical trials. Pacing Clin Electrophysiol 2004;27:1405-1410.[CrossRef][Medline]
71. Healey JS, Baranchuk A, Crystal E, Morillo CA, Garfinkle M, Yusuf S, Connolly SJ. Prevention of atrial fibrillation with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: a meta-analysis. J Am Coll Cardiol 2005;45:1832-1839.[Abstract/Free Full Text]
72. White CM, Kluger J, Lertsburapa K, Faheem O, Coleman CI. Effect of preoperative angiotensin converting enzyme inhibitor or angiotensin receptor blocker use on the frequency of atrial fibrillation after cardiac surgery: a cohort study from the atrial fibrillation suppression trials II and III. Eur J Cardiothorac Surg 2007;31:817-820.[Abstract/Free Full Text]
73. Knayzer B, Abramov D, Natalia B, Tovbin D, Ganiel A, Katz A. Atrial fibrillation and plasma troponin I elevation after cardiac surgery: relation to inflammation-associated parameters. J Card Surg 2007;22:117-123.[CrossRef][Medline]
74. Ishida K, Kimura F, Imamaki M, Ishida A, Shimura H, Kohno H, Sakurai M, Miyazaki M. Relation of inflammatory cytokines to atrial fibrillation after off-pump coronary artery bypass grafting. Eur J Cardiothorac Surg 2006;29:501-505.[Abstract/Free Full Text]
75. Ali IS, Buth KJ. Preoperative statin and in-hospital outcomes following heart surgery in patients with unstable angina. Eur J Cardiothorac Surg 2005;27:1051-1056.[Abstract/Free Full Text]
76. Novaro GM, Tiong IY, Pearce GL, Lauer MS, Sprecher DL, Griffin BP. Effect of hydroxylmethylglutaryl coenzyme A reductase inhibitors on the progression of calcific aortic stenosis. Circulation 2001;104:2205-2209.[Abstract/Free Full Text]
77. Aronow WS, Ahn C, Kronzon I, Goldman ME. Association of coronary risk factors and use of statins with progression of mild valvular aortic stenosis in older persons. Am J Cardiol 2001;88:693-695.[CrossRef][Medline]
78. Rosenhek R, Rader F, Loho N, Gabriel H, Heger M, Klaar U, Schemper M, Binder T, Maurer G, Baumgartner H. Statins but not angiotensin-converting enzyme inhibitors delay progression of aortic stenosis. Circulation 2001;110:1291-1295.[CrossRef]
79. Palta S, Palta AM, Gill KS, Pai RG. New insights into the progression of aortic stenosis: implications for secondary prevention. Circulation 2000;101:2497-2502.[Abstract/Free Full Text]
80. O’Brien KD, Reichenbach DD, Marcovina SM, Kuusisto J, Alpers CE, Otto CM. Apolipoproteins B, (a), and E accumulate in the morphologically early lesion of ‘degenerative’ valvular aortic stenosis. Arterioscler Thromb Vasc Biol 1996;16:523-532.[Abstract/Free Full Text]
81. Helske S, Kupari M, Lindstedt KA, Kovanen PT. Aortic valve stenosis: an active atheroinflammatory process. Curr Opin Lipidol 2007;18:483-491.[Medline]
82. Edwards JE, Moore RA. Statins in hypercholesterolemia: a dose-specific meta-analysis of lipid changes in randomised, double blind trials. BMC Fam Pract 2003;4:18.[CrossRef][Medline]
83. Curran MP, Goa KL. Lovastatin extended release: a review of its use in the management of hypercholesterolemia. Drugs 2003;63:685-699.[CrossRef][Medline]
84. Wierzbicki AS. Lipid-altering therapies and the progression of atherosclerotic disease. Cardiovasc Intervent Radiol 2007;30:155-160.[CrossRef][Medline]
85. Rosenson RS. Statins in atherosclerosis: lipid-lowering agents with antioxidant capabilities. Atherosclerosis 2004;173:1-12.[CrossRef][Medline]
86. Shavelle DM, Takasu J, Budoff MJ, Mao S, Zhao XQ, O’Brien KD. HMG CoA reductase inhibitor (statin) and aortic valve calcium. Lancet 2002;359:1125-1126.[CrossRef][Medline]
87. Pohle K, Maffert R, Ropers D, Moshage W, Stilianakis N, Daniel WG, Achenbach S. Progression of aortic valve calcification: association with coronary atherosclerosis and cardiovascular risk factors. Circulation 2001;104:1927-1932.[Abstract/Free Full Text]
88. Antonini-Canterin F, Zuppiroli A, Popescu BA, Granata G, Cervesato E, Piazza R, Pavan D, Nicolosi GL. Effect of statins on the progression of bioprosthetic aortic valve degeneration. Am J Cardiol 2003;92:479-482.
89. Antonini-Canterin F, Zuppiroli A, Baldessin F, Popescu BA, Nicolosi GL. Is there a role of statins in the prevention of aortic biological prostheses degeneration?. Cardiovasc Ultrasound 2006;4:26.[CrossRef][Medline]
90. Verma S, Szmitko PE, Fedak PW, Errett L, Latter DA, David TE. Can statin therapy alter the natural history of bicuspid aortic valves?. Am J Physiol Heart Circ Physiol 2005;288:H2547-H2549.[Free Full Text]
91. Ejiri J, Inoue N, Tsukube T, Munezane T, Hino Y, Kobayashi S, Hirata K, Kawashima S, Imajoh-Ohmi S, Hayashi Y, Yokozaki H, Okita Y, Yokoyama M. Oxidative stress in the pathogenesis of thoracic aortic aneurysm: protective role of statin and angiotensin II type 1 receptor blocker. Cardiovasc Res 2003;59:988-996.[Abstract/Free Full Text]
92. Nagashima H, Aoka Y, Sakomura Y, Sakuta A, Aomi S, Ishizuka N, Hagiwara N, Kawana M, Kasanuki H. A 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, cerivastatin, suppresses production of matrix metalloproteinase-9 in human abdominal aortic aneurysm wall. J Vasc Surg 2002;36:158-163.[CrossRef][Medline]
93. Steinmetz EF, Buckley C, Shames ML, Ennis TL, Vanvickle-Chavez SJ, Mao D, Goeddel LA, Hawkins CJ, Thompson RW. Treatment with simvastatin suppresses the development of experimental abdominal aortic aneurysms in normal and hypercholesterolemic mice. Ann Surg 2005;241:92-101.[CrossRef][Medline]
94. Tsiara S, Elisaf M, Mikhailidis DP. Early vascular benefits of statin therapy. Curr Med Res Opin 2003;19:540-556.[CrossRef][Medline]
95. Chello M, Goffredo C, Patti G, Candura D, Melfi R, Mastrobuoni S, Di Sciascio G, Covino E. Effects of atorvastatin on arterial endothelial function in coronary bypass surgery. Eur J Cardiothorac Surg 2005;28:805-810.[Abstract/Free Full Text]
96. Tjang YS, van Hees Y, Korfer R, Grobbee DE, van der Heijden GJ. Predictors of mortality after aortic valve replacement. Eur J Cardiothorac Surg 2007;32:469-474.[Abstract/Free Full Text]
97. Tonelli M. The effect of statins on preservation of kidney function in patients with coronary artery disease. Curr Opin Cardiol 2006;21:608-612.[Medline]
98. Agarwal R. Effect of statins on renal function. Am J Cardiol 2006;97:748-755.[CrossRef][Medline]
99. Kapur NK. Rosuvastatin: a highly potent statin for the prevention and management of coronary artery disease. Expert Rev Cardiovasc Ther 2007;5:161-175.[CrossRef][Medline]
100. Bittner V. Perspectives on dyslipidemia and coronary heart disease in women: an update. Curr Opin Cardiol 2006;21:602-607.[Medline]
101. Chan KL, Teo K, Tam J, Dumesnil JG. Astronomer Investigators. Rationale, design, and baseline characteristics of a randomized trial to assess the effect of cholesterol lowering on the progression of aortic stenosis: the Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER) Trial. Am Heart J 2007;153:925-931.[CrossRef][Medline]
102. Rossebo AB, Pedersen TR, Allen C, Boman K, Chambers J, Egstrup K, Gerdts E, Gohlke-Barwolf C, Holme I, Kesaniemi VA, Malbecq W, Nienaber C, Ray S, Skjaerpe T, Wachtell K, Willenheimer R. Design and baseline characteristics of the simvastatin and ezetimibe in aortic stenosis (SEAS) study. Am J Cardiol 2007;99:970-973.[CrossRef][Medline]
103. Mehra MR. Contemporary concepts in prevention and treatment of cardiac allograft vasculopathy. Am J Transplant 2006;6:1248-1256.[CrossRef][Medline]
104. Rahmani M, Cruz RP, Granville DJ, McManus BM. Allograft vasculopathy versus atherosclerosis. Circ Res 2006;99:801-815.[Abstract/Free Full Text]
105. Tan CD, Baldwin 3rd WM, Rodriguez ER. Update on cardiac transplantation pathology. Arch Pathol Lab Med 2007;131:1169-1191.[Medline]
106. Kass M, Haddad H. Cardiac allograft vasculopathy: pathology, prevention and treatment. Curr Opin Cardiol 2006;21:132-137.[Medline]
107. Kobashigawa JA. Statins and cardiac allograft vasculopathy after heart transplantation. Sem Vasc Med 2004;4:401-406.[CrossRef]
108. Segovia J, Gomez-Bueno M, Alonso-Pulpon L. Treatment of allograft vasculopathy in heart transplantation. Expert Opin Pharmacother 2006;7:2369-2383.[CrossRef][Medline]
109. Cutts JL, Scallen TJ, Watson J, Bankhurst AD. Role of mevalonic acid in the regulation of natural killer cell cytotoxicity. J Cell Physiol 1989;139:550-557.[CrossRef][Medline]
110. Cutts JL, Bankhurst AD. Reversal of lovastatin-mediated inhibition of natural killer cell cytotoxicity by interleukin 2. J Cell Physiol 1990;145:244-252.[CrossRef][Medline]
111. Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med 2000;6:1399-1402.[CrossRef][Medline]
112. Meiser BM, Wenke K, Thiery J, Wolf S, Devens C, Seidel D, Hammer C, Billingham ME, Reichart B. Simvastatin decreases accelerated graft vessel disease after heart transplantation in an animal model. Transplant Proc 1993;25:2077-2079.[Medline]
113. Ogawa N, Koyama I, Shibata T, Watanabe T, Akimoto N, Taguchi Y, Shinozuka N, Omoto R. Pravastatin prevents the progression of accelerated coronary artery disease after heart transplantation in a rabbit model. Transplant Int 1996;9:S226-S229.[Medline]
114. Kobashigawa JA, Katznelson S, Laks H, Johnson JA, Yeatman L, Wang XM, Chia D, Terasaki PI, Sabad A, Cogert GA, Trosian K, Hamilton MA, Moriguchi JD, Kawata N, Hage A, Drinkwater DC, Stevenson LW. Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med 1995;333:621-627.[Abstract/Free Full Text]
115. Kobashigawa JA. Statins and solid organ transplantation: is there an immunosuppressive effect?. Am J Transplant 2004;4:1013-1018.[CrossRef][Medline]
116. Yin R, Zhu J, Shao H, Cheng X, Feng X, Li Z, Jing H. Inhibition of chemokine receptor CCR2 and CCR5 expression contributes to simvastatin-induced attenuation of cardiac allograft vasculopathy. J Heart Lung Transplant 2007;26:485-493.[CrossRef][Medline]
117. Palinski W, Tsimikas S. Immunomodulatory effects of statins: mechanisms and potential impact on arteriosclerosis. J Am Soc Nephrol 2002;13:1673-1681.[Abstract/Free Full Text]
118. Shimizu K, Aikawa M, Takayama K, Libby P, Mitchell RN. Direct anti-inflammatory mechanisms contribute to attenuation of experimental allograft arteriosclerosis by statins. Circulation 2003;108:2113-2120.[Abstract/Free Full Text]
119. Horimoto H, Nakai Y, Nakahara K, Nomura Y, Mieno S, Sasaki S. HMG-CoA reductase inhibitor cerivastatin prolonged rat cardiac allograft survival by blocking intercellular signals. J Heart Lung Transplant 2002;21:440-445.[CrossRef][Medline]
120. Kwak B, Mulhaupt F, Veillard N, Pelli G, Mach F. The HMG-CoA reductase inhibitor simvastatin inhibits IFN-gamma induced MHC class II expression in human vascular endothelial cells. Swiss Med Wkly 2001;131:41-46.[Medline]
121. Hognestad A, Endresen K, Wergeland R, Stokke O, Geiran O, Holm T, Simonsen S, Kjekshus JK, Andreassen AK. Plasma C-reactive protein as a marker of cardiac allograft vasculopathy in heart transplant recipients. J Am Coll Cardiol 2003;42:477-482.[Abstract/Free Full Text]
122. Ventura HO, Mehra MR. C-reactive protein and cardiac allograft vasculopathy: is inflammation the critical link?. J Am Coll Cardiol 2003;42:483-485.[Free Full Text]
123. Eisenberg MS, Chen HJ, Warshofsky MK, Sciacca RR, Wasserman HS, Schwartz A, Rabbani LE. Elevated levels of plasma C-reactive protein are associated with decreased graft survival in cardiac transplant recipients. Circulation 2000;102:2100-2104.[Abstract/Free Full Text]
124. Weis M, Pehlivanli S, Meiser BM, von Scheidt W. Simvastatin treatment is associated with improvement in coronary endothelial function and decreased cytokine activation in patients after heart transplantation. J Am Coll Cardiol 2001;38:814-818.[Abstract/Free Full Text]
125. Wallace CK, Stetson SJ, Kucuker SA, Becker KA, Farmer JA, McRee SC, Koerner MM, Noon GP, Torre-Amione G. Simvastatin decreases myocardial tumor necrosis factor alpha content in heart transplant recipients. J Heart Lung Transplant 2005;24:46-51.[CrossRef][Medline]
126. Holschermann H, Hilgendorff A, Kemkes-Matthes B, Schonburg M, Bauer EP, Tillmanns H, Haberbosch W. Simvastatin attenuates vascular hypercoagulability in cardiac transplant patients. Transplantation 2000;69:1830-1836.[CrossRef][Medline]
127. Jenkins GH, Grieve LA, Yacoub MH, Singer DR. Effect of simvastatin on ejection fraction in cardiac transplant recipients. Am J Cardiol 1996;78:1453-1456.[CrossRef][Medline]
128. Lubitz SA, Pinney S, Wisnivesky JP, Gass A, Baran DA. Statin therapy associated with a reduced risk of chronic renal failure after cardiac transplantation. J Heart Lung Transplant 2007;26:264-272.[CrossRef][Medline]
129. Aharinejad S, Krenn K, Zuckermann A, Schafer R, Paulus P, Seebacher G, Wolner E, Grimm M. Matrix metalloproteinases and their tissue inhibitor in cardiac transplantation. Eur J Cardiothorac Surg 2007;32:48-51.[Abstract/Free Full Text]
130. Suzuki J, Isobe M, Kawauchi M, Endoh M, Amano J, Takamoto S. Altered expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in acutely rejected myocardium and coronary arteriosclerosis in cardiac allografts of nonhuman primates. Transplant Int 2000;13:106-113.[CrossRef][Medline]
131. Campbell LG, Ramachandran S, Liu W, Shipley JM, Itohara S, Rogers JG, Moazami N, Senior RM, Jaramillo A. Different roles for matrix metalloproteinase-2 and matrix metalloproteinase-9 in the pathogenesis of cardiac allograft rejection. Am J Transplant 2005;5:517-528.[CrossRef][Medline]
132. Hariya A, Takazawa K, Yamamoto T, Amano A. ONO-4817, a novel matrix metalloproteinase inhibitor, attenuates allograft vasculopathy in a rat cardiac transplant. J Heart Lung Transplant 2004;23:1163-1169.[CrossRef][Medline]
133. Nomura S, Yoshimura K, Akiyama N, Mikamo A, Furutani A, Aoki H, Matsuzaki M, Hamano K. HMG-CoA reductase inhibitors reduce matrix metalloproteinase-9 activity in human varicose veins. Eur Surg Res 2005;37:370-378.[CrossRef][Medline]
134. Turner NA, Aley PK, Hall KT, Warburton P, Galloway S, Midgley L, O’Regan DJ, Wood IC, Ball SG, Porter KE. Simvastatin inhibits TNF-alpha-induced invasion of human cardiac myofibroblasts via both MMP-9-dependent and -independent mechanisms. J Mol Cell Cardiol 2007;43:168-176.[CrossRef][Medline]
135. Furman C, Copin C, Kandoussi M, Davidson R, Moreau M, McTaggiart F, Chapman MJ, Fruchart JC, Rouis M. Rosuvastatin reduces MMP-7 secretion by human monocyte-derived macrophages: potential relevance to atherosclerotic plaque stability. Atherosclerosis 2004;174:93-98.[CrossRef][Medline]
136. Grauhan O, Siniawski H, Dandel M, Lehmkuhl H, Knosalla C, Pasic M, Weng YG, Hetzer R. Coronary atherosclerosis of the donor heart – impact on early graft failure. Eur J Cardiothorac Surg 2007;32:634-638.[Abstract/Free Full Text]
137. Nissen SE, Nicholls SJ, Sipahi I, Libby P, Raichlen JS, Ballantyne CM, Davignon J, Erbel R, Fruchart JC, Tardif JC, Schoenhagen P, Crowe T, Cain V, Wolski K, Goormastic M, Tuzcu EM, ASTEROID Investigators Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006;295:1556-1565.[Abstract/Free Full Text]
138. Sipahi I, Nicholls SJ, Tuzcu EM, Nissen SE. Coronary atherosclerosis can regress with very intensive statin therapy. Cleve Clin J Med 2006;73:937-944.[Abstract/Free Full Text]
139. Shirakawa I, Sata M, Saiura A, Kaneda Y, Yashiro H, Hirata Y, Makuuchi M, Nagai R. Atorvastatin attenuates transplant-associated coronary arteriosclerosis in a murine model of cardiac transplantation. Biomed Pharmacother 2007;61:154-159.[CrossRef][Medline]
140. Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W, Krobot K, Steinbeck G, Seidel D, Reichart B. Simvastatin initiated early after heart transplantation: 8-year prospective experience. Circulation 2003;107:93-97.[Abstract/Free Full Text]
141. Mehra MR, Uber PA, Vivekananthan K, Solis S, Scott RL, Park MH, Milani RV, Lavie CJ. Comparative beneficial effects of simvastatin and pravastatin on cardiac allograft rejection and survival. J Am Coll Cardiol 2002;40:1609-1614.[Abstract/Free Full Text]
142. Mehra MR, Raval NY. Metaanalysis of statins and survival in de novo cardiac transplantation. Transplant Proc 2004;36:1539-1541.[CrossRef][Medline]
143. Kobashigawa JA, Moriguchi JD, Laks H, Wener L, Hage A, Hamilton MA, Cogert G, Marquez A, Vassilakis ME, Patel J, Yeatman L. Ten-year follow-up of a randomized trial of pravastatin in heart transplant patients. J Heart Lung Transplant 2005;24:1736-1740.[CrossRef][Medline]
144. Wenke K, Meiser B, Thiery J, Reichart B. Impact of simvastatin therapy after heart transplantation: an 11-year prospective evaluation. Herz 2005;30:431-432.[CrossRef][Medline]
145. Krobot KJ, Wenke K, Reichart B. Simvastatin after orthotopic heart transplantation. Costs and consequences. Pharmacoeconomics 1999;15:279-289.[CrossRef][Medline]
146. Gazi IF, Liberopoulos EN, Athyros VG, Mikhailidis DP. Statins and solid organ transplantation. Curr Pharm Des 2006;12:4771-4783.[CrossRef][Medline]
147. Ross H, Hendry P, Dipchand A, Giannetti N, Hirsch G, Isaac D, Singh N, West L, White M, Ignaszewski A, Chung AM, Straatman L, Modry D, Tymchak W, Burton J, Warnica W, Azevedo JE, Kostuk W, Menkis A, Pflugfelder P, Quantz M, Davies R, Haddad H, Masters R, Cusimano R, Delgado D, Feindel C, Rao V, Cantarovich M, Cecere R, Carrier M, Pellerin M, Doyle D, LeBlanc MH, Howlett J. 2001 Canadian Cardiovascular Society Consensus Conference on cardiac transplantation. Can J Cardiol 2003;19:620-654.[Medline]
148. Aranda Jr. JM, Hill J. Cardiac transplant vasculopathy. Chest 2000;118:1792-1800.[CrossRef][Medline]
149. Eich D, Thompson JA, Ko DJ, Hastillo A, Lower R, Katz S, Katz M, Hess ML. Hypercholesterolemia in long-term survivors of heart transplantation: an early marker of accelerated coronary artery disease. J Heart Lung Transplant 1991;101:45-49.
150. Sharples LD, Caine N, Mullins P, Scott JP, Solis E, English TA, Large SR, Schofield PM, Wallwork J. Risk factor analysis for the major hazards following heart transplantation – rejection, infection, and coronary occlusive disease. Transplantation 1991;52:244-252.[Medline]
151. Chin C, Gamberg P, Miller J, Luikart H, Bernstein D. Efficacy and safety of atorvastatin after pediatric heart transplantation. J Heart Lung Transplant 2002;21:1213-1217.[CrossRef][Medline]
152. Penson MG, Fricker FJ, Thompson JR, Harker K, Williams BJ, Kahler DA, Schowengerdt KO. Safety and efficacy of pravastatin therapy for the prevention of hyperlipidemia in pediatric and adolescent cardiac transplant recipients. J Heart Lung Transplant 2001;20:611-618.[CrossRef][Medline]
153. Mahle WT, Vincent RN, Berg AM, Kanter KR. Pravastatin therapy is associated with reduction in coronary allograft vasculopathy in pediatric heart transplantation. J Heart Lung Transplant 2005;24:63-66.[CrossRef][Medline]
154. Seipelt IM, Crawford SE, Rodgers S, Backer C, Mavroudis C, Seipelt RG, Pahl E. Hypercholesterolemia is common after pediatric heart transplantation: initial experience with pravastatin. J Heart Lung Transplant 2004;23:317-322.[CrossRef][Medline]
155. de Denus S, Al-Jazairi A, Loh E, Jessup M, Stanek EJ, Spinler SA. Dyslipidemias and HMG-CoA reductase inhibitor prescription in heart transplant recipients. Ann Pharmacother 2004;38:1136-1141.[Abstract/Free Full Text]
156. Kato T, Tokoro T, Namii Y, Kobayashi T, Hayashi S, Yokoyama I, Morimoto S, Chan M, Giannetti N, Hunt SA. Early introduction of HMG-CoA reductase inhibitors could prevent the incidence of transplant coronary artery disease. Transplant Proc 2000;32:331-333.[CrossRef][Medline]
157. O’Rourke B, Barbir M, Mitchell AG, Yacoub MH, Banner NR. Efficacy and safety of fluvastatin therapy for hypercholesterolemia after heart transplantation: results of a randomised double blind placebo controlled study. Int J Cardiol 2004;94:235-240.[CrossRef][Medline]
158. See Jr. VY, DeNofrio D, Goldberg L, Chang G, Sasseen B, Kolansky DM, Pickering F, Kao A, Loh E, Wilensky RL. Effect of atorvastatin on postcardiac transplant increase in low-density lipoprotein cholesterol reduces development of intimal hyperplasia and progression of endothelial dysfunction. Am J Cardiol 2003;92:11-15.[CrossRef][Medline]
159. Wu AH, Ballantyne CM, Short BC, Torre-Amione G, Young JB, Ventura HO, Eisen HJ, Radovancevic B, Rayburn BK, Lake KD, Yancy Jr. CW, Taylor DO, Mehra MR, Kubo SH, Fishbein DP, Zhao XQ, O’Brien KD. Statin use and risks of death or fatal rejection in the Heart Transplant Lipid Registry. Am J Cardiol 2005;95:367-372.[CrossRef][Medline]
160. Lubitz SA, Baran DA, Alwarshetty MM, Zucker MJ, Arroyo LH, Chan M, Courtney MC, Correa R, Spielvogel D, Lansman SL, Gass AL. Improved survival with statins, angiotensin receptor blockers, and steroid weaning after heart transplantation. Transplant Proc 2006;38:1501-1506.[CrossRef][Medline]
161. Patel DN, Pagani FD, Koelling TM, Dyke DB, Baliga RR, Cody RJ, Lake KD, Aaronson KD. Safety and efficacy of atorvastatin in heart transplant recipients. J Heart Lung Transplant 2002;21:204-210.[CrossRef][Medline]
162. Marzoa-Rivas R, Crespo-Leiro MG, Paniagua-Marin MJ, Llinares-Garcia D, Muniz-Garcia J, Aldama-Lopez G, Pinon-Esteban P, Campo-Perez R, Castro-Beiras A. Safety of statins when response is carefully monitored: a study of 336 heart recipients. Transplant Proc 2005;37:4071-4073.[CrossRef][Medline]
163. Grigioni F, Carigi S, Potena L, Fabbri F, Russo A, Musuraca AC, Coccolo F, Magnani G, Ortolani P, Leone O, Asperella G, Magelli C, Branzi A. Long-term safety and effectiveness of statins for heart transplant recipients in routine clinical practice. Transplant Proc 2006;38:1507-1510.[CrossRef][Medline]
164. Simeoni E, Dudler J, Fleury S, Li J, Pagnotta M, Pascual M, von Segesser LK, Vassalli G. Gene transfer of a soluble IL-1 type 2 receptor-Ig fusion protein improves cardiac allograft survival in rats. Eur J Cardiothorac Surg 2007;32:90-95.[Abstract/Free Full Text]
165. Li Y, Koster T, Morike C, v Horsten S, Martin U, Bader M, Haverich A, Simon AR. Pravastatin prolongs graft survival in an allogeneic rat model of orthotopic single lung transplantation. Eur J Cardiothorac Surg 2006;30:515-524.[Abstract/Free Full Text]
166. Johnson BA, Iacono AT, Zeevi A, McCurry KR, Duncan SR. Statin use is associated with improved function and survival of lung allografts. Am J Respir Crit Care Med 2003;167:1271-1278.[Abstract/Free Full Text]
167. van de Visse EP, van der Heijden M, Verheij J, van Nieuw Amerongen GP, van Hinsbergh VW, Girbes AR, Groeneveld AB. Effect of prior statin therapy on capillary permeability in the lungs after cardiac or vascular surgery. Eur Respir J 2006;27:1026-1032.[Abstract/Free Full Text]
168. Meyers BF, Lynch J, Trulock EP, Guthrie TJ, Cooper JD, Patterson GA. Lung transplantation: a decade of experience. Ann Surg 1999;230:362-370.[CrossRef][Medline]
169. Giroux LM, Davignon J, Naruszewicz M. Simvastatin inhibits the oxidation of low-density lipoproteins by activated human monocyte-derived macrophages. Biochim Biophys Acta 1993;1165:335-338.[Medline]
170. Wagner AH, Kohler T, Ruckschloss U, Just I, Hecker M. Improvement of nitric oxide-dependent vasodilatation by HMG-CoA reductase inhibitors through attenuation of endothelial superoxide anion formation. Arterioscler Thromb Vasc Biol 2000;20:61-69.[Abstract/Free Full Text]
171. Naidu BV, Woolley SM, Farivar AS, Thomas R, Fraga C, Mulligan MS. Simvastatin ameliorates injury in an experimental model of lung ischemia–reperfusion. J Thorac Cardiovasc Surg 2003;126:482-489.[Abstract/Free Full Text]
172. Siwik DA, Pagano PJ, Colucci WS. Oxidative stress regulates collagen synthesis and matrix metalloproteinase activity in cardiac fibroblasts. Am J Physiol Cell Physiol 2001;280:C53-C60.[Abstract/Free Full Text]
173. Freestone T, Turner RJ, Coady A, Higman DJ, Greenhalgh RM, Powell JT. Inflammation and metalloproteinases in the enlarging abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol 1995;15:1145-1151.[Abstract/Free Full Text]
174. Knox JB, Sukhova GK, Whittemore AD, Libby P. Evidence for altered balance between matrix metalloproteinases and their inhibitors in human aortic diseases. Circulation 1997;95:205-212.[Abstract/Free Full Text]
175. Herron GS, Unemori E, Wong M, Rapp JH, Hibbs MH, Stoney RJ. Connective tissue proteinases and inhibitors in abdominal aortic aneurysms. Involvement of the vasa vasorum in the pathogenesis of aortic aneurysms. Arterioscler Thromb 1991;11:1667-1677.[Abstract/Free Full Text]
176. Shah PK. Inflammation, metalloproteinases, and increased proteolysis: an emerging pathophysiologal paradigm in aortic aneurysm. Circulation 1997;96:2115-2117.[Free Full Text]
177. Paraskevas KI, Liapis CD, Hamilton G, Mikhailidis DP. Are statins an option in the management of abdominal aortic aneurysms? Vasc Endovascular Surg, in press.
178. Kalyanasundaram A, Elmore JR, Manazer JR, Golden A, Franklin DP, Galt SW, Zakhary EM, Carey DJ. Simvastatin suppresses experimental aortic aneurysm expansion. J Vasc Surg 2006;43:117-124.[CrossRef][Medline]
179. Sukhija R, Aronow WS, Sandhu R, Kakar P, Babu S. Mortality and size of abdominal aortic aneurysm at long-term follow-up of patients not treated surgically and treated with or without statins. Am J Cardiol 2006;97:279-280.[CrossRef][Medline]
180. Schouten O, van Laanen JH, Boersma E, Vidakovic R, Feringa HH, Dunkelgrun M, Bax JJ, Koning J, van Urk H, Poldermans D. Statins are associated with a reduced infrarenal abdominal aortic aneurysm growth. Eur J Vasc Endovasc Surg 2006;32:21-26.[CrossRef][Medline]
181. Kertai MD, Boersma E, Westerhout CM, van Domburg R, Klein J, Bax JJ, van Urk H, Poldermans D. Association between long-term statin use and mortality after successful abdominal aortic aneurysm surgery. Am J Med 2004;116:96-103.[CrossRef][Medline]
182. O’Neil-Callahan K, Katsimaglis G, Tepper MR, Ryan J, Mosby C, Ioannidis JP, Danias PG. Statins decrease perioperative complications in patients undergoing noncardiac vascular surgery: the Statins for Risk Reduction in Surgery (StaRRS) study. J Am Coll Cardiol 2005;45:336-342.[Abstract/Free Full Text]
183. Durazzo AE, Machado FS, Ikeoka DT, De Bernoche C, Monachini MC, Puech-Leao P, Caramelli B. Reduction in cardiovascular events after vascular surgery with atorvastatin: a randomized trial. J Vasc Surg 2004;39:967-975.[CrossRef][Medline]
184. Paraskevas KI, Liapis CD, Hamilton G, Mikhailidis DP. Can statins reduce perioperative morbidity and mortality in patients undergoing non-cardiac vascular surgery?. Eur J Vasc Endovasc Surg 2006;32:286-293.[CrossRef][Medline]
185. Amar D. Perioperative atrial tachyarrhythmias. Anesthesiology 2002;97:1618-1623.[CrossRef][Medline]
186. Amar D, Zhang H, Heerdt PM, Park B, Fleisher M, Thaler HT. Statin use is associated with a reduction in atrial fibrillation after non-cardiac thoracic surgery independent of C-reactive protein. Chest 2005;128:3421-3427.[CrossRef][Medline]
187. Misthos P, Katsaragakis S, Theodorou D, Milingos N, Skottis I. The degree of oxidative stress after lung resection: a prospective study. Eur J Cardiothorac Surg 2006;29:591-595.[Abstract/Free Full Text]
188. Hamilton CA, Miller WH, Al-Benna S, Brosnan MJ, Drummond RD, McBride MW, Dominiczak AF. Strategies to reduce oxidative stress in cardiovascular disease. Clin Sci (Lond) 2004;106:219-234.[Medline]
189. Davignon J, Jacob RF, Mason RP. The antioxidant effects of statins. Coron Artery Dis 2004;15:251-258.[CrossRef][Medline]
190. Lahera V, Goicoechea M, de Vinuesa SG, Miana M, de las Heras N, Cachofeiro V, Luno J. Endothelial dysfunction, oxidative stress and inflammation in atherosclerosis: beneficial effects of statins. Curr Med Chem 2007;14:243-248.[CrossRef][Medline]
191. Wassmann S, Nickenig G. Interrelationship of free oxygen radicals and endothelial dysfunction – modulation by statins. Endothelium 2003;10:23-33.[CrossRef][Medline]
192. Fonarow GC, French WJ, Parsons LS, Sun H, Malmgren JA. Use of lipid-lowering medications at discharge in patients with acute myocardial infarction: data from the National Registry of Myocardial Infarction 3. Circulation 2001;103:38-44.[Abstract/Free Full Text]
193. Yan AT, Yan RT, Tan M, Hackam DG, Leblanc KL, Kertland H, Tsang JL, Jaffer S, Kates ML, Leiter LA, Fitchett DH, Langer A, Goodman SG. Vascular protection (VP) and guidelines oriented approach to lipid-lowering (GOALL) Registries Investigators. Contemporary management of dyslipidemia in high-risk patients: targets still not met. Am J Med 2006;119:676-683.[CrossRef][Medline]
194. Kinikini D, Sarfati MR, Mueller MT, Kraiss LW. American Heart Association; American College of Cardiology. Meeting AHA/ACC secondary prevention goals in a vascular surgery practice: an opportunity we cannot afford to miss. J Vasc Surg 2006;43:781-787.[CrossRef][Medline]
195. Baessler A, Fischer M, Huf V, Mell S, Hengstenberg C, Mayer B, Holmer S, Riegger G, Schunkert H. Failure to achieve recommended LDL cholesterol levels by suboptimal statin therapy relates to elevated cardiac event rates. Int J Cardiol 2005;101:293-298.[CrossRef][Medline]
196. Brown LC, Johnson JA, Majumdar SR, Tsuyuki RT, McAlister FA. Evidence of suboptimal management of cardiovascular risk in patients with type 2 diabetes mellitus and symptomatic atherosclerosis. CMAJ 2004;171:1189-1192.[Abstract/Free Full Text]
197. Lloyd GM, Newton JD, Norwood MG, Franks SC, Bown MJ, Sayers RD. Patients with abdominal aortic aneurysm: are we missing the opportunity for cardiovascular risk reduction?. J Vasc Surg 2004;40:691-697.[CrossRef][Medline]
198. Austin PC, Mamdani MM, Juurlink DN, Alter DA, Tu JV. Missed opportunities in the secondary prevention of myocardial infarction: an assessment of the effects of statin underprescribing on mortality. Am Heart J 2006;151:969-975.[CrossRef][Medline]
199. Anderson RE, Brismar K, Ivert T. Only a minority of patients referred for elective coronary artery bypass surgery has risk factors diagnosed and treated according to established guidelines. Diab Vasc Dis Res 2007;4:112-116.[Abstract/Free Full Text]
200. Khanderia U, Faulkner TV, Townsend KA, Streetman DS. Lipid-lowering treatment at hospital discharge after coronary artery bypass grafting. Am J Health Syst Pharm 2002;59:548-551.[Free Full Text]
201. Northridge DB, Shandall A, Rees A, Buchalter MB. Inadequate management of hyperlipidemia after coronary bypass surgery shown by medical audit. Br Heart J 1994;72:466-467.[Abstract/Free Full Text]
202. Khanderia U, Townsend KA, Eagle K, Prager R. Statin initiation following coronary artery bypass grafting: outcome of a hospital discharge protocol. Chest 2005;127:455-463.[CrossRef][Medline]
203. Igel M, Sudhop T, von Bergmann K. Metabolism and drug interactions of 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors (statins). Eur J Clin Pharmacol 2001;57:357-364.[CrossRef][Medline]
204. Lazar HL. Should all patients receive statins before cardiac surgery? Are more data necessary?. J Thorac Cardiovasc Surg 2006;131:520-522.[Free Full Text]
205. Flaker GC, Warnicka JW, Sacks FM, Moye LA, Davis BR, Rouleau JL, Webel RR, Pfeffer MA, Braunwald E. Pravastatin prevents clinical events in revascularized patients with average cholesterol concentrations. Cholesterol and Recurrent Events CARE Investigators. J Am Coll Cardiol 1999;34:106-112.[Abstract/Free Full Text]
206. Clark LL, Ikonomidis JS, Crawford Jr. FA, Crumbley 3rd A, Kratz JM, Stroud MR, Woolson RF, Bruce JJ, Nicholas JS, Lackland DT, Zile MR, Spinale FG. Preoperative statin treatment is associated with reduced postoperative mortality and morbidity in patients undergoing cardiac surgery: an 8-year retrospective cohort study. J Thorac Cardiovasc Surg 2006;131:679-685.[Abstract/Free Full Text]
207. Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W, Steinbeck G, Seidel D, Reichart B. Simvastatin reduces graft vessel disease and mortality after heart transplantation: a four-year randomized trial. Circulation 1997;96:1398-1402.[Abstract/Free Full Text]
208. Stojanovic I, Vrtovec B, Radovancevic B, Radovancevic R, Yazdanbakhsh AP, Thomas CD, Frazier OH. Survival, graft atherosclerosis, and rejection incidence in heart transplant recipients treated with statins: 5-year follow-up. J Heart Lung Transplant 2005;24:1235-1238.[CrossRef][Medline]

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