Abstract
3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statins) is one of the most commonly prescribed agents for controlling hyperlipidemia. Apart from their lipid-lowering property, statins are well known for their pleiotropic effects, such as improvement of vascular endothelial dysfunction, attenuation of inflammatory responses, stabilization of atherosclerotic plaques, inhibition of vascular smooth muscle proliferation, and modulation of procoagulant activity and platelet function. The vasculoprotective effect of statins is mainly mediated by inhibition of the mevalonate pathway and oxidized low-density lipoprotein generation, thereby enhancing the biosynthesis of endothelium-derived nitric oxide. Accumulating clinical evidence strongly suggests that administration of statins reduces overall mortality, the development myocardial infarction and atrial fibrillation, and length of hospital stay after a major cardiac/noncardiac surgery. This review updates the clinical pharmacology and therapeutic applications of statins during major operations, and highlights the anesthesia considerations for perioperative statin therapy.
Keywords
endothelium; hydroxymethylglutaryl-CoA reductase inhibitors; mevalonic acid: mevalonate; nitric oxide; terpenes: isoprenoids;
1. Introduction
The biosynthesis of cholesterol mainly occurs in the liver and intestine by condensation of acetyl-CoA and acetoacetyl-CoA in the cytoplasm and endoplasmic reticulum. The formation of the precursor compound, hydroxymethylglutaryl-coenzyme A (HMG-CoA), is catalyzed by HMG-CoA reductase to form mevalonate (Fig. 1).1, 2 Following a series of catalyzing reactions, mevalonate is converted into isoprenoid derivatives to finally yield squalene and cholesterol. In this process, HMG-CoA reductase is the rate-limiting enzyme, and therefore, a number of drugs were developed by inhibiting the action of HMG-CoA reductase in order to reduce the generation of cholesterol.2 Statins are the pharmaceutical agents that can competitively inhibit the enzymatic activity of HMG-CoA reductase and thus effectively reduce the blood levels of cholesterol (Fig. 1).3 Table 1 lists the HMG-CoA reductase inhibitors (statins) that are currently available in Taiwan. Hypercholesterolemia is a major risk factor for the development of cardiovascular diseases, coronary artery disease, and stroke secondary to the prothrombotic and atherosclerotic effects. On average, administrations of statins reduce serum concentrations of total cholesterol and low-density lipoprotein cholesterol (LDL-C) by 17–35% and 24–49%, respectively.4Furthermore, levels of triglyceride are reduced by 13% and high-density lipoprotein are increased by 5% following treatment with statins.5 Instead of discussing the well-known lipid-lowering effect of statins, this brief review focuses mainly on the pleiotropic vascular protection and their applications in perioperative medicine.
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2. Mevalonate pathway and endothelial function
The synthesis of cholesterol generates mevalonate and other intermediate compounds, such as isopentenyl pyrophosphates (Fig. 1). In cultured endothelial cells, the upregulation of endothelial nitric oxide synthase (eNOS) and biosynthesis of NO following incubation with HMG-CoA inhibitors were completely reversed in the presence of L-mevalonate,6, 7, 8 probably by inhibition of the Akt-mediated eNOS phosphorylation.9 The formation of isoprenoid derivatives (or the so-called isoprenes), particularly geranylgeranyl pyrophosphate (GGPP), prenylates the activity of Rho guanosine triphosphatase (GTPase) and activates the small GTP-binding protein Rho by post-translational modification (Fig. 1).10 Geranylgeranylation of Rho proteins destabilizes the transcription of eNOS and inhibits its activation.10 Activation of Rho A/Rho kinase pathway downregulates eNOS expression and enzymatic activity on the vascular endothelium (Figs. 1 and 2).
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3. Oxidized LDL-C and endothelial function
Arterial expression of oxidized LDL receptor (LOX-1) is upregulated by enhanced angiotensin II, endothelin, cytokines, and nonuniform shear stress in patients with hypertension, dyslipidemia, and diabetes mellitus.11 LDL-C is oxidized by the overproduction of superoxide anions in these highly oxidized states and is internalized by the activation of LOX-1 on the membrane of endothelial cells (Fig. 2).12 Oxidized LDL dephosphorylates Akt impairing the enzymatic activity of eNOS and inhibiting the migration of endothelial cells.13Other previous studies also demonstrated that oxidized LDL displaces eNOS protein with caveolae14 and Hsp90.15 The enzymatic activity is reduced in the uncoupled eNOS, and it generates more superoxide anions rather than NO.15By contrast, oxidized LDL activates the renin–angiotensin system through LOX-1, and accelerates atherogenesis and endothelial dysfunction.16, 17Oxidation of LDL-C also stimulates the expression of preproendothelin messenger RNA (mRNA) in the endothelial cells, leading to a time- and concentration-dependent release of the endothelin.18 Increase of endothelin causes arterial vasospasm, promotes vascular smooth muscle proliferation and progression of atherosclerosis.18, 19
4. Pleiotropic effect of statins on vascular function
Competitive inhibition of HMG-CoA reductase by administration of statins effectively reduced the production of mevalonate and isoprenoids. Treatment with cerivastatin and rosuvastatin significantly enhanced NO bioavailability and upregulated eNOS expression in cultured endothelial cells by blocking mevalonate and isoprenoid synthesis.20, 21 Administration of statins inhibited the formation of superoxide anions by preventing the isoprenylation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and thus improved vascular endothelial function in isolated rat aorta.22 In diabetic animals, atorvastatin promoted vascular endothelial function by inhibiting the action of Rac-1, and this protective effect was significantly abolished by the addition of GGPP, indicating that the reduction in isoprenoid formation is an important molecular mechanism responsible for the vascular antioxidant effect of atorvastatin in patients with diabetes mellitus.23 Nishimatsu et al24 demonstrated that fluvastatin potentiated the endothelium-dependent relaxation response in obese Zucker rats by restoring eNOS expression, enhancing Akt phosphorylation, and inhibiting Rho kinase activity in the arterial system.
In addition to reducing serum levels of LDL-C, sustained evidence supports the direct effect of statins in the suppression of LOX-1 expression25, 26 and LDL-mediated oxidative stress27, 28, 29 in the cardiovascular system of animals and humans. We have recently reported that prolonged administration of rosuvastatin suppressed the expression of NADPH oxidase, reduced superoxide generation, attenuated proinflammatory reactions, and thereby enhanced blood flow in the arteriovenous fistula of rats with streptozotocin-induced diabetes.30, 31 Furthermore, simvastatin relaxed the tonic contraction response induced by endothelin-1 in a concentration-dependent manner and inhibited the endothelin-1-mediated DNA synthesis of Rho proteins.32
Statin therapy increases mobilization and differentiation of bone marrow-derived endothelial progenitor cells through the PI3K/Akt pathway.33 In our laboratory, we also found that treatment with rosuvastatin increased the number of circulating endothelial progenitor cells and improved vascular endothelial function in diabetic rats.30 Augmentation in the numbers and function of endothelial progenitor cells provides therapeutic and preventive beneficial effects in a wide range of cardiovascular diseases.34
Collectively, statins may improve cardiovascular outcomes of patients with normal plasma cholesterol level, suggesting that the pleiotropic vascular protective effect of statins is independent from their lipid-lowering property. The improvement in cardiovascular outcomes is well correlated with improved endothelial function by upregulating eNOS expression and NO bioavailability following treatment with statins. At subcellular levels, statins stabilize the eNOS mRNA, enhance eNOS enzymatic activity through the PI3K/Akt signaling pathway, reduce inflammatory responses in the vasculature, inhibit Rho isoprenylation, and suppress oxidized LDL-induced endothelin-1 expression (Figs. 1 and 2). Readers are referred to several precise review articles for more detailed mechanistic discussion on the pleiotropic vascular protective effect of statins.35, 36
5. Cardiovascular outcomes of perioperative statin use
5.1. Outcomes in cardiac surgery
The first prospective randomized study reported in 1999 demonstrated that a 4-week treatment with simvastatin (20 mg/day) significantly improved the events of postoperative thrombocytosis, myocardial infarction, and renal insufficiency in hypercholesterolemic patients after coronary artery bypass grafting (CABG).37 A most recent comprehensive meta-analysis summarized 54 observational and randomized controlled trials (inclusion of 91,491 patients) to identify the effects of preoperative statin therapy on the major adverse outcomes after cardiac surgery.38 Their analysis suggested that preoperative statin therapy resulted in 31% odds reduction for early all-cause mortality [odds ratio (OR) = 0.69; 95% confidence interval (CI) = 0.59–0.81] and a substantial reduction in postoperative atrial fibrillation (OR = 0.71; 95% CI = 0.61–0.82). Administration of statin also significantly reduced the incidence of postoperative stroke and period of intensive care unit (ICU) stay. The beneficial effects of preoperative use of statins in patients receiving valvular heart surgery are less conclusive. A retrospective study analyzed the outcomes of patients undergoing valve operation.39 This cohort study showed that the odds for the composite end points of death, stroke, and renal failure were lower in patients taking statins (unadjusted OR = 1.90; 95% CI = 0.95–3.76; p = 0.068). However, the patients included in the statin group had higher comorbidities (i.e., stroke, diabetes, cerebrovascular disease, and dyslipidemia). Therefore, prospective randomized controlled trials are warranted to further elucidate the actual effects of perioperative statin use in valvular heart surgery.40
5.2. Outcomes in vascular surgery
Poldermans et al41 conducted an important case-controlled study to determine the effect of statin on the survival outcome among 2816 patients who underwent major vascular surgery. Their results provided the first evidence demonstrating that statin therapy significantly reduced the mortality (8% vs. 25%) during the perioperative phase with an adjusted odds ratio of 0.22 (95% CI = 0.10–0.47). These findings were supported by a retrospective study, which included 570 patients who underwent elective open infrarenal abdominal aortic aneurysm surgery.42 The incidence of perioperative mortality and myocardial infarction within 30 days of surgery was lower in statin users (3.7% vs. 11.0%; OR = 0.31; 95% CI = 0.13–0.74; p = 0.01). In symptomatic patients admitted for carotid endarterectomy, administration of statins was associated with reduced in-hospital mortality and in-hospital ischemic stroke or death (adjusted OR = 0.25; 95% CI = 0.07 to 0.90–0.55; 95% CI = 0.32–0.95, respectively).43 The most solid evidence of cardiovascular-protective effect of statins in noncardiac vascular surgery came from the landmark randomized controlled trial reported by the Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group in 2009.44 Incidence of postoperative myocardial ischemia was reduced in patients treated with fluvastatin [10.8% vs. 19.0%; hazard ratio (HR) = 0.55; 95% CI = 0.34–0.88; p = 0.01]. Cardiovascular death or myocardial infarction occurred in 12 patients (4.8%) in the fluvastatin group and in 25 patients (10.1%) in the placebo group (HR = 0.47; 95% CI = 0.24–0.94; p = 0.03).
Most recently, a large-scale systemic meta-analysis study assessed the available randomized controlled trials reporting the effect of perioperative statins in statin-naïve patients undergoing cardiac/noncardiac surgery.45 Fifteen randomized controlled trials involving 2292 patients were included in this analysis. Postoperative development of atrial fibrillation was decreased in the statin-treatment group [relative risk (RR) = 0.56; 95% CI = 0.45–0.69; number needed to treat (NNT) = 6]. In cardiac and noncardiac surgeries, perioperative administration of statin reduced the risk of myocardial infarction (RR = 0.53; 95% CI = 0.38–0.74; NNT = 23) and the mean length of hospital stay (standardized mean difference = −0.32; 95% CI = −0.53 to −0.11). Statin use also tended to reduce the risk of death (RR = 0.62; 95% CI = 0.34–1.14) and length of ICU stay (standardized mean difference = −0.08; 95% CI = −0.25–0.10). The key results of this important meta-analysis are listed in Table 2. Furthermore, the authors also carried out a sensitivity analysis by excluding cardiac surgery (11 of 15 eligible studies) and found that statin treatment continued to demonstrate reduction of risk of myocardial infarction in patients who underwent noncardiac surgery (Table 2).
6. Anesthesia consideration of perioperative statin use
6.1. Withdrawal of perioperative statin therapy
The National Registry of Myocardial Infarction recommends that statin therapy within 24 hours of hospitalization for acute myocardial infarction is associated with reduced early complications and in-hospital death, and discontinuation of statin therapy is associated with increased mortality.46 Similar findings were found in a prospective cohort study comparing the continuation and discontinuation of statin therapy during the perioperative period in patients undergoing infrarenal aortic surgery.47 Withdrawal of statin therapy after the operation (>4 days) significantly increased the risk of postoperative myocardial necrosis (OR = 2.9; 95% CI = 1.6–5.5). Therefore, the American College of Cardiology/American Heart Association (ACC/AHA) strongly recommends that patients who are currently under statin therapy should continue taking statins during the perioperative period of noncardiac and vascular surgery.48 Likewise, expert opinions also suggest that early resumption of statins should be exercised after all major operations.49 The adverse responses secondary to acute statin withdrawal may be caused by overshoot translocation and activation of Rho, thereby downregulating eNOS enzymatic activity and reducing baseline production of NO.50
7. ACC/AHA recommendations
The ACC/AHA Joint Task Force published guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery in 2007, and has made clear recommendations for statin use in patients undergoing noncardiac surgery (Table 3).48 This clinical practice guideline also suggests that consideration should be given to starting statin therapy in surgical patients who meet the National Cholesterol Education Program criteria.
8. Doses and regimens of perioperative statins
Based on current clinical data, the hydrophilic rosuvastatin is considered as the most potent statin for the lipid-lowering and pleiotropic effects, followed by atorvastatin.51 Extended-release statin formulas are preferable during the perioperative period to cover the first 1–2 days after the procedure when oral intake may not be feasible.52 Individual studies also indicated that higher doses of statin use seem to provide better clinical outcomes in patients with coronary artery disease or after CABG surgery.53, 54 However, the cost effectiveness of increased therapeutic dose of perioperative statins should be justified individually according to the health of patients and types of statins.40 Although expert opinions suggest that 4–6 weeks of preoperative statin therapy is desired,55 the appropriate timing for commencing statin treatment prior to surgery remains inconclusive.52 It is recommended that perioperative statin use should be started early with an appropriate high therapeutic dose and continued for the long term after surgical procedures.55
9. Adverse effects of statin therapy
Based on the large clinical trials conducted, administration of statin appears to be safe, except for a small excess risk of hepatic transaminase elevations.56 However, anesthesiologists should be aware of the fact that the most common adverse events related to statin therapy are myopathy/rhabdomyolysis and elevated liver enzymes, with incidences of 0.04–0.07% and 1.18%, respectively.57 Patients with advanced age (>80 years), small body frame, coexisting with chronic diseases (such as chronic renal failure and severe liver impairment), multiple medications, and chronic alcoholism are at an increased risk for the development of statin-related adverse effects.58
10. Perioperative drug–drug interactions with statins
Statins are metabolized by the cytochrome P450 (mainly by CYP3A4 and CYP2C9; Table 1). Therefore, they interact with a wide array of medicines or compounds at the pharmacokinetic level, particularly during drug transformation in the liver.3Concurrent administration of statins with CYP450 inhibitors may thus elevate their concentration in blood and increase the risk of toxicity. The most common concern about perioperative use of statins is the co-administration with succinylcholine, which could be deleterious in causing muscle injury. Turan et al59 included 70 patients who were under chronic statin therapy (>3 months) and delivered succinylcholine (1.5 mg/kg) for general anesthesia in 38 patients. Their results showed that plasma concentrations of myoglobin were higher and fasciculations in statin users were more intense than that in nonusers. However, plasma potassium and creatine kinase concentrations were similar in statin users and nonusers, as was muscle pain. Therefore, the authors concluded that the effect of succinylcholine given to patients taking statins is likely to be small and probably of limited clinical consequence.59 In clinical practice, adverse responses due to perioperative drug interaction with statins are probably overlooked, but one should be aware that statin-induced muscle and hepatic toxicity could be amplified in high-risk patients.
11. Future perspectives
It is clear that the mechanisms responsible for the tissue-protective effects of statins are pleiotropic and multifactorial. In clinical settings, the evidence on the exclusive vascular protection of statins (independent from their lipid-lowering property) is relatively insufficient, as therapeutic indications of statins usually do not include vascular protection (Table 1). Clinical studies investigating the pleiotropic effect of statins in patients without dyslipidemia are therefore warranted in order to extend their clinical applications. Currently, our research group is conducting a randomized controlled trial in diabetic patients with a normal blood lipid profile to determine the perioperative vascular protection of rosuvastatin on the function of arteriovenous fistula, which is created for hemodialysis (ClinicalTrials.gov, protocol record 101-2314-B-006-045). This ongoing clinical trial is expected to manifest the vascular protective effects of rosuvastatin in the arteriovenous fistula of diabetic patients, as well as to enhance our ability to prevent and manage vascular access failure in diabetic patients with end-stage renal disease.
The optimal dose and treatment period for perioperative administration of statins are still a subject of debate. Dose-ranging and time-course studies are necessary to provide a more accurate use of different statins during the perioperative period. In addition, more clinical evidence is required to support the use of statins as part of acute-phase therapy prior to a major operation. Because surgical patients are most likely to suffer from prolonged fasting prior to and after a major operation, the development of parenteral preparations for statins would be highly desirable to enhance the bioavailability of perioperative statin delivery.40
12. Conclusion
Apart from the lipid-lowering property, statins mediate important pleiotropic effects in vascular protection, and are apparently applicable to other systemic organ protection (renal, neurological, and psychosomatic systems) during the perioperative period. Perioperative statin use reduces overall mortality, the development of myocardial infarction and atrial fibrillation, and duration of hospital stay after a major cardiac and noncardiac surgery. Patients who are currently undergoing long-term statin treatment should continue it perioperatively, because discontinuation of statins may result in adverse cardiovascular events. Perioperative use of statins is generally well tolerated, but attention should be paid to patients with old age, small body size, and advanced stage comorbidities.
Acknowledgments
This work is supported in part by research grants from the Multidisciplinary Center of Excellence for Clinical Trial and Research Department of Health (Grant No. DOH101-TD-111-102 to CFL) and from the National Science Council of Taiwan National Institutes of Health (Grant No. 98-2314-B-006-055-MY2 to CFL), Taiwan.