HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Francesco Alamanni Paolo Biglioli Alessandro Parolari Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Werba, J. P. Articles by Parolari, A. Search for Related Content PubMed PubMed Citation Articles by Werba, J. P. Articles by Parolari, A. Related Collections Cardiac - pharmacology

Ann Thorac Surg 2003;76:2132-2140
© 2003 The Society of Thoracic Surgeons

---

Review

Statins in coronary bypass surgery: rationale and clinical use

^a Atherosclerosis Unit, Centro Cardiologico Monzino IRCCS, University of Milan, Milan, Italy,
^b Department of Cardiac Surgery, Centro Cardiologico Monzino IRCCS, University of Milan, Milan, Italy
^c Department of Pharmacological Sciences, University of Milan, Milan, Italy

^* Address reprint requests to Dr Parolari, Department of Cardiac Surgery, Centro Cardiologico Monzino IRCCS, Via Parea, 4, 20138, Milan, Italy.
e-mail: aparolari{at}ccfm.it

	Abstract

Top Abstract Introduction Statins and prevention of... Early changes after CABG... Late changes after CABG... Do statins actually prevent... Do statins actually reduce... When should statins be... Should we still take... Comment References

 
Statin therapy prevents the first occurrence and recurrence of coronary events and reduces cardiovascular and general mortality in patients with coronary artery disease. These compounds modulate a variety of processes involved in the pathophysiology of arteriosclerosis and vascular graft disease by lipid-dependent and lipid-independent (pleiotropic) mechanisms. As a result, statins produce angiographic and clinical benefits in patients undergoing coronary bypass surgery. We review the present knowledge about the effects of statins on this pathologic condition and the evidence supporting an early treatment initiation.

	Introduction

Top Abstract Introduction Statins and prevention of... Early changes after CABG... Late changes after CABG... Do statins actually prevent... Do statins actually reduce... When should statins be... Should we still take... Comment References

 
Coronary artery bypass graft (CABG) surgery relieves debilitating myocardial ischemia and in some patients, it prolongs life [1]. The intervention, however, is palliative as a consequence of accelerated arteriosclerosis in grafts and progression of disease in native vessels. Although arterial conduits are less prone to develop graft disease than saphenous vein grafts, these are usually necessary for multiple vessel revascularization, which is the typical indication for CABG. Therefore, prevention of early graft occlusion, chronic graft disease, and recurrence of symptomatic coronary arteriosclerosis in native vessels continues at the forefront of clinical research. Clinical studies have clearly demonstrated that reduction of plasma cholesterol, particularly cholesterol transported in low-density lipoproteins (LDL), lowers the risk of cardiovascular events for both primary and secondary prevention. Significant cholesterol reductions may be produced by the 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors, commonly named statins. It is implicit that the beneficial effect of statins on coronary events is related to their hypocholesterolemic properties. However the immediate product of HMG-CoA reductase, mevalonic acid, is not only the substrate for cholesterol synthesis but also the precursor of isoprenoids and other metabolites involved in different cellular pathways of atherogenesis and thrombosis [2]. As a consequence, statins have the potential to result in pleiotropic effects, which are independent of cholesterol reduction and may explain many of the direct antiatherosclerotic and antithrombotic properties of these compounds [2–7]. These mechanisms of action of statins are depicted in Figure 1. The pathogenesis of and general measures to prevent graft disease have been extensively reviewed elsewhere [8]. In this article, we focus on the accumulated and recent experimental and clinical data supporting the role of statins in patients undergoing CABG.

View larger version (25K): [in this window] [in a new window]   Fig 1. Dual mechanism of action of statins. Reversible inhibition of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase reduces intracellular mevalonic acid (MVA), which is the precursor of cholesterol and other numerous metabolites (isoprenoids) necessary for relevant cell functions. The MVA depletion induces the up-regulation of the low-density lipoprotein (LDL) receptor expression, mainly in liver cells, which explains most of the LDL cholesterol lowering effect of statins. Conversely, the reduction of specific cellular isoprenoids (geranyl-pyrophosphate, farnesyl-pyrophosphate, geranylgeranyl-pyrophosphate) relates to a growing list of antiatherogenic and antithrombotic actions, the so-called "pleiotropic" effects of statins. These include reduction of cholesterol esterification in macrophages, inhibition of smooth muscle cell migration and proliferation, enhancement of nitric oxide and tissue plasminogen activator synthesis, and reduction of endothelin-1 and plasminogen activator inhibitor 1 in endothelial cells, and inhibition of matrix metalloproteinases and tissue factor expression in monocytes.

	Statins and prevention of graft disease

Top Abstract Introduction Statins and prevention of... Early changes after CABG... Late changes after CABG... Do statins actually prevent... Do statins actually reduce... When should statins be... Should we still take... Comment References

	Early changes after CABG and effects of statins

Top Abstract Introduction Statins and prevention of... Early changes after CABG... Late changes after CABG... Do statins actually prevent... Do statins actually reduce... When should statins be... Should we still take... Comment References

Statins and endothelial layer recovery
Reendothelialization at sites of iatrogenic disruption results from the migration and proliferation of endothelial cells (ECs) from viable endothelium adjacent to the site of injury. In addition, circulating cells derived from the bone marrow are capable of homing to sites of endothelial disruption and incorporating into nascent endothelium [14]. Previous data suggest that statins mobilize bone marrow-derived endothelial progenitor cells (EPCs) [15]. More recently, Walter and colleagues [16] reported that simvastatin at physiologic doses accelerate reendothelialization after balloon denudation of arterial segments. Interestingly, at 2 weeks after endothelial removal, statins induced almost complete reendothelialization at least in part by promoting incorporation of EPCs into the carotid artery neoendothelium. If statins produce these effects in coronary grafts these data may acquire special clinical relevance.

Statins and platelets
Preoperative control of hypercholesterolemia with simvastatin seems to significantly reduce the incidence of postoperative thrombocytosis [17]. Unfortunately these intriguing data are not still corroborated by subsequent investigations. Studies on the effects of statins on platelet function provided contrasting results. Fluvastatin was reported to modestly reduce platelet aggregation, but pravastatin was ineffective [18, 19]. In some studies [20, 21], but not in others [22], simvastatin reduced platelet aggregation as well as urinary excretion of 11-dehydrothromboxane B2, a marker of in vivo platelet thromboxane A2 biosynthesis. Moreover, diverse experimental conditions were used to evaluate platelet function. For instance, although pravastatin failed to influence platelet reactivity induced by exogenous agonists and platelet eicosanoid synthesis, platelet thrombus formation evaluated by exposing porcine aortic media to the patient's venous blood was significantly inhibited by pravastatin [23, 24] but not by simvastatin [24]. The magnitude of vessel injury may determine the ability of a statin to prevent the formation of platelet thrombus in vivo. In fact, Badimon and colleagues [25] found that atorvastatin significantly diminishes platelet deposition on a mildly damaged but not on a severely injured vessel wall. These data suggest that statins may prevent platelet attachment to eroded vessels, reducing the thrombotic risk associated with erosions of the luminal surface. The implications of these findings on CABG patients are evident, at least on a theoretical basis.

Statins and local fibrinolysis
In vitro culture studies of smooth muscle and endothelial cells, and ex vivo studies in rat aortas show that a short-term exposure to different statins induces tPA and reduces plasminogen activator inhibitor 1 (PAI-1) [26–29], potentially offsetting the fibrinolytic imbalance that characterizes vascular grafts. Moreover, in the in vivo situation, the effects of statins on fibrinolysis may be potentiated by their LDL-cholesterol lowering action. In fact, oxidized LDL (ox-LDL) stimulates PAI-1 release and inhibits tPA release by cultured ECs [30] and LDL reduction induced by statins may diminish lipoprotein availability for oxidation, which may add up to the direct antioxidant action of some members of this class of drugs [31, 32].

Statins and vasoactive factors
The propensity of the graft to vasoconstriction may not only reduce lumen diameter and relative blood supply to the myocardium but also determine acute flow changes leading to thrombotic phenomena. Statins may potentially counterbalance this perturbation. In cultured bovine aortic ECs, atorvastatin and simvastatin inhibit preproendothelin-1 mRNA expression and reduce immunoreactive endothelin-1 levels. In addition, these compounds prevent the inhibitory action of ox-LDL on endothelial NO synthase (eNOS) mRNA and protein levels [33]. A series of in vitro and in vivo studies demonstrate that up-regulation of eNOS expression is a common pharmacodynamic action of statins [34–36], which is independent, at least in part, from changes in serum cholesterol levels [37]. Importantly, eNOS expression declines rapidly after statin withdrawal [38], suggesting that a continuous administration of the compound is required to preserve endothelial function.

Statins and tissue factor
Tissue factor expression in different cell types is modulated by statins. Colli and colleagues [39] first demonstrated that fluvastatin and simvastatin, but not pravastatin, decreased TF activity, protein, and mRNA in monocyte-derived human macrophages in culture. Inhibition of TF was shown to be independent on the inhibition of cholesterol biosynthesis as it was observed in the presence of exogenously added cholesterol. Rather geranylgeraniol prevented the effect of the statin on TF biosynthesis. This observation suggests that at least in vitro the effect of statins on TF is not dependent on cholesterol lowering.

Inhibition of TF expression concomitant with cholesterol reduction has been shown in rabbits fed a high cholesterol diet [40]. Moreover macrophage accumulation and TF content was reduced by statins in rabbit carotid neointimal lesions even in the absence of changes in blood cholesterol [41]. Finally evidence for an in vivo effect of statins on TF expression in human vessels was recently provided by the Atorvastatin and Thrombogenicity of the Carotid Atherosclerotic Plaque (ATROCAP) study [42] in patients undergoing bilateral carotid endarterectomy with an average interval time between the first and second carotid endarterectomy of 4 to 6 months. Atorvastatin significantly reduced TF protein and activity as well as macrophage infiltration in atherectomy specimens. These data strongly suggest that lipophylic statins by reducing cell-mediated generation of thrombin are capable of attenuating atherosclerotic plaque thrombogenicity.

Statins and fibrinogen
We have previously reported that fibrinogen augments perioperatively in CABG patients [43]. Data indicate that some of the statins may mildly augment fibrinogen levels [44] in hypercholesterolemic patients by mechanisms not clearly established. Whether this undesirable effect of statins may in part offset the antithrombotic properties of these compounds is unknown.

Statins and inflammation
In some aspects, arteriosclerosis may be regarded as a rather stereotyped response of the vessel to a diversity of stimuli, with an inflammatory component that includes early leukocyte infiltration [45] and local release of different chemoattractants and cytokines [46, 47]. Statins display antiinflammatory properties that may be of relevance during the early stages of neointima formation, beyond the postulated antiinflammatory actions that presumably lead to the stabilization of advanced lesions [48]. In this regard, several studies indicate that statins reduce C-reactive protein (CRP), an inflammatory biomarker and an accepted prognostic index of coronary instability [47].

Clinical data about acute antiinflammatory actions of statins in patients submitted to first elective CABG with cardiopulmonary bypass were reported. In a cohort study, Brull and colleagues [49] compared immediate postoperative variations in plasma interleukin-6 (IL-6) levels between CABG patients who were receiving chronic therapy with statins at the time of surgery and in a group who were not. Although peak IL-6 levels increased many fold after the intervention in both groups, levels were significantly lower in patients receiving statins, a finding that suggests that these drugs may ameliorate acute inflammatory phenomena occurring perioperatively. In contrast, Florens and colleagues [50] reported that acute perioperative administration of atorvastatin (40 mg the evening before and 40 mg the morning of surgery) failed to attenuate the increase in several inflammatory markers after cardiopulmonary bypass. Although longer statin treatment before surgery might be necessary to inhibit the acute response, further studies are warranted to define whether statins exert antiinflammatory effects perioperatively in CABG patients.

	Late changes after CABG and effects of statins

Top Abstract Introduction Statins and prevention of... Early changes after CABG... Late changes after CABG... Do statins actually prevent... Do statins actually reduce... When should statins be... Should we still take... Comment References

 
After the first month and throughout the first postoperative year, intimal hyperplasia represents the major histologic change in the graft. A combination of conditions promote smooth muscle cell (SMC) proliferation. These include (1) transient attenuation of endothelial antiproliferative signals (NO, transforming growth factor-ß, prostacyclin, adenosine); (2) release of growth factors from adhering platelets and nonocclusive thrombi (platelet-derived growth factor); and (3) up-regulation of vein graft receptors for growth factors (basic fibroblast growth factor) [8]. A prerequisite for SMC proliferation and migration in vivo is degradation of the basement membrane, achieved by activation of matrix metalloproteinases, mostly the matrix-degrading gelatinases matrix metalloproteinase-2 (MMP-2) and MMP-9 [51]. In this hyperplastic period and thereafter, lipoprotein-derived cholesterol esters accumulate in the vessel wall. Lipid accretion occurs initially into smooth muscle and macrophage-derived foam cells and then extracellularly, progressively developing a mature atheromatous plaque, indistinguishable from the typical lesions found in native arteries. Statins may influence various of the steps involved in this process.

Statins and SMC migration and proliferation
Some studies indicate that statins affect MMP-9 secretion from unstimulated monocytes (cerivastatin) [52] and mouse macrophages or human monocyte-derived macrophages (fluvastatin and simvastatin) [53]. Moreover, recent studies using organ-cultured human saphenous veins show that simvastatin reduces neointima formation as a result of a combined inhibition of SMC proliferation and migration, the latter associated with a reduction of MMP-9 activity [54]. Conversely, the antiproliferative action of statins has been reported consistently on SMC from different species (including humans), both in vitro [4, 35, 54, 55] and in vivo [56], and with different members of the statin family [4, 56]. The antiproliferative action of statins has been ascribed to inhibition of the farnesylation as well as geranyl-geranylation of proteins involved in cell signaling processes [4, 7, 57].

Statins and atheroma progression
The association between hyperlipidemia and aggravation of graft vessel disease has long been recognized [58]. In denuded vessels, high levels of circulating atherogenic lipoproteins enhance neointima formation, at least in part by increasing the number of SMC- and macrophage-derived foam cells [59]. Conversely, lipid lowering by itself ameliorates the rate and extent of this change [60]. Although the potent hypocholesterolemic effect of statins may explain the inhibitory effect of these drugs on lipid accretion some statins also show antioxidant properties [31, 32], which may reduce LDL oxidation. Therefore, statins may reduce atheroma development by affecting lipoproteins not only quantitatively but also qualitatively.

	Do statins actually prevent graft disease and occlusion?

Top Abstract Introduction Statins and prevention of... Early changes after CABG... Late changes after CABG... Do statins actually prevent... Do statins actually reduce... When should statins be... Should we still take... Comment References

 
The Cholesterol Lowering Arteriosclerosis Study (CLAS) has shown that aggressive cholesterol reduction with a resin plus niacin in hypercholesterolemic subjects (mean LDL-C reduction -43%) for a period of 2 to 4 years significantly reduces new lesion formation in native vessels and bypass grafts [61]. It is worth noting, however, that both resins and nicotinic acid are not well tolerated in practice by most patients, particularly at the high doses used in the CLAS, making this treatment program highly unfeasible.

The Post-Coronary Artery Bypass Graft (Post-CABG) trial evaluated the effects of a statin/low-dose cholestyramine regimen in CABG patients [62]. In this study, angiographic changes were assessed in CABG patients with moderate hypercholesterolemia receiving lovastatin at high or low doses for an average of 4.3 years. Titration of the statin (2.5 to 5 mg/d in moderate and 40 to 80 mg/d in aggressive treatment) and addition of 8 g cholestyramine, if necessary, reduced mean LDL-C levels to 136 and 93 mg/dL in patients assigned to moderate or aggressive treatment, respectively. The percentage per patient of vein grafts with progression (27% versus 39%), new vein graft occlusions (10% versus 21%), or new vein graft lesions (10% versus 16%) were all significantly lower in the latter group.

Coronary benefits obtained in the Post-CABG trial with aggressive treatment do not restrict to the venous grafts but also affect native coronary arteries. Indeed, a recent subanalysis of changes in the native left main coronary artery in a sample of 402 Post-CABG trial participants showed a significantly reduced lesion progression with aggressive statin treatment as compared with moderate treatment (in 24.1% versus 13.8% of the patients, respectively) [63]. Thus, both venous grafts and native arteries benefit angiographically from a program of intensive postoperative intervention with statins.

	Do statins actually reduce clinical events in CABG patients?

Top Abstract Introduction Statins and prevention of... Early changes after CABG... Late changes after CABG... Do statins actually prevent... Do statins actually reduce... When should statins be... Should we still take... Comment References

 
Beyond any favorable change in intermediate variables (either humoral or angiographic), the relevant issue is the effect of the intervention on a patient's cardiovascular and global health. Lovastatin, pravastatin, or simvastatin were the compounds administered in the large studies performed so far addressing the efficacy of statins to reduce "hard outcomes" in secondary prevention. Yet, there is a general opinion and there are reasonable bases to support a drug class effect. Short- and long-term clinical benefits were reported in CABG patients treated with statins.

Short- and medium-term clinical trials
In a retrospective analysis, Dotani and colleagues [64] addressed the efficacy of statins administered preoperatively. In this study, "hard" short-term outcomes after elective CABG were compared between patients who were receiving or were not receiving statins at the time of the surgical intervention. Use of statins was associated with a reduced incidence of clinical events (death, acute myocardial infarction [AMI], unstable angina, or arrhythmias) both at 60 days and 1 year after CABG. It should be recognized, however, that differences in sex distribution, prevalence of hypertension, and presence or severity of dyslipidemia, as well as other unmeasured traits, may have introduced relevant biases in this nonrandomized study. Moreover, Christenson [65] reported the short-term effects of preoperative statins on angiographic and clinical outcomes in hypercholesterolemic subjects. In particular, a preoperative 4-week simvastatin treatment not only reduced the occurrence of graft lesions and graft occlusions but also the incidence of AMI during the first year after CABG (7 of 37 untreated versus 0 of 40 statin treated; p = 0.03). The study, however, was not placebo controlled and data are far from conclusive.

Although the results of these reports are encouraging, further investigations with proper design are mandatory to define the efficacy of statins in preventing early clinical events in CABG patients.

Long-term clinical trials
In the Cholesterol and Recurrent Events (CARE) trial [66], patients of both sexes with a documented AMI and an average total and LDL-C levels were treated with either pravastatin or placebo for a mean period of 5 years. Pravastatin produced a statistically significant reduction (24%) in the relative risk of a composite endpoint of fatal coronary event or nonfatal AMI and significant reductions in the need of coronary revascularization or in the incidence of stroke. The CARE trial included 1,091 patients (527 allocated to pravastatin and 564 allocated to placebo) who had previously undergone CABG surgery. An analysis of treatment effect in this subgroup of patients [67] revealed that pravastatin significantly reduced by 33% the incidence of the composite primary endpoint of coronary heart disease (CHD) death or nonfatal AMI (absolute risk 9.1% versus 12.9% in the placebo group), by 41% the incidence of coronary death (4.6% versus 7.8%), and by 35% total mortality (8% versus 12.4%).

In the Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) study, patients of both sexes with a history of AMI or hospitalization for unstable angina and a broad range of cholesterol levels were treated with either pravastatin or placebo for a mean period of 6.1 years [68]. In the entire treated population, pravastatin produced a significant 24% relative reduction in the primary study outcome of mortality from coronary heart disease and also reduced by 24% the combined incidence of CHD death or nonfatal AMI. The LIPID study included a 27% of patients with a history of CABG (n = 2,436 patients; 1,217 and 1,219 allocated to pravastatin or placebo, respectively). Unfortunately, this was not a predefined subgroup and published data do not allow subgroup analyses.

The results of long-term follow-up of the patients included in the Post-CABG trial were recently published [69]. Follow-up during the main trial averaged 4.3 years whereas the extended follow-up added another 3 years. At this time, the aggressive hypocholesterolemic approach was associated with 30% reduction in revascularization procedures and 24% reduction in a composite clinical endpoint (death from cardiovascular or unknown causes, nonfatal AMI, stroke, CABG, or percutaneous coronary angioplasty) compared with patients assigned to moderate strategy, both differences statistically significant. Yet, the occurrence of the primary endpoint (cardiovascular death or nonfatal AMI) was 15.1% in the aggressive strategy group and 20.3% in the moderate strategy group, a 26% reduction that was not significantly different by study criteria. At least two considerations may be of help in explaining these results. The first is that moderate treatment is not "placebo" and favorable effects may have occurred in the comparative group even at low statin doses. The second is that an unknown number of patients in the moderate approach may have been shifted to an aggressive approach during the period of extended follow-up.

Further support for the use of statins in a variety of high coronary risk conditions emerge from the favorable results of the recently published Heart Protection Study (HPS), which addressed the clinical long-term effect of simvastatin in high-risk patients with a wide range of cholesterol levels [70, 71]. In the HPS, patients with coronary disease (including a nonspecified number of subjects with previous CABG surgery), other occlusive arterial disease, or diabetes were randomly allocated to receive simvastatin or matching placebo. After a mean 5-year follow-up, simvastatin significantly reduced total mortality (13%), vascular mortality (17%), and the incidence of major coronary events (27%) and strokes (25%), as well as the need for coronary or extracoronary revascularizations (24%). These effects in the whole treated population are highly encouraging, and information about the specific treatment effect in the subgroup of patients with previous CABG is eagerly awaited.

	When should statins be started in CABG patients according to present data?

Top Abstract Introduction Statins and prevention of... Early changes after CABG... Late changes after CABG... Do statins actually prevent... Do statins actually reduce... When should statins be... Should we still take... Comment References

 
In the Post-CABG trial, lipid-lowering therapy was started long after the bypass procedure. In fact, saphenous vein grafts had been placed 1 to 11 years before study entry. Similarly, a minimum of 3 months between CABG and enrollment was required in CARE and LIPID, and the period that elapsed between a previous bypass and randomization was not specified in HPS. Consequently, the gap between surgical intervention and statin initiation prevents any assessment of potential treatment effects on early changes occurring after CABG. This aspect is not unimportant inasmuch as early phenomena account for as many as 15% to 25% of venous graft occlusions during the first postoperative year and probably explain a much higher number of grafts with nonocclusive disease.

Although the term "preoperative" was explicit in the titles of the studies from Dotani and colleagues [64] and Christenson [17], these studies did not rigorously assess whether preoperative initiation of the statin provided any incremental benefit above a postoperative start. Indeed, to answer this relevant question both groups should have been treated similarly postoperatively, which was not the case. Therefore, more robust and properly designed clinical studies are necessary to obtain rigorous evidence about the efficacy, safety, and cost/benefit ratio of preoperative initiation of statins. Yet, statins generally show a very good safety profile and, therefore, unless the use of these compounds is formally contraindicated (patients with active liver disease or primary myopathy) or whenever caution is generally recommended (elderly women, hypothyroidism, renal insufficiency, concomitant use of interacting drugs), the potential benefits associated with an early start of statins might warrant their empiric preoperative use. Indeed, the reported favorable effects of statins on endothelial recovery, postoperative inflammatory phenomena, and postoperative thrombocytosis (see above) may be further potential advantages to justify the initiation of statin treatment preoperatively. More conservatively and according to current expert recommendations [72], patients undergoing CABG with a preoperative LDL-C level of 130 mg/dL or higher (or 100 to 129 mg/dL based on clinical judgment) should be administered a statin—and have a follow-up plan—as a part of their hospital discharge indications, unless contraindicated. Indeed, prescription of statins at the time of discharge as a part of hospital programs for risk factor management has been shown useful for substantially reducing morbidity and mortality [73].

	Should we still take into account LDL-C level for statin prescription in CABG subjects?

Top Abstract Introduction Statins and prevention of... Early changes after CABG... Late changes after CABG... Do statins actually prevent... Do statins actually reduce... When should statins be... Should we still take... Comment References

 
Clinical evidence is starting to emerge suggesting that the current recommendations and goals in secondary prevention may not be aggressive enough. The Post-CABG study shows that the angiographic benefits in grafts and native arteries are associated with an aggressive statin treatment capable of achieving and maintaining LDL-C levels lower than 100 mg/dL. An even lower goal is suggested by the HPS results, demonstrating that statin treatment significantly and safely reduces the risk of major coronary events in subjects with a high coronary risk, even among those presenting with LDL-C below 100 mg/dL [71]. Indeed, the optimal LDL-C goal in coronary patients has not been definitely determined and results from ongoing studies (SEARCH, TNT) might provide an answer. In addition, the direct antithrombotic and antiatherosclerotic actions of statins may have a protective role against graft disease independently of starting and resulting LDL-C levels. One may anticipate that these and further upcoming data will support the conception of renewed guidelines, with the proposal of an earlier and more aggressive use of statins for patients with CABG as well as for other high-risk patients.

	Comment

Top Abstract Introduction Statins and prevention of... Early changes after CABG... Late changes after CABG... Do statins actually prevent... Do statins actually reduce... When should statins be... Should we still take... Comment References

 
Native artery arteriosclerosis and graft vessel disease are complex processes with many pathophysiologic overlappings. Statins favorably modulate the expression of molecules involved in atherothrombotic properties of blood and vascular cells, either by reducing the levels of plasma cholesterol or through lipid-independent mechanisms. More importantly, statins started postoperatively exert benefits that can be documented angiographically, both in native vessels and in grafts, and may reduce morbidity and mortality among patients with previous CABG. Inasmuch as the thrombotic and inflammatory components dominate the early stages of graft disease, additional information on the nonhypolipidemic effects of the statins, including those on the prothrombotic and fibrinolytic systems, may provide an additional rationale for the preoperative initiation of these drugs.

	References

Top Abstract Introduction Statins and prevention of... Early changes after CABG... Late changes after CABG... Do statins actually prevent... Do statins actually reduce... When should statins be... Should we still take... Comment References

 

1. Eagle K.A., Guyton R.A., Davidoff R., et al. ACC/AHA guidelines and indications for coronary artery bypass graft surgery. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 1999;34:1262-1347.[Free Full Text]
2. Goldstein J.L., Brown M.S. Regulation of the mevalonate pathway. Nature 1990;343:425-430.[Medline]
3. Bernini F., Didoni G., Bonfadini G., Bellosta S., Fumagalli R. Requirement for mevalonate in acetylated LDL induction of cholesterol esterification in macrophages. Atherosclerosis 1993;104:19-26.[Medline]
4. Corsini A., Mazzotti M., Raiteri M., et al. Relationship between mevalonate pathway and arterial myocyte proliferation: in vitro studies with inhibitors of HMG-CoA reductase. Atherosclerosis 1993;101:117-125.[Medline]
5. Grunler J., Ericsson J., Dallner G. Branch-point reactions in the biosynthesis of cholesterol, dolichol, ubiquinone and prenylated proteins. Biochim Biophys Acta 1994;1212:259-277.[Medline]
6. Corsini A, Raiteri M, Soma MR, Bernini F, Fumagalli R, Paoletti R. Pathogenesis of atherosclerosis and the role of drug intervention: focus on HMG-CoA reductase inhibitors. Am J Cardiol 1995;76:21A–8A
7. Bellosta S., Ferri N., Arnaboldi L., Bernini F., Paoletti R., Corsini A. Pleiotropic effects of statins in atherosclerosis and diabetes. Diabetes Care 2000;23(Suppl 2):B72-78.
8. Motwani J.G., Topol E.J. Aortocoronary saphenous vein graft disease. Pathogenesis, predisposition, and prevention. Circulation 1998;97:916-931.[Abstract/Free Full Text]
9. Davies M.G., Dalen H., Kim J.H., Barber L., Svendsen E., Hagen P.O. The influence of the combined presence of diabetes mellitus and hypercholesterolaemia on the function and morphology of experimental vein grafts. Eur J Vasc Endovasc Surg 1995;10:142-155.[Medline]
10. Holt C.M., Francis S.E., Newby A.C., et al. Comparison of response to injury in organ culture of human saphenous vein and internal mammary artery. Ann Thorac Surg 1993;55:1522-1528.[Abstract]
11. Muluk S.C., Vorp D.A., Severyn D.A., Gleixner S., Johnson P.C., Webster M.W. Enhancement of tissue factor expression by vein segments exposed to coronary arterial hemodynamics. J Vasc Surg 1998;27:521-527.[Medline]
12. Allaire E., Clowes A.W. Endothelial cell injury in cardiovascular surgery: the intimal hyperplastic response. Ann Thorac Surg 1997;63:582-591.[Abstract/Free Full Text]
13. Christenson J.T., Gras P.A., 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]
14. Asahara T., Krasinski K., Chen D., et al. Circulating endothelial progenitor cells in peripheral blood incorporate into re-endothelialization after vascular injury. Circulation 1997;96(Suppl 1):725.
15. Llevadot J., Murasawa S., Kureishi Y., et al. HMG-CoA reductase inhibitor mobilizes bone marrow-derived endothelial progenitor cells. J Clin Invest 2001;108:399-405.[Medline]
16. Walter D.H., Rittig K., Bahlmann F.H., et al. Statin therapy accelerates reendothelialization: a novel effect involving mobilization and incorporation of bone marrow-derived endothelial progenitor cells. Circulation 2002;105:3017-3024.[Abstract/Free Full Text]
17. Christenson J.T. Preoperative lipid-control with simvastatin reduces the risk of postoperative thrombocytosis and thrombotic complications following CABG. Eur J Cardiothorac Surg 1999;15:394-399.
18. Osamah H., Mira R., Sorina S., Shlomo K., Michael A. Reduced platelet aggregation after fluvastatin therapy is associated with altered platelet lipid composition and drug binding to the platelets. Br J Clin Pharmacol 1997;44:77-83.[Medline]
19. Broijersen A., Eriksson M., Larsson P.T., et al. Effects of selective LDL-apheresis and pravastatin therapy on platelet function in familial hypercholesterolaemia. Eur J Clin Invest 1994;24:488-498.[Medline]
20. Davi G., Averna M., Novo S., et al. Effects of synvinolin on platelet aggregation and thromboxane B2 synthesis in type IIa hypercholesterolemic patients. Atherosclerosis 1989;79:79-83.[Medline]
21. Notarbartolo A., Davi G., Averna M., et al. Inhibition of thromboxane biosynthesis and platelet function by simvastatin in type IIa hypercholesterolemia. Arterioscler Thromb Vasc Biol 1995;15:247-251.[Abstract/Free Full Text]
22. Broijersen A., Eriksson M., Leijd B., Angelin B., Hjemdahl P. No influence of simvastatin treatment on platelet function in vivo in patients with hypercholesterolemia. Arterioscler Thromb Vasc Biol 1997;17:273-278.[Abstract/Free Full Text]
23. Lacoste L., Lam J.Y.T., Hung J., Letchacovski G., Solymoss C.B., Waters D. Hyperlipidemia and coronary disease. Correction of the increased thrombogenic potential with cholesterol reduction. Circulation 1995;92:3172-3177.[Abstract/Free Full Text]
24. Lacoste L., Lam J.Y.T. Comparative effect of pravastatin and simvastatin on platelet-thrombus formation in hypercholesterolemic coronary patients. J Am Coll Cardiol 1996;27:413.
25. Alfon J., Royo T., Garcia-Moll X., Badimon L. Platelet deposition on eroded vessel walls at a stenotic shear rate is inhibited by lipid-lowering treatment with atorvastatin. Arterioscler Thromb Vasc Biol 1999;19:1812-1817.[Abstract/Free Full Text]
26. Essig M., Nguyen G., Prie D., Escoubet B., Sraer J.D., Friedlander G. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors increase fibrinolytic activity in rat aortic endothelial cells. Role of geranylgeranylation and Rho proteins. Circ Res 1998;83:683-690.[Abstract/Free Full Text]
27. Bourcier T., Libby P. HMG CoA reductase inhibitors reduce plasminogen activator inhibitor-1 expression by human vascular smooth muscle and endothelial cells. Arterioscler Thromb Vasc Biol 2000;20:556-562.[Abstract/Free Full Text]
28. Mussoni L., Banfi C., Sironi L., Arpaia M., Tremoli E. Fluvastatin inhibits basal and stimulated plasminogen activator inhibitor 1, but induces tissue type plasminogen activator in cultured human endothelial cells. Thromb Haemost 2000;84:59-64.[Medline]
29. Wiesbauer F., Kaun C., Zorn G., Maurer G., Huber K., Wojta J. HMG CoA reductase inhibitors affect the fibrinolytic system of human vascular cells in vitro: a comparative study using different statins. Br J Pharmacol 2002;135:284-292.[Medline]
30. Kugiyama K., Sakamoto T., Misumi I., et al. Transferable lipids in oxidized low-density lipoprotein stimulate plasminogen activator inhibitor-1 and inhibit tissue-type plasminogen activator release from endothelial cells. Circ Res 1993;73:335-343.[Abstract/Free Full Text]
31. Wassmann S., Laufs U., Muller K., et al. Cellular antioxidant effects of atorvastatin in vitro and in vivo. Arterioscler Thromb Vasc Biol 2002;22:300-305.[Abstract/Free Full Text]
32. Girona J., La Ville A.E., Sola R., Plana N., Masana L. Simvastatin decreases aldehyde production derived from lipoprotein oxidation. Am J Cardiol 1999;83:846-851.[Medline]
33. Hernandez-Perera O., Perez-Sala D., Navarro-Antolin J., et al. Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. J Clin Invest 1998;101:2711-2719.[Medline]
34. Laufs U., Liao J.K. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem 1998;273:24266-24271.[Abstract/Free Full Text]
35. Yang Z., Kozai T., van der Loo B., et al. 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]
36. Laufs U., La Fata V., Plutzky J., Liao J.K. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 1998;97:1129-1135.[Abstract/Free Full Text]
37. LaRosa J. Pleiotropic effects of statins and their clinical significance. Am J Cardiol 2001;88:291-293.[Medline]
38. Laufs U., Endres M., Custodis F., et al. Suppression of endothelial nitric oxide production after withdrawal of statin treatment is mediated by negative feedback regulation of rho GTPase gene transcription. Circulation 2000;102:3104-3110.[Abstract/Free Full Text]
39. Colli S., Eligini S., Lalli M., Camera M., Paoletti R., Tremoli E. Vastatins inhibit tissue factor in cultured human macrophages. A novel mechanism of protection against atherothrombosis. Arterioscler Thromb Vasc Biol 1997;17:265-272.[Abstract/Free Full Text]
40. Aikawa M., Rabkin E., Sugiyama S., et al. An HMG-CoA reductase inhibitor, cerivastatin, suppresses growth of macrophages expressing matrix metalloproteinases, and tissue factor in vivo, and in vitro. Circulation 2001;103:276-283.[Abstract/Free Full Text]
41. Baetta R., Camera M., Comparato C., Altana C., Ezekowitz M.D., Tremoli E. Fluvastatin reduces tissue factor expression and macrophage accumulation in carotid lesions of cholesterol-fed rabbits in the absence of lipid lowering. Arterioscler Thromb Vasc Biol 2002;22:692-698.[Abstract/Free Full Text]
42. Cortellaro M., Cofrancesco E., Arbustini E., et al. Atorvastatin and thrombogenicity of the carotid atherosclerotic plaque: the ATROCAP study. Thromb Haemost 2002;88:41-47.[Medline]
43. Mannucci L., Gerometta P.S., Mussoni L., et al. One month follow-up of haemostatic variables in patients undergoing aortocoronary bypass surgery. Effect of aprotinin. Thromb Haemost 1995;73:356-361.[Medline]
44. Maison P., Mennen L., Sapinho D., et al. A pharmacoepidemiological assessment of the effect of statins and fibrates on fibrinogen concentration. Atherosclerosis 2002;160:155-160.[Medline]
45. Donetti E., Baetta R., Comparato C., et al. Polymorphonuclear leukocyte-myocyte interaction: an early event in collar-induced rabbit carotid intimal thickening. Exp Cell Res 2002;274:197-206.[Medline]
46. Ross R. Atherosclerosis. An inflammatory disease. N Engl J Med 1999;340:115-126.[Free Full Text]
47. Libby P., Ridker P.M., Maseri A. Inflammation and atherosclerosis. Circulation 2002;105:1135-1143.[Abstract/Free Full Text]
48. Shovman O., Levy Y., Gilburd B., Shoenfeld Y. Antiinflammatory and immunomodulatory properties of statins. Immunol Res 2002;25:271-285.[Medline]
49. Brull D.J., Sanders J., Rumley A., Lowe G.D., Humphries S.E., Montgomery H.E. Statin therapy and the acute inflammatory response after coronary artery bypass grafting. Am J Cardiol 2001;88:431-433.[Medline]
50. Florens E., Salvi S., Peynet J., et al. Can statins reduce the inflammatory response to cardiopulmonary bypass? A clinical study. J Card Surg 2001;16:232-239.[Medline]
51. Southgate K.M., Mehta D., Izzat M.B., Newby A.C., Angelini G.D. Increased secretion of basement membrane-degrading metalloproteinases in pig saphenous vein into carotid artery interposition grafts. Arterioscler Thromb Vasc Biol 1999;19:1640-1649.[Abstract/Free Full Text]
52. Ganne F., Vasse M., Beaudeux J.L., et al. Cerivastatin, an inhibitor of HMG-CoA reductase, inhibits urokinase/urokinase-receptor expression, and MMP-9 secretion by peripheral blood monocytes—a possible protective mechanism against atherothrombosis. Thromb Haemost 2000;84:680-688.[Medline]
53. Bellosta S., Via D., Canavesi M., et al. HMG-CoA reductase inhibitors reduce MMP-9 secretion by macrophages. Arterioscler Thromb Vasc Biol 1998;18:1671-1678.[Abstract/Free Full Text]
54. Porter K.E., Naik J., Turner N.A., Dickinson T., Thompson M.M., London N.J. Simvastatin inhibits human saphenous vein neointima formation via inhibition of smooth muscle cell proliferation and migration. J Vasc Surg 2002;36:150-157.[Medline]
55. Indolfi C., Cioppa A., Stabile E., et al. Effects of hydroxymethylglutaryl coenzyme A reductase inhibitor simvastatin on smooth muscle cell proliferation in vitro and neointimal formation in vivo after vascular injury. J Am Coll Cardiol 2000;35:214-221.[Abstract/Free Full Text]
56. Soma M.R., Donetti E., Parolini C., et al. HMG CoA reductase inhibitors. In vivo effects on carotid intimal thickening in normocholesterolemic rabbits. Arterioscler Thromb 1993;13:571-578.[Abstract/Free Full Text]
57. Raiteri M., Arnaboldi L., McGeady P., et al. Pharmacological control of the mevalonate pathway: effect on arterial smooth muscle cell proliferation. J Pharmacol Exp Ther 1997;281:1144-1153.[Abstract/Free Full Text]
58. Campeau L., Enjalbert M., Lesperance J., et al. 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]
59. Klyachkin M.L., Davies M.G., Svendsen E., et al. Hypercholesterolemia and experimental vein grafts: accelerated development of intimal hyperplasia and an increase in abnormal vasomotor function. J Surg Res 1993;54:451-468.[Medline]
60. Klyachkin M.L., Davies M.G., Kim J.H., et al. Postoperative reduction of high serum cholesterol concentrations and experimental vein bypass grafts. Effect on the development of intimal hyperplasia and abnormal vasomotor function. J Thorac Cardiovasc Surg 1994;108:556-566.[Abstract/Free Full Text]
61. Cashin-Hemphill L., Mack W.J., Pogoda J.M., Sanmarco M.E., Azen S.P., Blankenhorn D.H. Beneficial effects of colestipol-niacin on coronary atherosclerosis. A 4-year follow-up. JAMA 1990;264:3013-3017.[Abstract/Free Full Text]
62. The Post Coronary Artery Bypass Graft Trial Investigators. 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. N Engl J Med 1997;336:153-162.[Abstract/Free Full Text]
63. White C.W., Gobel F.L., Campeau L., et al. Effect of an aggressive lipid-lowering strategy on progression of atherosclerosis in the left main coronary artery from patients in the post coronary artery bypass graft trial. Circulation 2001;104:2660-2665.[Abstract/Free Full Text]
64. Dotani M.I., Elnicki D.M., Jain A.C., Gibson C.M. Effect of preoperative statin therapy and cardiac outcomes after coronary artery bypass grafting. Am J Cardiol 2000;86:1128-1130.[Medline]
65. Christenson J.T. Preoperative lipid control with simvastatin reduces the risk for graft failure already 1 year after myocardial revascularization. Cardiovasc Surg 2001;9:33-43.[Medline]
66. Sacks F.M., Pfeffer M.A., Moye L.A., et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996;335:1001-1009.[Abstract/Free Full Text]
67. Flaker G.C., Warnica J.W., Sacks F.M., et al. 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]
68. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349-1357.[Abstract/Free Full Text]
69. Knatterud G.L., Rosenberg Y., Campeau L., et al. Long-term effects on 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]
70. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering therapy and of antioxidant vitamin supplementation in a wide range of patients at increased risk of coronary heart disease death: early safety and efficacy experience. Eur Heart J 1999;20:725-741.[Abstract/Free Full Text]
71. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7-22.[Medline]
72. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001;285:2486–97
73. Fonarow G.C., Gawlinski A., Moughrabi S., Tillisch J.H. Improved treatment of coronary heart disease by implementation of a Cardiac Hospitalization Atherosclerosis Management Program (CHAMP). Am J Cardiol 2001;87:819-822.[Medline]

This article has been cited by other articles:

				A. Parolari, C. Loardi, L. Mussoni, L. Cavallotti, M. Camera, P. Biglioli, E. Tremoli, and F. Alamanni Nonrheumatic calcific aortic stenosis: an overview from basic science to pharmacological prevention Eur. J. Cardiothorac. Surg., March 1, 2009; 35(3): 493 - 504. [Abstract] [Full Text] [PDF]

				K. I. Paraskevas Applications of statins in cardiothoracic surgery: more than just lipid-lowering Eur. J. Cardiothorac. Surg., March 1, 2008; 33(3): 377 - 390. [Abstract] [Full Text] [PDF]

				V. Aboyans, L. Labrousse, P. Lacroix, J. Guilloux, S. Sekkal, A. Le Guyader, E. Cornu, and M. Laskar Predictive factors of stroke in patients undergoing coronary bypass grafting: statins are protective. Eur. J. Cardiothorac. Surg., August 1, 2006; 30(2): 300 - 304. [Abstract] [Full Text] [PDF]

				J. Feng and F. W. Sellke Invited commentary Ann. Thorac. Surg., June 1, 2006; 81(6): 2225 - 2226. [Full Text] [PDF]

				T. Schachner Pharmacologic inhibition of vein graft neointimal hyperplasia J. Thorac. Cardiovasc. Surg., May 1, 2006; 131(5): 1065 - 1072. [Abstract] [Full Text] [PDF]

				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., March 1, 2006; 131(3): 679 - 685.

				J. F. Sabik III, E. H. Blackstone, A. M. Gillinov, M. K. Banbury, N. G. Smedira, and B. W. Lytle Influence of patient characteristics and arterial grafts on freedom from coronary reoperation J. Thorac. Cardiovasc. Surg., January 1, 2006; 131(1): 90 - 98. [Abstract] [Full Text] [PDF]

				B. W. Lytle, E. H. Blackstone, J. F. Sabik, P. Houghtaling, F. D. Loop, and D. M. Cosgrove The Effect of Bilateral Internal Thoracic Artery Grafting on Survival During 20 Postoperative Years Ann. Thorac. Surg., December 1, 2004; 78(6): 2005 - 2014. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Francesco Alamanni Paolo Biglioli Alessandro Parolari Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Werba, J. P. Articles by Parolari, A. Search for Related Content PubMed PubMed Citation Articles by Werba, J. P. Articles by Parolari, A. Related Collections Cardiac - pharmacology