An Overview of the Pleioptropic Effects of Statins and Their Impact on Postoperative Outcomes in Cardiovascular Surgery Patients

Review Article

J Cardiovasc Disord. 2017; 4(1): 1033.

An Overview of the Pleioptropic Effects of Statins and Their Impact on Postoperative Outcomes in Cardiovascular Surgery Patients

Hearps T and Du Toit EF*

Menzies Health Institute of Queensland, School of Medical Science, Griffith University, Gold Coast, QLD, Australia

*Corresponding author: EF du Toit, School of Medical Science, Griffith University, Gold Coast Campus, Parklands Drive, Southport, 9726, QLD, Australia

Received: May 02, 2017; Accepted:May 26, 2017; Published: June 02, 2017


Obesity and its comorbidities (dyslipidaemia, hypertension and insulin resistance/diabetes) are all risk factors that significantly contribute to Cardiovascular Disease (CVD) morbidity and mortality. Although statins form the cornerstone of most CVD prevention strategies and are effective for the management of blood lipids, their pleiotropic cholesterol-independent effects have generated significant interest. There is compelling evidence to suggest that statins may influence perioperative outcomes after cardiovascular surgery.

The pleiotropic effects of statins include the attenuation of; 1) inflammation, 2) vascular dysfunction, 3) platelet and smooth muscle cell aggregation, and, 4) atherothrombogenic enzyme activity. These effects all potentially contribute to attenuation of atherosclerotic lesion formation, plaque development and rupture, and atherothrombosis. Clinical trials report a significantly diminished incidence of adverse cardiac outcomes when statin therapy is implemented during the perioperative period in cardiovascular surgery. Similarly, some studies have reported an increase in adverse postoperative cardiac outcomes after postoperative withdrawal of chronic statin therapy. The view that these beneficial effects of statins are due to their pleiotropic effects is further supported by data showing that normocholesterolaemic patients on statins also exhibit cardioprotective benefits in response to statin therapy. The data reviewed in this paper suggests that sustained perioperative statin therapy could potentially be adopted and incorporated into the perioperative treatment regime of patients undergoing high-risk cardiac and vascular surgical procedures to diminish the risk of postoperative adverse cardiac events.

Keywords: Statins; Pleiotropic Effects; Post-operative outcomes; Cardiac


Adiposity is becoming increasingly prevalent, with overweight affecting 39 and obesity 13% of the global adult population [1]. It is well established that both obesity and the associated dyslipidaemia are risk factors for Cardiovascular Disease (CVD) with statin therapy used as a primary preventative measure for CVD in these at risk patients. Statins inhibit cholesterol biosynthesis and are widely prescribed to lower serum cholesterol and prevent CVD.

Although significant research focus has been on the lipid lowering effects of statins, less is known about the pleiotropic effects of statins and how they impact patient postoperative outcomes. The pleiotropic effects of statins are varied; with many of the beneficial effects being ascribed to not only directs cardiovascular effects, but also systemic effects of these compounds. There have been several studies investigating the role of these pleiotropic effects on clinical outcomes following ischaemic events, including myocardial infarctions [2,3], cardiac surgery, vascular surgery, and non- cardiovascular surgery [4-12]. Here we highlight the proposed pleiotropic mechanisms of statins and examine the clinical outcomes of studies using statin therapy.

Statins, their primary effects and their efficacy

Statins act to lower serum cholesterol levels by reducing hepatic and intestinal HMG-CoA reductase activity which is involved in the production of mevalonate [13] and the subsequent biosynthesis of cholesterol [14]. Statins vary in their action and the extent to which they lower plasma lipids. A dose- specific meta-analysis conducted by Edwards and Moore [15] found that statins lowered total cholesterol by 17-35%, LDL cholesterol by 24-49%, and increased HDL by roughly 5%. They also performed a study in which they determined that rosuvastatin and atorvastatin were the two most potent lipidlowering statins [16] which would suggest that hydrophilic statins have the greatest lipid lowering efficacy. Clinical outcomes after an Acute Myocardial Infarct (AMI) did however not differ significantly when comparing hydrophilic and lipophilic statins in a one year follow-up study [3].

Pleiotropic effects of statins

A pleiotropic effect of statins refers to their effects that are independent of their lipid-lowering effects [17]. These effects are ascribed to a range of mechanisms elicited in the cardiovascular, immune and central nervous systems and include improving vascular endothelial function, modulating pro- coagulant and platelet activity, stabilising atherosclerotic plaques, inhibiting smooth muscle proliferation and attenuating inflammatory responses [4]. Many of the pleiotropic effects of statins are mediated through inhibition of isoprenylation, reducing the function of isoprenoids such as Rho and Rac, which impacts on inflammation and vascular function [5]. Statins also improve cardiovascular outcomes in patients with normal healthy cholesterol levels [4] which would suggest that the benefits are independent of their effects on circulating lipids.

Perioperative use of statins

A number of studies have investigated the impact of statins on cardiovascular outcomes when used in the perioperative period. The surgical procedures these studies assessed were generally limited to high risk invasive cardiac and vascular surgery. Data from these studies provide compelling evidence to suggest that statin therapy may reduce mortality, myocardial infarction and the duration of hospitalisation following both cardiac and non-cardiac surgery [4].

An early prospective randomised trial investigating the use of statins in the lead-up to cardiac surgery found that preoperative statin treatment significantly lowered the incidence of postoperative thrombocytosis and myocardial infarction following coronary artery bypass grafting in hypercholesterolemia patients [6]. The effect of preoperative statins on postoperative mortality (during the in-hospital stay) was investigated in a case controlled study [7]. Peri-operative statin use was significantly higher in those that survived in-hospital stay (25% vs 8%, p<0.001). The mortality odds ratio was 0.22 (0.10 to 0.47) when comparing statin users and nonusers [7]. Mortality rates were also 4.5 times greater in patients not on preoperative statin therapy [7]. A recent meta-analysis of preoperative statin use involving ~90,000 cardiac surgery patients, found that preoperative statin therapy resulted in a 31% odds reduction for all-cause mortality in the postoperative period (odds ratio 0.69; P < 0.0001) [8]. Statin therapy was also associated with a significant decrease in postoperative endpoints of atrial fibrillation (odds ratio = 0.71), stroke (odds ratio = 0.83) and duration of in-hospital treatment (weighted mean difference = -0.57) [8]. This study however reported that preoperative statin treatment did not reduce postoperative myocardial infarction or renal failure [8].

A study conducted by Kennedy and co-workers [9] found that patients who were on statin therapy prior to carotid endarterectomies had reduced in-hospital mortality and ischaemic stroke. A metaanalysis assessing the clinical outcomes of 2292 patients undergoing cardiac or non-cardiac surgery found that perioperative statin treatment decreased: 1) the risk of atrial fibrillation in cardiac surgery patients and, 2) Myocardial infarction risk in both cardiac and noncardiac patients. Statins however had no effect on mortality rates in either cardiac or non-cardiac patients [2]. These investigators proposed that the use of statin therapy to ameliorate adverse cardiac outcomes in patients undergoing high-risk surgical interventions may be warranted.

Impact of discontinuation of statins in the perioperative period

Discontinuation of statin therapy during the postoperative period appears to have significant adverse effects on the cardiovascular outcomes following high-risk interventional procedures [4]. An increasing number of studies report improved postoperative cardiac outcomes due to attenuated inflammation associated with statin therapy [10], while statin withdrawal possibly causes an inflammatory upsurge and adverse cardiac outcomes [11].

A prospective study compared the postoperative cardiovascular outcomes of patients who either continued or discontinued statin therapy after surgery [12]. The odds risk ratio as a predictor of myonecrosis in the continuation and discontinuation groups was 0.38 and 2.1 respectively, which translates to a relative risk reduction of 5.4 for those on continued statin therapy. Withdrawal of statins following vascular surgery served as an independent predictor of postoperative myonecrosis (odds ratio = 2.9). The outcomes of this and another study [18] strongly suggest that postoperative discontinuation of statin therapy contributes to adverse cardiovascular outcomes in these patients.

Mechanisms underpinning the pleiotropic effects of statins

The pleiotropic effects of statins potentially play an important role in the reduction of ischaemic events in the perioperative period. The most significant pleiotropic effects that potentially reduce the risk of adverse cardiovascular events include improving endothelial function, stabilising atherosclerotic plaques, inhibiting the thrombogenic response, decreasing oxidative stress, attenuating inflammation, modulating platelet function and inhibiting smooth muscle aggregation [17]. The mechanisms underlying each of these pleiotropic effects and how they decrease adverse cardiovascular events will be explored.

Statins and endothelial function

While statins protect against atherosclerosis by lowering cholesterol, endothelial function in patients on statins is improved before overt changes in cholesterol levels are detected. These observations have led to the proposal that statins directly enhance endothelial function [19]. Statins are known to preserve tissue Nitric Oxide (NO) signalling, protecting against vascular endothelial injury and myocardial dysfunction [20]. NO is a key mediator of vascular dilatation and protection and is derived from endothelial Nitric Oxide Synthase (eNOS) which is a critical enzyme for the maintenance of normal vascular function [21].

Statins upregulate eNOS activity, augment NO production and enhance endothelial function while also protecting the myocardium [22]. Statin treatment also blocks mevalonate synthesis in cultured endothelial cells [23]. However, under conditions where ROS generation may be exacerbated by risk factors such as smoking, hypertension and hypercholesterolaemia, Reactive Oxygen Species (ROS) can react with NO to form peroxynitrite which uncouples eNOS. Endothelial NOS then produces more ROS, particularly peroxynitrite, in place of NO, thus exacerbating oxidative stress, as a consequence of the imbalance between ROS production and elimination [24]. Increased vascular ROS production impairs endothelial function and contributes to vascular dysfunction [25] and myocardial injury [26]. Wagner and co-workers [27] found that statin treatment of healthy rats attenuated ROS formation and improved aortic endothelial function.

The loss of these effects of statins on the endothelium potentially underpins the increase in adverse postoperative outcomes associated with discontinuation of statin therapy. When statin therapy is withdrawn a rebound effect occurs in which isoprenylation of Rho is disinhibited, down-regulating eNOS activity to below pre-statin therapy levels, thus lowering NO bioavailability [5] (Figure 1).

Citation: Hearps T and Du Toit EF. An Overview of the Pleioptropic Effects of Statins and Their Impact on Postoperative Outcomes in Cardiovascular Surgery Patients. J Cardiovasc Disord. 2017; 4(1): 1033.