As mentioned before, statins are competitive inhibitors of HMG-CoA reductase, which converts HMG-CoA to mevalonate (Fig. 48.3). This initial step is the rate-limiting step in the synthesis of cholesterol. Statins decrease low-density lipoprotein (LDL) through a multistep process that occurs initially in the liver hepatocytes. Statins interfere with hepatic cholesterol synthesis, which leads to an enhanced expression of the LDL receptor gene. The increase in triggered transcription factors then signals an increase in the synthesis of LDL receptors, which also limits degradation of LDL receptors. Finally, this increased number of LDL receptors augments the removal of LDL from the blood [1, 2]. Another theory as to how statins ultimately lower LDL levels is through the removal of LDL precursors. These precursors, very-low-density lipoprotein and intermediate-density lipoprotein (VLDL and IDL), are made up of apoB-100. The increased numbers of LDL receptors function to eliminate apoB-100 and ultimately decrease further LDL production [1, 3].

Statins are primarily metabolized via hepatic enzymes and the cytochrome P450 3A4 hydroxylation pathway. Intestinal absorption of statins can reach up to 85 % after oral intake. The main form of drug elimination is via hepatic biliary excretion with less than 2 % recovered in the urine [22]. All statins are either administered in their active, B-hydroxy acid, form or as inactive lactones, which require transformation into active B-hydroxy acid forms. The already active statins, atorvastatin, pravastatin, fluvastatin, and rosuvastatin, are capable of inhibiting HMG-CoA reductase prior to undergoing transformation. However, the inactive statins, simvastatin and lovastatin, must first be transformed in the liver to their respective B-hydroxy acids prior to having downstream effects. Due to the transformation process required for activation, these statins undergo high intestinal clearance and first-pass metabolism and have a low systemic availability (5–30 %). Food has been shown to reduce the rate of statin absorption as well. Most statins reach a maximum plasma concentration in about 1–4 h. However, rosuvastatin and atorvastatin, two of the long-acting statins, have half-lives of 15–20 h with a maximum plasma concentration of 2–4 h. The longer half-lives yield greater efficacy of cholesterol-lowering capability [15].

Multiple studies have demonstrated the effects of statin use on reducing coronary events in multiple patient populations, including men, women, African American, diabetics, smokers, and hypertensive patients [9–14]. It has been proven that reduction in LDL cholesterol concentration can potentially prevent cardiovascular disease, such as myocardial infarction (MI). There is a 25–30 % reduction in mortality when statin derivatives are used for primary and secondary prevention of cardiovascular disease in patients 60–80 years of age [5, 33, 34] (Fig. 48.4).

Studies have proven that statins have multiple cholesterol-related cardiovascular benefits. These studies have also proven that statins also provide other cholesterol-independent effects on protecting the cardiovascular system. The main studied cholesterol-independent benefits include the anti-inflammatory response, antithrombosis, enhanced fibrinolysis, vasodilation, and decreased platelet reactivity. These are described below and are outlined in Fig. 48.5 [6].

The figure below (Fig. 48.6) graphically helps demonstrate the anti-inflammatory effects of statins. One of the many by-products of the cholesterol synthesis pathway is isoprenoids. The entire cholesterol synthesis pathway is disrupted by statins influence on inhibiting HMG-CoA reductase. Therefore, the inhibition of HMG-CoA in turn downregulates and inhibits the formation of isoprenoids. The inhibition of isoprenoids in turn prevents downstream inflammatory signaling via the obstruction of Rho and Ras. Rho and Ras are two inflammatory signals in the human body. Rho eventually activates nuclear factor, NF-κB, which signals inflammatory responses and reduces endothelial nitric oxide synthase. Therefore, through a multistep inhibition pathway, statins inhibit Rho and Ras and help to inhibit the inflammatory pathway [7].

Another important anti-inflammatory effect of statins is through their effect on the cytokine pathway and inhibiting plaque rupture [8]. Many studies have shown that fatal postoperative MIs are a result of plaque rupture and that this adverse event occurs secondary to rupture just as often as perioperative oxygen/supply mismatch. Statins have been shown to be effective at inhibiting the proinflammatory cytokines (IL-1, IL-6, and IL-8) and increasing the anti-inflammatory cytokine (IL-10). Figure 48.5 graphically demonstrates these effects [6]. All of these combined effects have an overall capability of reducing the possibility of plaque rupture by stabilizing the lipid core and decreasing the inflammation of the cells in the fibrous cap [8, 9]. Reducing the incidence of plaque rupture has helped to reduce the incidence of adverse cardiovascular outcomes in medical patients [9–14].

Lastly, the idea of continuing statins postoperatively has gained a lot of attention over the years. Surgery on the human body causes a massive amount of inflammatory markers to be released into circulation. Studies have shown that the discontinuation of statins postoperatively has led to an increase in cardiovascular events. These adverse events are secondary to an increase in CRP and other proinflammatory markers, which were being inhibited while on statin therapy [11].

There are multiple pathways in which statins ultimately have an effect on vasodilation. Probably the most important pathway affected involves the nitric oxide pathway. Nitric oxide is a powerful vasodilator in the human body, as well as an important cellular signaling molecule. Nitric oxide bioavailability is rapidly increased with the use of statins [12, 13]. Statins, as stated before, inhibit HMG-CoA reductase, which then upregulates endothelial nitric oxide synthase (Fig. 48.5) [6]. Other lipid-independent vasodilatory effects of statins include reduced expression of intercellular adhesion molecule, such as E-selectin; upregulation of heme oxygenase 1 by monocytes; inhibition of angiotensin II-induced reactive oxygen species (ROS) production through downregulation of angiotensin 1 receptors; and inhibition of activation of Rac, a small G protein that contributes to nicotinamide adenine dinucleotide phosphate [NAD(P)H].

Antithrombotic effects of statins can be endothelium dependent and endothelium independent. Statins cause thrombolysis by increasing endothelial thrombotic expression and altering the balance between plasminogen activator inhibitor and tissue plasminogen activator [14]. Moreover, statins can manipulate effects on coagulation factors V, VII, and XII. It is postulated that statins reduce the inflammatory atherosclerotic processes that lead to plaque instability [8, 10]. This reduction can therefore help reduce morbidity and mortality associated with perioperative cardiovascular disease.