Statins: cardiovascular risk reduction in percutaneous coronary intervention-basic and clinical evidence of hyperacute use of statins

Abstract

Reduction of LDL-cholesterol concentration in serum, blocking the isoprenylation of GTPases and the activation of myocyte-protective enzyme systems are three mechanisms that currently explain the lipid and non-lipid effects of statins. However, the decrease of LDL-cholesterol, the reduction of inflammation biomarkers and even the atheroregresion, as surrogate effects to the mechanisms of action of statins would be irrelevant if not accompanied by a significant decrease in the incidence of cardiovascular events. Statins like no other pharmacological group have proven to reduce the incidence of cardiovascular events and prolong life in any clinical scenario. This article review the basic and clinical evidence that support a new indication for HMG-CoA reductase inhibitors "pharmacological myocardial preconditioning before anticipated ischemia" or hyperacute use of statins in subjects with any coronary syndrome eligible for elective, semi-urgent or primary percutaneous coronary intervention: ARMYDA-Original, NAPLES I-II, ARMYDA-ACS, ARMYDA-RECAPTURE, Non-STEMI-Korean, Korean-STEMI trials.

Figure 1

Regulation of LDL-R in 5 steps. Step 1. The LDL is recognized in apo-B100 by the LDL-R located in the membrane structures “clathrin-coated pits.” Step 2. It forms an endocytic vesicle or endosome containing LDL and LDL-R, the LDL-R is dissociated through lowering of the pH within the endosome, and the LDL is transferred to the lysosomes. Step 3. In lysosomes, apo-B100 is hydrolyzed into amino acids and cholesteryl ester is deesterified by enzymatic hydrolysis. Step 4. Nonesterified cholesterol (hydrophobic) is transported to the cell membranes by the “hydrophobic handoff mechanism”; in this mechanism Niemann Pick 2 and 1 proteins form a hydrophobic core containing nonesterified cholesterol. Step 5. Nonesterified cholesterol is transferred by the binomial NP2-NP1 to cell membranes, its concentration in the Sarcoplasmic Reticulum/Golgi Apparatus membranes is the signal that inhibits the dissociation of SCAP-SREBP and thus blocks the synthesis of LDL-R.

Figure 2

Statins reduce cholesterol, and isoprenoids synthesis. The statins inhibit HMG-CoA-R and block the synthesis of mevalonate, cholesterol, and isoprenoids. In the hepatocyte, the reduction in cholesterol synthesis determines a reduction in VLDL synthesis and increase in the synthesis of LDL-R; thus, the reduced production of VLDL, IDL, and LDL and increased elimination of circulating IDL, and LDL, explain the reduction in LDL concentration. In the endothelial cells the reduction in the synthesis of isoprenoids determines a reduction of the inflammatory response mediated by inactivation of smgs from different families (Rho, Ras, Rab).

Figure 3

Statins, mechanisms, and myocyte-protective effects. Statins increase the expression of KLF2 and eNOS synthesis and also increase the activation of eNOS and nitric oxide production. In the myocyte the activation of AMPK increases the income and energy substrate utilization, as well as the production of ATP.

Figure 4

Statins and recapture of the RISK pathway. This modified graphic of Mensah's work, shows how the quotient (necrosis/ischemia) is similar in rats treated for 1 or 2 weeks with methylcellulose (red bars) or atorvastatin (blue bars). This loss of myocyte-protective effect is “recaptured” significantly with the reload of atorvastatin (green bars).

Figure 5

ARMYDA-Original study. This modified graphic of the ARMYDA-Original study (Vincenso Pasceri as first author) demonstrated for the first time as a randomized study the favorable effect of statins before PCI. In individuals with stable coronary syndromes, statin-naïve, undergoing elective PCI, the administration of atorvastatin 40 mg/7 days before PCI significantly reduces the incidence of MI-PCI associated (CPK-MB > 2x ULN, 2004 criteria). The MI-PCI associated was 18% in the placebo group versus 5% in the atorvastatin group with P = .025.

Figure 6

ARMYDA-CAMs study. This modified graphic of the ARMYDA-CAMs study showed that, in a preselected subgroup or the ARMYDA-Original study, in individuals with stable coronary syndromes, statin-naïve, and undergoing elective PCI, the administration of atorvastatin 40 mg/7 days before PCI significantly reduced the percentage of elevation 24 hours after PCI of ICAM and E-selectin. This reduction was not observed with VCAM (not shown in the graphic).

Figure 7

NAPLES II Study. This modified graphic of the NAPLES II study, confirmed with a randomized study, as compared to a control group, the favorable effect of statins before PCI. In individuals with stable coronary syndromes, statin-naive undergoing elective PCI, the administration of atorvastatin 80 mg/24 hours before PCI significantly reduces the incidence of MI-PCI associated (CPK-MB > 3x ULN, 2007 criteria). As can be seen, the benefit was especially significant in the subgroup of individuals with CRP > 6 mg/L before PCI, in this subgroup the incidence of MI-PCI associated was 16.5% in the control group versus 4.6% in the atorvastatin group with P = .016.

Figure 8

ARMYDA-RECAPTURE study. This modified graphic of the ARMYDA-RELOAD (RECAPTURE) study, showed with a randomized design, as compared to patients treated with placebo, the recapture effect of statins. In individuals with stable and unstable coronary syndromes, chronically treated with statins and LDL <100 mg/dl, who underwent elective or semiurgent PCI, the administration of 120 mg of atorvastatin before PCI significantly reduces the incidence of MACEs on day 30 after PCI. This benefit was very significant in the subgroup of individuals with unstable coronary syndromes, with an MACEs incidence of 14.8% in the placebo group versus 3.3% in the atorvastatin group with P = .015.

Figure 9

Statin-STEMI study. This modified graphic of the Statin-STEMI study, demonstrated the favorable effect of high doses of atorvastatin before primary PCI on the Myocardial Reperfusion Indicators (cTFC, CSTR, and MBG) after procedure in individuals with STEMI.