Atorvastatin induces associated reductions in platelet P-selectin, oxidized low-density lipoprotein, and interleukin-6 in patients with coronary artery diseases

The development and progression of atherosclerosis comprises various processes, such as endothelial dysfunction, chronic inflammation, thrombus formation, and lipid profile modification. Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that have pleiotropic effects in addition to cholesterol-lowering properties. However, the mechanisms of these effects are not completely understood. Here, we investigated whether atorvastatin affects the levels of malondialdehyde-modified low-density lipoprotein (MDALDL), an oxidized LDL, the proinflammatory cytokine interleukin-6 (IL-6), or platelet P-selectin, a marker of platelet activation, relative to that of LDL cholesterol (LDL-C). Forty-eight patients with coronary artery disease and hyperlipidemia were separated into two groups that were administered with (atorvastatin group) or without (control group) atorvastatin. The baseline MDA-LDL level in all participants significantly correlated with LDL-C (r = 0.71, P < 0.01) and apolipoprotein B levels (r = 0.66, P < 0.01). Atorvastatin (10 mg/day) significantly reduced the LDL-C level within 4 weeks and persisted for a further 8 weeks of administration. Atorvastatin also reduced the MDA-LDL level within 4 weeks and further reduced it over the next 8 weeks. Platelet P-selectin expression did not change until 4 weeks of administration and then significantly decreased at 12 weeks, whereas the IL-6 level was gradually, but not significantly, reduced at 12 weeks. In contrast, none of these parameters significantly changed in the control group within these time frames. The reduction (%) in IL-6 between 4 and 12 weeks after atorvastatin administration significantly correlated with that of MDALDL and of platelet P-selectin (r = 0.65, P < 0.05 and r = 0.70, P < 0.05, respectively). These results suggested that the positive effects of atorvastatin on the LDL-C oxidation, platelet activation and inflammation that are involved in atherosclerotic processes are exerted in concert after lowering LDL-C.     

Statin treatment is associated with improved prognosis in patients with AF-related stroke

Background/objectives

The most recent ACC/AHA guidelines recommend high-intensity statin therapy in ischemic stroke patients of presumably atherosclerotic origin. On the contrary, there is no specific recommendation for the use of statin in patients with non-atherosclerotic stroke, e.g. strokes related to atrial fibrillation (AF). We investigated whether statin treatment in patients with AF-related stroke is associated with improved survival and reduced risk for stroke recurrence and future cardiovascular events.

Methods

All consecutive patients registered in the Athens Stroke Registry with AF-related stroke and no history of coronary artery disease nor clinically manifest peripheral artery disease were included in the analysis and categorized in two groups depending on whether statin was prescribed at discharge. The primary outcome was overall mortality; the secondary outcomes were stroke recurrence and a composite cardiovascular endpoint comprising of recurrent stroke, myocardial infarction, aortic aneurysm rupture or sudden cardiac death during the 5-year follow-up.

Results

Among 1602 stroke patients, 404 (25.2%) with AF-related stroke were included in the analysis, of whom 102 (25.2%) were discharged on statin. On multivariate Cox-proportional-hazards model, statin treatment was independently associated with a lower mortality (hazard-ratio (HR): 0.49, 95%CI:0.26–0.92) and lower risk for the composite cardiovascular endpoint during the median 22 months follow-up (HR: 0.44, 95%CI:0.22–0.88), but not with stroke recurrence (HR: 0.47, 95%CI:0.22–1.01, p: 0.053).

Conclusions

In this long-term registry of patients with AF-related stroke, statin treatment was associated with improved survival and reduced risk for future cardiovascular events.     

Stroke severity and outcomes for octogenarians receiving statins

Pre-exposure to 3-hydroxy-3-methylgutaryl-coenzyne A reductase inhibitors (statins) appears to improve outcomes in patients with acute ischemic stroke (AIS). Whether this extends to patients over 80 is not known. Patients ≥80 years of age with AIS were retrospectively reviewed from the stroke registry of a tertiary stroke center. Pre-admission statin use, demographics, vascular risk factors, and comorbid conditions were assessed. Primary outcomes were admission National Institutes of Health Stroke Scale (NIHSS) scores and in-hospital mortality/discharge to hospice, and secondary outcomes included subsequent intracerebral hemorrhage (ICH) and modified Barthel index (mBI) at 3 months. Multivariable logistic regression was used to evaluate the association between pre-admission statin use and outcomes among elderly patients. Among 804 patients ≥80, those taking statins prior to AIS admission were overall younger, were more likely to have hypertension, coronary artery disease, diabetes, hyperlipidemia, and were more likely to be on an antiplatelet, but less likely to receive treatment with IV tissue plasminogen activator (tPA). Patients on statin had lower stroke severity (NIHSS > 16: 21.9% vs. 27.6%) and in-hospital mortality/discharge to hospice (22.8% vs. 27.6%), but neither was significant. There was no difference in ICH (1.2% vs. 1.9%), and patients on statins had a non-significant trend toward less disability on mBI (27.5% vs. 35.7%). Pre-admission statin use did not show a statistical difference in either outcome, but it did show a trend toward lower stroke severity and improved short-term outcomes. In addition, our study suggests that statins may be safe in elderly stroke patients and may not increase the risk of ICH.     

Preloading with atorvastatin before percutaneous coronary intervention in statin-naïve Asian patients with non-ST elevation acute coronary syndromes: A randomized study

BackgroundData on atorvastatin pretreatment in Asian patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) are limited. However, there have been studies in other populations in Asia which demonstrated that statins can reduce the risk of periprocedural myocardial infarction (MI).Methods and resultsStatin-naïve patients with non-ST-segment-elevation (NSTE)-ACS scheduled for PCI were randomized to usual care or atorvastatin preloading groups. All patients received usual care including atorvastatin 40 mg/day. The atorvastatin group received atorvastatin 80 mg 12 h and 40 mg 2 h pre-PCI. Of 499 patients randomized, 247 were assigned to atorvastatin preloading. Following coronary angiography, 335 patients (163 atorvastatin) received PCI. During the 30 days post-PCI, major adverse cardiac events (death, MI, and target vessel revascularization) occurred in 24 (15%) atorvastatin and 27 (16%) usual care patients (p = NS). Post hoc analyses showed that at 8 h post-PCI, 3.82% of the atorvastatin group and 7.22% of the usual care group had a post-procedural creatine kinase-myocardial band (CK-MB) above 3 times the upper limit of normal (p = 0.27) and at 24 h post-PCI, the rate was 7.64% versus 9.47% (p = 1.0). Safety profile suggests that high-dose atorvastatin (40 mg) for up to 1 month, in conjunction with usual care, is relatively safe and well tolerated.ConclusionsThis study of statin-naïve Korean and Chinese patients with NSTE-ACS who received additional atorvastatin loading doses of 80 mg at 12 h, and 40 mg at 2 h, pre-PCI did not find a beneficial effect compared with usual post-PCI atorvastatin 40 mg/day treatment. Atorvastatin was found to be well tolerated in Asian patients with NSTE-ACS undergoing PCI. Results of the current study merit further investigation of the early use of statins in patients with NSTE-ACS to delineate patient subgroups who may benefit from this therapy.     

Atherogenic mononuclear cell recruitment is facilitated by oxidized lipoprotein-induced endothelial junctional adhesion molecule-A redistribution

Background

Junctional adhesion molecule (JAM-) A is a transmembrane protein expressed in many cell types and maintains junctional integrity in endothelial cells. Upon inflammatory stimulation, JAM-A relocates to the apical surface and might thereby facilitate the recruitment of leukocytes.

Objective

Although inflammatory JAM-A redistribution is an established process, further effort is required to understand its exact role in the transmigration of mononuclear cells, particularly under atherogenic conditions.

Methods

By the use of RNA interference and genetic deletion, the role of JAM-A in the transmigration of T cells and monocytes through aortic endothelial cells was investigated. JAM-A–localization and subsequent mononuclear cell rolling, adhesion and transmigration were explored during endothelial inflammation, induced by oxidized LDL or cytokines.

Results

RNA interference or genetic deletion of JAM-A in aortic endothelial cells resulted in a decreased transmigration of mononuclear cells. Treatment of the endothelial cells with oxLDL resulted in an increase of both permeability and apical JAM-A presentation, as shown by bead adhesion and confocal microscopy experiments. Redistribution of JAM-A resulted in an increased leukocyte adhesion and transmigration, which could be inhibited with antibodies against JAM-A or by lovastatin-treatment, but not with the peroxisome proliferator activated receptor gamma-agonist pioglitazone.

Conclusions

This study demonstrates that redistribution of JAM-A in endothelial cells after stimulation with pro-atherogenic oxidized lipoproteins results in increased transmigration of mononuclear cells. This inflammatory dispersal of JAM-A could be counteracted with statins, revealing a novel aspect of their mechanism of action.     

Factors associated with 2-year persistence in fully non reimbursed lipid-lowering treatments

Objective

to evaluate the main factors associated with long-term persistence in fully paid lipid-lowering treatment.

Methods

We selected 628 moderately hypercholesterolemic subjects (M: 307; F: 311, mean age 59 ± 9 years old), to whom we firstly prescribed a statin (N. 397) or different kinds of lipid-lowering nutraceuticals (N. 231). Then, depending on their will, patients took brand statin (N. 194) or generic statins (N. 203).

Results

The main determinants of long-term persistence in therapy are female sex (OR 1.21, 95%CI 1.08–1.42), family history of early cardiovascular disease (OR 1.31, 95%CI 1.13–1.49), baseline LDL-C (OR 1.19, 95%CI 1.02–1.33) and treatment with nutraceuticals versus statins (OR 1.29, 95%CI 1.14–1.38). Persistence appears not to be influenced by patient's age, smoking habit, adverse events during treatment, and estimated cardiovascular risk.

Conclusion

Among self-paying patients with mild hyperlipidemia, medication persistence is highest among those taking nutraceuticals, followed by brand statins, followed by generic statins.     

Peripheral microvascular dysfunction predicts residual risk in coronary artery disease patients on statin therapy

Objective

Although lowering of low-density lipoprotein cholesterol (LDL-C) by statins is essential in treatment of coronary artery disease (CAD) patients, there is considerable residual risk of secondary coronary artery events (CAE). We examined whether microvascular dysfunction (MiD), measured by peripheral artery tonometry (PAT), can predict prognosis of CAD patients previously treated with statins.

Methods

We measured log-transformed reactive hyperemia index (L_RHI) in 213 CAD patients who had already achieved LDL-C <100 by statin therapy. Patients were followed-up for secondary CAE for a median of 2.7 years. Patients were divided into two groups: L_RHI ≥ 0.54 (n = 99) and L_RHI < 0.54 (n = 114).

Results

During follow-up, CAE occurred in 4 (4.0%) patients in the L_RHI ≥ 0.54 group and 18 (15.8%) patients in the L_RHI < 0.54 group (P = 0.006). Cox regression analysis indicated that L_RHI was an independent predictor for CAE even after adjustment by Framingham traditional risk factors (FRF; age, T-C/HDL-C ratio, systolic blood pressure, diabetes, current smoker, and gender) and estimated glomerular filtration rate (eGFR) for secondary CAE (HR 0.79, 95% CI: 0.66–0.95). ROC analysis for CAE prediction showed that the AUC for models including FRF only, FRF + eGFR, and FRF + eGFR + L_RHI were 0.60, 0.71, and 0.77, respectively. Moreover, adding eGFR to FRF only (0.63, P = 0.003) and adding L_RHI to the FRF + eGFR model were associated with significant improvement of net reclassification improvement (0.79, P = 0.007).

Conclusion

MiD measured by non-invasive PAT adds incremental predictive ability to traditional risk factors for prognosis of CAD patients successfully treated with statins.     

A kindred with fish eye disease,corneal opacities,marked high-density lipoprotein deficiency,and statin therapy

A kindred affected with fish eye disease (FED) from Oklahoma is reported. Two probands with corneal opacification had mean levels of high-density lipoprotein (HDL) cholesterol (C), apolipoprotein (apo) A-I, and apoA-I in very large alpha-1 HDL particles that were 9%, 17%, and 5% of normal, whereas their parents and 1 sibling had values that were 61%, 77%, and 72% of normal. The probands had no detectable lipoprotein-X, and had mean low-density lipoprotein cholesterol (LDL-C) and triglyceride levels that were elevated. Their mean lecithin cholesterol acyltransferase (LCAT) activities, cholesterol esterification rates, and free cholesterol levels were 8%, 42%, and 258% of normal, whereas their parents and 1 sibling had values that were 55%, 49%, and 114% of normal. The defect was due to 1 common variant in the LCAT gene in exon 1: c101t causing a proline34leucine substitution and a novel mutation c1177t causing a threonine37methionine substitution, with the former variant being found in the father and 1 sibling, and the latter mutation being found in the mother, and both mutations being present in the 2 probands. FED is distinguished from familial LCAT deficiency (FLD) by the lack of anemia, splenomegaly, and renal insufficiency as well as normal or increased LDL-C. Both FLD and FED cases have marked HDL deficiency and corneal opacification, and FED cases may have premature coronary heart disease in contrast to FLD cases. Therapy, using presently available agents, in FED should be to optimize LDL-C levels, and 1 proband responded well to statin therapy. The investigational use of human recombinant LCAT as an enzyme source is ongoing.