Beneficial Effects Of Statins Research Articles

Atorvastatin prevents angiotensin II-induced high permeability of human arterial endothelial cell monolayers via ROCK signaling pathway

Intracranial aneurysm, as a common cause of cerebral hemorrhage, is often discovered when the aneurysm ruptures, causing subarachnoid hemorrhage. Unfortunately, the formation of cerebral aneurysm, which is associated with endothelial damage and macrophage migration, still cannot be prevented now. Tight junctions (TJs) open due to the disappearance of TJ proteins occludin and zona occludens-1 (ZO-1) in damaged endothelia, thus allowing macrophage migration and forming cerebral aneurysm. Therefore, cerebral aneurysm formation can be prevented by increasing TJs of the artery endothelium. Interestingly, statin, which can reduce saccular aneurysm, may prevent aneurysm formation through acting on different steps, but the underlying mechanism remains unclear. In this study, angiotensin II (Ang II) significantly increased the permeability of human arterial endothelial cell (HAEC). Moreover, the distribution of ZO-1 in cell-cell junction area and the total expression in HAECs were significantly decreased by Ang II treatment. However, the abnormal distribution and decreased expression of ZO-1 and hyperpermeability of HAECs were significantly reversed by pretreatment with atorvastatin. Furthermore, Ang II-induced phosphorylations of MYPT1, LIMK and MLC2 were significantly inhibited with atorvastatin or Rho kinase (ROCK) inhibitor (H1152) pretreatment. Knockdown of ROCK-II probably abolished Ang II-induced abnormal ZO-1 distribution and expression deficiency and hyperpermeability of HAECs. In conclusion, atorvastatin prevented Ang II-induced rupture of HAEC monolayers by suppressing the ROCK signaling pathway. Our results may explain, at least in part, some beneficial effects of statins on cardiovascular diseases such as intracranial aneurysm.

The rapid lipopolysaccharide-induced release of matrix metalloproteinases 9 is suppressed by simvastatin.

A rapid increase in matrix metalloproteinase-9 (MMP-9) expression by stimulated leukocytes is common in many diseases. Recent evidence suggests that the beneficial effects of statins are mediated in part by the suppression of MMP-9 release. In this study, we investigated the effect of statin on MMP-9 expression and its antagonist, tissue inhibitor of metalloproteinase-1 (TIMP-1) in LPS-stimulated leukocytes. Rat neutrophils and monocytes were stimulated with lipopolysaccharide (LPS) in the presence of simvastatin. MMP-9 secretion and mRNA expression were analyzed using ELISA and RT-PCR, respectively. Total MMP-9 protein production was measured by Western blot analysis. Potential signal transduction pathways responsible for MMP-9 production were investigated using luciferase reporter assays (NF-κB), pull-down assays (RhoA), and pharmacological inhibition. Our data show that MMP-9 and TIMP-1 expression are differentially induced by LPS in neutrophils and monocytes. We showed that rapid MMP-9 release occurred mainly via secretion from intracellular stores. Moreover, we showed that statin significantly suppressed LPS-induced MMP-9 release and mRNA expression in a time- and concentration-dependent manner. We also evaluated that simvastain postponed the rapid LPS-induced MMP-9 release for about 20 min. In conclusion, we demonstrated that the suppressive effect of simvastatin on LPS-stimulated MMP-9 release does not occur via the NF-κB pathway and the MAPKs pathway, but via the RhoA/ROCK pathway.

Effects of rosuvastatin correlated with the down-regulation of CYP4A1 in spontaneously hypertensive rats

The effects of long-term rosuvastatin treatment on the regulation of cytochrome P450 (CYP) 4A1 expression and vascular homeostasis of spontaneously hypertensive rat (SHR) are still unknown. In this study SHRs were randomly divided into three groups (n=10 per group): SHR group, H-Rv group (rosuvastatin 2.5mg·kg−1·d−1), L-Rv group (rosuvastatin 0.5mg·kg−1·d−1), and 10 male Wistar–Kyoto (WKY) rats in the control group (WKY group). All rats were treated with rosuvastatin for 12weeks. The systolic blood pressure (SBP), left ventricle weight index (LVWI) and plasma lipids were measured during or after treatment. The expression of CYP4A1 mRNA and protein in different tissues was detected by real-time PCR and Western blot. In the heart, kidney and aorta, the CYP4A1 expressions were down-regulated at both mRNA and protein levels in rosuvastatin-treated groups compared with the untreated SHR group (P<0.05 or P<0.01), and high-dose rosuvastatin exerted a stronger down-regulatory effect. The increasing trend of blood pressure was markedly blunted in the rosuvastatin-treated groups versus the untreated SHR group, and a stronger effect was observed in high-dose group (P<0.05 and P<0.01 at different time points). LVWI, an indicator of ventricle hypertrophy, was improved in the high-dose group compared with the untreated SHR group (P<0.05). The plasma concentrations of TC, TG and LDL-C in three SHR groups (high-dose, low-dose and untreated group) were all significantly lower than those of WKY group (P<0.05 or P<0.01), which seemed unrelated to the treatment of rosuvastatin. These findings suggested that hypertension in SHRs was possibly associated with CYP4A1 overexpression, and the effects of rosuvastatin on blood pressure and ventricle hypertrophy were potentially correlated with CYP4A1 and its metabolite other than lipid profiles. Multiple mechanisms are likely involved in the beneficial effects of statins with respect to the regulation of CYP4A1.

Adverse Effects of Statins - Myths and Reality

Statins reduce cardiovascular mortality and morbidity as well as cardiovascular events in patients with a very high risk of cardiovascular disease (CVD) and also in subjects with high or moderate risk by reducing the levels of low-density lipoprotein cholesterol (LDL-C). Although they are considered to be drugs with a very good safety profile, because of their wide use there are many concerns that their adverse effects might compromise their proven beneficial effects. Therefore this article reviews all the data and provides an evidence- based insight what are the proven adverse effects of statins and what are the "myths" about them. The most important side effects include myopathy and rhabdomyolysis. Another side effect is increased activity of liver tests which occurs occasionally and is reversible. However, recent studies even suggest that statin therapy can improve hepatic steatosis. It is beyond any doubt that statins do slightly increase the incidence of type 2 diabetes mellitus in people with two or more components of metabolic syndrome but the cardiovascular benefits of such a treatment by far exceed this risk. Statin therapy has also been associated with some adverse renal effects, eg. acute renal failure, but recent data suggest even a possible protective effect of these drugs on renal dysfunction. Concerns that statins might increase cancer have not been proven. On the contrary, several studies have indicated a possible benefit of these drugs in patients with different types of cancer. Early concerns about cognitive dysfunction and memory loss associated with statins use could not be proven and most recent data even suggest a possible beneficial effect of statins in the prevention of dementia. Systematic reviews and clinical guidelines suggest that the cardiovascular benefits of statins by far out-weight non-cardiovascular harms in patients with cardiovascular risk.

Endometrial Cancer and The Role of Statins.

Dear Editor, According to the new guidelines published by the American College of Cardiology, it is predicted by experts that statins will become one of the most commonly prescribed drugs in the age group of 40-75 years.[1] Statins have been clearly shown to improve morbidity and mortality in patients with cardiovascular diseases. Recently, the beneficial effect of statins on the prognosis and risk of various cancers including gynecological malignancies has also been highlighted in multiple studies. Endometrial cancer, the most common cancer of the female genital tract, has already caused more than 10,000 mortalities in the United States alone in the year 2015.[2] With advanced-stage endometrial cancer presenting with an extremely poor outcome, it is important that factors that can help to decrease the risk of endometrial cancer should be thoroughly investigated. The role of statins in this regard has been highly debatable in the recent past. In an attempt to collect updated evidence, we conducted an extensive literature search utilizing Medline (PubMed and OvidSP) and Cochrane Library to identify all possible studies that have investigated the impact of statins on the risk and prognosis of endometrial cancer. Thirteen relevant citations were found[3,4,5,6,7,8,9,10,11,12,13,14,15] and are shown in Tables ​Tables11 and ​and2.2. Three studies[5,6,7] showed that statins significantly reduce the risk of developing endometrial cancer while seven studies[8,9,10,11,12,13,14] reported no such relationship. The three studies that documented favorable impact of statins on endometrial cancers were all limited by lack of randomization, single center locations, relatively small sample sizes, and confounders as patients had multiple comorbidities. Only three studies[3,4,12] were found that investigated the effect of statins on endometrial cancer survival, which are shown in Table 2. Nevadunsky et al.[3] reported that statins significantly (HR = 0.63) prolong survival in patients with endometrial cancer while the other two studies[4,12] concluded that statins have no significant effect on mortality. These studies have not mentioned if they have looked at progression-free survival or overall survival versus a cancer specific outcome such as time to recurrence. Table 1 Summary of the evidence regarding role of statins in the risk of endometrial cancer Table 2 Summary of evidence regarding statins and outcome of endometrial cancer It is vital to consider the duration of statin usage as well. In a recent meta-analysis by Liu et al.,[15] it was shown that when statins were taken for greater than 5 years, the risk of endometrial cancer was reduced by 31%. Moreover, they reported that studies conducted in Asian populations only had a significant relationship when all potential confounders were considered. It is important to note that patients who take statins tend to be elderly, have multiple comorbidities, and medication regimens including use of hormonal therapy; hence it is imperative to take these confounders into account. These conflicting outcomes warrant further clinical investigation on the role of statins in endometrial cancer. We suggest that histological differentiation of endometrial cancer must also be analyzed in the future studies as different subtypes of endometrial cancer are closely linked with the prognosis. Moreover, randomized clinical trials are needed in this field urgently to eliminate selection, recall, and confounding bias inherent to observational studies. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Cholesterol-lowering statin therapy to prevent atherosclerotic cardiovascular disease — Is the new guideline based on best evidence?

The American College of Cardiology (ACC) and the American HeartAssociation (AHA) expert panel, together with other partner organisa-tions, have recently published a clinical guideline on lowering bloodcholesterol to prevent cardiovascular disease (Stone et al., 2014). Incontrast to a previous comprehensive guideline on the identificationand treatment of dyslipidaemia (National Cholesterol EducationProgram Expert Panel on Detection, E, and Treatment of High BloodCholesterol in Adults (Adult Treatment Panel III), 2002), this currentreportaddressesalimitedbutcriticalsetofclinicalquestions,whichpri-marily relate to the use of statins as the primary pharmacologic treat-ment strategy for adults aged ≥21 years. Key to the development ofthis guideline is recognising that randomised clinical trials (RCTs) andmeta-analyses of these RCTs provide the highest quality of evidence.The panel recognises that most RCTs have been on statins, and strongevidence exists that the beneficial effect of statins in reducing athero-sclerotic cardiovasculardisease (ASCVD) is through their effecton low-ering blood low-density lipoprotein (LDL) cholesterol. However, in aclear departure from the previous guideline which used target levelsofbloodcholesteroltoguidetreatmentstrategies,thenewguidelinefo-cusesontreatmentusingfixeddosesofstatinstoreduceatheroscleroticcardiovascular disease for which good quality evidence from RCTs ex-ists.Thereportsuggeststhatthehighertheintensityofstatintreatment,the greater the reduction in blood LDL-cholesterol, the greater the re-ductioninASCVD. Except inafewclinicalscenarios,thisdictumapplieslargely in a wide variety of clinical settings. Thus, statin treatment maybe recommended for use for individuals with different characteristics(although dosages or intensity of treatment may vary depending onthe individual's background risk and patient preference).InthisissueofPreventiveMedicine,Dr.Nuneshasarguedthatthereisan apparent inconsistency between this ‘philosophy’ espoused by theACC/AHA expert panel of using high quality evidence from RCTs andtheactualrecommendationsthatit developed(Nunes, 2014). Inpartic-ular,Dr.Nunescitedthelackofclinicaltrialevidencetosupporttheuseof 20 mg rosuvastatin as high-intensity therapy and 2 to 4 mgpitavastatin as moderate-intensity therapy for secondary preventionof ASCVD (Table 5 in the published guideline). There is some validityin raising these points. The expert panel based their recommendationslargelyonthefindingsoftheJUPITERtrialwhichisaprimarypreventionRCTforrosuvastatintherapy(Ridkeretal.,2008).TherehasbeennoRCTthathasexaminedtheeffectofthistreatmentforsecondaryprevention.Readingthedetailsoftheguidelinehighlightsanimportantperspectivetakenbytheexpertpanel.Asindicatedabove,theexpertpanelhascon-cluded that the use of statins is effective in a wide range of clinical set-tings. Indeed, it has been estimated that cardiovascular eventsdecrease by 20% for each mmol/l reduction in LDL-cholesterol due tostatin treatment, an effect seen in those with or without any priorhistory of cardiovascular disease (Cholesterol Treatment Trialists et al.,2010). Thus, the expert panel suggests that there is ‘no differentiationbetween the specific statins and doses used in primary and secondaryprevention RCTs’ since high quality evidence suggest that reducingASCVD by statin therapy is a ‘class effect related to the reduction inLDL-cholesterol’. Thus, the lack of secondary prevention RCT forrosuvastatin does not preclude its recommendation for the use of thisdrug either for primary or for secondary prevention of ASCVD. It alsobears reading the full report of the panel which, in fact, recommendsusing20mgrosuvastatinasanalternativetohigh-intensityatorvastatintreatment,forwhichthereissubstantialevidence fromRCTstosupportits use, if the latter drug could not be tolerated.Moreover, the guideline also lists recommended drugs for high-,moderate-, and low-intensity statin therapy (Table 5 in the report).Dr. Nunes rightly questions the inclusion of moderate-intensity therapyof 2 to 4 mg pitavastatin since there is currently no RCT for this therapyinvolving clinical cardiovascular disease endpoints. Table 5 of thepublished report shows that a number of drugs, including pitavastatin,have been written in italics. The footnote indicates that these italiciseddrugsarestatinswhichtheexpertpanelhasnotreviewedforthisreportbut are approved for use by the U.S. FederalDrug Agency (FDA). It is pos-sible that some of these drugs have shown efficacy in reducingLDL-cholesterol but RCTs showing their effect in reducing ASCVDremain to be seen, or at least, have not been reported just yet withinthe time frame of the review conducted for this guideline. It is useful toknow which statins are approved by the FDA (or any other relevant reg-ulatory agency) but to list these drugs together with the panel'srecommendations, without any apparent rationale, could easily lead toconfusion.Dr. Nunes then digresses towards the issue of using all-causemortality as the key outcome for RCTs to inform therapeutic strategiesfor secondary prevention. It may help to look back again at the firstsentence of the preamble of the guidelines which states that goals ofthe ACC and the AHA are to ‘prevent cardiovascular disease …, improvemanagement of people with the disease …, and develop guidelines … thatpromote optimal patient care and cardiovascular health ’. To an extent, the

Benefit of statin pretreatment in prevention of contrast-induced nephropathy in different adult patient population: systematic review and meta-analysis

ObjectivePrevious studies have suggested that statin pretreatment prevents contrast-induced nephropathy (CIN). However, single randomised trials are limited in their number of patients. This meta-analysis aims to assess the role of...

Statins demonstrate a broad anti-cytomegalovirus activity in vitro in ganciclovir-susceptible and resistant strains.

Vasculoprotective and cholesterol-lowering properties are hallmarks of statins. Recently, statins have been found to exhibit antiviral activity. Little is known about the potential of statins against human cytomegalovirus (HCMV), a risk factor in the pathogenesis of atherosclerosis. In this study, the in vitro anti-CMV activity of four statins (atorva-, fluva-, prava-, and simvastatin) was explored in human aortic endothelial cells (HAEC) and fibroblasts. All statins dose-dependently reduced HCMV titers in both cell types. Whereas atorva-, fluva-, and simvastatin showed comparable EC50 and EC90 within a low micromolar range in HAEC, pravastatin exhibited only limited effects. In metabolite rescue experiments, mevalonate almost completely abrogated the anti-CMV activity of all statins, whereas cholesterol failed to counteract the effects. Geranylgeranyl-pyrophosphate partially reversed the anti-CMV activity of most statins, suggesting an involvement of the non-sterol isoprenoid arm of the mevalonate pathway as the mode-of-action. The accumulation of immediate early viral antigens was blocked after 1 dpi onwards, and early and late antigen expression was completely abolished in HAEC. The antiviral activity of statins was comparable to ganciclovir and was retained in a ganciclovir-resistant HCMV strain. These findings provide new insight into the beneficial effects of statins, adding antiviral activity against HCMV to their list of pleïotropic properties, and support further clinical investigations on combined therapy for the management of active HCMV disease.

Meta-Analysis of the Effect of Statins on Renal Function

Statins can significantly improve the lipid profile and reduce cardiovascular events. However, beneficial effects of statins on renal function are still controversial. PubMed, the Cochrane Central Register of Controlled Trials, Web of Knowledge, and ClinicalTrials.gov Web sites were searched for randomized controlled trials. The selected studies reported renal function during treatment with statins and control. Forty-one studies with a total of 88,523 participants were included in this analysis. Compared with statins, placebo group had significantly decreased estimated glomerular filtration rate (eGFR): the standardized mean difference (SMD) of eGFR in change from baseline was 0.15 (95% confidence interval [CI] 0.07 to 0.23, p= 0.0004) in patients with eGFR >60ml/min and 0.09 (95% CI 0.01 to 0.17, p= 0.02) in patients with eGFR 30 to 60ml/min. Compared with placebo, statin group had significantly greater reduction of proteinuria: the SMD of proteinuria in change from baseline was-1.12 (95% CI-1.95 to-0.30, p= 0.008) in patients with urinary protein excretion 30 to 300mg/day and-0.77 (95% CI-1.35 to-0.18, p= 0.01) in patients with urinary protein excretion > 300mg/day. eGFR was significantly greater with high-intensity statins than with moderate-intensity statins (SMD 0.12, 95% CI 0.08 to 0.16, p= 0.00001). Placebo group had significantly decreased eGFR for 1 to 3years (SMD 0.05, 95% CI 0.02 to 0.08, p= 0.003) and >3years (SMD 0.14, 95% CI 0.04 to 0.25, p= 0.007) of statin therapy. The beneficial effect of statins on renal function may be dosage related and duration dependent. In conclusion, statins appear to decrease the rate of reduction of eGFR and slow the progression of pathologic proteinuria moderately.

Statin Use in Patients With Acute Pancreatitis and Symptomatic Gallstone Disease

The long-term use of statins may be associated with a decreased risk for gallstones and biliary-induced acute pancreatitis (AP). Our aim was to study the relationship of statin use and outcome of AP. We investigated the records of 461 consecutive patients with AP and 1140 patients with symptomatic gallstones during 2008 to 2010. The use of lipid-lowering drugs, patient's characteristics, and outcome of patients were recorded. All known risk factors for AP and particularly statin use in idiopathic AP were analyzed. Statin use was comparable between the patients with AP (22%) and patients with cholelithiasis (24%). The frequencies of surgical treatment, duration of hospital stay, or mortality were not different between the statin users compared with the nonusers. Idiopathic AP was more often associated with the use of statins than alcohol- or gallstone-induced AP (44% vs 30% vs 13%, P < 0.002). The etiology of AP was alcohol in 56% of the patients, gallstones in 28% of the patients, and unknown (idiopathic) or miscellaneous in 16% of the patients. No beneficial effect of statins was observed in mortality or other outcome parameters of patients with AP. Statin use was more frequent in patients with idiopathic AP than in patients with biliary- or alcohol-induced AP.

Possible modification of Alzheimer's disease by statins in midlife: interactions with genetic and non-genetic risk factors.

The benefits of statins, commonly prescribed for hypercholesterolemia, in treating Alzheimer’s disease (AD) have not yet been fully established. A recent randomized clinical trial did not show any therapeutic effects of two statins on cognitive function in AD. Interestingly, however, the results of the Rotterdam study, one of the largest prospective cohort studies, showed reduced risk of AD in statin users. Based on the current understanding of statin actions and AD pathogenesis, it is still worth exploring whether statins can prevent AD when administered decades before the onset of AD or from midlife. This review discusses the possible beneficial effects of statins, drawn from previous clinical observations, pathogenic mechanisms, which include β-amyloid (Aβ) and tau metabolism, genetic and non-genetic risk factors (apolipoprotein E, cholesterol, sex, hypertension, and diabetes), and other clinical features (vascular dysfunction and oxidative and inflammatory stress) of AD. These findings suggest that administration of statins in midlife might prevent AD in late life by modifying genetic and non-genetic risk factors for AD. It should be clarified whether statins inhibit Aβ accumulation, tau pathological features, and brain atrophy in humans. To answer this question, a randomized controlled study using amyloid positron emission tomography (PET), tau-PET, and magnetic resonance imaging would be useful. This clinical evaluation could help us to overcome this devastating disease.

Decreased prevalence of dementia associated with statins: a national population‐based study

Dementia is a neurodegenerative disorder that presents a progressive decline in cognitive function and loss of short-term memory with age. Several studies have shown that statin, an oral lipid-lowering drug, may reduce the risk of developing dementia. The objective of this study is to explore the association between statin and the development of dementia. The data analyzed in this study were retrieved from the National Health Insurance Research Database in Taiwan. The sample consisted of 123300 patients ≥20years of age, including 61650 dementia patients with statin use and 61650 patients without statin use who were eligible for inclusion in this study. Univariate and multivariate Cox proportional hazard regression analyses were performed to measure the effects of statin use on the risk of dementia. The beneficial effect of statin on dementia was significant after adjusting for sociodemographic factors and comorbidities (adjusted hazard ratio of 0.92, 95% confidence interval 0.86-0.98). The sex- and age-specific analysis of adjusted hazard ratios showed a higher beneficial effect from statin treatment in women than in men, and the effect became more significant with age. Statin therapy may help prevent the development of dementia, and both hydrophilic and lipophilic statins produce similar effects. However, the preventive characters and associated mechanisms must be further explored and identified.

Dyslipidemia, malnutrition, inflammation, cardiovascular disease and mortality in chronic kidney disease

Dyslipidemia, malnutrition and inflammation are common in patients with chronic kidney disease (CKD) and are strongly associated with cardiovascular disease (CVD) and increased mortality. The epidemiology of dyslipidemia and its interactions with malnutrition and inflammation in CKD patients have been the subject of much interest in the past decade. Recent clinical trials have explored the effects of statins on CVD specifically in CKD patients. Whereas the risk relationship between total cholesterol level and CVD morbidity and mortality is direct, strong and progressive in CKD patients without malnutrition and inflammation, it is inconsistent and often paradoxical in those with malnutrition and inflammation. Accumulating evidence demonstrates that statins reduce significantly the risk of CVD in CKD patients before the initiation of dialysis. However, the beneficial effect of statins in CKD patients on dialysis is uncertain. In CKD patients on dialysis, malnutrition and inflammation pose a higher risk for CVD than dyslipidemia. In CKD patients, the risk of CVD associated to dyslipidemia is complex and is modified by malnutrition and inflammation.

The Relationship Between Inflammatory Markers and Coronary Collateral Circulation Should be Evaluated Together With Cardiovascular Medications in Stable Coronary Artery Disease

We were grateful to read an interesting article by Uysal et al, evaluating the association of neutrophil to lymphocyte ratio (NLR) with coronary collateral circulation (CCC) in a total of 521 consecutive patients with stable coronary artery disease (CAD). They have found that increased NLR (odds ratio [OR]: 0.70, 95% confidence interval [CI]: 0.62-0.80; P 2.75 to predict poor CCC has 65% sensitivity and 68% specificity (area under the curve: 0.714, 95% CI: 0.66-0.75). The degree of CCC is highly variable among patients with CAD. Also, the exact pathophysiological mechanisms of CCC development have not been highlighted completely yet. There were controversial data regarding the relationship between inflammatory markers (particularly C-reactive protein [CRP]) and CCC, and also no data regarding such association with NLR level. As a simple, available, and noninvasive marker, NLR is a recently emerged better reflector of inflammation and oxidative stress which has been studied widely in several cardiovascular diseases. So, first time in the literature, the study by Uysal et al demonstrated the relationship between NLR level and CCC. However, the study should be interpreted with some drawbacks. First, the study lacks any data and correlation of NLR levels with other inflammatory markers, such as CRP. Second, as an important issue, the study by Uysal et al has no data regarding the cardiovascular medications of study population. Among the various drugs, statins should be considered during interpretation of studies with inflammatory markers. It has been known that beneficial effects of statins are not only due to the improvement in plasma lipid levels but also due to the direct action on vasculature including the improvement in endothelial function, anti-inflammatory and antithrombotic actions, and attenuation of atherogenesis. Previous animal studies have shown that statins promote angiogenesis and increase CCC development. However, there are conflicting data in clinical trials. In another study, Dincer et al reported that the dosage and duration of statin therapy ( 10 mg atorvastatin-equivalent dose and on therapy for >3 months) were associated with enhanced CCC. Furthermore, it has been shown that antihypertensive medications might also affect NLR levels. In a study including 72 newly diagnosed patients with hypertension, Fici et al showed that nebivolol has significantly reduced the NLR levels after 6 months of treatment period. In conclusion, the results of the study by Uysal et al showed that higher levels of NLR were associated with poor CCC in stable CAD, but these results should be interpreted with some limitations, particularly statin and antihypertensive therapy among the study groups.

Statins: The paradigm shift in periodontal regeneration

Statins, the lipid-lowering drugs, provide an important and effective approach for the treatment of hyperlipidemia and arteriosclerosis. They function by reducing the blood cholesterol levels which came as a marked discovery to intervene in cardiovascular and cerebrovascular diseases related to increased lipid levels. Their long-term systemic administration in humans has been shown to result in increased bone mineral density. In recent scenario, statins thus modulate bone metabolism exhibiting antibone resorbing properties by upregulating the bone morphogenic proteins and blocking the intermediate metabolites of the mevalonate pathway, made evident by various in vivo and in vitro studies thus providing a new direction in the field of periodontal regeneration. Statins also offered the added advantage of anti-inflammatory and antioxidant properties. Thus, the use of statins both systemically and locally gained wide acceptance by the periodontists as they have shown to increase the bone mineral density and may be effective for periodontal regeneration by stimulation of regenerative factors. This article reviews the beneficial effect of statins and examines their potential role in regenerative periodontal therapy.

Simvastatin inhibits transforming growth factor‐β1‐induced expression of type I collagen, CTGF, and α‐SMA in keloid fibroblasts

Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitor, is used to reduce cholesterol levels. Accumulating evidence has revealed the immunomodulatory and anti-inflammatory effects of simvastatin that prevent cardiovascular diseases. In addition, the beneficial effects of statins on fibrosis of various organs have been reported. However, the functional effect of statins on dermal fibrosis of keloids has not yet been explored. The objective of this study was to determine whether simvastatin could affect dermal fibrosis associated with keloids. We examined the effect of simvastatin on transforming growth factor (TGF)-β1-induced production of type I collagen, connective tissue growth factor (CTGF or CCN2), and α-smooth muscle actin (α-SMA). Keloid fibroblasts were cultured and exposed to different concentrations of simvastatin in the presence of TGF-β1, and the effects of simvastatin on TGF-β1-induced collagen and CTGF production in keloid fibroblasts were determined. The type I collagen, CTGF, and α-SMA expression levels and the Smad2 and Smad3 phosphorylation levels were assessed by Western blotting. The effect of simvastatin on cell viability was evaluated by assessing the colorimetric conversion of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide. Simvastatin suppressed TGF-β1-induced type I collagen, CTGF, and α-SMA production in a concentration-dependent manner. The TGF-β1-induced Smad2 and Smad3 phosphorylation levels were abrogated by simvastatin pretreatment. The inhibition of type I collagen, CTGF, and α-SMA expression by simvastatin was reversed by geranylgeranyl pyrophosphate, suggesting that the simvastatin-induced cellular responses were due to inhibition of small GTPase Rho involvement. A RhoA activation assay showed that preincubation with simvastatin significantly blocked TGF-β1-induced RhoA activation. The Rho-associated coiled kinase inhibitor Y27632 abrogated TGF-β1-induced production of type I collagen, CTGF, and α-SMA. However, Y27632 had no significant effect on TGF-β1-induced phosphorylation of Smad2 and Smad3. In conclusion, the present study suggests that simvastatin is an effective inhibitor of TGF-β1-induced type I collagen, CTGF, and α-SMA production in keloid fibroblasts.

A Review on the Use of Statins and Tocotrienols, Individually or in Combination for the Treatment of Osteoporosis

Skeletal tissue undergoes continuous remodeling which makes it unique among other body tissues. Osteoporosis is a common bone metabolic disorder affecting both men and women. Osteoporosis and its complications mainly osteoporotic fractures, have a high impact on health and economy. Current approved medications are associated with numerous side effects, which limit their use. Identification of a new and safe therapy is mandatory. Statins, also known as HMGCoA reductase inhibitors, are frequently used for the treatment of hypercholesterolemia and for the prevention of morbidity and mortality associated with cardiovascular disease. Statins improved bone health status in intact and ovariectomised rodents following high clinically intolerable oral doses. However, this beneficial effect of statins could not be significantly demonstrated in humans. The reason behind this discrepancy might be due to the safety and bioavailability of the currently used oral statins. Vitamin E, especially the tocotrienols at the dose 60 mg/kg/day provided significant antiosteoporotic effects in different animal models of osteoporosis. The use of the aforementioned dose of tocotrienols was shown to be safe in both humans and animals. Enhancement of bone formation and reduction of bone resorption were achieved more effectively by a combination of tocotrienols and statins than by either treatment when supplemented separately at clinically tolerable doses. Therefore, the adverse effects associated with high statin doses might be avoided with the coadministration of tocotrienols. Moreover, the combination therapy strategy might be useful for patients who are at high risk of osteoporosis, cardiovascular events and hypercholesterolaemia.

Statins decrease mean platelet volume irrespective of cholesterol lowering effect

Recent clinical observations have demonstrated that the beneficial effects of statins are not limited to LDL lowering effect. They have also favourable effects on platelet activation, endothelial function, inflammation, and coagulation cascade. To investigate the effects of statins on mean platelet volume (MPV) which is a simple measure of platelet activation volume in patients who have been prescribed statins. Atorvastatin and rosuvastatin were also compared in respect to effects on MPV. One hundred and forty five patients were retrospectively included in the study from the outpatient cardiology clinic. Patients who had been given statin treatment were recruited based on the records. Baseline and 4-8 weeks biochemical analysis and haematological measurements and cardiovascular risk factors were recorded. Both statins significantly decreased the MPV. MPV of patients did not show any significant correlation with lipid parameters. Linear regression analysis revealed that there were no statistically significant associations of ∆ MPV with the ∆LDL-cholesterol (beta coefficient = 0.13; p = 0.24), ∆DL-cholesterol (beta coefficient = 0.17; p = 0.18) or ∆triglyceride (beta coefficient = -0.11; p = 0.21) after statin treatment. Both statins had comparable effects on lipid parameters at the end of the one month follow up period. Statins significantly reduce MPV irrespective of cholesterol levels, and atorvastatin and rosuvastatin have comparable effects in this regard.

The beneficial effects of statins in patients undergoing hemodialysis

The beneficial effects of statins in patients undergoing hemodialysis are controversial. Our study aimed to investigate the use of statins and the subsequent risk of cardiovascular morbidity and mortality in patients undergoing hemodialysis. We conducted a cohort study using data from the Taiwan National Health Insurance Research Database. Cox regressions were performed to determine the hazard ratio (HR) of cardiovascular morbidity and mortality in the HD patients taking statins (statin cohort) compared with a propensity-matched comparison cohort. The statin cohort included a total of 4074 patients who received statin treatment while also undergoing hemodialysis (mean age 53.3 ± 13.5 years, male 34.9%). The comparison cohort included 8148 propensity-matched hemodialysis patients who were not using statins. During the three years of follow-up, the statin cohort had lower incidence of ischemic stroke (p < 0.001), hospitalizations due to unstable angina (p < 0.001), deep vein thrombosis (p < 0.001), cardiovascular mortality (p < 0.001), and all-cause mortality (p < 0.001). After Cox regression analysis, statin use was independently associated with lower risk of future ischemic stroke (HR, 0.49; 95% confidence interval [CI], 0.39-0.63), hospitalization for unstable angina (HR, 0.57; 95% CI, 0.47-0.70), deep vein thrombosis (HR, 0.11; 95% CI, 0.05-0.27), cardiovascular mortality (HR, 0.29; 95% CI, 0.18-0.46), and all-cause mortality (HR, 0.49; 95% CI, 0.41-0.58). Statin use was associated with a lower incidence of cardiovascular morbidity and mortality in patients undergoing hemodialysis.

Statin use and infections in Veterans with cirrhosis

Evidence about the beneficial effects of statins on reducing infections is accumulating. Identifying ways to reduce infection risk in patients with cirrhosis is important because of increased mortality risk and costs associated with infections. To estimate the extent to which statin use prolongs time to infection among patients with cirrhosis. We identified Veterans with cirrhosis, but without decompensation (n=19379) using US Veterans Health Administration data from 2001 to 2009. New users of statins were identified and propensity matched to non-users and users of other cholesterol-lowering medications (1:1 matching). The cohort was followed up for hospitalisations with infections. Cox regression models with time-varying exposures provided estimates of adjusted hazard ratios (HR) and 95% confidence intervals (CI). New statin use was present among 13% of VA patients with cirrhosis without decompensation. Overall, 12.4% of patients developed a serious infection, and 0.1% of patients died. In the propensity-matched sample, statin users experienced hospitalisations with infections at a rate 0.67 less than non-users (95% Confidence Interval: 0.47-0.95). Infections are a major concern among cirrhotic patients and have the potential to seriously impact both life expectancy and quality of life. Statin use may potentially reduce the risk of infections among patients with cirrhosis.