The Effect of Statins on the Functionality of CD4+CD25+FOXP3+ Regulatory T-cells in Acute Coronary Syndrome: A Systematic Review and Meta-analysis of Randomised Controlled Trials in Asian Populations

Abstract

Acute coronary syndrome (ACS) is characterised by increased effector cells and decreased regulatory T-cells (Tregs). Statins have been shown to be clinically beneficial in ACS patients. This effect could be mediated via the induction of Tregs in ACS patients. The aim of this systemic review and meta-analysis was to evaluate whether statin therapy enhances the frequency of Tregs determined by CD4+CD25+FOXP3+ in this subset of patients. A comprehensive search of PubMed and Embase was performed. Studies were restricted to randomised controlled trials that quantified CD4+CD25+FOXP3+ cell frequency by flow cytometric analysis before and after statin treatment in adults diagnosed with ACS. A minimum of at least two of the conventional markers to identify Tregs was compulsory. Four randomised controlled trials studies (439 participants) were included, all with low-to-moderate risk of bias. Pooled data showed a significant increase in Treg frequency after statin therapy in ACS patients. A further meta-regression and subgroup analysis also showed a negative dose-related effect, and a statin type-related effect (rosuvastatin versus atorvastatin), respectively. The results confirmed that statins positively alter the frequency of Tregs, which may indicate a potential mechanism of their therapeutic effect. However, there was a risk of information bias due to the markers used to identify Tregs, which was not fully explored, therefore, further randomised controlled trials should utilise markers of Tregs, such as the FOXP3 locus (Treg-specific demethylated region), for identification.

Medical Treatment Can Unintentionally Alter the Regulatory T-Cell Compartment in Patients with Widespread Pathophysiologic Conditions

“…74 Studies in Asia recently reported that acute coronary syndrome is characterized by increased effector cells and decreased Tregs and that statins increase the frequency of CD4 þ CD25 þ T cells, although FOXP3 expression was not examined. 75 In a setting of acute myocardial infarction, patients were evaluated and found that atorvastatin treatment (80 mg) resulted in increased Treg frequency in peripheral blood and infarct-related coronary arteries accompanied by higher FOXP3 and TGF-b (TGFB) mRNA levels compared with the control group. 21 Moreover, in a retrospective study, patients with hypercholesterolemia treated with simvastatin (20 mg) or pravastatin (10 to 40 mg) for 4 or 8 weeks, respectively, exhibited increased frequency of CD4 þ CD25 high cells with upregulation of FOXP3 expression in the peripheral blood.…”

Ischemia/Reperfusion Injury: Pathophysiology, Current Clinical Management, and Potential Preventive Approaches

“…Another potentially important strategy to limit MIRS may be the use of statins, as they have been rendered as potent cardioprotectors that have an interesting effect on T-cell activation [105]. For instance, rosuvastatin has been shown to limit MIRS through Treg expansion in a murine model [106], but the effect may not be exclusive to animal models, as a meta-analysis performed by Sorathia et al shows a vast increase in Tregs in patients that use rosuvastatin [107] ( Figure 3) (Table 1).…”

Promoting cardiovascular health post‐transplant through early diagnosis and adequate management of hypertension and dyslipidemia

“…Atorvastatin treatment of human peripheral blood mononuclear cells (PBMCs) increased the number of CD4 + CD25+Foxp3 + Treg cells 137 . By increasing the proportion of Treg cells and decreasing Teff cells, statins may reduce rejection and have direct anti‐atherogenic activity 138‐140 …”

“…128 However, in a 2-year extension study, a statistically significant difference in MACE was seen in the fluvastatin group without an observed difference in overall mortality or graft loss. 129 [138][139][140] Ezetimibe inhibits the absorption of cholesterol at the jejunal enterocyte brush border and is effective at lowering LDL in both adults and children. 141,142 A small study in pediatric kidney transplant recipients using ezetimibe in combination therapy with statins showed a notable decrease in LDL, total cholesterol, and triglycerides with no change in calcineurin inhibitor trough levels or allograft function.…”