Targeting inflammation and oxidative stress in atrial fibrillation: role of 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibition with statins

Abstract

Significance: Atrial fibrillation (AF) is a burgeoning health-care problem, and the currently available therapeutic armamentarium is barely efficient. Experimental and clinical evidence implicates inflammation and myocardial oxidative stress in the pathogenesis of AF.

Recent advances: Local and systemic inflammation has been found to both precede and follow the new onset of AF, and NOX2-dependent generation of reactive oxygen species in human right atrial samples has been independently associated with the occurrence of AF in the postoperative period in patients undergoing cardiac surgery. Anti-inflammatory and antioxidant agents can prevent atrial electrical remodeling in animal models of atrial tachypacing and the new onset of AF after cardiac surgery, suggesting a causal relationship between inflammation/oxidative stress and the atrial substrate that supports AF.

Critical issues: Statin therapy, by redressing the myocardial nitroso-redox balance and reducing inflammation, has emerged as a potentially effective strategy for the prevention of AF. Evidence indicates that statins prevent AF-induced electrical remodeling in animal models of atrial tachypacing and may reduce the new onset of AF after cardiac surgery. However, whether statins have antiarrhythmic properties in humans has yet to be conclusively demonstrated, as data from randomized controlled trials specifically addressing the relevance of statin therapy for the primary and secondary prevention of AF remain scanty.

Future directions: A better understanding of the mechanisms underpinning the putative antiarrhythmic effects of statins may afford tailoring AF treatment to specific clinical settings and patient's subgroups. Large-scale randomized clinical trials are needed to support the indication of statin therapy solely on the basis of AF prevention.

Figures

FIG. 1.

Right atrial (RA) NADPH-stimulated superoxide production (an index of NOX2 activity) is independently associated with an increased risk of postoperative atrial fibrillation (AF) (A) and longer in-hospital stay (B) in patients undergoing elective cardiac surgery. Hazard ratio (HR [95% confidence interval (CI)]). p value derived from the Cox regression, after adjustment for age, use of beta-blockers, EuroSCORE (European System for Cardiac Operative Risk Evaluation), and postoperative AF (in B only). Three-day treatment with atorvastatin (atorva) 40 mg once daily decreases RA NADPH-stimulated superoxide production in statin-naïve patients undergoing cardiac surgery in a randomized, placebo-controlled comparison (C). **p<0.01 versus placebo; RLU, relative light units. Modified from Antoniades et al. (8). To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 2.

C-reactive protein (CRP) levels are higher in patients with AF who fail electrical cardioversion. df=degrees of freedom; SMD=standardized mean difference. Reprinted with permission from Liu et al. (94). To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 3.

Cumulative incidence of incident AF by inflammation score. The inflammation score, which included high-sensitivity CRP, soluble intercellular adhesion molecules, and fibrinogen, partitioned 24,734 middle-aged women free of overt cardiovascular disease or cancer at baseline into four groups with a proportionally higher risk of incident AF, and independently predicted the new-onset AF over a median follow up of 14.4 years. Reprinted with permission from Conen et al. (34).

FIG. 4.

Schema illustrating the role of acute and low-grade inflammation in AF. Inflammatory conditions (e.g., myocarditis, pericarditis, and cardiac surgery) activate a rapid pro-inflammatory cascade involving cytokine release, leukocyte infiltration, and myeloperoxidase (MPO) activation, thus leading to atrial structural changes that provide a substrate for the maintenance of AF. Rapid atrial activation is in itself sufficient to generate local and systemic low-grade inflammation, leading to further atrial remodeling and a pro-thrombotic state. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 5.

A diagram depicting possible mechanisms by which oxidative stress and inflammation contribute to the formation of the electrical and structural substrate for AF. Some of the described targets of statin therapy (S) are shown in red. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 6.

After 2 weeks of AF (2W-AF), NOX2 protein expression and NADPH-stimulated superoxide production were increased in the goat left atria (LA) (A, B) compared with SR.Ex vivo incubation with atorvastatin caused a mevalonate-reversible inhibition of Rac1 activity (C, D) and of NADPH-stimulated superoxide production (E) in patients who went on to develop AF after cardiac surgery. RLU, Relative Light Units; postop AF, postoperative AF; RA, right atria; SR, sinus rhythm. Modified from Reilly et al. (131). *P<0.05 vs. SR, 1-way ANOVA (n=10 to 19); #P<0.05 for the mevalonate-reversible effect of atorvastatin; 1-way ANOVA (n=8 to 19).

FIG. 7.

Kaplan–Meier curve showing the effect of corticosteroid treatment on the incidence of AF after cardiac surgery(A)or recurrence of AF after pulmonary vein isolation(B). Reprinted with permission from Halonen et al. (58) (A) and modified from Koyama et al. (80) (B). To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 8.

A meta-analysis of 10 randomized trials (only four of which had postoperative AF as a predefined outcome) suggests that statin therapy might reduce the risk of developing postoperative AF by 63%. CI–confidence interval, OR–odds ratio. Modified from Fauchier et al. (46).