Statins Decrease Oxidative Stress and ICD Therapies

Heather L Bloom, Irfan Shukrullah, Emir Veledar, Rebecca Gutmann, Barry London, Samuel C Dudley, Heather L Bloom, Irfan Shukrullah, Emir Veledar, Rebecca Gutmann, Barry London, Samuel C Dudley

Abstract

Recent studies demonstrate that statins decrease ventricular arrhythmias in internal cardioverter defibrillator (ICD) patients. The mechanism is unknown, but evidence links increased inflammatory and oxidative states with increased arrhythmias. We hypothesized that statin use decreases oxidation. Methods. 304 subjects with ICDs were surveyed for ventricular arrhythmia. Blood was analyzed for derivatives of reactive oxygen species (DROMs) and interleukin-6 (IL-6). Results. Subjects included 252 (83%) men, 58% on statins, 20% had ventricular arrhythmias. Average age was 63 years and ejection fraction (EF) 20%. ICD implant duration was 29 +/- 27 months. Use of statins correlated with lower ICD events (r = 0.12, P = .02). Subjects on statins had lower hsCRP (5.2 versus 6.3; P = .05) and DROM levels (373 versus 397; P = .03). Other factors, including IL-6 and EF did not differ between statin and nonstatin use, nor did beta-blocker or antiarrhythmic use. Multivariate cross-correlation analysis demonstrated that DROMs, statins, IL-6 and EF were strongly associated with ICD events. Multivariate regression shows DROMs to be the dominant predictor. Conclusion. ICD event rate correlates with DROMs, a measure of lipid peroxides. Use of statins is associated with reduced DROMs and fewer ICD events, suggesting that statins exert their effect through reducing oxidation.

Figures

Figure 1
Figure 1
Comparison of mean DROM, CRP, IL-6 and EF by statin use or non-use with respective P values. Statin use = 1, non-use = 0.
Figure 2
Figure 2
Comparison of events (any events = 1 versus no events = 0) by statin use (= 1) or non-use (= 0). Patients on statins are less likely to experience ICD events.

References

    1. Zheng Z-J, Croft JB, Giles WH, Mensah GA. Sudden cardiac death in the United States, 1989 to 1998. Circulation. 2001;104(18):2158–2163.
    1. de Luna AB, Coumel P, Leclercq JF. Ambulatory sudden cardiac death: mechanisms of production of fatal arrhythmia on the basis of data from 157 cases. American Heart Journal. 1989;117(1):151–159.
    1. Vyas AK, Guo H, Moss AJ, et al. Reduction in ventricular tachyarrhythmias with statins in the multicenter automatic defibrillator implantation trial (MADIT)-II. Journal of the American College of Cardiology. 2006;47(4):769–773.
    1. Goldberger JJ, Subacius H, Schaechter A, et al. Effects of statin therapy on arrhythmic events and survival in patients with nonischemic dilated cardiomyopathy. Journal of the American College of Cardiology. 2006;48(6):1228–1233.
    1. Stoll LL, McCormick ML, Denning GM, Weintraub NL. Antioxidant effects of statins. Drugs of Today. 2004;40(12):975–989.
    1. Delbosc S, Morena M, Djouad F, Ledoucen C, Descomps B, Cristol J-P. Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are able to reduce superoxide anion production by NADPH oxidase in THP-1-derived monocytes. Journal of Cardiovascular Pharmacology. 2002;40(4):611–617.
    1. Choi M, Rolle S, Rane M, Haller H, Luft FC, Kettritz R. Extracellular signal-regulated kinase inhibition by statins inhibits neutrophil activation by ANCA. Kidney International. 2003;63(1):96–106.
    1. Dechend R, Fiebeler A, Park J-K, et al. Amelioration of angiotensin II-induced cardiac injury by a 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor. Circulation. 2001;104(5):576–581.
    1. Amin-Hanjani S, Stagliano NE, Yamada M, et al. Mevastatin, an HMG-CoA reductase inhibitor, reduces stroke damage and upregulates endothelial nitric oxide synthase in mice. Stroke. 2001;32:980–986.
    1. Laufs U, Fata VL, Liao JK. Inhibition of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase blocks hypoxia-mediated down-regulation of endothelial nitric oxide synthase. The Journal of Biological Chemistry. 1997;272(50):31725–31729.
    1. Stoll LL, McCormick ML, Denning GM, Weintraub NL. Antioxidant effects of statins. Timely Topics in Medicine. Cardiovascular Diseases. 2005;9:p. E1.
    1. Korantzopoulos P, Kolettis TM, Kountouris E, et al. Oral vitamin C administration reduces early recurrence rates after electrical cardioversion of persistent atrial fibrillation and attenuates associated inflammation. International Journal of Cardiology. 2005;102(2):321–326.
    1. Korantzopoulos P, Kolettis TM, Galaris D, Goudevenos JA. The role of oxidative stress in the pathogenesis and perpetuation of atrial fibrillation. International Journal of Cardiology. 2007;115(2):135–143.
    1. Kim YH, Lim DS, Lee JH, et al. Gene expression profiling of oxidative stress on atrial fibrillation in humans. Experimental Molecular Medicine. 2003;35:336–349.
    1. Fukuda K, Davies SS, Nakajima T, et al. Oxidative mediated lipid peroxidation recapitulates proarrhythmic effects on cardiac sodium channels. Circulation Research. 2005;97(12):1262–1269.
    1. Ward CA, Giles WR. Ionic mechanism of the effects of hydrogen peroxide in rat ventricular myocytes. Journal of Physiology. 1997;500(3):631–642.
    1. Jones DP, Mody VC, Jr., Carlson JL. Redox analysis of human plasma allows separation of pro-oxidant events of aging from decline in antioxidant defenses. Free Radical Biology & Medicine. 2002;33:1290–1300.
    1. Cesarone MR, Belcaro G, Carratelli M, et al. A simple test to monitor oxidative stress. International Angiology. 1999;18(2):127–130.
    1. Abramson JL, Hooper WC, Jones DP, et al. Association between novel oxidative stress markers and C-reactive protein among adults without clinical coronary heart disease. Atherosclerosis. 2005;178(1):115–121.
    1. Jones DP, Carlson JL, Samiec PS, et al. Glutathione measurement in human plasma. Evaluation of sample collection, storage and derivatization conditions for analysis of dansyl derivatives by HPLC. Clinica Chimica Acta. 1998;275(2):175–184.
    1. Fortmann SP, Ford E, Criqui MH, et al. CDC/AHA workshop on markers of inflammation and cardiovascular disease: application to clinical and public health practice: report from the population science discussion group. Circulation. 2004;110(25):e554–559.
    1. Jialal I, Stein D, Balis D, Grundy SM, Adams-Huet B, Devaraj S. Effect of hydroxymethyl glutaryl coenzyme a reductase inhibitor therapy on high sensitive C-reactive protein levels. Circulation. 2001;103(15):1933–1935.
    1. Lindholm MW, Nilsson J. Simvastatin stimulates macrophage interleukin-1β secretion through an isoprenylation-dependent mechanism. Vascular Pharmacology. 2007;46(2):91–96.
    1. Erikstrup C, Ullum H, Pedersen BK. Short-term simvastatin treatment has no effect on plasma cytokine response in a human in vivo model of low-grade inflammation. Clinical and Experimental Immunology. 2006;144(1):94–100.
    1. Yokota K, Miyazaki T, Hirano M, Akiyama Y, Mimura T. Simvastatin inhibits production of interleukin 6 (IL-6) and IL-8 and cell proliferation induced by tumor necrosis factor-α in fibroblast-like synoviocytes from patients with rheumatoid arthritis. Journal of Rheumatology. 2006;33(3):463–471.
    1. Fukuda K, Davies SS, Nakajima T, et al. Oxidative mediated lipid peroxidation recapitulates proarrhythmic effects on cardiac sodium channels. Circulation Research. 2005;97(12):1262–1269.
    1. Shang LL, Dudley SC., Jr. Tandem promoters and developmentally regulated 5′- and 3′-mRNA untranslated regions of the mouse Scn5a cardiac sodium channel. The Journal of Biological Chemistry. 2005;280(2):933–940.
    1. Adams JD, Jr., Lauterburg BH, Mitchell JR. Plasma glutathione and glutathione disulfide in the rat: regulation and response to oxidative stress. Journal of Pharmacology and Experimental Therapeutics. 1983;227(3):749–754.

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