Do Anti-Ischemic Medications Have a Role in the Treatment of Ventricular Tachyarrhythmias?
The prevalence of sudden cardiac death (SCD) or hemodynamically unstable ventricular tachyarrhthmias (VTA) in patients with heart failure can be as high as 50%.1,2 The use of ICDs have significantly reduced mortality from SCD in patients at the highest risk. However while ICD discharges save lives, they also have associated physical and psychological morbidity.3 Anti-arrhythmic drugs (classes I, II, and III) commonly used for suppression of VTA, have many side effects and can be pro-arrhythmic. Several classes of medications that are used to treat and prevent coronary heart disease may have favorable anti-arrhythmic effects on VTA, including statins, very long chain omega-3 polyunsaturated fatty acids (omega-3 PUFA), and ranolazine.
A meta-analysis of 25 trials of statin versus placebo indicated that there was significant reduction in sudden cardiac death in the statin arm OR 0.90 (95% CI 0.82-0.97).24 In general, the majority of these trials were in patients with ischemic cardiomyopathy. There have been several proposed mechanisms for the anti-arrhythmic properties of statins. A widely held opinion is that this is simply an epiphenomenon as statins have a clear benefit in plaque stabilization and in decreasing ischemia.20 Statins also have antioxidant and anti-inflammatory properties. Also, statins improve heart rate variability, QT dispersion, and negative remodeling, all of which have all been shown to increase risk for ventricular tachycardia.21-23 In patients with nonischemic cardiomyopathy, sub-study of the DEFINITE trial showed that statin use was associated with a significant reduction in mortality even following multivariate analysis, HR 0.23; 95% CI 0.09-0.58; p=0.002). Secondary analysis of arrhythmic death was also significantly lowered in the statin group 0.9% vs. 5.2%, p=0.04. From the above trials, it can be concluded that statin therapy clearly has a benefit for reduction of SCD and mortality.25 Whether this effect is due to direct anti-arrhythmic effects or due to reduction in ischemia remains unclear.
Studies in the 1980s showed that omega-3 PUFA including eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA)6 decreased the incidence of ventricular fibrillation in small animal models. The electrophysiologic basis of their anti-arrhythmic properties is blockade of fast voltage dependent sodium currents and L-type calcium currents. The overall effect that this has on the myocardial membrane is decreased excitability and slowed conduction.7 Epidemiological studies investigating the correlation of ventricular ectopy burden, invasive inducibility of VTA during electrophysiologic testing, and heart rate found inverse relationships to PUFA.7-11 Other observational studies found that patients with SCD had lower levels of omega-3 fatty acids than a healthy cohort, with one study showing that even a 1% increase in omega-3 index reduced the incidence of SCD by 58% (95% CI 0.25-0.76).7,12 However, a meta-analysis of three randomized controlled trials evaluating patients with ICDs showed a non-significant reduction in appropriate shocks in patients receiving fish oil versus placebo, OR=0.90 [95% CI 0.55-1.46], as well as SCD, OR 0.81 [95% CI 0.52-1.25]. There is a great deal of heterogeneity amongst trials evaluating the use of omega-3 PUFA in patient characteristics, plasma levels of PUFA achieved in the intervention arm, and the formulation of the supplement administered13-16. Several studies have even suggested that fish oil supplementation has pro- arrhythmic characteristics due to decreasing the AP conduction velocity and decreasing refractory periods. Thus, although VTA through triggered activity may be suppressed, re-entry mechanism may become manifest.15,17-19 Thus, there is inconclusive evidence that fish oil supplementation has any significant clinical benefit in high-risk patients for the suppression of VTA or in the prevention of SCD.
In 2006, the FDA approved the piperazine derivative, ranolazine, for chronic angina. Through the years, there have been several promising studies extolling its anti-arrhythmic virtues for both atrial arrhythmias as well as VTA. Possible mechanism of action is by inhibiting the fast acting voltage-gated sodium channel (INa). The net effect is to shorten the APD which can help decrease VTA when caused by DAD and triggered activity.26 In MERLIN TIMI, 36 trial patients with NSTEMI were randomized to ranolazine versus placebo and followed for one year. Although ranolazine did not significantly impact the incidence of symptomatic arrhythmia, there was a significant decrease in VT greater than eight beats seven days post MI (30% vs. 38%, p<0.001).27 Ranolazine does slightly inhibit the delayed rectifier K current (Ikr); it was shown that there was a mild prolongation of the QT interval but this did not result in any significant increase in polymorphic VT in the ranolazine arm.26-28 In an observational study, 12 patients with drug refractory VTA were given 500 mg-1000 mg ranolazine twice daily and monitored long term with ICD interrogations. At six months, 11 of the 12 patients had a significant reduction of their VT burden and no ICD shocks were observed. Of note, the mean QRS and the QTc interval increased insignificantly.29 In summary, ranolazine has shown promise in a few small trials. There does not appear to be any adverse arrhythmic effect of the drug, certainly more studies are needed.
Many classes of non-arrhythmic medications are associated with decreased incidence of VTA in high risk patients. Medications such as statins, aldosterone antagonists, ACE inhibitors most likely show this relationship through an epiphenomenon of decreasing ischemia and heart failure. The pleiotropic effects of omega-3 fish oils and ranolazine have been investigated in animal studies. Statins and ranolazine have shown promise in clinical trials for the reduction of VTA, whereas the data for fish oils has been less convincing. To what extent these effects are due to direct anti-arrhythmic effects, versus secondary to their anti ischemic properties, requires further study. VTA has profound effects on both morbidity and mortality. Future work is needed in fully understanding the potential role of non-arrhythmic medications in preventing and treating VTA.
- Stevenson WG, Epstein LM. Predicting Sudden Death Risk for Heart Failure Patients in the Implantable Cardioverter-Defibrillator Age. Circulation 2003;107:514-516.
- Berger R, Huelsman M, Strecker K, et al. B-Type Natriuretic Peptide Predicts Sudden Death in Patients With Chronic Heart Failure. Circulation 2002;105:2392-2397
- Moss AJ, Zareba W, Hall WJ, et al. Prophylactic Implantation of a Defibrillator in Patients with Myocardial Infarction and Reduced Ejection Fraction. N Engl J Med 2002; 346:877-883.
- Bhandari AK, Hong RA, Rahimtoola SH. Triggered activity as a mechanism of recurrent ventricular tachycardia. Br Heart J 1988;59:501–505.
- Den Ruijter HD, Berecki G, Opthof T et al. Pro- and antiarrhythmic properties of a diet rich in fish oil. Cardiovascular Research 2007;73:316-325.
- McLennon PL, Abeywardena MY, Charnock JS. Dietary fish oil prevents ventricular fibrillation following coronary artery occlusion and reperfusion. Am Heart J 1988;116:709-717.
- Von schacky C. Omega-3 fatty acids: anti-arrhythmic, pro-arrhythmic or both? Frontiers in Physiology 2012;4:88.
- Metcalf RG, Sanders P, James M, et al. Effect of dietary n-3 polyunsaturated faty acids on the inducibility of ventricular tachycardia in patients with ischemic cardiomyopathy. Am J Cardiol 2008.101;758-761.
- Smith PJ, Blumenthal JA, Babyak MA et al. Association between n-3 fatty acid consumption and ventricular ectopy after myocardial infarction. Am J Clin Nutr 2009; 89:1315-1320.
- Madsen T, Christensen J, Thorgersen AM et al. Intravenous infusion of n-3 polyunsaurated fatty acids and inducibility of ventricular tachycardia in patients with implantable cardioverter defibrillator. Europace 2010;12:941-946.
- Ebbesson SO, Devereux RB, Cole S, et al. Heart rate is associated with red blood cell fatty acid concentration: the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) Study. Am Heart J 2010;159:1020-1025.
- Aarsetoey H, Aarsetoey R, Lindner T et al. Low levels of the omega-3 index are associated with sudden cardiac arrest and remain stable in survivors in the subacute phase. Lipids 2011;46:151-161.
- Brouwer IA, Raitt MH, Dullemeijer C, et al. Effect of fish oil on ventricular tachyarrhythmia in three studies in patients with implantable cardioverter defibrillators. Eur H J 2009; 30:820–826.
- Leaf A, Albert CM, Josephson M, Steinhaus D, et al. Prevention of fatal arrhythmias in high-risk subjects by fish oil n-3 fatty acid intake. Circulation 2005;112:2762-2768.
- Raitt MH, Connor WE, Morris C, et al. Fish oil supplementation and risk of ventricular tachycardia and ventricular fibrillation in patients with implantable defibrillators: a randomized controlled trial. JAMA 2005;293:2884-2891.
- Brouwer IA, Zock PL, Camm AJ, et al. Effect of fish oil on ventricular tachyarrhythmia and death in patients with implantable cardioverter defibrillators: the Study on Omega-3 Fatty Acids and Ventricular Arrhythmia (SOFA) randomized trial. JAMA 2006;295:2613-2619.
- Mines GR. On circulating excitations in heart muscle and their possible relation to tachycardia and fibrillation. Trans R Soc Can 1914; 8:43–52.
- Verkerk AO, van Ginneken ACG, Berecki G, et al. Incorporated sarcolemmal fish oil fatty acids shorten pig ventricular action potentials. Cardiovasc Res 2006;70:509-20.
- Dhein S, Michaelis B, Mohr FW. Antiarrhythmic and electrophysiological effects of long-chain omega-3 polyunsaturated fatty acids. Naunyn-Schmiedeberg's Arch Pharmacol 2005;371:202-11.
- Abuissa H, O'Keefe JH, Bybee KA. Statins as antiarrhythmics: a systematic review part I: effects on risk of atrial fibrillation. Clin Cardiol 2009; 32:544-8.
- Kostapanosa EN, Liberopoulosa JA, Goudevenosb DP, et al. Do statins have an antiarrhythmic activity? Cardiovasc Res 2007; 75:10-20.
- Ridker PM, Rifai N, Pfeffer MA, et al. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with averaged cholesterol levels. Circulation 1998;98:839-44.
- De Sutter J, Tavernier R, De Buyzere M, et al. Lipid lowering drugs and recurrences of life-threatening ventricular arrhythmias in high-risk patients. J Am Coll Cardiol 2000;36:766-72.
- Wanahita N, Chen J, Bangalore S, et al. Effect of statin therapy on ventricular tachyarrhythmias: a meta-analysis. Am J Ther 2012;19:16-2325.
- Goldberger JJ, Subacius H, Schaechter A, et al. Effects of Statin Therapy on Arrhythmic Events and Survival in Patients With Nonischemic Dilated Cardiomyopathy. J Am Coll Cardiol 2006;48:1228-33.
- Antzelevitch C, Belardinelli L, Zygmunt AC, et al. Electrophysiological Effects of Ranolazine, a Novel Antianginal Agent With Antiarrhythmic Properties. Circulation 2004;110:904-910.
- Scirica BM, Morrow DA, Hod H, et a. Effect of Ranolazine, an Antianginal Agent With Novel Electrophysiological Properties, on the Incidence of Arrhythmias in Patients With Non −ST-Segment−Elevation Acute Coronary Syndrome: Results From the Metabolic Efficiency With Ranolazine for Less Ischemia in Non−ST-Elevation Acute Coronary Syndrome−Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) Randomized Controlled Trial. Circulation 2007;116:1647-1652.
- Dhalla AK, Wang WQ, Dow J, et al. Ranolazine, an antianginal agent, markedly reduces ventricular arrhythmias induced by ischemia and ischemia-reperfusion. Am J Physiol Heart Circ Physiol 2009; 297:H1923-H1929.
- Bunch TJ, Mahapatra S, Murdock D, et al. Ranolazine Reduces Ventricular Tachycardia Burden and ICD Shocks in Patients with Drug-Refractory ICD Shocks. PACE 2011; 34:1600-1606.
Clinical Topics: Arrhythmias and Clinical EP, Dyslipidemia, Heart Failure and Cardiomyopathies, Implantable Devices, EP Basic Science, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Lipid Metabolism, Nonstatins, Acute Heart Failure
Keywords: Angina Pectoris, Angiotensin-Converting Enzyme Inhibitors, Anti-Arrhythmia Agents, Arrhythmias, Cardiac, Cardiomyopathies, Coronary Disease, Death, Sudden, Cardiac, Docosahexaenoic Acids, Eicosapentaenoic Acid, Epidemiologic Studies, Fatty Acids, Omega-3, Heart Conduction System, Heart Failure, Mineralocorticoid Receptor Antagonists, Multivariate Analysis, Neurofibromin 2, Sodium, Sodium Channels, Tachycardia, Ventricular, Ventricular Fibrillation
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