Sudden cardiac death (SCD) remains a major public health issue with an estimated annual incidence of 300,000 cases per year. The ACC/AHA/ESC 2006 guidelines define SCD as “death from an unexpected circulatory arrest, usually due to a cardiac arrhythmia occurring within an hour of the onset of symptoms” . Trials on traditional antiarrhythmic drugs have failed to show any mortality benefit even when compared to placebo or implantable cardiovertor defibrillators (ICDs) . Most of the patients experiencing sudden cardiac arrest have left ventricular ejection fraction (LVEF) > 50%, with the majority of these patients having a history of coronary artery disease (CAD). Majority of Sudden Cardiac Arrests (85-90%) are the first arrhythmic event a patient experiences.Beta blocker therapy, Angiotensin enzymes inhibitors (ACE-I) as well as aldosterone antagonists have been shown to decrease the risk of sudden cardiac death especially in post myocardial infarction (MI) patients and in patients with congestive heart failure. This chapter will review the data on the effects of traditional heart failure medications, especially beta blockers, Renin Angiotensin system blockers, as well as Statin therapy on sudden cardiac death in post MI patients and in patients with cardiomyopathy.
2. β-blockers and sudden cardiac death prevention
2.1. Potential mechanisms of β-blockers on sudden cardiac death prevention
Multiple studies have suggested that the major mechanisms responsible for the cardiac arrhythmias associated with sudden cardiac death are ventricular tachycardia (VT) and ventricular fibrillation (VF). For these arrhythmias to occur, an interaction between substrate (ventricular enlargement and/or hypertrophy, myocardial scar due to ischemic or non-ischemic injury) and triggers (electrolyte abnormalities, changes in the sympathetic and parasympathetic activity, neuro-humeral factors, and premature ventricular contractions) is necessary to initiate reentry leading to ventricular tachycardia and ventricular fibrillation (Figure 1).
Many anatomic or functional substrates such as coronary artery disease, cardiomyopathy or primary electrophysiological disease can lead to sudden cardiac death. Progression of these disease states leads to sympathetic activation. At the cellular level, sympathetic and vagal denervation caused by myocardial ischemia leads to an increase in interstitial potassium and intracellular calcium concentrations . This results in slowed conduction and induces spontaneous electrical activity. All these factors contribute to reentry; which is the most common mechanism of ventricular tachycardia in patients with ischemic heart disease .
As myocardial ischemia progresses the neurohumoral system exerts further stimulation of the sympathetic system and the renin-angiotensin-aldosterone system (RAAS). This neurohumoral cascade leads to increasing levels of norepinephrine, angiotensin II, aldosterone, endothelin and vasopressin. Increased norepinephrine levels lead to increased preload and after-load, which in turn increases myocardial oxygen demand. Furthermore, the activation of these systems promotes fibrosis and necrosis [5-7], which over time will lead to cardiac remodeling, left ventricular dilatation, fibrosis and progression into heart failure .
Three types of β-receptors are known, designated β1, β2 and β3 receptors. β1 receptors are located mainly in the heart and in the kidneys and are down regulated in heart failure due to chronically elevated norepinephrine levels. β2 receptors are located mainly in the lungs, gastrointestinal tract, liver, uterus, vascular smooth muscle, and skeletal muscle. β3 receptors are located in fat cells. β1and β2receptors activate cyclic adenosine mono-phosphate (cAMP), which acts as a second messenger and leads to increased contractility (inotropy), increased heart rate (which increases myocardial oxygen demand), increased conduction velocity (which may promote reentry) and have a positive lusitropic effect, which improves active relaxation . β2receptors promote the release of renin, which in turn activates angiotensin II and aldosterone, both of which elevate the blood pressure, increase after-load, promote potassium wasting and activate fibroblasts leading to fibrosis.
β-blockers exert their protective effect on the heart via different mechanisms. β-blockers reduce ischemia by decreasing the heart rate, which is the major determinant of myocardial oxygen demand. At the cellular level, β-blockers decrease electrical excitability by limiting calcium entry via catecholamine-dependent channels . All this helps decrease left ventricular mass and volume, decrease LV end diastolic pressure and improve LV function . β-blockers are also considered a class II antiarrhythmic medications. They decrease spontaneous depolarization, prolong the sinus node cycle length, atrioventricular conduction times and atrioventricular refractory periods. They also increase the excitable gap, which prevents reentry and increases the success of anti-tachycardia pacing .
2.2. Effect of β-blockers on sudden cardiac death prevention in post myocardial infarction patients
β-blockers therapy has been studied in the post myocardial infarction (MI) patients since 1965 when propranolol was found to reduce mortality after acute MI. Pivotal trials such as the
A meta-analysis evaluated several randomized clinical trials looking at the benefits of β-blockers treatment post MI. This analysis revealed a significant reduction in mortality with β-blocker therapy (HR= 0.77, 95% confidence interval: 0.69 to 0.85). Secondary to lack of physician prescription of β-blocker therapy despite evidence of its benefit the Cooperative Cardiovascular Project was undertaken. This was an observational report that evaluated the care of 200,000 Medicare patients with the diagnosis of MI. Only 34% of the patients were given β-blockers. The mortality reduction for patients who were prescribed beta- blockers at the time of discharge from the hospital was 40% .
A sub-analysis of
2.3. Effect of β-blockers on sudden cardiac death prevention in patients with congestive heart failure
β-blockers were initially thought to be contra-indicated in patients with heart failure due to their negative inotropic effects in the short term. However, later studies showed they consistently improve morbidity and mortality in patients with heart failure; they also lead to a 40% reduction in hospitalization. Currently, there are 3 medications available in the United States that have shown mortality benefits in patients with heart failure. Carvedilol is a non-selective β1, β2and α1 blocker that was tested in two trials and was shown to improve mortality. The first is the
2.4. Effect of β-blockers on sudden cardiac death prevention in patients who survived a cardiac arrest
In patients who have implantable cardioverter defibrillators (ICDs), β-blockers have been shown to decrease the frequency of ICD shocks . In an analysis of the Antiarrhythmics Versus Implantable Defibrillators Registry (
Furthermore, the higher the dose of β-blockers used, the less patients experience VT and the more likely the therapies are successful. In a study of 282 patients with left ventricular dysfunction (EF < 50%) with standard indications for ICD without cardiac resynchronization therapy, the higher the dose of β-blockers
3. Renin-Angiotensin-aldosterone system and sudden cardiac death prevention
3.1. Potential mechanisms of Renin-Angiotensin-aldosterone system inhibitors/blockers on sudden cardiac death prevention
The Renin-Angiotensin-aldosterone system (RAAS) is activated during many disease states, but especially during myocardial ischemia and heart failure. Renin activates the angiotensin converting enzyme, which converts Angtiotensin I to Angiotensin II. Angiotensin II is a potent vasoconstrictor; it activates fibroblasts promoting interstitial fibrosis and scar formation. Furthermore, Angiotensin II also activates the secretion of Aldosterone and Norepinephrine. All of these factors also increase after-load, which increases myocardial oxygen demand. At the cellular level, angiotensin II decreases the effective refractory period of the cardiac myocyte and enhances conduction .Furthermore, Aldosterone promotes sodium retention, increases potassium secretion in the urine and activates fibroblasts leading to myocardial and vascular fibrosis. This promotes remodeling, LV dilatation and creates the substrate for reentry . ACE-I inhibitors decrease pre-load and after-load, which decreases myocardial oxygen demand and LV end diastolic pressure. They also block Angiotensin II production and inhibit the breakdown of bradykinin . Blocking angiotensin II prevents the progression of ventricular remodeling, reduces ventricular dilatation and fibrosis. ACE-I inhibitors result in a reduction in potassium depletion and have several effects on the autonomic nervous system via enhanced baroreflex sensitivity and hemodynamics which can lead to reduced sympathetic and parasympathetic tone and circulating catecholamines. Angiotensin II could persist despite treatment with ACE-I inhibitors since it can be formulated by non-ACE-I-dependent pathways. ARBs can also block the angiotensin II receptor without an increase in bradykinin levels .
Even with the utilization of ACE-I inhibitors or Angiotensin-Receptor blockers (ARBs) there is not full suppression of Aldosterone synthesis. Aldosterone receptor blockers prevent sudden cardiac death by controlling potassium loss, blocking aldosterone effect on the formation of collagen and by increasing the myocardial uptake of norepinephrine, which decreases sympathetic activation [32, 33]. Myocardial fibrosis may increase the risk of ventricular arrhythmias by causing variations in the ventricular conduction times. Spirinolactone decreases the level of serum markers of collagen synthesis at 6 months, which correlates with survival benefit .
3.2. Effect of ACE-I on sudden cardiac death prevention in post myocardial infarction patients and in patients with heart failure
Three post myocardial infarction trials; Survival and Ventricular Enlargement (SAVE), Trandolapril Cardiac Evaluation (TRACE-I) and Acute Infarction Ramipril Efficacy (AIRE) specifically investigated the impact of ACE-I inhibitors on mortality and morbidity in post MI patients who have LV dysfunction.
A further Meta-analysis looked at 15 trials including SAVE, TRACE-I and AIRE to evaluate the effect of ACE-I inhibitors on sudden death post MI. This meta-analysis revealed a significant reduction in the risk for sudden death an odds ratio of 0.80 (95% CI 0.70-0.92).
Currently only three trials have reported results for sudden cardiac death in heart failure patients taking ACE-I.
3.3. Effect of Angiotensin-Receptor Blockers (ARBs) on sudden cardiac death prevention in patients with congestive heart failure
3.4. Effect of Aldosterone antagonists on sudden cardiac death prevention in post MI patients and in patients with congestive heart failure
4. Statins (3 hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors) and sudden cardiac death prevention
4.1. Potential mechanisms of 3 hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on sudden cardiac death prevention
Statins (3 Hydroxy-3-Methylglutaryl Coenzyme-A Reductase inhibitors) have been shown to decrease cardiovascular morbidity and mortality in both primary and secondary prevention trials. Statins are known to stabilize the plaque and to even promote plaque regression.This stabilization improves myocardial perfusion, oxidative stress and reduces the risk of plaque rupture. This leads to decreased ischemic events and arrhythmic events, since even small areas of ischemia can promote reentry, induce ventricular arrhythmias and lead to sudden cardiac death. Statins improve endothelial function by increasing nitric oxide production from endothelial cells and they reduce ischemia mediated oxidative stress and intracellular calcium overload [47, 48]. They also have anti-inflammatory actions and reduce C-reactive protein, and they decrease endothelin-1 secretion . All these effects will decrease myocardial ischemia, limit myocardial injury and prevent myocyte hypertrophy [50, 51].
4.2. Effect of statin therapy on shock burden and sudden cardiac death in post MI patients and in patients with congestive heart failure
Statins are widely accepted as preventing coronary heart disease death and MI; however their effect on sudden cardiac death prevention is unclear.
Randomized trial in post myocardial infarction patients showed the benefits of statins on overall mortality but failed to show benefit on sudden cardiac death prevention [52-54]. However, observational data from hospitalized patients with myocardial infarction showed that early statin administration (within 24 hours) of an acute MI led to a decrease in the incidence of VT/VF .
Furthermore, statins appear to decrease appropriate shocks in patients who have ICDs whether or not they received them for primary or secondary prevention of sudden cardiac death. In a subanalysis of AVID trial, a secondary prevention trial which compared anti-arrhythmic drugs to ICDs in patients who survived a cardiac arrest, patients who received statins had a lower risk of ventricular arrhythmias compared to those who are not on statins . This was also demonstrated in the Multicenter Automatic Defibrillator Implantation Trial-II (MADIT-II). Post hoc analysis of MADIT-II showed that patients receiving statin therapy > 90% of the time had a significantly reduced cumulative rate of ICD therapy for VT/VF or cardiac death.
Subsequently, an analysis of SCD-HeFT trial data was undertaken to evaluate the impact of statin use in heart failure. SCD-HeFT studied 2521 functional class II and III heart failure patients with left ventricular ejection fractions ≤ 35%. The cause of CHF was ischemic in 52% of the study patients. Statin use was reported in 965 (38%) of 2521 patients at baseline and 1187 (47%) at last follow-up with the median time to follow up of 45.5 months. This analysis revealed that mortality reduction related to statin therapy (HR= 0.70, 95% CI: 0.58-0.83] was identical in both ischemic and non-ischemic cardiomyopathy (HR 0.69 vs 0.67 respectively) .
5. Conclusions and future directions
Sudden cardiac death remains a challenge for health providers and policy makers. Whether more stringent guidelines for prevention and screening will be applied is balanced by the enormous costs. In order to identify the groups at risk for sudden cardiac death there must first be a standardization of the definition. The worldly variation in this definition of sudden cardiac death of 1 hour from onset of symptoms to 24 hours, not only effects epidemiological data but also alters clinical trial outcomes when evaluating the effectiveness of treatment options.
Currently, antiarrhythmic medications have failed to show any benefit of sudden cardiac death prevention, while traditional heart failure medications have been shown to decrease total mortality, sudden cardiac death and defibrillator shocks. They are only used in a small subset of patients that present in sudden cardiac death, since most of the patients who have sudden cardiac death have it as a first presentation and do not have congestive heart failure or history of coronary artery disease. This poses a diagnostic and therapeutic challenge for the clinician. Taking statins as an example, most of the primary prevention algorithms used to start lipid lowering agents usually leads to delayed intervention, especially since coronary atherosclerosis has been shown to start at a young age. The cost of starting this treatment is also enormous, especially if it is started on a global scale at a young age and it is not without side effects. Genetic studies to identify patients at risk for coronary atherosclerosis are still under development. Preventing sudden cardiac death is definitely a challenge for the 21st century clinician and might remain so for the near future.
Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death). J Am Coll Cardiol. 2006;48(5):e247-346.
Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. 2005;352(3):225-237.
Cabassi A, Vinci S, Calzolari M, Bruschi G, Borghetti A. Regional sympathetic activity in pre-hypertensive phase of spontaneously hypertensive rats. Life Sci. 1998;62(12):1111-1118.
Huikuri HV, Castellanos A, Myerburg RJ. Sudden death due to cardiac arrhythmias. N Engl J Med. 2001;345(20):1473-1482.
Mann DL. Basic mechanisms of disease progression in the failing heart: the role of excessive adrenergic drive. Prog Cardiovasc Dis. 1998;41(1 Suppl 1):1-8.
Chidsey CA, Sonnenblick EH, Morrow AG, Braunwald E. Norepinephrine stores and contractile force of papillary muscle from the failing human heart. Circulation. 1966;33(1):43-51.
Hasegawa K, Iwai-Kanai E, Sasayama S. Neurohormonal regulation of myocardial cell apoptosis during the development of heart failure. J Cell Physiol. 2001;186(1):11-18.
Francis GS, Benedict C, Johnstone DE, Kirlin PC, Nicklas J, Liang CS, et al. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A substudy of the Studies of Left Ventricular Dysfunction (SOLVD). Circulation. 1990;82(5):1724-1729.
Gorre F, Vandekerckhove H. Beta-blockers: focus on mechanism of action. Which beta-blocker, when and why? Acta Cardiol.65(5):565-570.
Swedberg K, Viquerat C, Rouleau JL, Roizen M, Atherton B, Parmley WW, et al. Comparison of myocardial catecholamine balance in chronic congestive heart failure and in angina pectoris without failure. Am J Cardiol. 1984;54(7):783-786.
Gilbert EM, Abraham WT, Olsen S, Hattler B, White M, Mealy P, et al. Comparative hemodynamic, left ventricular functional, and antiadrenergic effects of chronic treatment with metoprolol versus carvedilol in the failing heart. Circulation. 1996;94(11):2817-2825.
Jimenez-Candil J, Hernandez J, Martin A, Ruiz-Olgado M, Herrero J, Ledesma C, et al. Influence of beta-blocker therapy on antitachycardia pacing effectiveness for monomorphic ventricular tachycardias occurring in implantable cardioverter-defibrillator patients: a dose-dependent effect. Europace.12(9):1231-1238.
Snow PJ. Effect of propranolol in myocardial infarction. Lancet. 1965;2(7412):551-553.
Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med. 1981;304(14):801-807.
A randomized trial of propranolol in patients with acute myocardial infarction. II. Morbidity results. JAMA. 1983;250(20):2814-2819.
Vantrimpont P, Rouleau JL, Wun CC, Ciampi A, Klein M, Sussex B, et al. Additive beneficial effects of beta-blockers to angiotensin-converting enzyme inhibitors in the Survival and Ventricular Enlargement (SAVE) Study. SAVE Investigators. J Am Coll Cardiol. 1997;29(2):229-236.
Spargias KS, Hall AS, Greenwood DC, Ball SG. beta blocker treatment and other prognostic variables in patients with clinical evidence of heart failure after acute myocardial infarction: evidence from the AIRE study. Heart. 1999;81(1):25-32.
Freemantle N, Cleland J, Young P, Mason J, Harrison J. beta Blockade after myocardial infarction: systematic review and meta regression analysis. BMJ. 1999;318(7200):1730-1737.
Gottlieb SS, McCarter RJ, Vogel RA. Effect of beta-blockade on mortality among high-risk and low-risk patients after myocardial infarction. N Engl J Med. 1998;339(8):489-497.
Chadda K, Goldstein S, Byington R, Curb JD. Effect of propranolol after acute myocardial infarction in patients with congestive heart failure. Circulation. 1986;73(3):503-510.
Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. Lancet. 2001;357(9266):1385-1390.
McMurray J, Kober L, Robertson M, Dargie H, Colucci W, Lopez-Sendon J, et al. Antiarrhythmic effect of carvedilol after acute myocardial infarction: results of the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) trial. J Am Coll Cardiol. 2005;45(4):525-530.
Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med. 1996;334(21):1349-1355.
Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344(22):1651-1658.
The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999;353(9146):9-13.
Hjalmarson A, Goldstein S, Fagerberg B, Wedel H, Waagstein F, Kjekshus J, et al. Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). MERIT-HF Study Group. JAMA. 2000;283(10):1295-1302.
Seidl K, Hauer B, Schwick NG, Zahn R, Senges J. Comparison of metoprolol and sotalol in preventing ventricular tachyarrhythmias after the implantation of a cardioverter/defibrillator. Am J Cardiol. 1998;82(6):744-748.
Anderson JL, Hallstrom AP, Epstein AE, Pinski SL, Rosenberg Y, Nora MO, et al. Design and results of the antiarrhythmics vs implantable defibrillators (AVID) registry. The AVID Investigators. Circulation. 1999;99(13):1692-1699.
Hreybe H, Bedi M, Ezzeddine R, Barrington W, Jain S, Ngwu O, et al. Indications for internal cardioverter defibrillator implantation predict time to first shock and the modulating effect of beta-blockers. Am Heart J. 2005;150(5):1064.
Schrier RW, Abraham WT. Hormones and hemodynamics in heart failure. N Engl J Med. 1999;341(8):577-585.
Zannad F, Dousset B, Alla F. Treatment of congestive heart failure: interfering the aldosterone-cardiac extracellular matrix relationship. Hypertension. 2001;38(5):1227-1232.
Minisi AJ, Thames MD. Distribution of left ventricular sympathetic afferents demonstrated by reflex responses to transmural myocardial ischemia and to intracoronary and epicardial bradykinin. Circulation. 1993;87(1):240-246.
Zannad F, Alla F, Dousset B, Perez A, Pitt B. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the randomized aldactone evaluation study (RALES). Rales Investigators. Circulation. 2000;102(22):2700-2706.
Rutherford JD, Pfeffer MA, Moye LA, Davis BR, Flaker GC, Kowey PR, et al. Effects of captopril on ischemic events after myocardial infarction. Results of the Survival and Ventricular Enlargement trial. SAVE Investigators. Circulation. 1994;90(4):1731-1738.
Kober L, Torp-Pedersen C, Carlsen JE, Bagger H, Eliasen P, Lyngborg K, et al. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group. N Engl J Med. 1995;333(25):1670-1676.
Cleland JG, Erhardt L, Murray G, Hall AS, Ball SG. Effect of ramipril on morbidity and mode of death among survivors of acute myocardial infarction with clinical evidence of heart failure. A report from the AIRE Study Investigators. Eur Heart J. 1997;18(1):41-51.
Domanski MJ, Exner DV, Borkowf CB, Geller NL, Rosenberg Y, Pfeffer MA. Effect of angiotensin converting enzyme inhibition on sudden cardiac death in patients following acute myocardial infarction. A meta-analysis of randomized clinical trials. J Am Coll Cardiol. 1999;33(3):598-604.
Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group. N Engl J Med. 1987;316(23):1429-1435.
Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. The SOLVD Investigattors. N Engl J Med. 1992;327(10):685-691.
Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med. 1991;325(5):303-310.
Pitt B, Segal R, Martinez FA, Meurers G, Cowley AJ, Thomas I, et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet. 1997;349(9054):747-752.
Pitt B, Poole-Wilson PA, Segal R, Martinez FA, Dickstein K, Camm AJ, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial--the Losartan Heart Failure Survival Study ELITE II. Lancet. 2000;355(9215):1582-1587.
Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341(10):709-717.
Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348(14):1309-1321.
Nissen SE, Nicholls SJ, Sipahi I, Libby P, Raichlen JS, Ballantyne CM, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006;295(13):1556-1565.
Cascio WE. Myocardial ischemia: what factors determine arrhythmogenesis? J Cardiovasc Electrophysiol. 2001;12(6):726-729.
Laufs U, La Fata V, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation. 1998;97(12):1129-1135.
Rikitake Y, Kawashima S, Takeshita S, Yamashita T, Azumi H, Yasuhara M, et al. Anti-oxidative properties of fluvastatin, an HMG-CoA reductase inhibitor, contribute to prevention of atherosclerosis in cholesterol-fed rabbits. Atherosclerosis. 2001;154(1):87-96.
Ridker PM, Rifai N, Pfeffer MA, Sacks FM, Moye LA, Goldman S, et al. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators. Circulation. 1998;98(9):839-844.
Weber KT, Anversa P, Armstrong PW, Brilla CG, Burnett JC, Jr., Cruickshank JM, et al. Remodeling and reparation of the cardiovascular system. J Am Coll Cardiol. 1992;20(1):3-16.
Lee TM, Chou TF, Tsai CH. Effects of pravastatin on cardiomyocyte hypertrophy and ventricular vulnerability in normolipidemic rats after myocardial infarction. J Mol Cell Cardiol. 2003;35(12):1449-1459.
Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344(8934):1383-1389.
Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ, Holme I, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA. 2005;294(19):2437-2445.
LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352(14):1425-1435.
Fonarow GC, Wright RS, Spencer FA, Fredrick PD, Dong W, Every N, et al. Effect of statin use within the first 24 hours of admission for acute myocardial infarction on early morbidity and mortality. Am J Cardiol. 2005;96(5):611-616.
Mitchell LB, Powell JL, Gillis AM, Kehl V, Hallstrom AP. Are lipid-lowering drugs also antiarrhythmic drugs? An analysis of the Antiarrhythmics versus Implantable Defibrillators (AVID) trial. J Am Coll Cardiol. 2003;42(1):81-87.
Vyas AK, Guo H, Moss AJ, Olshansky B, McNitt SA, Hall WJ, et al. Reduction in ventricular tachyarrhythmias with statins in the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II. J Am Coll Cardiol. 2006;47(4):769-773.
Dickinson MG, Ip JH, Olshansky B, Hellkamp AS, Anderson J, Poole JE, et al. Statin use was associated with reduced mortality in both ischemic and nonischemic cardiomyopathy and in patients with implantable defibrillators: mortality data and mechanistic insights from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). Am Heart J. 2007;153(4):573-578.