**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**

*Survival and Ventricular Enlargement (SAVE)* was a randomized double-blind placebo controlled trial that evaluated the use of captopril (n=1115) versus placebo (n= 1116) in post MI patients with LVEF ≤ 40%. Randomization was done 3-16 days post MI. During an average of 42 months, there was an 18% RRR in all-cause mortality with captopril compared to placebo. However, there was a non-significant trend towards lower SCD in patients taking captopril (odds ratio

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*Trandolapril Cardiac Evaluation (TRACE-I)* was designed to examine whether patients with a recent MI and LV dysfunction would benefit from long term ACE-I inhibitor therapy. A total of 1749 patients 3-7 days post MI with echocardiographic evidence of LV dysfunction (EF≤ 35%) were randomized to Trandolapril (n=876) or placebo (n=873). During follow up the relative risk for death from any cause in the Trandolapril group versus the placebo group was 0.78 (95 percent confidence interval, 0.67 to 0.91). The Trandolapril group also showed a significant reduction in sudden death versus the placebo group (HR 0.76, 95% CI 0.59-.98, p=0.03) [35]. TRACE-I was the first placebo-controlled trial to show a significant reduction in

*The Acute Infarction Ramipril Efficacy (AIRE)* Trial once again looked at the use of ACE-I inhibitors in the post MI patient who had clinical or radiological evidence of congestive heart failure (CHF) to receive Ramipril (n=1014) versus placebo (n=992). After 15 months of follow up,there was a 27% reduction in the risk of death with Ramipril compared to placebo. In this study Ramipril also reduced the risk for sudden death by approximately 30% compared to

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 signifi‐ cant reduction in the risk for sudden death an odds ratio of 0.80 (95% CI 0.70-0.92)[37].

Currently only three trials have reported results for sudden cardiac death in heart failure patients taking ACE-I. *The Cooperative North Scandinavian Enalapril Survival (CONSENSUS)* Study was designed to evaluate the effect of Enalapril compared to placebo on mortality in patients with severe heart failure (class IV). This study randomized 253 patients to either Enalapril (n=127) or placebo (n=126) in addition to conventional therapy. CONSENSUS showed a 40% reduction in mortality after 6 months of treatment and a 27% reduction at the end of the study. The greatest reduction in mortality was in death caused by progression of

*The Studies of Left Ventricular Dysfunction (SOLVD)-Prevention trial*was designed to determine whether and ACE-I inhibitor, Enalapril, could reduce mortality, the incidence of heart failure and the rate of hospitalizations in patients with EF ≤ 35% with mild to moderate heart failure (class II or III). Following randomization, patients received double-blind treatment with either placebo (n=1284) or Enalapril (n=1285). There was noted a reduction in mortality due to progression of heart failure with a risk reduction of 16% but no clear reduction in sudden

*The V-HeFT-II trial* was the first trial to suggest an effect of ACE-I inhibitors on sudden death in patients with heart failure. This trial compared the effects of Enalapril with hydralazine and

0.83, 95% CI 0.63-1.8)[34].

placebo (p=0.011)[36].

pump failure[38].

cardiac death was noted[39].

sudden death with the use of the ACE-I inhibitors.

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. Angio‐ tensin II is a potent vasoconstrictor; it activates fibroblasts promoting interstitial fibrosis and scar formation. Furthermore, Angiotensin II also activates the secretion of Aldoster‐ one 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 [30].Furthermore, Al‐ dosterone promotes sodium retention, increases potassium secretion in the urine and ac‐ tivates fibroblasts leading to myocardial and vascular fibrosis. This promotes remodeling, LV dilatation and creates the substrate for reentry [31]. ACE-I inhibitors decrease preload and after-load, which decreases myocardial oxygen demand and LV end diastolic pressure. They also block Angiotensin II production and inhibit the breakdown of brady‐ kinin [23]. Blocking angiotensin II prevents the progression of ventricular remodeling, re‐ duces ventricular dilatation and fibrosis. ACE-I inhibitors result in a reduction in potassium depletion and have several effects on the autonomic nervous system via en‐ hanced 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-depend‐ ent pathways. ARBs can also block the angiotensin II receptor without an increase in bradykinin levels [32].

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 de‐ creases the level of serum markers of collagen synthesis at 6 months, which correlates with survival benefit [33].

#### **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.

*Survival and Ventricular Enlargement (SAVE)* was a randomized double-blind placebo controlled trial that evaluated the use of captopril (n=1115) versus placebo (n= 1116) in post MI patients with LVEF ≤ 40%. Randomization was done 3-16 days post MI. During an average of 42 months, there was an 18% RRR in all-cause mortality with captopril compared to placebo. However, there was a non-significant trend towards lower SCD in patients taking captopril (odds ratio 0.83, 95% CI 0.63-1.8)[34].

**3. Renin-Angiotensin-aldosterone system and sudden cardiac death**

**3.1. Potential mechanisms of Renin-Angiotensin-aldosterone system inhibitors/blockers on**

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. Angio‐ tensin II is a potent vasoconstrictor; it activates fibroblasts promoting interstitial fibrosis and scar formation. Furthermore, Angiotensin II also activates the secretion of Aldoster‐ one 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 [30].Furthermore, Al‐ dosterone promotes sodium retention, increases potassium secretion in the urine and ac‐ tivates fibroblasts leading to myocardial and vascular fibrosis. This promotes remodeling, LV dilatation and creates the substrate for reentry [31]. ACE-I inhibitors decrease preload and after-load, which decreases myocardial oxygen demand and LV end diastolic pressure. They also block Angiotensin II production and inhibit the breakdown of brady‐ kinin [23]. Blocking angiotensin II prevents the progression of ventricular remodeling, re‐ duces ventricular dilatation and fibrosis. ACE-I inhibitors result in a reduction in potassium depletion and have several effects on the autonomic nervous system via en‐ hanced 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-depend‐ ent pathways. ARBs can also block the angiotensin II receptor without an increase in

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 de‐ creases the level of serum markers of collagen synthesis at 6 months, which correlates with

**3.2. Effect of ACE-I on sudden cardiac death prevention in post myocardial infarction**

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

**prevention**

218 Cardiomyopathies

**sudden cardiac death prevention**

bradykinin levels [32].

survival benefit [33].

**patients and in patients with heart failure**

patients who have LV dysfunction.

*Trandolapril Cardiac Evaluation (TRACE-I)* was designed to examine whether patients with a recent MI and LV dysfunction would benefit from long term ACE-I inhibitor therapy. A total of 1749 patients 3-7 days post MI with echocardiographic evidence of LV dysfunction (EF≤ 35%) were randomized to Trandolapril (n=876) or placebo (n=873). During follow up the relative risk for death from any cause in the Trandolapril group versus the placebo group was 0.78 (95 percent confidence interval, 0.67 to 0.91). The Trandolapril group also showed a significant reduction in sudden death versus the placebo group (HR 0.76, 95% CI 0.59-.98, p=0.03) [35]. TRACE-I was the first placebo-controlled trial to show a significant reduction in sudden death with the use of the ACE-I inhibitors.

*The Acute Infarction Ramipril Efficacy (AIRE)* Trial once again looked at the use of ACE-I inhibitors in the post MI patient who had clinical or radiological evidence of congestive heart failure (CHF) to receive Ramipril (n=1014) versus placebo (n=992). After 15 months of follow up,there was a 27% reduction in the risk of death with Ramipril compared to placebo. In this study Ramipril also reduced the risk for sudden death by approximately 30% compared to placebo (p=0.011)[36].

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 signifi‐ cant reduction in the risk for sudden death an odds ratio of 0.80 (95% CI 0.70-0.92)[37].

Currently only three trials have reported results for sudden cardiac death in heart failure patients taking ACE-I. *The Cooperative North Scandinavian Enalapril Survival (CONSENSUS)* Study was designed to evaluate the effect of Enalapril compared to placebo on mortality in patients with severe heart failure (class IV). This study randomized 253 patients to either Enalapril (n=127) or placebo (n=126) in addition to conventional therapy. CONSENSUS showed a 40% reduction in mortality after 6 months of treatment and a 27% reduction at the end of the study. The greatest reduction in mortality was in death caused by progression of pump failure[38].

*The Studies of Left Ventricular Dysfunction (SOLVD)-Prevention trial*was designed to determine whether and ACE-I inhibitor, Enalapril, could reduce mortality, the incidence of heart failure and the rate of hospitalizations in patients with EF ≤ 35% with mild to moderate heart failure (class II or III). Following randomization, patients received double-blind treatment with either placebo (n=1284) or Enalapril (n=1285). There was noted a reduction in mortality due to progression of heart failure with a risk reduction of 16% but no clear reduction in sudden cardiac death was noted[39].

*The V-HeFT-II trial* was the first trial to suggest an effect of ACE-I inhibitors on sudden death in patients with heart failure. This trial compared the effects of Enalapril with hydralazine and isosorbide dinitrate on mortality in patients with NYHA class II-III. After randomization, double blind treatment was instituted with Enalapril (n= 403) versus hydralazine/isosorbide dinitrate (n=401). Interestingly the mortality curves of the treatment arms separate early after randomization. There was a 28% relative risk reduction with Enalapril compared to hydrala‐ zine and isosorbide dinitrate (p=0.16).The overall reduction in mortality associated with Enalapril was due to a reduction in the incidence of sudden death [40].

**4. Statins (3 hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors)**

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**4.1. Potential mechanisms of 3 hydroxy-3-methylglutaryl coenzyme A reductase inhibitors**

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[45].This stabilization improves myocardial perfusion, oxidative stress and reduces the risk of plaque rupture[46]. 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 [49]. All these effects will decrease myocardial ischemia,

**4.2. Effect of statin therapy on shock burden and sudden cardiac death in post MI patients**

Statins are widely accepted as preventing coronary heart disease death and MI; however their

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

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 [56]. 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[57]. 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) [58].

**and sudden cardiac death prevention**

**and in patients with congestive heart failure**

incidence of VT/VF [55].

effect on sudden cardiac death prevention is unclear.

limit myocardial injury and prevent myocyte hypertrophy [50, 51].

**on sudden cardiac death prevention**

#### **3.3. Effect of Angiotensin-Receptor Blockers (ARBs) on sudden cardiac death prevention in patients with congestive heart failure**

*The Evaluation of Losartan in the Elderly Study (ELITE)* is the only ARB trial to demonstrate a reduction in sudden death. This prospective, double-blind, randomized, parallel group controlled clinical trial compared the safety and efficacy in the treatment of CHF with the use of Losartan vs Captopril. Patients were randomly assigned to losartan (n=352) versus captopril (n=370). Follow up at 48 weeks showed a 45% reduction in all-cause mortality with a relative risk reduction of 36% in the incidence of sudden cardiac death [41].

*ELITE II* was designed to compare the effects of losartan and captopril on all-cause mortality and sudden death or resuscitated cardiac arrest. Similar to ELITE patients were randomly assigned to losartan (n=1578) or captopril (n=1574). After 1.5 years of follow there was no statistically difference in all-cause mortality, sudden death or resuscitated cardiac arrest (losartan 9% versus captopril 7.3%, p= 0.08) between the two groups[42].

#### **3.4. Effect of Aldosterone antagonists on sudden cardiac death prevention in post MI patients and in patients with congestive heart failure**

*The Randomized Aldactone Evaluation Study (RALES)* was a randomized double-blind place‐ bo controlled trial. This trial hypothesized that daily treatment with Spirinolactone would reduce the risk of death from all causes among patients who had severe heart failure. Patients enrolled had class III or IV heart failure and were being treated with an ACE-I inhibitor, loop diuretic and had an EF ≤ 35%. They were randomly assigned to ei‐ ther Spirinolactone (n=822) or placebo (n=841). This trial was ended prematurely when analysis found that Spirinolactone demonstrated a 31% reduction in cardiac death. This reduction was due to a 36% in death related to progressive heart failure and a 29% re‐ duction in sudden cardiac death [43].

*The Eplerone Post Myocardial Heart Failure Efficacy and Survival Study (EPHESUS)* was con‐ ducted to evaluate the effect of aldosterone blocker, Eplerenone on morbidity and mor‐ tality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure. In this double-blind, placebo-controlled study patients were randomly assigned to Eplerenone (n=3313) versus placebo (n=3319) in addition to optimal medical therapy. Eplerenone demonstrated a reduction in death from cardiovas‐ cular causes or hospitalization for cardiovascular events (relative risk, 0.83; 95% CI, 0.72-0.94; p=0.005). There was also a reduction in sudden death from cardiac causes (rela‐ tive risk, 0.79; 95% CI 0.64-0.97; p=0.03) [44].
