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Prevention of Recurrences of Ventricular
Arrhythmias in Patients with Coronary
Artery Disease and Defibrillator Implants

Johan De Sutter, MD, PhD

Department of Cardiology, University Hospital Gent, Belgium

INTRODUCTION
   Sudden death accounts for more than 300.000 deaths yearly in the United States alone and is predominantly caused by ventricular arrhythmias such as syncopal ventricular tachycardia (VT) or ventricular fibrillation (VF) (1,2). Coronary artery disease is the underlying structural heart disease in >80% of victims of these life-threatening arrhythmias. Since treatment of hypercholesterolemia in patients with coronary artery disease reduces the risk of major coronary events by about 30% (3-7), one could speculate that this treatment could also result in a reduction of arrhythmic episodes in high risk patients with coronary artery disease. In this review we will further explore this hypothesis and discuss the mechanisms of sudden death in patients with coronary artery disease and the possible effects of anti-ischemic treatments including lipid-lowering drugs on life threatening ventricular arrhythmias.

MECHANISMS OF SUDDEN DEATH IN PATIENTS WITH CORONARY ARTERY DISEASE
   Ventricular tachyarrhythmias are the most frequent cause of sudden death in patients with coronary artery disease. They can be caused by acute ischemia in patients without a prior history of heart disease in whom a fatal ventricular arrhythmia is the first manifestation of coronary atherosclerosis. In contrast, in patients with previous myocardial infarction, these arrhythmias are most frequently caused by re-entry circuits that principally involve surviving subendocardial tissue and probably also surviving deeper myocardial and epicardial tissue (2). The onset of ventricular arrhythmias in these patients can be triggered by neurohormonal, electrolyte and acid-base changes, hypoxemia, proarrhythmic effects of medication and superposition of acute ischemia on prior infarction. As pointed out by Mehta et al. (2), a considerable overlap exists between these two broad categories and in a large proportion of patients, the combination of ischemia and scar is probably responsible for the genesis of lethal arrhythmias. Experimental studies have clearly shown that acute ischemia superimposed on myocardial scar is arrhythmogenic, while the same degree of acute ischemia in the absence of myocardial scar tissue is not (8,9). Also in experimental models it was shown that ischemia at the border zone of the infarcted tissue, where re-entry circuits are formed, is more arrhythmogenic than ischemia at a distance from the infarct zone (10). In humans however, similar mechanisms are difficult to document in vivo. This is probably the reason why several studies have shown that arrhythmic events in patients with coronary artery disease are not necessarily associated with detectable transient myocardial ischemia or an acute myocardial infarction (11,12). Also in patients with coronary artery disease and defibrillator implants recurrences of ventricular arrhythmias are not clearly related to measurable ischemia, whether detected by patient symptoms, electrocardiographic changes, Holter recordings, enzyme abnormalities or reversible defects on perfusion imaging (13-17). However, as pointed out by several authors (2,13,18), clinically inapparent ischemia and especially ischemia at the border zone of the infarcted tissue cannot be excluded as an arrhythmic trigger in a population of patients with extensive coronary artery disease.

   Regardless of whether ischemic or substrate related mechanisms predominate, there are numerous other factors that contribute to the development of terminal arrhythmias, including autonomic nervous system influences, circadian variations and mechanoelectric feedback (2). However, complex interactions between these factors and myocardial ischemia exist. Regarding autonomic nervous system influences for example, Cao et al (19) showed in a pathological study in native hearts of transplant recipients that there is an inhomogeneous distribution of sympathetic nerve fibers in patients with previous myocardial infarction, which is characterized by regional hyperinnervation in the periphery of injured myocardium and regional denervation in the regions with necrosis or dense fibrosis. The density of these sympathetic nerves correlated directly with the occurrence of life-threatening ventricular arrhythmias. However, Matsunari et al (20) reported that sympathetic nerve fibers, compared with myocardial cells, are very sensitive to myocardial ischemia suggesting that ischemia can influence regional innervation of the myocardium.

   In view of these pathophysiological aspects, it is clear that ischemia is a potentially important trigger for the substrate in patients with coronary artery disease and ventricular arrhythmias. Therefore we will first review the effect of anti-ischemic therapies including beta-blockers and revascularization. Then the available data regarding lipid-lowering drugs will be discussed.

EFFECT OF BETA-BLOCKERS AND REVASCULARIZATION ON VENTRICULAR ARRHYTHMIAS IN PATIENTS WITH CORONARY ARTERY DISEASE
   Systematic documentation of ventricular arrhythmias in patients with coronary artery disease is difficult since the first occurrence of these arrhythmias is largely unpredictable. Therefore, sudden death is frequently used as a marker for life-threatening ventricular arrhythmias in large-scale clinical trials. However, sudden death can also be caused by bradycardia and electromechanical dissociation, especially in patients with heart failure. One way to accurately evaluate recurrences of ventricular arrhythmias is to study patients with documented life-threatening ventricular arrhythmias treated with a recent generation implantable cardioverter defibrillator (ICD). These devices can document accurately the nature, the timing and the need of treatment by antitachycardia pacing and/ or shock of recurrences of ventricular arrhythmias. As such they allow a precise follow-up of a selected population of patients at high risk for recurrences of life-threatening arrhythmias. However, when using this approach, it should be taken into account that recurrences of ventricular arrhythmias cannot always be regarded as a substitute for cardiac death since not all ventricular arrhythmias are lethal. Some can sometimes be hemodynamically well tolerated or they can terminate spontaneously.

Beta-blockers
   Based on 25 clinical trials including 23000 patients post myocardial infarction in the prethrombolytic era, the meta-analysis by Yusuf et al (21) showed already in 1988 that beta-blockers significantly decrease the risk of death by 22% (p<0.001) and the risk of sudden death by 32% (p<0.001). These results have been extended to a broad range of patients after myocardial infarction including patients with older age, diabetes, pulmonary disease and non-Q wave myocardial infarction (22). More recently, trials on the use of beta-blockers in heart failure have consistently shown a reduction in the incidence of sudden death in the group of patients treated with beta-blockers. For example in the CIBIS-II study a reduction of 44% (p=0.0011) was noted (23) and a similar reduction of 41% (p=0.0002) in the MERIT-HF study (24). Several smaller studies (25-28) have also shown that treatment with beta-blockers is associated with a later occurrence of ventricular arrhythmias requiring ICD intervention in patients with coronary artery disease, documented life-threatening ventricular arrhythmias and an ICD implant. Besides the anti-ischemic properties of beta-blockers, different other mechanisms, including an antagonizing effect on the effect of catecholamines and a possible increase of the threshold for ventricular fibrillation, can explain this association (29-31). It should be mentioned however that placebo controlled randomized studies on the effectiveness of beta-blocker therapy in patients with ventricular tachycardia or fibrillation and ICD implants are not available.

Revascularization
   The Coronary Artery Surgery Study (CASS) and subsequent trials (32,33) have shown that surgical treatment, as compared to medical therapy, has an independent protective effect on sudden death in patients with coronary artery disease. In the CASS registry for example, the relative risk of dying suddenly in the medical group compared with the surgical group was 2.94 during the 5-year follow-up (32). It is however still a matter of debate whether revascularization by means of coronary artery bypass grafting or coronary angioplasty is sufficient to prevent recurrences of ventricular arrhythmias in patients with reversible ischemia and documented sustained ventricular arrhythmias. Several smaller studies support the view that if myocardial ischemia is the only substrate for ventricular tachyarrhythmias, isolated coronary revascularization (without ICD implantation) results in an excellent control of ventricular tachyarrhythmias (34-36). However when scar tissue due to previous myocardial infarction is part of the substrate most studies have still noticed a high recurrence rate of ventricular arrhythmias after coronary revascularization. These data indicate that correction of ischemia alone is not sufficient to prevent recurrences of ventricular arrhythmias in these patients (17,28,37,38). It has also been postulated that an open infarct artery, even if opened too late for myocardial salvage, may result in survival benefit by limiting infarct expansion, preventing ventricular dilatation, promoting electrical stability and providing a source of collateral flow should occlusion occur in another coronary artery (39,40). However, regarding electrical stability, the benefits of late opening of the infarct-related artery (especially > 24 hours after acute myocardial infarction) remain to be substantiated by large randomized clinical trials. As already pointed out in 1988 by Brugada et al (41), late opening of the infarct related artery could be arrhythmogenic. More recently the British Total Open Artery Trial (TOAT) has observed a relatively greater (though small) number of arrhythmic deaths among patients with later opening of the infarct-related artery by PTCA (42). Also, Steinberg et al (43) have observed the de novo occurrence of ventricular arrhythmias (sustained polymorphic VT) among in-hospital, post CABG patients. These ventricular arrhythmias occurred only in patients who received a graft to a noncollateralized, totally occluded infarct related artery. This study has raised the legitimate concern of electrical destabilization by reperfusion of electrically hibernating peri-infarct myocardium, thereby forming new reentrant circuits. Currently, international trials such as the Aggressive versus Conservative Treatment of the Infarcted Related Artery (ACTOR) and the Occluded Artery Trial (OAT) are underway to assess the true benefits of late reperfusion (42).

EFFECT OF LIPID LOWERING DRUGS ON VENTRICULAR ARRHYTHMIAS IN PATIENTS WITH CORONARY ARTERY DISEASE
   In 1990, a meta-analysis by Marchioli et al (44) based on 34 secondary prevention studies including a total of 24968 patients, showed that treatment of hypercholesterolemia by lipid-lowering drugs significantly decreased all cause mortality by 13%, coronary mortality by 16% and cardiovascular mortality by 13%. Statins achieved the most obvious benefit in terms of reduction of the odds of death. More recently, two large secondary prevention trials with statins have provided some direct evidence in support of the hypothesis that treatment of hypercholesterolemia can result in a reduction of arrhythmic events in patients with coronary artery disease. In the Scandinavian Simvastatin Survival Study (4S) the primary study end point was total mortality but data on instantaneous death and death within 1 hour (both most likely due to VT or VF) were also provided. In the placebo group (2223 patients) this event accounted for 63 of 189 coronary deaths, as compared with 37 of 111 coronary deaths in the simvastatin group (2221 patients). This reduction in presumable arrhythmic death was comparable to the reduction of death due to definite acute myocardial infarction (63 versus 30 deaths) (3). The second trial is the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) study. Among the 4502 patients in the placebo group, 211 deaths were classified as sudden death, as compared with 182 sudden deaths in the 4512 pravastatin-treated deaths (5). In both trials no separate statistical analysis of this mode of death was reported but, as already pointed out by Hohnloser (18), these observations support a beneficial effect of statins on the incidence of arrhythmia-related death in patients with coronary artery disease.

   To the best of our knowledge no single prospective randomized trial has been performed to study a possible effect of lipid lowering drugs on recurrences of arrhythmias in patients with coronary artery disease, documented ventricular arrhythmias and ICD implants. (Table 1) summarizes the prevalence of coronary artery disease and the medication at discharge in the seven largest randomized ICD trials published up until December 2000. Although the vast majority of patients studied were patients with coronary artery disease and a significant reduction of left ventricular function, only a moderate number of patients were treated with aspirin (48%-84%), beta-blockers (17%-33%) and ACE-inhibitors (43%-75%). More strikingly, the use of lipid lowering drugs was frequently not reported or very low (9%-25%). Also, no single trial reported lipid values at the time of randomization or at the end of follow-up (45-51). Only one trial reported data on the use of lipid-lowering therapy and outcome. In the Antiarrhythmics Versus Implantable Defibrillators trial (AVID) 132 of 1016 patients (13%) received lipid-lowering therapy and there was no difference regarding the primary endpoint of total mortality between patients with and without lipid-lowering drugs. This finding was consistent in patients treated with the ICD or antiarrhythmic drug therapy. However the effect of lipid lowering drugs on recurrences of ventricular arrhythmias was not reported in this trial which studied a mixed population of patients with ischemic and nonischemic cardiomyopathy. Also data on lipid values were not available in this study (13).

   We recently reported our results of a retrospective study in 78 patients with coronary artery disease and a history of life-threatening ventricular arrhythmias that were treated with a defibrillator (52). At discharge after ICD implantation 27 of these patients were receiving lipid-lowering drugs and 51 were not. After a mean follow-up of 490 days, recurrences of ventricular arrhythmias requiring ICD intervention were more frequently noticed in uni-and multivariate analysis in patients without versus with lipid-lowering drugs. The results of this study seem to further support the hypothesis that lipid-lowering drug therapy can result in a reduction of arrhythmic episodes in high risk patients with coronary artery disease.

   Furthermore, although in our study total cholesterol and LDL-cholesterol levels were comparable at the moment of ICD implantation, most of the patients who were not treated with lipid-lowering drugs showed a sharp increase in lipid levels, requiring lipid-lowering therapy according to actual guidelines. A practical consequence of this observation is that the decision to treat ICD patients with lipid lowering drugs should not only be based on a lipoprotein analysis at the moment of ICD implantation, but also on a control lipoprotein analysis performed at early follow-up. A possible explanation for the lower total and LDL-cholesterol levels at the moment of ICD implantation compared to the levels at follow-up, is that a considerable number of patients at that moment were recovering from resuscitation and its consequences such as aspiration pneumonia. These factors are indeed known to induce an acute phase response, causing a reduction in lipid levels comparable to the situation during the first months after myocardial infarction (53).

POSSIBLE MECHANISMS OF LIPID LOWERING DRUGS ON VENTRICULAR ARRHYTHMIAS
   In view of the pathophysiology of ventricular arrhythmias in patients with CAD it is possible that the potential antiarrhythmic effects of these drugs are linked to their ability to reduce the ischemic burden of the myocardium. Although a direct effect of lipid lowering drugs on reentry circuits can also be a possible explanation, it is indeed more likely that lipid lowering drugs can reduce the number of ischemic episodes that act as a trigger on the myocardial substrate to initiate recurrences of ventricular arrhythmias. Especially for statins, it has been shown that they exert beneficial effects above and beyond their hypercholesterolemia-lowering capability (54). Several mechanisms have been documented, including normalization of endothelial dysfunction, anti-inflammatory effects, depletion of the plaque lipid core, strengthening of the fibrous cap, inhibition of platelet thrombus formation and deposition and reduction of the thrombogenic response (55). All these effects can contribute to the prevention of new episodes of myocardial ischemia, and can explain the early effect (after already 16 weeks) of statin therapy on ischemic episodes detected by Holter monitoring (56) or on clinical events early after myocardial infarction (57,58). Also fibrates that target primarily triglyceride-rich lipoproteins and HDL-cholesterol can influence the process of atherosclerosis by their effect on the inflammatory response in patients with atherosclerosis (59). Furthermore, fibrates can also play a role in the improvement of the microcirculation by decreasing fibrinogen and plasma viscosity (60). However, at the present time no hard data from clinical trials in secondary prevention are available regarding a possible effect of fibrates on sudden cardiac death.

CONCLUSIONS AND FUTURE STUDIES
   Lipid lowering drugs and particularly statins reduce cardiovascular mortality and morbidity in patients with coronary artery disease. Some results from large secondary prevention trials with statins (3,5) and a smaller retrospective study in ICD patients (52) suggest that part of this beneficial effect is due to a reduction of ventricular arrhythmia-related sudden cardiac death. Clearly, further prospective, well-designed randomized trials are needed to confirm this hypothesis. Results of such trials could also help to define more precisely the role of myocardial ischemia as a trigger for sudden cardiac death. Recently, we started such a trial in patients with coronary artery disease and ICD implants. The aim of the Cholesterol Lowering and Arrhythmias Recurrences after Internal Defibrillator Implantation trial (CLARIDI trial) is to determine whether aggressive cholesterol lowering with atorvastatin can reduce recurrent ventricular arrhythmias in patients with coronary artery disease and ICD implants who have normal or borderline cholesterol levels. In this multicentre study (8 centers in Belgium, 5 centers in Greece) 220 patients will be randomly assigned to receive atorvastatin 80 mg or placebo in a double-blind design over a one-year follow-up period. The primary outcome measure is the first recurrence of a ventricular arrhythmia requiring appropriate ICD treatment (antitachycardia pacing or shock). Secondary outcome measures are the combination of total mortality and major cardiovascular events (defined as acute myocardial infarction, stroke, PTCA and CABG), the total number of appropriate ICD interventions for ventricular arrhythmias and the total number of episodes of electrical storm, and the combination of the above. The sample size of 220 patients is expected to provide 80% power to detect a 20% reduction in the primary outcome measure with a 5% level of significance. After approval by the local ethical committees, recruitment started in April 2000 and definite results are to be expected in 2003. This study will not give an answer to the clinical question whether lipid-lowering drugs can reduce recurrences of ventricular arrhythmias in high-risk patients. It will also offer a unique opportunity to study in detail the anatomic and functional properties of the substrate of these arrhythmias by means of non-invasive cardiac imaging tools such as echocardiography. Furthermore, potential new triggers of this substrate such as ongoing inflammation, activated platelets and oxidative stress will be evaluated in detail.

SUMMARY
   Ventricular arrhythmias are the most common cause of sudden cardiac death in patients with coronary artery disease. Since treatment of hypercholesterolemia in patients with coronary artery disease reduces the risk of major coronary events by about 30%, one could speculate that this treatment could also result in a reduction of arrhythmic episodes in high risk patients. In this review the importance of myocardial ischemia as a trigger for ventricular arrhythmias as well as the available data that suggest a possible effect of anti-ischemic treatments including lipid-lowering drugs on these arrhythmias will be presented. Also, possible mechanisms and future research to test the hypothesis that lipid-lowering drugs can reduce life-threatening ventricular arrhythmias will be discussed.

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2nd Virtual Congress of Cardiology

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