Ventricular arrhythmias occur commonly in clinical practice and range from benign asymptomatic premature ventricular complexes (PVCs) to ventricular fibrillation (VF) resulting in sudden death. The presence of structural heart disease plays a major role in risk stratification; however, it is important to recognize potentially lethal arrhythmias that may occur in structurally normal-appearing hearts. In general, management depends on the associated symptoms, hemodynamic consequences, and associated long-term prognosis. Initial management, risk stratification, and treatment of ventricular arrhythmias pose a significant challenge to clinicians. This chapter provides an overview of the clinical presentation, natural history, diagnosis, and therapeutic options for the ventricular arrhythmias encountered in clinical practice.

Care has been taken to incorporate the American College of Cardiology/American Heart Association/European Society of Cardiology (ACC/AHA/ESC) 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death and the ACC/AHA/Heart Rhythm Society (HRS) 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities.1,2 As with all ACC/AHA guidelines, these documents provide specific categories of recommendation, according to the level of evidence available (Table 42–1).

PVCs are commonly seen in clinical practice. The significance of PVCs depends on the frequency of PVCs, the presence and severity of structural heart disease, and the presence of associated symptoms.

PVCs in the Absence of Organic Heart Disease

PVCs occur frequently in the general population.3 In general, PVCs that occur in patients without structural heart disease are not associated with excess risk of sudden death. Kennedy and coworkers4 studied 73 patients with frequent ventricular ectopy and no structural heart disease on a 24-hour ambulatory (Holter) monitor. Patients were followed for an average of 6.5 years with no excess in mortality. PVCs that occur in patients with a structurally normal heart warrant no therapy, unless significant symptoms are present.

PVCs after Myocardial Infarction

The relationship between PVCs after myocardial infarction (MI) and sudden death has been studied extensively. In general, the presence of PVCs after an MI is associated with an increased risk of sudden death when the frequency of PVCs exceeds >10 per hour. Patients with larger MIs and lower left ventricular ejection fractions (LVEFs) are at the greatest risk of sudden death.5-9

Data from trials of thrombolytic therapy have also shown an association between PVCs and sudden death. In an analysis of Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-2, Statters and colleagues10 compared the prognostic value of PVCs among 680 patients who received or did not receive thrombolytics. They reported the greatest risk of sudden death among the patients who had >10 PVCs per hour and did not receive thrombolytics. In contrast, PVCs did not predict sudden death in patients who received thrombolytics until the frequency of PVCs were >25 per hour. These observations reflect the contribution of infarct size and, by association, ejection fraction (EF) to the prognosis of patients who have experienced an MI.

Treatment of PVCs Associated with an Acute MI

The association of PVCs with sudden death led to the routine use of intravenous lidocaine in patients suffering MIs.11 Subsequent randomized controlled studies have demonstrated worse survival when PVCs or ventricular arrhythmias were treated with antiarrhythmic agents.12,13 Based on these findings, the routine prophylactic use of antiarrhythmic agents for patients after an MI is not recommended. The treatment of PVCs and nonsustained ventricular tachycardia (VT) with antiarrhythmics is also not recommended unless they are associated with hemodynamic compromise (ACC/AHA/ESC practice guidelines1). In patients with frequent ventricular ectopy, electrolyte and acid-base imbalance should be vigilantly corrected. If frequent and persistent ventricular ectopy results in hemodynamic instability, a β-adrenergic blocking agent or amiodarone is the preferred pharmacologic intervention in this setting. Lidocaine may be considered temporarily when recurrent hemodynamically significant ventricular arrhythmias occur in the setting of acute MI.

The use of amiodarone in patients during and after an acute MI is debated. Amiodarone has unique pharmacologic properties beyond its effects on the cardiac sodium and potassium channels. It is also a β-adrenergic receptor blocker and a calcium channel blocker and has anti-ischemic effects.14 The European Myocardial Infarction Amiodarone Trial (EMIAT) was a study that randomized 1486 patients with an EF of <40% and prior MI to amiodarone or placebo. No difference in total mortality was observed in both groups after a mean follow-up of 21 months.15 In the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT), patients with prior MI and frequent ventricular ectopy (>10 PVCs/h) were randomized to amiodarone or placebo. The primary end point (combined arrhythmic death and resuscitated VF) was observed in 0.6% of the amiodarone group and 3.3% of the placebo group (P = .016). Most of the benefit was in patients who were treated concomitantly with β-adrenergic blockers. Although a significant benefit in arrhythmic death was observed in the amiodarone group, no significant difference in total mortality was observed in this study.16 A recent meta-analysis of 13 trials of amiodarone after MI or congestive heart failure reported a reduction in mortality and arrhythmic death in patients treated with amiodarone.17 However, based on the available information on amiodarone after MI, the prophylactic use of amiodarone in patients after an MI is not recommended for primary prevention. However, the use of amiodarone for the treatment of hemodynamically significant ventricular arrhythmias or other arrhythmias, such as atrial fibrillation, in the postinfarct setting appears to be safe.

PVCs and Nonsustained VT in Nonischemic Cardiomyopathy

The association between PVCs in nonischemic cardiomyopathy and sudden death is less clear. Several large trials, including the Grupo de Estudio de la Sobrevida en la Insufficiencia Cardiaca en Argentina (GESICA) trial and the Vasodilator-Heart Failure Trial (VHeFT), have found that nonsustained VT is a risk factor for sudden death.18,19 In contrast, Von Olshausen and coworkers20 found that only presence of a bundle-branch block and depressed EF predicted sudden death when they followed 73 patients with nonischemic cardiomyopathy and frequent PVCs for 3 years. In another study of ambulatory monitors performed in 674 patients with dilated cardiomyopathy, nonsustained VT was not associated with a lower survival rate.21 Therefore, the clinical significance of asymptomatic nonsustained VT in patients with dilated cardiomyopathy remains unclear.

Outflow Tract PVCs

PVCs originating from the right ventricular outflow tract (RVOT) are characterized on the 12-lead electrocardiogram by a left bundle-branch block pattern in V1 and tall, monophasic R waves in the inferior leads (Fig. 42–1). Although most outflow tract PVCs originate from the RVOT, 10% to 20% of outflow tract VTs been found to originate from other sites (left and right coronary cusp, mitral annulus, and on the epicardium near the left ventricular [LV] outflow tract) by mapping studies. For most patients with structurally normal hearts who have RVOT PVCs, the prognosis is good. This group of patients may manifest with frequent single PVCs or as repetitive salvos of monomorphic VT. The frequency of RVOT PVCs is often augmented by exercise; therefore, an exercise treadmill test is a useful diagnostic test. Symptomatic RVOT PVCs may respond to β-adrenergic blocking agents and calcium channel blockers. Radiofrequency catheter ablative therapy can be a curative treatment option for patients with symptomatic PVCs from the RVOT when drug therapy is proven ineffective (ACC/AHA/ESC practice guidelines [see Chap. 44]1). In the workup of these patients, it is important to rule out other causes of RVOT ectopy, such as arrhythmogenic right ventricular (RV) cardiomyopathy, a condition associated with sudden death and progressive RV failure.

PVCs as a Cause of Cardiomyopathy

Recently, clinical evidence of an association between frequent PVCs and a dilated cardiomyopathy has been demonstrated. In a study by Niwano et al,22 239 patients with frequent PVCs and no evidence of primary cardiomyopathy by echocardiography and cardiac magnetic resonance imaging were followed for >4 years. Additional follow-up at 5.6 ± 1.7 years was available in 189 patients. Forty-six patients had highly frequent PVCs (>20,000/24 h), 105 patients had moderately frequent PVCs (5000-20,000/24 h), and 88 patients had less frequent PVCs (1000-5000/24 h). A small but significant negative correlation was observed between PVC frequency and LVEF at 4 years and 5.6 years. It is notable that only 13 patients in this study experienced a change in LVEF of greater than –6%. Several studies have also demonstrated that elimination of PVCs among patients with depressed LV function may improve LV function.23 In a series of 60 consecutive patients with frequent PVCs (>10 PVCs/h), reduced LV function (mean LVEF 34% ± 13%) was present in 22 patients (37%). Patients with depressed LV function had more frequent PVCs than patients with normal LV function (37% ± 13% vs 11% ± 10% of all QRS complexes, respectively; P = .0001). Radiofrequency catheter ablation was completely successful in eliminating PVCs in 48 (80%) of 60 patients. Among the 22 patients with abnormal LV function, LV function assessed 6 months after the procedure returned to normal in 18 (82%) of 22 patients (LVEF of 34% ± 10% to LVEF of 59% ± 7%; P < .0001). Among patients with LV dysfunction at baseline who were not successfully ablated, the LV function further declined (LVEF of 34% ± 10% to LVEF of 25% ± 7%; P = .06).24 Therefore, preliminary data regarding the role of PVCs in the development of a cardiomyopathy demonstrate the following: (1) LV dysfunction occurs rarely and over a prolonged period of time; (2) LV dysfunction occurs among patients with a very high frequency of PVCs; and (3) among patients with a PVC-induced cardiomyopathy, LVEF may improve in the majority of patients when the PVCs can be eliminated with radiofrequency catheter ablation.

Exercise-Induced PVCs

The significance of PVCs in patients that occur during or in the recovery phase of exercise stress testing has been controversial, especially in patients with structurally normal hearts. A recent report of 6101 asymptomatic men who underwent exercise stress testing from the Paris Prospective Study reported that ventricular ectopy during exercise was associated with a relative risk of death from cardiovascular causes of 2.63 (95% confidence interval [CI], 1.93-3.59) when followed for an average of 23 years.25 In another study of 29,244 patients (70% men) without a history of heart failure or valve disease, the presence of frequent ventricular ectopy (defined by >7 PVCs/min) during recovery predicted an increased risk of death with an adjusted hazard ratio (HR) of 1.5 (95% CI, 1.1-1.9; P = .003), but frequent ventricular ectopy during exercise did not predict increased risk of death. The mean follow-up of this study was 5.3 years.26 Specific treatment recommendations cannot be derived based on these observational studies.

Malignant PVCs

Rarely, PVCs may be associated with more malignant conditions. Premature ventricular contractions among patients with a predisposition to ventricular arrhythmias (ie, Brugada syndrome, long QT syndrome, and catecholaminergic polymorphic VT) may serve as an important triggering mechanism.27,28 Recently, a clinical entity of PVC-triggered VF among patients without evidence of a cardiomyopathy or ion channelopathy has been described. In a multicenter observational series of 27 patients who had suffered from recurrent VF, Haisseguerre et al29 reported that the initiating trigger for VF was a PVC. In this series, 23 patients had PVCs that were found to originate in the Purkinje conduction system and the remaining patients had PVC triggers mapped to the RVOT. The PVCs were successfully mapped and eliminated with radiofrequency catheter ablation, and after a follow-up period of 24 ± 28 months, 89% had no recurrences of VF on no antiarrhythmic drug therapy.29 Long-term follow-up (median, 63 months) of 38 patients with idiopathic VF triggered by PVCs demonstrated that 7 (18%) of 38 patients had recurrence of VF after catheter ablation of the PVC trigger. Therefore, patients with this syndrome should receive an implantable cardioverter-defibrillator (ICD) despite successful ablation of the PVC.30 The clinical characteristics of this rare variant of patients with PVCs associated with malignant ventricular arrhythmias remain a mystery. Generally, patients with PVCs triggering VF have more tightly coupled PVCs than patients with benign PVCs. Patients with recurrent syncope or seizures with frequent PVCs on ambulatory monitoring warrant closer evaluation. This should include longer term monitoring and a careful evaluation to rule out electrical (ion channelopathies) and structural heart abnormalities.

Management of Patients with PVCs

Patients with PVCs should have an echocardiogram to assess LV function. Patients with structurally normal hearts and asymptomatic PVCs do not require specific therapy. Patients with PVCs from the RV, with RV dysfunction or enlargement, should undergo further workup to rule out arrhythmogenic RV cardiomyopathy. This workup should include a cardiac magnetic resonance imaging. Additional workup with a signal-averaged electrocardiogram and an electrophysiologic study may be considered.

In patients with symptomatic PVCs, therapy aimed at alleviating symptoms may be necessary. Initial treatment should include reassurance and the avoidance of exogenous stimulants or a trial of β-adrenergic blocking agents.

VT in patients with coronary disease ranges from nonsustained VT (NSVT) to sustained VT that leads to hemodynamic compromise and sudden death. The understanding of the pathophysiology of VT in patients with coronary artery disease has been greatly enhanced by animal studies, electrophysiologic studies in humans, and the results from recent multicenter randomized trials.

Pathophysiology

The anatomic substrate from which sustained monomorphic VT originates usually involves an extensive healed scar after an acute MI. This substrate of healthy and damaged myocardium interlaced with fibrous scar is found primarily at the border zone of the scar (transition between scar and healthy tissue) and serves as a substrate for slowed conduction and reentry.31,32 Evolution of the electrophysiologic substrate occurs over 2 weeks after an MI and then remains indefinitely.33 The substrate may continue to be modified by subsequent ischemic insults as well as late ventricular remodeling and worsening pump function. These changes may lead to neurohormonal activation and progressive LV dilatation with regional and global elevations in wall tension, all of which may contribute to proarrhythmia. Patients with VT have a high risk of recurrence of VT even when heart failure and coronary ischemia are controlled. Early data demonstrated that the risk of VT is highest during the first year (3%-5%) after an MI but that new onset of VT may occur many years later.7 However, recent evidence suggests that the risk of sudden death from ventricular arrhythmias remains high and may increase with time after an MI.34-36 In general, patients with larger infarctions and lower EFs are at highest risk of fatal ventricular arrhythmias.

Mechanism

The mechanism of VT in most cases is reentry. Ischemic VT usually is initiated, terminated, and reset with programmed electrical stimulation in the electrophysiology laboratory; this response to programmed electrical stimulation supports reentry as the mechanism for this form of VT.37 The reentry circuit most frequently exists within the border zone of the scar.31

Clinical Presentation and Management

Symptoms associated with ischemic VT are variable. The main determinants of hemodynamic tolerance are the rate of the VT38 and the degree of LV dysfunction.39 The hemodynamic stability of sustained VT is not prognostic of mortality risk. In the Antiarrhythmics Versus Implantable Defibrillators (AVID) registry, patients with hemodynamically tolerated VT at presentation had similar mortality compared with patients with syncopal VT.40

Sustained VT

Patients who present in clinically stable VT may be treated with antiarrhythmic drugs, antitachycardia pacing when available, or synchronized direct current (DC) cardioversion. Patients in VT with hemodynamic compromise, congestive heart failure, chest pain, or ischemia should be treated promptly with DC cardioversion (ACC/AHA/ESC practice guidelines1). In patients with stable sustained VT, intravenous procainamide is a reasonable first choice (ACC/AHA/ESC practice guidelines1). However, intravenous procainamide may cause hemodynamic instability because of its negative inotropic effects. When antiarrhythmic drug therapy is chosen to prevent recurrence or when VT is accompanied by hemodynamic instability, amiodarone is the treatment of choice. The efficacy of amiodarone is superior to lidocaine or procainamide in this setting41,42 (ACC/AHA/ESC practice guidelines1). All patients with VT should be treated with a β-blocker unless prohibited by hypotension, bradycardia, or other clinical factors (ie, reactive airway disease, vasospastic coronary disease). Reversible factors contributing to VT, such as congestive heart failure exacerbation, acute ischemia, or electrolyte abnormalities, should be diagnosed rapidly and treated. In patients who have refractory VT despite aggressive treatment, a subset of patients may be treated successfully with an emergent radiofrequency catheter ablation procedure, mechanical ventricular assist devices, and cardiac transplantation.43,44

The primary goal for long-term management in patients who have presented with sustained VT is to prevent recurrence of VT and sudden death. LV function is a well-established independent risk factor for sudden cardiac death in patients with ventricular arrhythmias.45-48 In a subanalysis of the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) study, evaluation of the impact of LVEF quartiles on long-term survival revealed a 39% relative risk of increased mortality for every 10% reduction in LVEF.49

Patients who present with sustained VT and an LVEF <35% should be considered for an implantable defibrillator. In patients with preserved LV function, the implantation of a defibrillator is controversial. A meta-analysis of the secondary-prevention ICD trials revealed that the patients who benefited from ICD therapy over amiodarone therapy were patients with EF <35%. Amiodarone was equivalent to ICD in patients with EF >35%.50 Most patients with sustained VT should receive an implantable defibrillator (Table 42–2), but for some patients with preserved LV function, amiodarone is a reasonable alternative. Long-term toxicities (eg, pulmonary, hepatic, thyroid, skin) and the high rate of drug cessation as a result of intolerance remain practical limitations for chronic amiodarone therapy.

Before implantation of a cardiac defibrillator, it is important that VT is clinically well controlled to prevent multiple shocks from the ICD. Reversible causes of VT should be corrected. Continued episodes of VT despite correcting reversible causes should be treated aggressively. Several studies have demonstrated the efficacy of antiarrhythmic agents in preventing ICD shocks. In a randomized controlled study of patients who had ICDs implanted for inducible or spontaneously occurring VT or VF, 412 patients were randomized to β-adrenergic blockers alone (n = 140), sotalol alone (n = 134), or amiodarone plus β-blocker (n = 140). After a mean follow-up of 359 days, ICD shocks occurred in 38.5% of patients assigned to the β-blocker group, 24.3% of patients in the sotalol group, and 10.3% of patients in the amiodarone plus β-blocker group. Amiodarone plus β-blocker resulted in significantly fewer shocks compared with β-blocker alone (P = .006).51 The decision for empiric therapy with antiarrhythmic agents at the time of ICD implantation depends on whether VT or VF can be controlled clinically. A β-adrenergic blocking agent should be administered in all patients unless contraindicated.

When antiarrhythmic agents are initiated in patients with an implantable defibrillator, care must be taken in programming the implantable defibrillator because antiarrhythmic medications can have varying effects on defibrillation thresholds and may slow the rate of the VT.

Patients with ischemic cardiomyopathy and persistent VT refractory to medications may be successfully treated with radiofrequency catheter ablation techniques.52,53 It should be emphasized that such ablation is adjuvant to ICD therapy and cannot be expected to obviate the need for an ICD (Table 42–3).

Nonsustained VT

The evaluation and management of patients with asymptomatic NSVT begins with the evaluation of the patient’s LVEF. Patients with preserved LV function are generally at low risk and generally require no further treatment. Patients with low EF are at risk of sudden death. In patients with an LVEF of <40%, annual mortality of patients post-MI is estimated to be 8% to 10%.54 The importance of treating these patients with an angiotensin-converting enzyme inhibitor (ACEI), aspirin, and a β-adrenergic receptor blocker cannot be overemphasized (ACC/AHA/ESC 2006 guidelines1).

Over the past several years, two important changes in the standard of care of patients with coronary artery disease at risk of malignant ventricular arrhythmias have occurred. First, programmed electrical stimulation at electrophysiologic study has been demonstrated to be a poor risk stratification tool. Second, clinical documentation of NSVT is no longer necessary to identify patients who would benefit from primary prevention with an ICD.

Previously, a diagnostic electrophysiologic study with programmed stimulation in the RV was used to risk stratify asymptomatic postinfarct patients with NSVT.55 However, an analysis of the Multicenter Unsustained Tachycardia Trial (MUSTT) registry data demonstrated that patients with negative electrophysiologic study who were followed in a registry had a high risk of arrhythmic death (12% over 12 months).56 The high mortality rate in the patients who were noninducible at electrophysiologic study in this study called into question the usefulness of programmed electrical stimulation as a risk stratification tool.

The need for NSVT to identify patients who would benefit from an ICD was invalidated by the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II study. This study randomized 1232 patients with ischemic cardiomyopathy based on LV function alone (LVEF ≤30%) with no requirement for the documentation of NSVT. After an average follow-up of 20 months, a significant reduction in all-cause mortality was observed in patients who received an ICD.57 The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) is the largest randomized primary prevention trial comparing ICD versus amiodarone versus optimal medical therapy in patients with LVEF <35%. This study did not require the presence of NSVT for enrollment. Patients enrolled in SCD-HeFT had New York Heart Association (NYHA) functional class II to III heart failure symptoms. After a 5-year follow-up period, this study demonstrated that (1) the annual mortality of patients on optimal medical therapy is 7% to 8% per year; (2) amiodarone, when used as a primary preventative agent, does not improve survival over good background medical therapy for heart failure; and (3) an ICD decreases mortality by 23% compared with optimal medical therapy (HR = 0.77; 95% CI, 0.62-0.96; P = .007).58

Based on the recent literature guiding the primary prevention of sudden death in patients with coronary artery disease and depressed LV function, patients with ischemic cardiomyopathy with an EF of <35% should be treated according to the ACC/AHA guidelines with appropriate pharmacologic therapy for heart failure including ACEIs, angiotensin II receptor blocking agents, β-adrenergic receptor blockers, and aldosterone antagonists. Once the patients are adequately treated, an ICD should be considered for primary prevention of sudden death regardless of whether they have NSVT clinically documented or not. The demonstration of spontaneously occurring NSVT or sustained VT inducible on programmed electrical stimulation is no longer a necessary prerequisite for the implantation of an ICD (see Table 42–2).

Dilated cardiomyopathy is caused by a heterogeneous group of etiologies resulting in LV and/or RV failure. Causes of dilated cardiomyopathy include valvular heart disease, chronic ethanol ingestion, viral infections, and cardiac sarcoidosis, among others. Sudden death in dilated cardiomyopathy is usually caused by a ventricular tachyarrhythmia. The contribution of bradyarrhythmias to the etiology of sudden death in patients with dilated cardiomyopathy may also be important. In a report of 157 cases of sudden death in idiopathic cardiomyopathy in which the rhythm preceding death was available from ambulatory monitoring, 62% of patients had organized VT that progressed to VF, and 13% had primary VF, but 17% had bradyarrhythmia.59 In another report of 20 patients with severe dilated cardiomyopathy awaiting cardiac transplantation, the cause of death was electromechanical dissociation/bradycardia in 13 of 20 patients, and only 7 of 20 died of a ventricular arrhythmia.60 Although ventricular arrhythmias are the most frequent cause of sudden death, bradyarrhythmias may also play a role in some patients with severe dilated cardiomyopathy.59-61

Pathophysiology

The pathogenesis of ventricular arrhythmias in dilated cardiomyopathy is not well understood and may reflect a variety of mechanisms. In a study of the autopsy findings in 152 patients with idiopathic dilated cardiomyopathy, subendocardial scarring was present in 33% of patients. Histologic sectioning revealed multiple patchy areas of fibrosis in 57% of patients. These patchy areas of fibrosis, intermingled with viable myocardium, may serve as the substrate for reentry.61 Changes in ventricular mechanics and geometry may alter regional refractoriness within the ventricle and also predispose to reentry, enhanced automaticity, or triggered activity.62 Furthermore, the conduction system may also serve as a substrate for reentry in patients with dilated cardiomyopathy. Bundle-branch reentry (BBR) is a type of VT that uses the left and right bundle branches and a portion of the ventricular myocardium as its circuit. BBR is a common cause of sustained monomorphic VT in patients with dilated cardiomyopathy and in one study represented up to 41% of VTs present in this subgroup.63 In another series of 26 patients with monomorphic VT and nonischemic cardiomyopathy, the etiology of VT was scar-related reentry in 62%, an ectopic focus in 27%, and BBR in 19% of patients.64 The identification of BBR is important in patients with dilated cardiomyopathy because this arrhythmia may be treated with radiofrequency catheter ablation (see also ACC/AHA/ESC 2006 practice guidelines1).

Clinical Presentation and Management

NSVT is common in patients with dilated cardiomyopathy. NSVT is seen on 24-hour ambulatory and telemetry monitoring in 50% to 60% of these patients. Sustained VT or VF is thought to be the most common cause of death in dilated cardiomyopathy. The prevalence of NSVT increases with worsening heart failure symptoms. In patients with class I to II congestive heart failure, the prevalence of NSVT is 15% to 20%, and in patients with class IV heart failure, the prevalence is 50% to 70%.65-69 The significance of NSVT as an independent predictor of sudden death in this setting is unclear.