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The Big Heart Disease Lie

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Atrial Fibrillation With
Fig. 2. Monomorphic VT in a patient with prior MI. (A) The initial rate of VT was 163 BPM. (B) Following a procainamide load, the VT has slowed to 118 BPM, and the QRS has widened.

patients had previous MI, and many had incessant VT or were receiving cardiopulmonary resuscitation (CPR). Both studies demonstrated a dose-dependent beneficial effect on mean time to first recurrence of VTA. Neither study demonstrated a statistically significant dose-related trend in mortality. Another trial compared iv amiodarone to standarddose iv bretylium in patients refractory to lidocaine and procainamide (28). At a dose of 1 g/24 h iv amiodarone was equivalent to standard-dose bretylium (2500 mg/24 h) with respect to arrhythmia event rate, the time to first arrhythmia recurrence, and

48-h survival. However, significantly more patients receiving bretylium developed hypotension or heart failure.

Although generally supportive, these trials failed to demonstrate the superiority of iv amiodarone to standard therapy based on "hard" survival end points. On the other hand, given the heterogeneous nature of the patients and disorders for whom the interventions were applied, the results seem impressive. In any case, iv amiodarone has achieved widespread acceptance and usage. Part of the enthusiasm for iv amiodarone may result from the positive reputation of the oral form. Many authorities believe that oral amiodarone is the drug with the best risk-to-benefit performance in control of sustained VTA. However, many of its electrophysiological effects develop weeks after initiation. It is not known which of the many effects of amiodarone are essential to its success, and it is probable that the critical elements vary according to the type and degree of cardiac dysfunction and arrhythmia characteristics. Therefore, the electrophys-iological profile of iv amiodarone differs from that of the oral form, and it can be expected to change over time. The rationale for early administration is not limited to the immediate effects of iv amiodarone; rather the more quickly amiodarone is administered, the sooner the effects on repolarization and other slowly developing properties will exert their benefits. The initial dose recommended by the Intravenous Amiodarone Multicenter Investigators Group is a bolus of 150 mg over 10 min followed by a 6-h infusion period at 1 mg/min, followed by a maintenance rate of 0.5 mg/min. This provides 1 g in the first 24 h. Supplemental doses of 150 mg iv are recommended to achieve suppression of breakthrough arrhythmias. The "Guidelines 2000" recommend an initial 300 mg bolus of iv amiodarone for VF/VT cardiac arrest with additional boluses of 150 mg as necessary/maximum cumulative dose 2.2g over 24 h (22).

Standard ACLS guidelines were developed to address the majority of cardiac-arrest cases, which are usually out-of-hospital events and often unwitnessed. In contrast, clinicians are more likely to encounter sustained VTA in the hospitalized patient. In such cases, more information and more therapeutic options may be available, such as circulatory assist devices, rapid-rate pacemakers, and access to catheter-based therapies (including revascularization and radiofrequency ablation). Because the distribution of response varies widely between situations, optimal treatment guidelines may differ from those proposed by national organizations.

Gillis has proposed an approach to intractable VTA (IVTA) directed toward the hospitalized patient (29). Patients who present with VTA are treated according to standard guidelines, and receive at least one trial of either lidocaine or procainamide and correction of immediately reversible causes. If beta-blockers are not contraindicated, atrial pacing is performed at 80-100 beats per minute (BPM), and 3 to 5 doses of the Pi-selective beta-blocker metoprolol 5 mg iv are administered every 5 min. Alternatively, a nonselective agent such as esmolol (0.5 mg/kg over 1 min, then 0.05-0.3 mg/kg/min continuous infusion) or propranolol (1 mg iv every min to total initial dose of 0.1 mg/ kg) may be used. Beta-blockers can be administered to most patients with heart failure. Small doses of beta-blockers are often tolerated, and are beneficial in patients with cardiogenic shock.

Nadamanee and colleagues (30) recently published their findings in 49 patients with electrical storm, defined as recurrent, multiple VF episodes. Patients treated with sympathetic blockade fared better than those treated according to ACLS algorithms with lidocaine, procainamide, and bretylium. Sympathetic blockade consisted of iv esmolol or propranolol, as well as left stellate ganglionic blockade in some patients; these patients also received oral amiodarone.

If beta-blockers are contraindicated or a trial is unsuccessful, Gillis recommends amiodarone iv at twice the dose recommended by the Intravenous Amiodarone Multicenter Investigators Group. The prospective multicenter study reported that patients initiated on higher doses had longer times to first ventricular tachyarrhythmia (VTA) recurrences and required fewer supplemental infusions, and that hypotension, which occurred in approx 25% of patients, was not significantly more frequent in the high-dose group. The suggested dosing schedule, based on a pharmacokinetic study, provides an iv dose of 2100 mg in the first 24 h, 300 mg iv over 10-20 min followed by an initial infusion rate of 2 mg/min for 6 h (720 mg), then a maintenance rate of 1 mg/min. The iv infusion at 1 mg/kg is then continued for 3 d(1440 mg/d) (29). The Gillis algorithm does not include the use of bretylium. The Intravenous Amiodarone Multicenter Investigators Group observed that amiodarone was as effective as bretylium, but was associated with fewer adverse effects. Other considerations could also guide the early use of amiodarone. If oral amiodarone therapy is a long-term option, then early use of iv amiodarone should accelerate the slowly developing antiarrhythmic effects of oral amiodarone. On the other hand, amiodarone has a very long elimination half-life. This can result in prolonged adverse effects, which may be particularly serious in the rare case of proarrhythmic properties and interactions that occur between amiodarone and many forms of therapy. The extended effects may also affect electrophysiological evaluation and complicate the use of other antiarrhythmic drugs.

Other pharmacological therapies may also play an important role in IVTA. Heavy sedation or general anesthesia (combined with assisted ventilation) could reduce sympathetic activity, energy utilization, myocardial oxygen demand, and congestive heart failure (CHF). Inotropic drugs and pressors are often necessary, although they may have proarrhythmic actions. Pharmacological therapy is only one element of the total approach to IVTA. Other strategies include internal defibrillation, cardiac pacing to inhibit or to terminate VTA, ablation of culprit myocardial tissue by catheter-based radiofrequency ablation, or surgical ablation and excision. Circulatory assist devices are of particular importance in reducing sympathetic drive, myocardial stretch, and oxygen demand, and allowing the use of medications that cause hypotension (31).

LONG-TERM MANAGEMENT OF VTA Initial Evaluation

Errors in the long-term management of patients who present with VTA often result from the failure to delineate the goals and targets of therapy. Most patients who present with VTA have severe underlying structural heart disease and comorbid conditions that may constitute risks for multiple mechanisms of death. A therapeutic strategy focused solely on the presenting arrhythmias may not fully address the ultimate goal: prolongation of survival. In some circumstances, effective prevention of the VTA increases the risk of other mechanisms of death. In other circumstances, risk modification reduces the risk of recurrent VTA so that additional specific treatment is unnecessary. The optimal treatment strategy provides the greatest reduction of all causes of mortality, with modifications for quality of life and other patient preferences. Risk assessment is the key step that ascertains the potential benefit of a therapeutic strategy. Unfortunately, adequate information regarding risk is almost always lacking. This results in estimates of arrhythmic death with large confidence intervals resulting from the inaccuracies of current data. The clinical response to this uncertainty is to offer ICD therapy, which is believed to be the most secure treatment available.

Overview

The last 10 yr have witnessed a tremendous change in approaches to the long-term management of VTA. Guided therapy of antiarrhythmic drugs, usually by serial invasive electrophysiologic studies (EPS), but sometimes by Holter monitoring, was the paradigm until the early 1990s. The CASCADE trial, however, showed that empiric amiodarone therapy was superior to electrophysiology-guided therapy with class I agents in cardiac-arrest survivors (32). The ESVEM trial showed that guided therapy with sotalol was superior to guided therapy with class I agents, either using electrophysiology or Holter guidance (33,34). These trials led to a marked decrease in class I drug use and guided therapy in general. Randomized trials such as AVID (16), CIDS (34a), and CASH (35), which documented the superiority of ICD therapy to amiodarone in patients with VTA, have led to a marked decrease in the use of pharmacologic therapy as a primary measure in patients with a history of VT or VF. Amiodarone continues to be used in patients for whom ICDs are not a good option or are undesirable.

Ischemic Heart Disease

Ischemic heart disease is the most common etiology of VTA. It is an extraordinarily complex syndrome with many potential influences that contribute to arrhythmogenesis. Four general processes can be considered: ischemia-reperfusion, acute MI, healed MI, and remodeling of noninfarcted myocardium. Ischemia followed by reperfusion is an extremely potent cause of arrhythmias. The resulting ventricular arrhythmia is usually a polymorphic VTA (i.e., polymorphic VT or VF). SMVT is rarely observed in the absence of a pre-existing scar. Ischemia-reperfusion VTA can occur in the absence of ischemic heart disease (IHD) because of vasospasm, thromboembolism followed by lysis, and other mechanisms. Because it may be transient, asymptomatic and completely reversible, ischemia-reperfusion can rarely be completely excluded as a possible contributor to arrhythmogenesis. The potential for ischemia should be evaluated in most cases. Although proper precautions must be taken, provocation of ischemia for diagnostic purposes is rarely contraindicated in patients who present with VTA. VTA are rarely induced during physical or pharmacological stress tests for ischemia. Failure to reproduce a VTA during provoked ischemia does not exclude a contribution of ischemia for the previous event or a future event. Therefore, prevention of ischemia is appropriate in most patients with IHD who present with VTA.

Cardiac arrest or VTA in the context of an acute MI is generally attributed to the electrophysiological and neurohormonal changes related to ischemia-reperfusion, followed by those caused by the acute necrotic process. About 65% of deaths from MI occur within the first few hours of symptoms, and most are a result of VF (36). Patients who develop sustained VT are older, have larger infarctions, and have high mortality rates. In one study, mortality was 27%, 39% and 45% at 7 d, 30 d, and 1 yr, respectively. This was higher than in patients who develop in-hospital VF or NSVT (37). This is clearly a group in which aggressive evaluation and therapy is warranted.

Ventricular tachyarrhythmia that occurs during an acute MI can be classified as early (<24 h) or late (>24 h after admission), and as primary (i.e. Killip class I), or secondary (i.e., Killip class II-IV). Patients with primary VF tend to have a more extensive infarction. In one report, in-hospital mortality was high if the arrhythmias occurred within 4 h of acute MI, but even higher if VF occurred between 4 and 48 h. On the other hand, after discharge, patients with primary VF have a similar 6-mo, 1-yr, and 5-yr mortality compared to controls. The in-hospital and 1-yr mortality of patients with secondary VF is very high: 58% at 1 yr in one study (37). Lidocaine is recommended for prevention of further episodes in patients who with VTA early after acute MI. The need for lidocaine should be reevaluated after about 12-24 h when the risk of recurrence of VTA declines markedly (36). Presentation with early primary VTA does not appear to select patients who will benefit from long-term antiarrhythmic drug treatment beyond standard therapy after MI.

Patients who develop late VF (>24 h after admission) have a worse in-hospital and subsequent prognosis than those with early VF. It is not known what time cut-off point after acute MI provides the most reliable segregation of low- and high-risk patients. Patients were excluded from the Canadian Implantation Defibrillator Study (CIDS) (38), and the AVID trial (16) if the presenting VTA occurred less than 3 d and 5 d after MI, respectively. The purpose was to exclude patients who would be unlikely to benefit from ICD therapy because of low risk for subsequent arrhythmic events.

The transition between acute, healing, and chronic MI is a continuum during which risk for VTA varies. Moreover, there are large interindividual differences in the pattern of variation. Risk is high during the first 6 mo after an acute MI, and usually declines. However, in some patients, remodeling results in continuous changes in the MI scar, which may form into a substrate for reentry at any time from days to decades after the acute MI. This process results in regions of unexcitable tissue that can form anatomic barriers, and areas of viable tissue with altered cell-to-cell coupling and other nonuniform properties that form the basis for slow conduction, unidirectional block and other factors that promote reentry. This underlies SMVT in many patients with ischemic heart disease. Remodeling also occurs in noninfarcted myocardium caused by an extensive acute MI, progressive ischemia, or concomitant cardiovascular disease such as hypertensive cardiovascular disease or superimposed dilated cardiomyopathy. This type of remodeling is a process associated with anatomic, electrophysiological, and neurohormal changes—all of which may facilitate arrhythmogenesis. The electrophysiological changes include reduction of potassium currents and action-potential prolongation. One theory is that this process results in an acquired form of LQTS because of reduced repolarization reserve. The observed arrhythmias are usually polymorphic VT (PVT) or VF with mechanisms similar or identical to those observed in some forms of LQTS.

Although separation of the various arrhythmogenic influences is helpful in understanding the pathogenesis of VTA in IHD, it oversimplifies the interactions between the electrophysiological, neurohormonal, and anatomical changes. In practice, it is rarely possible to distinguish between the four major influences or to completely exclude any single influence in the genesis of a clinical event. Most patients with ischemic heart disease (IHD) have multiple mechanisms or potential paths to arrhythmic death. This necessitates a comprehensive search for risk factors. All patients with IHD who present with VTA should undergo a careful evaluation to determine current symptoms, the degree of functional impairment, the presence of risk factors, evidence of other cardiovascular disease, and the presence of comorbid conditions. Most patients should undergo tests for risk stratification, including quantification of left ventricular function and a provocative test for myocardial ischemia. In some patients, assessment of neurohormonal function by heart-rate variability (HRV) and baroreflex sensitivity (BRS) analysis may be useful, although these techniques remain largely investigational. Invasive tests including cardiac catherization, coronary angiography, and EPS should be strongly considered. Treatment alternatives should address all modifiable risk factors. Most patients are candidates for optimal adjunctive therapy (lifestyle modifications, exercise programs, lipid-lowering therapy, platelet inhibitors or other anticoagulants, angiotensin-converting enzyme (ACE) inhibitors or related compounds, and beta-blockers). Complete revascularization is indicated in patients with evidence of stress-induced ischemia and significant coronary-artery stenoses. Although the role of EPS is debated, there is evidence that inducible SMVT predicts arrhythmic death in patients with NSVT and after acute MI. It is also probable that the induction of SMVT in patients who present with VTA indicates a heightened risk for arrhythmic death. This may affect the choice of long-term therapy and motivate more aggressive risk modification. Randomized clinical trials have established the benefit of ICD therapy over treatment with amiodarone in patients who present with cardiac arrest or hemodynamically significant VTA in the absence of reversible causes (16). However, the benefit of ICD therapy was marginal, patients with severe functional limitations were excluded, and subgroup analyses indicate that some categories of patients do not benefit from ICD implantation over treatment with amiodarone. Therefore, the decision for ICD therapy should be placed in the context of the overall treatment strategy. A risk-to-benefit analysis is used to develop the optimal treatment strategy for the individual patient.

An illustrative example is the patient who presents with symptomatic SMVT, or VF with a history of previous MI and class II heart failure. The patient often has a number of risk factors for progression of CAD, such as hypertension or smoking, but no major comorbid conditions such as terminal cancer. Risk assessment may demonstrate no provocable ischemia, moderately reduced left ventricular function (e.g., left ventricular ejection fraction (LVEF) 0.25-0.35), depressed HRV (SDNN <70 ms) and low BRS (<3 ms/mmHg). SMVT is induced at EPS. This patient has a substantial risk of total mortality (nonarrhythmic cardiovascular causes and arrhythmic death), but little contribution from noncardiovascular causes. The treatment strategy should include an aggressive program to reduce cardiovascular events caused by recurrent VTA, ischemia, thrombosis, and progressive myocardial remodeling. Optimal adjunctive therapy, as described here, is an essential component of long-term treatment. Many clinicians would recommend an ICD to reduce the risk of arrhythmic death from any cause (ischemia, acute MI, chronic MI, or remodeled ventricular myocardium).

The major treatment alternative to ICD therapy is amiodarone. Amiodarone therapy should be considered for patients who are not likely to benefit from ICD therapy because of a high risk of nonarrhythmic death or a low risk of arrhythmic death. Patients with severe functional limitations (e.g., NYHA class 4) or another condition with a poor 1-yr survival would fit into the former category. Patients with preserved left ventricular function (e.g., LVEF >0.40) and patients with possible transient factors that could have caused the presenting VTA may fit into the low arrhythmic death risk category. Patients at high risk for complications because of ICD therapy and patients who prefer pharmaco-logic therapy should also be considered for amiodarone therapy.

Racemic sotalol has been shown to reduce the recurrence rate of VTA and death compared to type I antiarrhythmic drugs. Although small studies suggest that it may be less effective than ICD therapy, a rigorous comparison has not been performed. The risk of proarrhythmia is increased in patients with significant left ventricular dysfunction and VTA, but it does not have many of the side effects associated with long-term use of amiodarone. If other therapeutic options are contraindicated, or if the contribution of risk of arrhythmic death to the overall mortality is small, then consideration could be given to treatment with beta-blockers plus optimal adjunctive therapy without additional specific antiarrhythmic drugs. The addition of beta-blockers to the other elements of optimal adjunctive therapy has demonstrated a marked reduction in sudden death in patients after MI and in patients with heart failure. Treatment with amiodarone was not superior to metoprolol therapy in the Cardiac Arrest Study of Hamburg (CASH) (35). Treatment with sodium-channel-blocking agents is not recommended in patients with IHD with VTA because of the high risk of proarrhythmic effects and relatively poor efficacy. Catheter-based ablation therapy may be useful for reducing the frequency of recurrent VTA, but in isolation probably does not protect against the multiple sources of risk for arrhythmic death in patients with IHD. Many patients with VTA associated with IHD who are treated with ICDs also require antiarrhythmic drug therapy for a number of indications discussed earlier. Amiodarone is often used with generally satisfactory results, but potential adverse effects on ICD function include an increase in defibrillation energy requirement (9,9a). Racemic sotalol has several characteristics that make it well-suited for this form of combination therapy: it inhibits ventricular and supraventricular arrhythmias and reduces the ventricular rate response to AF. As a beta-blocker, sotalol has antisympathetic activity which reduces the sinus rate and myocardial oxygen demand. Sotalol reduces the defibrillation energy requirement. Compared to other antiarrhythmic drugs, sotalol is less likely to interfere with capture thresholds, to cause QRS prolongation, to cause excessive reduction of the VTA rate, and to cause variability in the VTA cycle length (39). These characteristics could result in more uniform, predictable ICD function (18). Class Ib antiarrhythmic drugs should also be considered, particularly in combination (40). Class Ia antiarrhythmic drugs are used primarily when other therapies have failed. The risk of intractable or incessant ventricular arrhythmias would make class Ic drugs less than ideal for patients with IHD whether or not they had an ICD.

Coronary Artery Anomalies, Spasm, and Myocardial Bridges

Abnormal origin and course of coronary arteries and vasospasm are rare but important causes of sustained VTA. Myocardial bridging has been reported to cause acute myocar-dial ischemia, but this concept has been challenged. Therefore, although a contribution of myocardial bridging to VTA resulting from ischemia cannot be excluded, other mechanisms should be sought. Therapy of coronary spasm has included nitrates and calcium-channel blockers. Refractory cases have been reported, and some patients have been treated with ICDs. Amiodarone has vasodilatory and antifibrillatory properties that may be beneficial. However, class I and III antiarrhythmic drugs would not be expected to have a favorable risk-to-benefit ratio. The use of beta-blockers has been questioned because they could inhibit catecholamine-induced vasodilation, and lead to unopposed alpha-receptor mediated vasoconstriction.

Nonischemic Dilated Cardiomyopathies

Dilated cardiomyopathies arise in a number of clinical contexts, including valvular heart disease, the dilated phase of hypertrophic cardiomyopathies, and various neuromuscular disorders. The etiologies of the most common varieties—i.e., the idiopathic dilated cardiomyopathies—are unknown. Mortality is high in these conditions, and arrhythmic death constitutes a large percentage of total mortality. In patients with significant left ventricular dysfunction, the risk of arrhythmic death remains high even if reversible triggers of the presenting VTA are identified. Although a number of noninvasive methods for determining risk appear promising, none has been widely accepted. The imprecision of risk assessment has resulted in the recommendation for ICD therapy in most patients with dilated cardiomyopathy who present with VTA. It is important to recognize that most patients will not require an ICD. All patients should receive optimal medical therapy with beta-blockers, ACE inhibitors and, possibly spironolactone and angiotensin II-receptor blockers. Alternative pharmacological approaches would include amiodarone therapy. Nonpharmacological therapies include cardiac transplantation and permanent circulatory-assist devices. Bundle-branch reentry can be induced in some patients with dilated cardiomyopathies, and may be efficiently prevented (with low risk) by radiofrequency ablation. However, this form of therapy does not address other potential mechanisms of arrhythmic death. Therefore, if the risk of arrhythmic death is estimated to be high despite treatment—e.g., in the presence of moderate or severe ventricular dysfunction—then additional therapy with ICD or amiodarone should be considered. In the CHF-STAT trial, amiodarone appeared more effective in patients with nonischemic compared with ischemic cardiomyopathies (41).

Congenital Heart Diseases

Success in the management of congenital heart disease (CHD) has increased longevity and more physicians are encountering GUCH (Grown-Up Congenital Heart) patients, many of whom have undergone operative correction or palliation of the CHD. VTA and sudden death are relatively uncommon in congenital heart disease. Possible mechanisms are surgical scar and patch-related reentrant VTA, and VTA related to remodeling of ventricular myocardium that can occur after years of abnormal hemodynamic forces. Patients with VTA may present with syncope, but atrial arrhythmias may also be responsible and must be excluded. Excessive ventricular rates caused by atrial arrhythmias may also cause malignant VTA. The appearance of atrial and ventricular arrhythmias often reflects severe deterioration in hemodynamic function. Appropriate therapy requires a comprehensive evaluation of hemodynamic function and underlying anatomic abnormalities (congenital and iatrogenic) by experienced GUCH clinicians. The accumulated experience in management of VTA and outcome in patients with congenital heart disease is limited. Practice is often guided by experience in other more common disorders, such as ischemic heart disease. However, the youthful ages of many of the patients require special considerations for long-term medical therapy. Thus, anti-arrhythmic therapy with amiodarone, sotalol, and other beta-blockers would be considered. Catheter ablation of surgical-scar-related VTA has been performed. ICD therapy probably provides the most reliable protection, but implantation may be complicated by the abnormal course of vessels and inaccessibility of specific cardiac chambers. In addition, anecdotal evidence suggests a high rate of psychiatric complications in ICD-

treated young patients, particularly adolescents. Finally, heterodynamic abnormalities may require operative correction that could offer opportunities for ablation or better access to sites for pacing and defibrillation leads.

Hypertrophic Cardiomyopathies

Hypertrophic cardiomyopathies may exist in asymmetric forms with or without left ventricular outflow tract (LVOT) obstruction and concentric forms. These disorders are associated with multiple abnormalities that could contribute to arrhythmogenesis, including myocardial hypertrophy, myofiber disarray, fibrosis, myocardial ischemia, autonomic dysfunction, and abnormalities of cellular and subcellular functions (42). Some patients have genetic mutations associated with a high risk of sudden death but relatively few anatomic changes. Several reports indicate that supraventricular arrhythmias are important triggers of VTA. An unusual presentation of SMVT is observed in patients with midventricular obstruction who develop apical aneurysms. Risk assessment requires evaluation of the individual factors, family history, and results of noninvasive and invasive examinations. Methods of risk stratification have included long-term Holter monitoring to detect NSVT, TWA, exercise testing to identify abnormal hemodynamic-autonomic reflexes, and stress imaging to detect myocardial ischemia. EPS has been used to assess the ventricular response rate to induced supraventricular arrhythmias, evidence of AV conduction disturbances, fractionation of ventricular elec-trograms, and inducible VTA. For most patients who present with VTA, the indication for ICD therapy is so strong that further risk assessment would seem superfluous (43). However, some elements of evaluation may affect the type of ICD or additional therapy. Additional therapy could include catheter-based or operative reduction of septal hypertrophy and interruption of AV conduction. ICD selection could include dual-chamber pacing and capacity for AF. Many patients with malignant forms of hypertrophic cardiomyopathy are very young, and may have anatomical and psychological contraindications for ICD therapy. Amiodarone has been reported to be successful in preventing arrhythmic death, but a major problem exists in the inability to test its effectiveness in individual patients (44). Beta-blockers, calcium antagonists, and operative methods do not prevent arrhythmic death, but may be indicated to prevent ischemia, outflow-tract obstruction, and excessive sympathetic activity. Myocardial hypertrophy results in action-potential prolongation. Drugs that prolong action-potential duration (class IA and III) are relatively contraindicated caused by increased risk of pro-arrhythmia. Class Ic antiarrhythmic drugs are also contraindicated in the presence of ventricular hypertrophy. Adjunctive medical therapy is important in patients with hypertensive cardiomyopathy. Blood pressure control may reduce progression of ventricular hypertrophy, and experimental evidence suggests that ACE-inhibitors reduce vulnerability to VF (45).

Myocarditis and Inflammatory Cardiomyopathies

Myocarditis should be considered in patients who present with VTA or sudden death in the absence of other causes (45a). This suspicion should be confirmed with endomyocardial biopsy. Because there is often spontaneous resolution, antiarrhythmic control may be required only temporarily. There are several progressive disorders associated with varying degrees of active inflammation and fibrosis. Chaga's disease is an important cause of VTA in some South American countries, but it is a relatively rare cause of VTA elsewhere. Amiodarone is reported to be more effective than other antiarrhythmic drugs, but reliable comparisons with ICD therapy and catheter ablation have not been published (46). The optimal strategies for VTA associated with sarcoid heart disease and giant-cell myocarditis are unclear. Some inflammatory disorders respond to immunosuppression. Selection of therapy should be based on an estimate of reversible and permanent damage. Unfortunately, there are few guides to risk assessment or to pharmacological therapy. ICD therapy is likely to dominate the selection process in patients who present with VTA. Amiodarone is the major pharmacological alternative.

Arrhythmogenic Right Ventricular Cardiomyopathy (Dysplasia)

Arrhythmogenic right ventricular cardiomyopathy is a disorder—often familial—of unknown mechanism, which is characterized by fatty tissue replacement of myocardium in the free wall of the right ventricle (47). Several configurations of ventricular arrhythmias occur in this syndrome, and SMVT—usually with a left bundle-branch block (LBBB) morphology—is not an uncommon presentation. Unfortunately, cardiac arrest and sudden death, sometimes in association with physical activity, may be the initial presentation. Arrhythmogenic right ventricular cardiomyopathy is an important cause of sudden death in athletes. The substrate for VTA may be reentrant circuits created by separation of muscle bundles by fatty tissue. Optimal therapy has not been determined. Patients should be advised to avoid competitive athletic activity. Amiodarone—alone and in combination with beta-blockers and d,l-sotalol—has been successfully used to control VTA in this disorder. However, these drugs do not provide complete protection against sudden death. Suggested indicators of high risk include previous cardiac arrest, syncope, and left ventricular involvement. EPS has been suggested as a method for risk stratification and for guiding antiarrhythmic drug selection. However, based on the limited experience available and on poor results of EPS in other nonischemic disorders, these suggestions should be considered preliminary. Operative excision and catheter ablation have been reported to be effective for preventing recurrent SMVT. However, one problem with local ablation is arrhythmia recurrence caused by the development of sources and circuits at new locations. Complete operative disarticulation of the right ventricular free wall has also been used to control VTA. Reliable methods of identifying patients at particularly high risk or at very low risk have not been developed. The uncertain level of control with other methods promotes recommendation for ICD therapy in patients who present with VTA. The distinction between arrhythmo-genic right ventricular dysplasia and right ventricular outflow-tract tachycardia (RVOT) is critical because the latter disorder is treated differently; RVOT VT has an excellent prognosis, is not associated with structural heart disease, and is not heritable.

Idiopathic VF and RBBB ST Elevation (Brugada) Syndrome

Idiopathic VF (IVF) is used to describe disorders in which unexplained VF occurs in patients without detectable structural heart disease (48). No pharmacological therapy is widely accepted. There are reports of favorable responses to quinidine, but data from the European registry suggests that antiarrhythmic drugs and beta-blockers do not provide reliable protection. The reported recurrence rate of VF is 30%. ICD therapy is currently recommended for this syndrome. Brugada syndrome is a variety of IVF with a distinctive ECG pattern appearance of complete or partial right bundle-branch block (RBBB) and ST-segment elevation (49). Several genetic abnormalities produce the disorder, and the expression varies considerably. The characteristic ECG pattern is often intermittent, but can be elicited with variable reliability with certain class I antiarrhythmic drugs, including ajmaline, flecainide, pilsicainide, and procainamide. Quinidine has been reported to be effective in a small number of patients, and a theory exists to explain its therapeutic effect (50). Amiodarone and beta-blockers have not been found to be protective. No pharmacological approach has received widespread acceptance. ICDs are recommended for patients with a history of VTA (51).

Congenital and Acquired Long QT Syndromes

LQTS has been divided into congenital and acquired forms. The latter consists mostly of drug-induced LQTS. Drug-related LQTS is a common cause of polymorphic VTA and VF in hospitalized patients, and probably accounts for a significant number of sudden deaths because a large number of drugs cause this syndrome. Nevertheless, multiple contributing factors may be involved, including female gender, electrolyte disturbances (hypokalemia or hypomagnesemia), bradycardia, heart failure, and myocar-dial hypertrophy. An important cause is the administration of a drug or other substance (e.g., grapefruit juice) that interferes with elimination of a drug that delays repolarization. The interaction of several factors may explain why some patients develop LQTS weeks or years after initiation of the offending drug. It may be a challenge to determine each of the factors, avoid their repetition in the future and select safe alternatives to the culprit drugs. There is speculation that a genetic predisposition or "reduced repolarization capacity" accounts for the sensitivity of some persons to this complication. If true, it may become possible to identify susceptible patients.

Although remarkable progress has been made in the understanding of congenital LQTS, better information about the natural history and response to treatment has exposed deep uncertainties about identifying and treating individuals at risk for VTA (52). Only about 70% of carriers have unequivocal QT prolongation, and approx 12% have a normal QT interval. In addition, sudden death is the first manifestation of the syndrome in at least 10% of affected persons. There are probably several undiscovered genetic defects and sporadic mutations that cause this disorder. Moreover, the types of provocative factors, the long-term risk of sustained VTA, and the response to therapy varies with the specific genetic defect. Finally, severe myocardial dysfunction is often associated with action-potential prolongation, and could exacerbate arrhythmias associated with excessive delay of repolarization. Therefore, the possibility of LQTS should be considered in any patient who presents with VTA, if not as the primary disorder, then perhaps as a contributor. Therapy for LQTS depends on the estimated risk of sudden death based on the individual history of signs or symptoms of VTA, the family history, genetic subtype, and other considerations such as the patients' age and preference for type of therapy. Beta-blockers are the mainstay of treatment, and are usually prescribed to all affected patients (52a). Education about risk-factor avoidance is essential. Patients who present with VTA or syncope, those who experience symptoms despite beta-blockers, and other individuals at high risk are candidates for ICD therapy. Left cervicothoracic ganglionectomy and permanent pacing cannot be relied upon to prevent sudden death, but may be useful alternatives to patients who are intolerant of beta-blockers or who do not comply with drug therapy. Experimental therapies include administration of supplemental potassium chloride for HERG mutations and mexiletine for LQT subtypes 3, 2, and possibly 1. The presence of provocative factors should be sought in patients who present with VTA, as this may affect selection of long-term therapy. Many of the patients at risk are infants, young children, adolescents, and young adults. Poor compliance may be more prevalent in certain age groups of patients. Concern about effects of medications during pregnancy may result in inappropriate termination of therapy. Device therapy can improve compliance, and advanced ICDs can provide the sophisticated pacing programs to prevent VTA. However, the size of current-generation ICDs and lack of lead systems that meet the demand for the small physical size and rapid growth of young patients must be considered. The special psychological problems of ICDs in young persons are relevant, as noted earlier.

Short-Coupled Variant of Torsades de Pointes

This rare malignant arrhythmia usually occurs in the absence of detectable structural heart disease. Transient global hypokinesis has been noted in at least one case (53). Some authorities reserve the term "torsades de pointes" for the characteristic pattern that occurs in the presence of a prolonged QT. However, the name given by the authors of the first systematic characterization of the disorder highlights the essential feature needed to distinguish it from LQTS (54). There is little experience with this disorder. Given this uncertainty, ICD therapy may be recommended to patients who request maximum protection against sudden death. However, control of arrhythmias may still be required to reduce symptoms and ICD discharges. Anecdotal reports suggest that verapamil and amiodarone inhibit VTA in this syndrome.

Catecholaminergic PVT

Another disorder that occurs in children without detectable structural heart disease and a normal QT interval is called catecholaminergic PVT because of its strong relationship to exercise and provocation with isoproterenol. Although beta-blockers are recommended, experience with this disorder is very limited.

Idiopathic Ventricular Tachycardias and RVOT

Idiopathic VT refers to disorders in which VT, sustained or unsustained but generally monomorphic, occurs in association with no or minimal detectable structural changes. Patients with idiopathic VT account for approx 10% of VTA that present for evaluation. RVOT VT accounts for about 80% of idiopathic VT. The underlying etiology of RVOT VT is unknown, but the evidence indicates that the mechanism is cyclic adenosine monophosphate (cAMP)-mediated delayed after-depolarizations, a form of triggered activity (55). VTA with identical electrophysiological characteristics have been found to originate from the LVOT, epicardial locations, and other sites. Termination in response to adenosine is characteristic, and strongly supports the diagnosis of RVOT VT. Sudden cardiac death caused by RVOT VT is a rare event, but accumulated experience is insufficient for accurate determination of the risk. Treatment is indicated for patients with syncope, intolerable palpitations, and other disabling symptoms. The initial choice of pharmacological therapy is usually a beta-blocker or calcium-channel blocker. Flecainide and d,l-sotalol may also be effective. In a series of pediatric patients, the most effective control was observed with amiodarone followed by verapamil, class IC drugs, and sotalol. Other beta-blockers were associated with a low rate of effectiveness (56). Preliminary results suggest that nicorandil, an ATP-sensitive potassium-

channel opener, may be effective in this disorder. Catheter ablation is often the therapy selected first because of the high rate of permanent correction with few adverse sequellae. However, experience is required to avoid injury to coronary arteries and other complications. The distinction between RVOT VT and VT caused by ARVD is often difficult but essential because of the differences in treatment and prognosis.

Less commonly, idiopathic VT originates from the left ventricular septum. The mechanism is believed to be re-entry involving Purkinje fibers near the left posterior fascicle, which generates a RBBB/left axis morphology of VT. Pharmacologic therapy with verapamil and catheter ablation are first-line therapies.

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