Nonsustained Ventricular Tachycardia

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Chapter 43 Nonsustained Ventricular Tachycardia

Demosthenes G. Katritsis, Wojciech Zareba, A. John Camm

Nonsustained ventricular tachycardia (NSVT) has been recognized as a usually asymptomatic rhythm disorder detected in an extremely wide range of conditions, from asymptomatic, apparently healthy, young individuals to patients with significant heart disease. Because of its brevity, NSVT does not produce symptoms in most instances; it derives its clinical importance from the fact that its detection may have important prognostic implications, depending on the underlying pathology. In several clinical settings, NSVT is a marker of increased risk for subsequent sustained tachyarrhythmias and sudden cardiac death (SCD), whereas it may have no prognostic significance in a healthy individual, although evidence for occult pathology or an inherited channelopathy in apparently normal subjects who develop ventricular arrhythmia not related to physical exercise continues to accumulate.¹^–³ The main task of the physician is to detect the apparently healthy individuals in whom NSVT represents a sign of occult disease and to risk stratify patients with known disease who present with this arrhythmia. This, however, is not an easy task. The patient with NSVT still represents a clinical challenge with regard to proper management, and several crucial questions remain unanswered.

Definition

Traditionally, the term tachycardia (from the Greek words tachy, meaning fast, and cardia, meaning heart) is used to describe conditions in which the heart rate exceeds the conventional number of 100 beats/min for more than three consecutive beats, either in response to metabolic demand or other stimuli or because of disease.⁴ Sustained tachycardia is defined as tachycardia that lasts for more than 30 seconds (unless requiring termination because of hemodynamic collapse), whereas nonsustained tachycardia terminates spontaneously within 30 seconds.⁴ Thus, NSVT has been defined as three (sometimes five) or more consecutive beats arising below the atrioventricular (AV) node with an R-R interval of less than 600 ms (>100 beats/min) and lasting less than 30 seconds.⁵

This definition is by no means a universally accepted one. In the recent Cardiac Arrhythmias and Risk Stratification After Acute Myocardial Infarction (CARISMA) study,⁶ NSVT was detected by registering runs of 16 beats or more, with a rate of 125 beats/min, whereas a rate of 120 beats/min or more has been used by the Marburg trial and other studies.^7,⁸ The period of a tachycardia run to qualify for NSVT has also varied. In the Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM) study, the time cut-off was 15 seconds as opposed to the conventional number of 30 seconds, which has been used both by the Multicenter Automatic Defibrillator Implantation Trial (MADIT) and the Multicenter Unsustained Tachycardia Trial (MUSTT) .⁹^–¹¹ This implies that NSVT cases according to the MADIT and MUSTT criteria might well have been dealt with as sustained ventricular tachycardia (VT) episodes in the ESVEM cohort. In other studies, the terms ventricular ectopy or NSVT are often used without strictly defined diagnostic criteria.¹²

Epidemiology

Reliable epidemiologic data on NSVT are difficult to obtain. Usually, although not invariably, most patients remain asymptomatic, and the reproducibility of NSVT recordings is documented in only half of the patients with this arrhythmia. In the MADIT, NSVT was defined as reproducible when found in at least two recordings of three consecutive Holter electrocardiograms (ECGs) performed in weekly intervals. Reproducible NSVT was identified in only 50% of the patients with NSVT and did not seem to be an independent risk factor for future arrhythmic events.¹³ The reported prevalence of NSVT in various clinical conditions is presented in Table 43-1. Previous studies were based on Holter monitoring, thus reporting NSVT occurring within a short period. The advent of implantable permanent pacemakers, defibrillators, and monitoring devices with extensive ECG monitoring capabilities has allowed for a more accurate estimation of the incidence of NSVT in patients with heart disease. Evidence is now available from implantable cardioverter-defibrillator (ICD) data that NSVT is a distinct tachyarrhythmia that may cause syncope without causing death in patients with heart disease and that the incidence of polymorphic NSVT relative to sustained arrhythmia is greater than previously believed.¹⁴

Table 43-1 Reported Prevalence of Nonsustained Ventricular Tachycardia in Different Cardiac Conditions

CONDITION	PREVALENCE
Apparently healthy individuals	0%-3%
Non-ST ACS (2 to 9 days after admission)	18%-25%
Acute MI (early phase)	45%-75%
Reperfused acute MI (later than 1 week)	7%-13%
Heart failure (LVEF <30% to 40%)	30%-80%
DCM	40%-50%
HCM	25%-80%
Significant valve disease	≤25%
Hypertension	8%
Hypertension and left ventricular hypertrophy	12%-28%

DCM, Dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LVEF, left ventricular ejection fraction; MI, myocardial infarction; Non-ST ACS, non–ST-segment elevation acute coronary syndrome.

In asymptomatic, apparently healthy persons, Holter recordings in older studies revealed a frequency of NSVT ranging from 0% to 3%.^5,^15,¹⁶ In non–ST-segment elevation acute coronary syndromes, NSVT is detected in 18% to 25% of patients 2 to 9 days after admission.¹⁷ In acute myocardial infarction (MI), NSVT during the first 24 hours is frequent (43% in patients without thrombolysis and up to 75% in re-perfused patients).^5,¹⁸ In the first 7 days after MI, NSVT is detected in approximately 6.8% to 13.4% of patients in the reperfusion era, which is not much different from that reported in the pre-thrombolytic era (12%; Multicenter Postinfarction Research Program).¹⁸^–²³ NSVT can be detected in approximately 2% of patients with ischemia and preserved left ventricular function.²⁴ Recently, the CARISMA study group reported on long-term cardiac arrhythmias recorded by a cardiac monitor implanted 2 to 5 days after MI in patients with left ventricular ejection fraction (LVEF) of 40% or less. The detected incidence of NSVT over a 2-year period was 13%.⁶

In patients with heart failure and LVEF less than 30% to 40%, the reported prevalence of NSVT is 30% to 80%.^25,²⁶ It seems that ischemic heart failure carries a higher risk for NSVT. In the Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina (GESICA) trial, in which only one third of patients had ischemic heart disease, the prevalence of NSVT was 33%. Whereas in the Congestive Heart Failure: Survival Trial of Antiarrhythmic Therapy (CHF-STAT) trial, in which the ischemic patients comprised two thirds of the whole cohort, the prevalence was 80%.^25,²⁶ In dilated cardiomyopathy (DCM), NSVT has been detected in 40% to 50% of patients.²⁷^–²⁹ In hypertrophic cardiomyopathy (HCM), 20% to 30% of patients may have NSVT, whereas in patients with a history of cardiac arrest, this proportion approaches 80%.³⁰^–³² These estimations may not reflect the true incidence of NSVT in HCM, since they are based on highly selected referral populations. In patients with valvular disease, the incidence of NSVT is considerable (up to 25% in aortic stenosis and in significant mitral regurgitation) and appears to be a marker of underlying left ventricular pathology.^33,³⁴ In patients with arterial hypertension, NSVT is correlated to the degree of cardiac hypertrophy and subendocardial fibrosis.^35,³⁶ Approximately 12% to 28% of patients with hypertension and left ventricular hypertrophy present with NSVT as opposed to 8% of patients with hypertension alone.^35,³⁶ Ventricular extrasystolic activity can be detected with Holter monitoring in up to 50% of patients with repaired tetralogy of Fallot, and recent studies have detected a 4% to 14% prevalence of sustained VT.³⁷^–³⁹

Clinical Electrocardiography

NSVT represents an electrocardiographic diagnosis based on resting or exercise ECG and Holter monitoring recordings. Two major methodology problems may interfere with the recognition as well as interpretation of this condition. First, a universally accepted, established definition does not exist. Second, morphologic criteria such as those used in the description of sustained VT have not been adopted. The nature of the short-lived episodes of arrhythmia may not allow a clear distinction between monomorphic and polymorphic ventricular rhythms. Thus, in most published studies, the terms NSVT episodes or complex ventricular ectopy are used in a general way without any attempt to distinguish between regular, monomorphic rhythms and the salvos of ventricular depolarizations of variable morphology. This might have important implications in the assessment of the clinical significance of NSVT in various conditions.

Electrocardiographic Patterns

Nonsustained Ventricular Tachycardia Associated with a “Normal” Heart

In the apparently normal population, NSVT episodes without consistent morphology patterns may be recorded either at rest or after exercise. ^15,^16,⁴⁰^–⁴⁴ When NSVT is documented in the context of a history of established monomorphic VT, it may demonstrate the same morphology as clinical sustained arrhythmia. VTs with a left bundle branch block (LBBB) pattern and inferior axis originate in the right ventricular outflow tract (RVOT).⁴⁵ Left ventricular outflow tract (LVOT) tachycardias may produce a right bundle branch block (RBBB) morphology with inferior axis or a variable QRS morphology, depending on the site of origin. Tachycardias originating in the left coronary cusp have a QRS morphology consistent with an M or W pattern in lead V1, tachycardias originating in the right coronary cusp have an LBBB pattern, and those from the aortomitral continuity usually result in a qR pattern.⁴⁶ Idiopathic left VT may also be caused by re-entry within the Purkinje network and may originate within one of the fascicles of the left bundle branch (fascicular tachycardias), and usually the posterior fascicle is involved, resulting in a tachycardia with RBBB and left-axis deviation. However, cases with an inferior axis, that is, of anterior fascicular origin, have also been described.^47,⁴⁸

The most systematic attempts to characterize the electrocardiographic pattern of NSVT have been reported to be successful in patients with the so-called repetitive monomorphic VT, originally described by Gallavardin.⁴⁹ This arrhythmia represents a form of the spectrum of idiopathic ventricular outflow tachycardias, which includes repetitive uniform premature ventricular contractions (PVCs) and exercise-triggered paroxysmal VT. They usually originate in the RVOT and less often in the LVOT and are most probably caused by triggered activity secondary to cyclic adenosine monophosphate–mediated delayed afterdepolarizations.⁴⁵ The relatively consistent recording of frequent arrhythmia episodes in patients with repetitive monomorphic VT has made possible the accumulation of useful information on its morphology. Holter studies have revealed that the tachycardia begins with a fusion complex or with an ectopic beat that has the same morphology as the subsequent beats (Figure 43-1).⁵⁰ The salvos of VT are generally short (3 to 15 beats) and the coupling interval of the first beat is usually long (>400 ms). The coupling intervals of successive beats may gradually become prolonged.⁵¹^–⁵³ Many patients mostly have ventricular premature beats (VPBs) with only occasional episodes of tachycardia, whereas others manifest mainly with short runs of VT, where the tachycardia beats far exceed the number of sinus beats. The rate during tachycardia is generally 110 to 150 beats/min. The arrhythmia is only present within a critical window of heart rates (upper and lower thresholds).⁵⁰ Thus, the tachycardia often occurs during exercise but disappears as the heart rate increases and returns during the recovery period following exercise. Some patients develop sustained episodes (>30 seconds) during the recovery phase, and this behavior differentiates repetitive monomorphic VT from the exercise-triggered paroxysmal VT first described by Wilson and others in patients with apparently normal hearts.⁵⁴^–⁵⁶ It should be noted, however, that repetitive behavior has been documented in various clinical settings, including cardiomyopathy and previous MI, as well as tachycardias originating in the aortic valve cusps.^51,⁵⁷

FIGURE 43-1 Repetitive nonsustained episodes of ventricular tachycardia. The left bundle branch block–like QRS complexes suggest that the tachycardia arises from the right ventricle. This patient was asymptomatic, and no evidence of any cardiac pathology was present.

In catecholaminergic polymorphic VT, a familial condition mainly caused by mutations in the genes encoding the cardiac ryanodine receptor channel as well as calsequestrin involved in calcium kinetics, episodes of provoked tachycardia are typically nonsustained.⁵⁸ They may originate from the LVOT and less frequently from the RVOT or the right ventricular apex. QRS morphology suggests an outflow tract origin of the initiating beat in more than 50% of patients, and subsequent beats portray a polymorphic or typically bi-directional VT morphology.⁵⁹

Ischemic Heart Disease

Frequent and complex ventricular ectopy as well as NSVT occur more commonly in patients with left ventricular dysfunction. Usually, monomorphic VT is seen in the context of re-entry at the borders of a ventricular scar caused by previous MI, whereas ischemia most of time induces polymorphic VT or ventricular fibrillation (VF).^60,⁶¹ The QRS morphology during monomorphic tachycardia may show an RBBB or LBBB pattern or may even be nonspecific (Figure 43-2). Both RBBB and LBBB patterns can be seen in the same patient when the infarct scar involves the interventricular septum (Figure 43-3). Spontaneous reversions to sinus rhythm, thus documenting nonsustained VF, can occur (Figure 43-4), and data from patients with ICDs reveal that up to 40% of all VF episodes are nonsustained.¹⁴

FIGURE 43-2 Nonsustained ventricular tachycardia in a patient with previous myocardial infarction. The morphology of the complexes is similar but not identical.

FIGURE 43-3 Two runs of nonsustained ventricular tachycardia from a patient with a previous myocardial infarction. The first beat of tachycardia in the two runs probably represents fusion with sinus beats.

FIGURE 43-4 During electrophysiology testing in a patient with ischemic heart disease and nonsustained ventricular tachycardia on Holter monitoring, an episode of nonsustained polymorphic ventricular tachycardia or ventricular fibrillation is induced.

Cardiomyopathies and Other Conditions

VTs (both sustained and nonsustained) in DCM may present with multiple morphologies or an LBBB or RBBB pattern. In approximately one third of the cases of idiopathic DCM, and probably in a small percentage of ischemic patients, sustained or nonsustained VT is caused by bundle branch re-entry.⁶² The necessary condition for bundle branch re-entry seems to be prolonged conduction in the His-Purkinje system, which is reflected in the H-V interval that is prolonged during sinus rhythm and prolonged or equal to the baseline sinus rhythm during VT.⁶³ The circuit involves the right and left branch bundles, with antegrade conduction occurring most of the times through the right branch. As a rule, AV dissociation is present. These tachycardias are usually unstable; the 12-lead ECG, when obtainable, may show an LBBB or RBBB pattern, depending on the orientation of activation of the bundle branches.

No characteristic electrocardiographic morphology of NSVT exists in patients with HCM. Relatively slow, often asymptomatic nonsustained episodes of monomorphic VT may be documented on prolonged ambulatory recordings. When nonsustained or sustained VT is induced by programmed stimulation, it is more often polymorphic (60% of patients) than monomorphic (30%).^32,^64,⁶⁵

In other conditions such as valvular disease and systemic hypertension, ventricular arrhythmias are common but less well characterized and usually represent polymorphic rhythms.³⁴^–³⁶ Most of the reported patients with mitral valve prolapse demonstrate LBBB morphology during tachycardia, which raises the possibility that the mitral valve prolapse might be an incidental finding or that the arrhythmia is caused by other mechanisms not directly related to the mechanical stress imposed on the ventricle by the valvular apparatus.^66,⁶⁷

The tachycardias in arrhythmogenic right ventricular dysplasia (ARVD) arise from the right ventricle and typically present with LBBB morphology with a left- or even right-axis deviation.⁶⁸

Long QT Syndrome

The typical morphology of recorded arrhythmias in long QT syndrome (LQTS; congenital or acquired) is that of torsades de pointes.⁶⁹ The term refers to the electrocardiographic appearance of spike-like QRS complexes that rotate irregularly around the isoelectric line at rates of 200 to 250 beats/min (Figure 43-5). Typically, the coupling interval of the initial beat of the torsade is long (600 to 800 ms), whereas the last QRS complex of the episode is larger than the normal QRS during sinus rhythm. This is a VT that is frequently nonsustained and sometimes sustained. The tachycardia, which usually occurs in the setting of bradycardia or long postectopic pauses, is often repetitive and may trigger VF. It is seen primarily in association with prolongation of the Q-T interval that may be appreciable before the onset of arrhythmias or after a pause. Not all patients with the LQTS have polymorphic VT with a characteristic torsades de pointes configuration, and this pattern can be seen in some patients without the LQTS. A variety of torsade initiating with a short coupling interval in patients without any evidence of LQTS has also been described.⁷⁰

FIGURE 43-5 This is an example of torsades de pointes. Note the relatively rapid but variable rate, continually changing QRS morphology, and variable QRS axis. A polymorphic ventricular tachycardia is usually diagnosed as torsades de pointes when conducted QRS complexes (between episodes of tachycardia) have a prolonged Q-T interval or the tachycardia is initiated after a preceding pause or, as in this case, a (short-) long-short sequence of QRS complexes. SB, Sinus beat; VPB, ventricular premature beat.

Clinical Evaluation

Careful clinical assessment of the patient is the cornerstone of the diagnostic process. Age, general condition, previous medical history, and conditions such as electrolyte disturbances, metabolic imbalance, and proarrhythmic effect of drugs should be considered. A standard 12-lead ECG might indicate potential causes of NSVT, including signs of previous MI or active ischemia, conduction disturbances, prolonged Q-T interval, or other signs of electrical instability suggestive of Brugada syndrome or ARVD. In addition, several other clinical parameters and tests can provide specific information about the potential risk of future arrhythmic events in patients who have presented with nonsustained ventricular arrhythmias.

Trans-thoracic Echocardiography

Trans-thoracic echocardiography may detect signs of cardiomyopathy, ARVD and other structural abnormalities, and impaired left ventricular function. Overwhelming evidence indicates that in patients with heart disease, in general, LVEF is the major determinant of cardiac and total mortality.¹ The results of the MADIT, MUSTT, Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), and the Marburg Cardiomyopathy Study (MACAS) trials have also established the importance of LVEF as the most critical prognostic factor in patients with ischemic heart disease and NSVT.^8,^10,^11,⁷¹ Left ventricular function assessment with echocardiography or radionuclide ventriculography is therefore mandatory for the risk stratification and subsequent management of patients with NSVT. However, LVEF does not always predict ICD intervention in patients with ischemic or nonischemic cardiomyopathy.⁷² Analysis of arrhythmic death in 674 patients enrolled in MUSTT showed that patients whose only factor is ejection fraction (EF) of 30% or less have a predicted 2-year arrhythmic death risk of 5% or less.⁷³ Multiple additional factors influence arrhythmic death in patients with LVEF less than 40% and NSVT such as inducible VT, history of heart failure, NSVT not discovered within 10 days after coronary artery bypass grafting (CABG), and intraventricular conduction delay or LBBB.⁷³

Tests for Myocardial Ischemia

Functional tests such as treadmill exercise electrocardiography, myocardial perfusion, and stress echocardiography are required to demonstrate myocardial ischemia in patients with NSVT. Acute myocardial ischemia is an established cause of polymorphic ventricular rhythms.⁶¹ The association of monomorphic VT, a substrate-dependent arrhythmia, with acute ischemia is less well characterized, but ischemia may induce monomorphic VT in the presence of a myocardial scar.⁷⁴^–⁷⁶

Apart from demonstration of ischemia, exercise tasting may also be helpful in patients with LQTS, exercise-triggered RVOT tachycardia, and cathecholaminergic polymorphic VT. NSVT induced by treadmill exercise testing aimed at evaluating presumed LQTS suggests catecholaminergic polymorphic VT rather than LQTS.⁷⁷

Ambulatory Electrocardiographic Monitoring

Holter monitoring is a valuable diagnostic tool in detecting patients with NSVT, and 7-day Holter monitoring improves detection and allows better characterization of ventricular arrhythmic episodes.⁷⁸ Detection of NSVT has been reported to predict SCD in patients with non–ST-segment elevation acute coronary syndromes, thrombolysed MI, DCM, HCM, and arrhythmogenic right ventricular dysplasia.^17,^18,^25,^31,⁷⁹^–⁸¹ However, whether NSVT provokes arrhythmia or is simply a surrogate marker of a more severe underlying cardiac condition is not known. In patients with revascularization of most infarct-related arteries (78%), NSVT early after MI (4 to 16 days) carried a significant but low RR for the composite endpoint of cardiac death, VT, or VF but not for arrhythmic events considered alone.²⁰ In the Danish Multicenter Randomized Study on Thrombolytic Therapy Versus Acute Coronary Angioplasty in Acute Myocardial Infarction-2 (DANAMI-2) trial, the prognostic value of NSVT was limited regardless of reperfusion strategy, and in the study of Makikallio et al, no Holter variable predicted sudden death among infarct survivors with an LVEF of 35% or less.^22,⁷⁹ It seems that in the β-blocking era, all common arrhythmia risk variables, including NSVT, have diminished the predictive power in identifying patients with previous MI at risk of SCD.⁸²

Both in MACAS and CHF-STAT, in patients with CM or ischemic cardiomyopathy, NSVT was a predictor of arrhythmia in univariate analysis but not in multivariate analysis, as opposed to LVEF.^8,²⁶ In patients with HCM, NSVT was associated with SCD, but a relation between the risk of arrhythmic death and the frequency, duration, and rate of NSVT episodes could not be demonstrated.³¹

The suppression of frequent ventricular ectopy or NSVT runs following β-blockade or amiodarone therapy does not imply a favorable diagnosis. Mortality was increased in the Cardiac Arrhythmia Suppression Trials (CAST and CAST II) despite reduced ectopic activity, whereas mortality was not reduced by amiodarone in the Veterans Administration CHF-STAT despite the elimination of ventricular ectopy.⁸³^–⁸⁵ Thus, Holter monitoring may be useful for risk stratification purposes by means of detecting episodes of NSVT in certain clinical settings, but its use for the subsequent follow-up and evaluation of treatment is limited.

Assessment of Autonomic Tone

Heart rate variability (HRV) has been used as an independent risk factor for cardiac mortality in patients with previous MI and has been claimed to be a specific predictor of arrhythmic rather than total cardiac mortality.⁸⁶^–⁸⁸ In these patients, a depressed baroreflex sensitivity has been associated with increased cardiac mortality and SCD and with a higher predictive power (in values below 3 ms/mm Hg) compared with LVEF, signal-averaged ECG (SAECG), or HRV.^89,⁹⁰ Analysis of patients in the Autonomic Tone and Reflexes After Myocardial Infarction (ATRAMI) trial has shown that NSVT, HRV, and depressed baroreflex sensitivity were all significantly and independently associated with increased mortality. Depressed baroreflex sensitivity, in particular, identified a subgroup with the same mortality risk as patients with NSVT and reduced LVEF.²¹

However, the Multiple Risk Factor Analysis Trial (MRFAT) show that in the β-blocking era, the common arrhythmia risk variables, particularly the autonomic and standard ECG markers, have limited predictive power in identifying patients at risk of SCD.⁸² In 43 ± 15 months of follow-up in 675 patients, SCD was weakly predicted only by reduced LVEF (<40%), NSVT, and abnormal SAECG but not by autonomic markers or ECG variables. The positive predictive accuracy of these markers (low LVEF, NSVT, and abnormal SAECG), however, was low at 8%, 12%, and 13%, respectively.⁸² The smaller Bucindolo Evaluation in Acute Myocardial Infarction Trial (BEAT) study also refuted the predictive value of HRV, the prognostic information of which was found to be contained completely in heart rate.⁹¹ In patients with nonischemic cardiomyopathy, results on the value of HRV have been conflicting.^7,^92,⁹³ Heart rate turbulence and deceleration capacity are newer noninvasive measures of cardiac autonomic regulation that are currently under study.⁹⁴ More data are clearly needed to establish the clinical usefulness of autonomic markers, particularly in the setting of NSVT.

Signal-Averaged Electrocardiography

The clinical value of SAECG in patients with NSVT by means of determining prognosis and identifying patients in need for an aggressive antiarrhythmic management has not been established yet. In patients presenting with unexplained syncope, the presence of late potentials is a good predictor of induction of sustained VT, and in survivors of MI an abnormal SAECG has been associated with increased risk of arrhythmic and total mortality.⁹⁵^–⁹⁸ However, its positive predictive value in this setting is low (<30%) as opposed to its high negative predictive value (90%). Thus, a negative SAECG might obviate the need for further investigations when the suspicion of a ventricular arrhythmia is low, but in the case of a high suspicion of ventricular arrhythmia, a negative SAECG is not sufficient evidence for the exclusion of sustained VT or NSVT as the cause of syncope. Furthermore, in patients treated with thrombolysis or β-blockers, the predictive ability of SAECG is limited.^82,⁹⁹ In patients with DCM, SAECG does not predict SCD, but in arrhythmogenic right ventricular dysplasia, SAECG can identify those with more extensive disease and a propensity for inducible VT at programmed electrical stimulation, and is now considered a minor diagnostic criterion.^8,^81,¹⁰⁰

T-Wave Alternans

T-wave alternans (TWA) is a test that is thought to reflect dispersion of repolarization and has been shown to predict VT inducibility and future arrhythmic events better than SAECG.¹⁰¹ In patients similar to those in MADIT II, a microvolt TWA (MTWA) test was found to be better than QRS duration at identifying high-risk patients as well as patients unlikely to benefit from ICD therapy.¹⁰² Recently, in patients with reduced LV function (LVEF <40%) and NSVT, MTWA also predicted unstable ventricular tachyarrhythmias better than electrophysiology testing and LVEF less than 30%.¹⁰³ However, in a later study, although TWA predicted higher total mortality in a MADIT II–like population, the risk of tachyarrhythmic events did not differ according to TWA results.¹⁰⁴ The Alternans Before Cardioverter Defibrillator (ABCD) study was the first trial to use MTWA to guide prophylactic ICD insertion in patients with LVEF less than 40% and NSVT. Risk stratification strategies using noninvasive MTWA versus invasive electrophysiological study (EPS) were comparable at 1 year, with very low positive predictive values and very high negative predictive values and complementary when applied in combination. Strategies that use MTWA, EPS, or both might identify subsets of patients least likely to benefit from ICD insertion.¹⁰⁵

Electrophysiology Testing

EPS may be required for the establishment of initial diagnosis in patients presenting with nonsustained ventricular rhythms. Indications include the need for differential diagnosis of NSVT from short runs of AF in the context of an accessory pathway or other forms of aberration, drug testing for the diagnosis of Brugada syndrome, and programmed electrical stimulation for induction of VT.

Induction of sustained arrhythmia by programmed electrical stimulationstill retains a predictive power in patients with ischemia who have impaired left ventricular function. According to a meta-analysis, in patients with ischemia and NSVT, the induction of sustained VT is associated with a two- to three-fold increased risk of arrhythmia-related death in a previous meta-analysis.¹⁰⁶ In NSVT, in the context of reduced LVEF (<40%), inducibility of sustained monomorphic VT at baseline programmed electrical stimulation was associated with a 2-year actuarial risk of SCD or cardiac arrest of 50% compared with a 6% risk in patients without inducible VT.¹⁰⁷ Analysis of patients enrolled in the MUSTT as well as of those in the registry revealed that noninducible patients have a significantly lower risk of cardiac arrest or SCD compared with inducible patients at 2 and 5 years (12% vs. 24% and 18% vs. 32%, respectively).¹⁰⁸ Still, however, as these results indicate, patients with noninducible sustained VT are not free of risk of SCD. The MUSTT investigators have further analyzed the relation of EF and inducible ventricular tachyarrhythmias to mode of death in 1791 patients who were enrolled in MUSTT and did not receive antiarrhythmic therapy. Total and arrhythmic mortality were higher in patients with an EF less than 30% than in those whose EFs were 30% to 40%. The relative contribution of arrhythmic events to total mortality was significantly higher in patients with inducible tachyarrhythmia (58% of deaths in inducible patients vs. 46% in noninducible patients; P = .004). The higher percentage of events that were arrhythmic among patients with inducible tachyarrhythmia appeared more distinct among patients with an EF of 30% or greater (61% of events were arrhythmic among inducible patients with an EF ≥30% and only 42% among noninducible patients; P = .002). This study therefore suggested that the major usefulness of EPS may be restricted to patients having an EF between 30% and 40%.¹⁰⁹ The prognostic significance of VT inducibility appears to be similar to that of VT induced by one, two, or three extrastimuli.¹¹⁰ These results should be considered in the context of evidence from analysis of stored ICD data that has shown that little association exists between spontaneous and induced ventricular arrhythmias.¹¹¹

The role of programmed electrical stimulation has not been established in the patient with ischemia and relatively preserved left ventricular function (LVEF >40%), although some evidence indicates that inducibility of sustained VT or VF at programmed electrical stimulation might retain discriminative ability by means of identifying a higher risk patient cohort.^112,¹¹³ The prognostic usefulness of programmed stimulation in patients with nonischemic DCM, including those with NSVT, remains controversial.¹¹⁴^–¹¹⁶ Retrospective cohort analysis of 54 patients from the Mayo Clinic showed that programmed electrical stimulation did not differentiate patients with and those without appropriate ICD shocks.¹¹⁴ However, inducibility of polymorphic VT or VF is a much stronger predictor of recurrences of fast VT as opposed to sustained monomorphic VT induction in DCM patients with ICD for secondary prevention.¹¹⁷ Daubert et al, in the Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial, reported that inducibility tested via ICD was found in 29 of 204 patients (VT in 13, VF in 16) and that at follow-up, 34.5% of the inducible group (10 of 29) had ICD therapy for VT or VF or arrhythmic death versus 12% (21 of 175) of noninducible patients (hazard ratio [HR], 2.60; P = .014).¹¹⁸ Thus, inducibility of ventricular arrhythmias, especially polymorphic VT or VF, indicates increased likelihood of subsequent ICD therapies and might be considered a useful risk stratifier.

Programmed ventricular stimulation is of diagnostic as well as prognostic value in risk stratifying patients with repaired tetralogy of Fallot.¹¹⁹ In multivariate analysis of a study on 252 patients with repaired tetralogy, inducible sustained monomorphic or polymorphic VT was an independent risk factor for subsequent events (RR, 4.7; 95% confidence interval [CI], 1.2–18.5; P < .0268).¹¹⁹

Little evidence exists for benefit from EPS in patients with HCM and NSVT. In patients with a history of cardiac arrest, polymorphic VT that deteriorates into VF was induced in approximately half only.^32,^64,⁶⁵

Cardiac Magnetic Resonance Imaging

In patients with previous MI, necrotic myocardium and viable myocardium coexisting within the same wall segments, as detected by delayed enhancement cardiac magnetic resonance imaging (CMRI), predicts the occurrence of NSVT in patients without left ventricular dilation, whereas left ventricular mass and end-systolic volume are predictors of NSVT in those with left ventricular dilation.¹²⁰ In patients with HCM, the presence of delayed enhancement on contrast-enhanced CMRI is associated with increased likelihood of NSVT compared with those without this finding (28% vs. 4%), and the presence of two-dimensional strain, which is used to identify myocardial fibrosis, in more than three left ventricular segments is an independent predictor of NSVT.^121,¹²²

Clinical and Prognostic Significance

The physician who cares for a patient presenting with an episode of NSVT has two tasks. First, he or she needs to establish whether the underlying occult pathology is responsible for the arrhythmia; second, in a case of diagnosed heart disease, the patient should be risk stratified to determine the appropriate management and therapy. The clinical approach to the patient with NSVT should therefore always be considered within the particular clinical context in which the arrhythmia occurs. In several settings, the patient with NSVT represents a clinical challenge with regard to proper management, and several crucial questions remain unanswered.¹²³ The occurrence of an abrupt ventricular arrhythmia is a multi-factorial process involving a continually changing complex substrate of myocardial scarring, ischemia, and adrenergic and genetic factors. We are therefore dealing with a probabilistic event in which each of the currently considered risk factors such as NSVT identifies only a small fraction of the risk process.

Subjects with episodes of NSVT before 40 years of age should be evaluated primarily to rule out nonischemic causes of arrhythmia, including HCM, LQTS, idiopathic DCM, and arrhythmogenic right ventricular dysplasia. Episodes of polymorphic NSVT may indicate the presence of genetic arrhythmia disorders (e.g., LQTS, catecholaminergic polymorphic VT) or drug-induced repolarization abnormalities. ECG testing, history of SCD and syncopal episodes in family members, and current medication history may lead to a proper diagnosis. NSVT at 40 years of age and older requires that the rare causes mentioned earlier should be ruled out, but the main focus is ischemic heart disease.

In patients with known heart disease, the main task of the physician is the risk assessment of the patient; that is, the estimation of the probability that the patient will have future morbid arrhythmic events. Risk stratification attempts to identify the specific mechanisms of further morbidity to predict clinical outcomes and eventually propose clinical strategies for their prevention.

The independent prognostic significance of NSVT depends on the underlying condition (Table 43-2). It currently is not known whether NSVT bears a cause-and-effect relationship with sustained ventricular tachyarrhythmias or if it is merely a surrogate marker of left ventricular dysfunction and electric instability. Even when it does hold prognostic significance, NSVT does not necessarily imply the mechanism of death. Certain patient groups have a high mortality rate because of the progression of their disease. Death in these patients may be arrhythmic, but this does not imply that mere prevention of NSVT will unconditionally prolong life significantly. The cardiac mortality rate at 2 years in MADIT was still 11% despite the use of defibrillators.¹⁰ Furthermore, reduction of arrhythmic death does not necessarily imply a concomitant reduction in total mortality, and even a nonsignificant increase in mortality has been demonstrated despite the reduction of SCD by using amiodarone in patients with acute MI.¹²⁴^–¹²⁶

Table 43-2 Clinical Significance of Nonsustained Ventricular Tachycardia

CLINICAL SETTING	SIGNIFICANCE
APPARENTLY NORMAL HEART
Random finding	No adverse prognostic significance in the absence of occult pathology
During or after exercise	May predict IHD and increased cardiac mortality
Valvular disease, hypertension	Prognostic significance unknown
ISCHEMIC HEART DISEASE
Acute MI <13–24 h	No adverse prognostic significance
Acute MI >13–24 h	Adverse prognostic significance
Chronic IHD with LVEF >40%	Unknown. No adverse prognostic significance(?)
Chronic IHD with LVEF <40%	Adverse prognostic significance
DCM	Independent prognostic significance not established as opposed to LVEF
HCM	Adverse prognostic significance, especially in the young
Long QT syndrome, CPVT, repaired congenital abnormalities	Adverse prognostic significance
ARVC, Brugada syndrome	Probably adverse prognostic significance

ARVD, Arrhythmogenic right ventricular cardiomyopathy; CPVT, catecholaminergic polymorphic ventricular tachycardia; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; IHD, ischemic heart disease; LVEF, left ventricular ejection fraction; MI, myocardial infarction; VF, ventricular fibrillation.

Apparently Healthy Individuals

Early reports from longitudinal community-based studies indicated that the presence of complex ventricular ectopy and NSVT increase the risk of heart disease subsequently observed.¹⁵ In other studies, NSVT was not found to adversely influence prognosis, with cardiac event rates not exceeding those detected in age-matched populations without the arrhythmia.^16,⁴⁰ Polymorphic NSVT, as opposed to monomorphic NSVT, may indicate an increased risk.¹²⁷ Thus, recording of spontaneous NSVT in apparently healthy individuals does not imply an adverse prognosis, provided that occult cardiomyopathy and genetic arrhythmia disorders have been excluded. These conditions, however, may remain latent for several years, and although apparently healthy individuals presenting with NSVT can be reassured about their prognosis, long-term follow-up is advisable.

NSVT originating from the RVOT may occasionally cause syncope, although the risk of death is very low. Short cycle length during NSVT and a history of syncope are predictors of the coexistence of VF and polymorphic VT.¹²⁸ Subjects with RVOT VT might have subtle structural and functional abnormalities of RVOT as detected by CMRI.¹²⁹ Detection of NSVT in patients with ARVD indicates intermediate risk for future arrhythmic events.¹³⁰ The diagnosis of RVOT VT needs to be differentiated from the diagnosis of ARVD or cardiomyopathy, which can be accomplished by a series of noninvasive ECG and imaging studies such as Holter monitoring, SAECG, CMRI and, if needed, endomyocardial biopsy.⁸¹

Exercise-Induced Nonsustained Ventricular Tachycardia

The occurrence of premature ventricular demoralizations during exercise in apparently healthy subjects has not been associated with an increase in cardiovascular mortality and was considered to be a normal response to exertion.^41,⁴² However, the Paris Prospective Study, in agreement with earlier data, reported that runs of two or more consecutive ventricular depolarizations during exercise or at recovery may occur in up to 3% of healthy men and indicated an increase in cardiovascular mortality within the next 23 years by a factor of more than 2.5.^43,¹³¹ This increased RR persisted even after adjusting for other characteristics and known factors predisposing to coronary artery disease (CAD). Interestingly, among subjects with a positive exercise test for ischemia, only 3% had ectopy, whereas among subjects with exercise-induced ectopy, only 6% had a positive exercise test for ischemia. Thus, although the precise mechanism of arrhythmia is unknown in this setting and various forms of occult cardiomyopathy cannot be excluded, it does not appear to be a direct consequence of ischemia. This study argues that exercise-induced nonsustained ventricular arrhythmia may predict CAD, even in the absence of evidence of ischemia in asymptomatic individuals. These results were also verified in a later study on patients who had been referred for symptom-limited exercise testing without a history of heart failure, valve disease, or arrhythmia. Frequent ventricular ectopy during recovery after exercise is a better predictor of an increased risk of death than ventricular ectopy occurring only during exercise.⁴⁴ Exercise testing may also induce catecholaminergic polymorphic VT. When recognized, this condition requires aggressive management.⁵⁹

Ventricular tachyarrhythmias and NSVT commonly occur in trained athletes during ambulatory Holter electrocardiography and are usually associated with a benign course, and resumption of training is safe.¹³²

Ischemic Heart Disease

In non–ST-segment elevation acute coronary syndromes, NSVT is common after admission, and even short episodes of VT lasting 4 to 7 beats are independently associated with the risk of SCD over the subsequent year. In the Metabolic Efficiency With Ranolazine for Less Ischemia in Non–ST-segment Elevation Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) trial on 6300 patients who had 7-day continuous ECG monitoring, a greater than twofold increase in the risk of SCD was seen in patients with both short (4 to 7 beats) and longer (>8 beats) episodes of VT occurring greater than 48 hours after admission compared with patients with no VT (Figure 43-6).¹⁷ This relationship was unchanged after adjustment for clinical characteristics, including LVEF and natriuretic peptides. No increased risk of SCD was observed in patients with ventricular triplets. In several subgroups (history of heart failure, depressed ventricular function, QTc >450 ms), the presence of VT was associated with a greater than 10% incidence of SCD at 1 year. Earlier episodes within 48 hours after admission did not carry the same risk. Thus, extended continuous ECG monitoring beyond 48 hours after admission for non–ST-segment elevation acute coronary syndrome to detect the presence of even short episodes of VT may potentially identify patients at higher risk for SCD.

FIGURE 43-6 Risk of sudden cardiac death in patients with no ventricular ectopy, patients with ventricular triplets only, patients with the longest episode of ventricular tachycardia (VT) of 4 to 7 beats, and patients with the longest episode of at least 8 beats. HR, Hazard ratio; VT, ventricular tachycardia; TIMI, Thrombolysis in Myocardial Infarction; MI, myocardial infarction; HF, heart failure; CrCl, creatine clearance.

(From Scirica BM, Braunwald E, Belardinelli L, et al: Relationship between nonsustained ventricular tachycardia after non–ST-elevation acute coronary syndrome and sudden cardiac death: Observations from the Metabolic Efficiency with Ranolazine for Less Ischemia in Non–ST-Elevation Acute Coronary Syndrome—Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) randomized controlled trial, Circulation 122:455–462, 2010.)

In acute MI, NSVT during the first 13 to 24 hours does not carry a prognostic significance.^18,¹³³ Following this period, NSVT after MI predicted higher mortality in earlier studies. In the Multi-Center Postinfarction Research Program (MPIP) study in the pre-thrombolytic era, the presence of NSVT was associated with a twofold increase in total and arrhythmic deaths, independent of LVEF.^134,¹³⁵ A similar relationship between repetitive forms and mortality, and the joint predictive value of NSVT and low EF was noted in the Multicenter Investigation of Limitation of Infarct Size (MILIS).¹³⁶ Evidence from the reperfusion era suggests that in the patient with ischemic heart disease, NSVT no longer appears to be an independent predictor of death if other factors such as the EF are taken into account. In the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico 2 (GISSI-2) trial, NSVT was a significant predictor of mortality in univariate analysis, but not independently in multivariate analysis involving other clinical variables.¹⁹ Similarly, in ESVEM, although univariate analysis suggested an association between the presenting arrhythmia and the outcome, multivariate analysis failed to establish the predictive value of the presenting arrhythmia. LVEF was the single most important predictor of arrhythmic death or cardiac arrest in patients with life-threatening arrhythmias who were treated with antiarrhythmic drugs.⁹ NSVT has not been found to be an independent predictor of arrhythmic or total mortality in the studies of Hohnloser et al (325 patients with MI) and DANAMI-2 (501 patients with fibrinolysis and 516 patients with primary angioplasty).^20,²² In a study on 2130 infarct survivors, Makikallio et al reported that NSVT predicted SCD only in patients with LVEF greater than 35%. No Holter variable was predictive of outcome in the presence of an LVEF of 35% or more.⁷⁹ In the modern era, only ATRAMI has found NSVT to be an independent predictor of adverse prognosis.²¹ It seems that it is important not only how often but under what circumstances NSVT occurs. MUSTT data have shown prognostic differences in patients with in-hospital, as opposed to out-of-hospital, identified NSVT.¹³⁷ Overall mortality rates at 2-year and 5-year follow-up were 24% and 48%, respectively, for inpatients and 18% and 38%, respectively, for outpatients (adjusted P = .018). In patients subjected to surgical coronary revascularization, the occurrence of NSVT within the early (less than 10 days) post-revascularization period portends a far better outcome than when it occurs later after CABG (10 to 30 days) or in non-postoperative settings. Indeed, the approximate 2-year mortality rates for patients with early post-revascularization NSVT, late post-revascularization NSVT, and non-postoperative NSVT were 14%, 23% and 24%, respectively.¹³⁸ When, however, sustained VT is inducible in patients with early postoperative NSVT, the outcome is worse compared with noninducible patients.¹³⁹ In the MUSTT, racial differences were also shown to influence the outcome of patients with NSVT and reduced left ventricular function.¹⁴⁰

Recently, CARISMA reported on long-term cardiac arrhythmias recorded by a cardiac monitor implanted 2 to 5 days after MI in patients with an LVEF of 40% or less.⁶ Clinically significant bradyarrhythmias and tachyarrhythmias were documented in a substantial proportion of patients, most of them asymptomatic, within the next 2 years. The most significant arrhythmia was intermittent high-degree AV block (10% incidence), which was associated with a very high risk of cardiac death (>30% within the next 2 years), and the most frequent was atrial fibrillation (28%). Nonsustained VT (VT ≥125 beats/min for ≥16 beats lasting <30 seconds) was the most frequent ventricular arrhythmia recorded in the study (incidence of 13%) and was associated with cardiac death over the next 2 years only in univariate analysis (Figure 43-7). It seems, therefore, that with reperfusion and use of β-blockers, NSVT after MI may not be an independent predictor of mortality, especially after EF is taken into account, and its prognostic significance is ambiguous. In patients with non–ST-segment elevation acute coronary syndrome, NSVT occurring beyond 48 hours after admission may indicate an increased risk for SCD.

FIGURE 43-7 Electrograms of arrhythmias recorded with an implantable cardiac monitor in a patient with previous myocardial infarction. A, Paroxysmal second-degree to third-degree atrioventricular block. B, Two episodes of nonsustained ventricular tachycardia (VT) are recorded; the second episode provokes polymorphic VT degenerating to ventricular fibrillation (VF). The episode is automatically activated at the arrowhead. The VF converted back to polymorphic VT, which terminated spontaneously (not shown). The patient subsequently received an implantable cardioverter-defibrillator.

(From Bloch Thomsen PE, Jons C, Raatikainen MJ, et al, Cardiac Arrhythmias and Risk Stratification After Acute Myocardial Infarction (CARISMA) Study Group: Long-term recording of cardiac arrhythmias with an implantable cardiac monitor in patients with reduced ejection fraction after acute myocardial infarction: The Cardiac Arrhythmias and Risk Stratification After Acute Myocardial Infarction (CARISMA) study, Circulation 122:1258–1264, 2010.)

Not much data on patients with stable ischemic heart disease and an LVEF over 40% exist. In an older trial, NSVT was reported in approximately 2% of patients with ischemia and preserved left ventricular function, apparently excluding previous MI, and did not appear to carry a significant predictive ability.²⁴

Heart Failure

No convincing data exist in patients with heart failure. Although the GESICA–Grupo de Estudios Multicentricos en Argentina (GEMA) investigators identified NSVT as an independent predictor of total mortality in patients with heart failure (35% to 40% ischemic heart disease) and an LVEF of 35% or less, in CHF-STAT (70% to 75% ischemic heart disease), after adjusting other variables, especially for LVEF, NSVT was not an independent predictor of SCD or total mortality in patients with heart failure and an LVEF less than 35% to 50%.^26,⁸⁵ Similar results were published by the Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) investigators.¹² Only during the recovery period after exercise, frequent ventricular ectopy has been found to carry an adverse prognostic significance in patients with heart failure.¹⁴¹ However, in the study by Verma et al, in 421 primary prevention patients with both ischemic and nonischemic cardiomyopathy undergoing ICD implantation, 79 (19%) had received appropriate ICD therapies.⁷² NSVT detected on Holter monitoring and no β-blocker use, but not LVEF, was predictive for ICD-derived arrhythmias in patients with either ischemic or nonischemic cardiomyopathies.

Cardiomyopathies

Reports investigating the association between NSVT and cardiac mortality in patients with nonischemic DCM are not consistent. MACAS has reported on noninvasive arrhythmia risk stratification in patients with DCM.⁸ On univariate analysis, nonsustained VT and frequent VPBs showed a significant association with a higher arrhythmia risk, but on multivariate analysis, only LVEF was found to be a significant predictor of major arrhythmic events with an RR of 2.3 per 10% decrease of EF. SAECG, baroreflex sensitivity, HRV, and TWA were not helpful in arrhythmia risk stratification. Patients with NSVT in the context of LVEF less than 30% had an eightfold arrhythmia risk compared with patients with LVEF greater than 30% without nonsustained VT.⁸ In a recent study on 179 patients with DCM, multivariate analysis detected LVEF, NSVT, and QT dynamicity (QTe slope assessed by dedicated software) as significant predictors of arrhythmic events. Among the patients with a low LVEF, NSVT, steeper QTe-slope, or both identified a subgroup at highest arrhythmic risk.¹⁴² In another study, after medical stabilization with an angiotensin-converting enzyme inhibitor (88%) and a β-blocker, NSVT did not increase the risk of major ventricular arrhythmias in patients with DCM and LVEF of 35% or greater. Conversely, the number and length of NSVT runs were significantly related to the occurrence of major ventricular arrhythmias in the patients with an LVEF greater than 35%.¹⁴³ The frequency and complexity of ventricular arrhythmias increase with decreasing function of the left ventricle and with the presence of symptoms of congestive heart failure in patients with nonischemic DCM. However, cardiac death in patients with nonischemic DCM and functional class IV heart failure is more frequently caused by bradyarrhythmia or electromechanical dissociation rather than by ventricular tachyarrhythmias.^4,²⁹

Frequent and prolonged (>10 beats) episodes of NSVT on Holter monitoring most probably indicate an increased risk of SCD in HCM, especially in young patients.^31,^144,¹⁴⁵ In a study of 531 patients with HCM, a relation between arrhythmic mortality and the frequency, duration, and rate of NSVT episodes could not be demonstrated.³¹ However, NSVT was associated with a substantial increase in the risk of SCD in young patients with hypertrophic obstructive cardiomyopathy.³¹ Adabag et al reported NSVT in Holter recordings in 31% of 178 patients with HCM, and NSVT was associated with greater left ventricular hypertrophy and more severe symptoms.¹⁴⁶ Over a follow-up of 5.5 ± 3.4 years, 11 (6%) patients died suddenly (annual mortality rate, 1.1%), including 5 patients with NSVT. For SCD, NSVT on Holter ECG had negative and positive predictive values of 95% and 9%, respectively, and sensitivity and specificity of 45% and 69%, respectively. Therefore, NSVT had a low positive predictive value and relatively high negative predictive value for SCD in this HCM population. In another study from the same group, delayed enhancement on contrast-enhanced CMRI (believed to represent myocardial fibrosis) was found as an independent predictor of NSVT (RR, 7.3; 95% CI, 2.6–20.4; P < .0001).

Asymptomatic patients with ARVD and NSVT have a propensity for increased arrhythmic risk and a rate of appropriate ICD intervention of 3.7% per year.⁸⁰ However, the predictive value of NSVT has not been prospectively assessed in this setting.¹⁴⁷

Other Conditions

The presence of NSVT in patients with idiopathic ventricular outflow tract arrhythmias indicates a higher propensity for inducibility of VT during EPS compared with isolated PVCs (48% vs. 4%). At exercise, the incidence of VT in this group is 10%.⁴⁵

In patients with tachycardiopathy, the presence of nonsustained VT, in addition to the PVC burden, longer PVC duration, multi-form PVCs, and right ventricular PVCs may be associated with the development of cardiomyopathy.¹⁴⁸

The occurrence of NSVT in hypertensive patients requires evaluation of ischemic heart disease. However, the prognostic value of NSVT in patients with lone hypertension (without evidence for concomitant ischemic heart disease) remains unclear. Evidence that elimination of NSVT improves survival in patients with hypertension is not available.^35,³⁶ Also, no convincing evidence exists to prove that nonsustained VT is an independent predictor of SCD in patients with valve disease, including mitral leaflet prolapse. Initial studies suggested that patients with mitral valve prolapse had an increased incidence of NSVT and other arrhythmias.^149,¹⁵⁰ Kilgfield et al estimated the annual risk of SCD in patients with mitral valve prolapse at 1.9 per 10,000 patients, lower than the annual risk of SCD from all causes in the adult population in the United States.¹⁵¹ Thus, patients with mitral valve prolapse are not at increased risk of SCD. NSVT in patients with mitral valve prolapse is related primarily to coexisting mitral regurgitation and secondarily chronic hemodynamic and myocardial abnormalities, but they do not independently contribute to the risk of death.

Ventricular arrhythmias have an adverse prognosis in patients with repaired tetralogy of Fallot, and programmed stimulation carries a prognostic value.^38,^39,¹¹⁹

Patients with Chagas’ cardiomyopathy presenting with either sustained VT or NSVT have a major risk for mortality in the presence of moderate left ventricular systolic dysfunction (LVEF <40%).¹⁵²

In cases of LQTS, detection of spontaneous episodes of torsades de pointes indicate an adverse prognosis.⁴

Management and Evidence-Based Therapy

The management and evidence-based therapy of patients with NSVT depend on the underlying condition. Specific underlying conditions are classified as nonischemic and ischemic. Nonischemic conditions with NSVT may include a structurally normal heart, hypertension, valvular disorders, HCM, nonischemic DCM, LQTS, Brugada syndrome, and other rare genetic disorders. Ischemic disease with NSVT cannot be considered a uniform condition, and its management depends on the presence or absence of MI and the degree of left ventricular dysfunction.

Nonsustained Ventricular Tachycardia in Structurally Normal Heart

Sometimes, episodes of NSVT in patients without structural heart disease may cause symptoms and require treatment. Because RVOT VT does not increase the risk of SCD, asymptomatic patients do not require treatment. In symptomatic patients, treatment should be directed toward relief of tachycardia-related symptoms with β-blockers or calcium channel blockers and adenosine, if needed, in an acute setting. If medication is not effective, radiofrequency catheter ablation is recommended; it is successful in more than 80% of cases with a low risk of relapse during follow-up.¹⁵³

Nonsustained Ventricular Tachycardia in Inherited Channelopathies

β-Blocker therapy is the treatment of choice in cathecholaminergic polymorphic VT, and some evidence exists that combination of β-blockers with calcium channel blockers is superior to β-blockers alone.¹⁵⁴ Defibrillator implantation may be necessary in addition to β-blockers in some patients with catecholaminergic polymorphic VT.

Usually, cardiac events in patients with LQTS are caused by prolonged polymorphic NSVT or sustained VT (torsades de pointes) that might degenerate into VF.¹⁵⁵ However, transient, asymptomatic runs of polymorphic NSVT are also common. β-Blocker treatment is the therapy of choice in patients with LQTS (especially LQT1 and LQT2); it is effective in 70% of patients, whereas the remaining 30% of patients continue to have cardiac events despite β-blocker treatment.¹⁵⁶ Those patients with recurrent syncope despite β-blocker therapy and those with cardiac arrest should be considered for ICD therapy, which is successful in preventing death.¹⁵⁷

Although no systematic studies evaluating prognostic significance of NSVT in Brugada syndrome have been conducted, it is generally agreed that symptomatic patients (i.e., those with syncope or cardiac arrest presumably caused by NSVT or sustained VT) should be treated with ICDs.¹⁵⁸

Patients with ARVD are at high risk of sudden death.⁸¹ These patients may present with asymptomatic NSVT despite only subtle right ventricular abnormalities. The results of antiarrhythmic medications have been disappointing, and ICDs seem to be the therapy of choice in patients with documented arrhythmias or in those who are symptomatic.⁸⁰ Catheter ablation of VT, when feasible, is successful in reducing further episodes but cannot offer absolute protection without ICD backup.¹⁵⁹

Nonsustained Ventricular Tachycardia in Hypertension and Valve Disease

Aggressive treatment of hypertension (including β-blockers) is the therapy of choice in patients with hypertension and NSVT. The majority of patients with mitral valve prolapse and NSVT do not require extensive diagnostic evaluation or treatment. In symptomatic patients (palpitations, syncope) with NSVT, β-blocker treatment is considered the first-line therapy. Other antiarrhythmic agents may be used in cases refractory to β-blocker treatment. Treatment should be directed primarily at improvement of the overall quality of life while considering the potential adverse (potential proarrhythmic) effects of therapy. NSVT is common in patients with other valvular diseases, particularly aortic stenosis and mitral regurgitation. The presence of NSVT is usually associated with left ventricular hypertrophy or dysfunction, but no clear evidence exists that these arrhythmias indicate increased risk of mortality after valve replacement.

Nonsustained Ventricular Tachycardia in Hypertrophic Cardiomyopathy

The effects of pharmacologic antiarrhythmic therapy in patients with HCM are disappointing.^64,⁶⁵ β-Blockers may decrease the risk of SCD; however, the risk of death on β-blocker remains significant. Amiodarone was shown to suppress VT induction in some patients while causing conduction abnormalities and facilitating induction of VT in others.^64,⁶⁵ Therefore, this drug cannot be considered as therapy of choice in high-risk patients with HCM. Defibrillator implantation is the therapy of choice in the primary and secondary prevention of CD in patients with HCM.¹⁶⁰ Patients with a history of syncope, a family history of SCD, or history of NSVT who had received defibrillators as primary prevention had a 5% per year appropriate discharge rate. In patients resuscitated from cardiac arrest (secondary prevention), the rate of appropriate discharges was 11%. More than one third of the patients who had an appropriate discharge of the defibrillator were taking amiodarone, further emphasizing the limited role of antiarrhythmic therapy in these patients. ¹⁶⁰ These observations indicate that presence of high-risk factors, including frequent NSVT accompanied by history of syncope or family history of SCD at a young age, may justify defibrillator implantation as primary prevention in patients with HCM.

Nonsustained Ventricular Tachycardia in Dilated Cardiomyopathy

Two large trials evaluated amiodarone therapy in patients with ischemic and nonischemic cardiomyopathy. In the GESICA trial, amiodarone therapy was associated with decreased mortality, whereas no such effect was observed in the CHF-STAT trial.^25,⁸⁵ The reasons for the different frequencies of NSVT in both studies (34% and 79%, respectively) and the differences in the effectiveness of amiodarone therapy are not clear and might be related to the varying characteristics of patient populations (with the GESICA trial enrolling patients with more advanced left ventricular dysfunction and a high number of patients with Chagas’ disease). Results of SCD-HeFT demonstrated that amiodarone is not effective in preventing mortality in patients with nonischemic DCM (HR 1.07, in 813 patients randomized to amiodarone or placebo).⁷¹ The SCD-HeFT study of 2521 patients with ischemic (52%) and nonischemic (48%) cardiomyopathies (EF <36% and New York Heart Association [NYHA] class II or III) randomized the subjects to amiodarone, ICD therapy, or conventional therapy. A history of NSVT was reported in 23% of patients. During a mean 45-month follow-up, a 7.2% annual mortality was observed in the placebo group. ICD therapy was associated with a 23% reduction in mortality (HR 0.77, P = .007) in all patients combined. Patients with nonischemic cardiomyopathy had an HR of 0.73, and those with ischemic cardiomyopathy had an HR of 0.79 (no significant difference existed between the two subgroups). The SCD-HeFT data seem to end the controversy regarding the usefulness of amiodarone for primary prevention of SCD in patients with nonischemic (and also in ischemic) cardiomyopathy. Dronedarone also did not fulfill hopes regarding its prevention of mortality in patients with heart failure; therefore, this drug needs to be taken off the list of medications used in such patients.¹⁶¹

The effect of defibrillator implantation as primary prevention of cardiac mortality in patients with nonischemic DCM and NSVT or ventricular ectopy was the subject of the DEFINITE trial.¹⁶² In this study, 458 patients with nonischemic DCM with EF less than 36%, symptomatic congestive heart failure, and NSVT or more than 10 PVCs per hour were randomized to defibrillator versus no defibrillator therapy (229 patients in each arm). The mean age of the patients was 58 years. They were predominantly males (71%; mean EF, 21%). NSVT was present in 23% of the patients. During a mean 29-month follow-up, 68 deaths occurred, 28 in the ICD arm and 40 in the non-ICD arm (P = .08 from the log-rank test). Two-year mortality rate was 14.1% in the non-ICD arm and 7.9% in the ICD arm (HR, 0.65; CI, 0.40–1.06). The HR for SCD was 0.20 (P = .006). Patients with NYHA class III demonstrated significant benefit from ICD therapy with an HR of 0.37 (P = .02). A trend for reduced total mortality was observed with ICD. Thus, results from DEFINITE and SCD-HeFT show that patients with nonischemic cardiomyopathy with EF less than 36% and NYHA class II or III have a high (7%) annual mortality despite optimal pharmacologic therapy and that the risk of mortality could be substantially reduced by ICD therapy.

The purpose of the Amiodarone Versus Implantable Cardioverter-Defibrillator: Randomized Trial in Patients With Nonischemic Dilated Cardiomyopathy and Asymptomatic Nonsustained Ventricular Tachycardia (AMIOVIRT) was to compare total mortality during therapy with amiodarone or ICD in 103 patients with nonischemic DCM and NSVT.¹⁶³ The primary endpoint was total mortality. Secondary endpoints included arrhythmia-free survival, quality of life, and costs. The study was stopped when the prospective stopping rule for futility was reached. The percentage of patients surviving at 1 year (90% vs. 96%) and 3 years (88% vs. 87%) in the amiodarone and ICD groups, respectively, were not statistically different (P = .8). Quality of life was also similar with each therapy (P = not significant). A trend toward a more beneficial cost profile and improved arrhythmia-free survival was observed with amiodarone therapy. Mortality and quality of life in patients with nonischemic DCM and NSVT treated with amiodarone or ICD are not statistically different. ICD was also not found superior to amiodarone in the Cardiomyopathy Trial (CAT) study on patients with recent onset of DCM ≤9 months) and EF 30% or less.¹⁶⁴

Current indications for ICD or cardiac resynchronization therapy (CRT) therapy include primary prevention indications beyond those based on syncope or arrhythmic events. In light of the results from the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial and subsequently from the Cardiac Resynchronization–Heart Failure (CARE-HF) trial, CRT has been approved as treatment in patients with an LVEF of 35% or less, NYHA class III or IV, and QRS greater than 120 ms.^165,¹⁶⁶ CRT provides benefit in patients with heart failure with wide QRS complex; this benefit is observed in patients with ischemic and nonischemic cardiomyopathies, but it might be higher in patients with nonischemic cardimyopathy.^167,¹⁶⁸

Nonsustained Ventricular Tachycardia in Coronary Artery Disease

The management of patients with previous MI and NSVT should first include modern therapy for ischemic heart disease, including revascularization procedures, the use of β-blockers, statins, and angiotensin-receptor blockers or inhibitors. This therapy is the most effective antiarrhythmic measure in patients with CAD as demonstrated by the Coronary Artery Bypass Graft Patch (CABG-Patch) trial.¹⁶⁹ The CAST and CAST II trials demonstrated that class IC antiarrhythmic agents (encainide, flecainide, and moricizine) confer increased (not decreased) mortality in patients with previous MI.^83,^84,¹⁷⁰ Subsequently, d-sotalol (class III drug) tested in the Survival With Oral d-Sotalol (SWORD) trial also was associated with increased mortality in comparison with placebo.¹⁷¹ The European Myocardial Infarct Amiodarone Trial (EMIAT) and the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT) failed to demonstrate beneficial effect of amiodarone on survival.^125,¹²⁶ Therefore, no antiarrhythmic drug is suitable for the primary prevention of cardiac death, with the exception of β-blockers, which were shown in several studies to reduce total and cardiac mortality in patients with previous MI. However, in low-risk to moderate-risk patients with previous MI and NSVT from the Beta-Blocker Heart Attack Trial, there was no reduction in mortality in patients with NSVT.¹⁷²

In the MERLIN study, among patients assigned to ranolazine, an episode of VT lasting at least 8 beats was not associated with SCD compared with patients with no VT lasting at least 8 beats (2.5% vs. 1.6%; HR, 1.1; 95% CI, 0.3–3.5; P = .90), whereas among patients assigned to placebo, VT lasting at least 8 beats was significantly associated with SCD (5.4% vs. 1.5%; HR, 2.9; 95% CI; 1.6–5.3; P < .001) (P for interaction = .15).¹⁷ These findings indicate that ranolazine most likely contributed to decreased mortality in patients with NSVT. However, these findings require confirmation in prospective studies.

In the 1990s, the implantable defibrillator became a feasible alternative to pharmacologic antiarrhythmic therapy for primary prevention of SCD in patients with CAD and NSVT. In the MADIT study, 196 patients with previous MI, an EF of 35% or less, a documented episode of NSVT, and inducible and nonsuppressible sustained VT were randomized to receive an implanted defibrillator or conventional (primary amiodarone) non-ICD therapy. Fifteen deaths occurred in 95 patients randomized to ICD therapy and 39 deaths in 101 patients randomized to conventional therapy, yielding a 54% reduction in total mortality associated with ICD during a mean 27-month follow-up. This was the first study demonstrating that ICD therapy is beneficial as primary prevention in high-risk patients with previous MI. Antiarrhythmic therapy guided by invasive EPS has historically been used to treat patients with NSVT and inducible sustained VT. MUSTT used the concept of EPS-guided antiarrhythmics to determine whether this approach can reduce mortality in survivors of MI with EF 40% or less and NSVT.¹¹ The main study enrolled 704 patients with CAD, asymptomatic NSVT, EF 40% or less, and inducible sustained VT. Patients with induced, sustained VT were randomized to no antiarrhythmic therapy or to EPS-guided therapy. The EPS-guided therapy included pharmacologic antiarrhythmic therapy and implantable defibrillators as indicated, based on EPS. The risk of cardiac arrest or death from arrhythmia among patients who received treatment with defibrillators in MUSTT was significantly lower than that among patients who did not receive ICDs (RR, 0.24; 95% CI, 0.13–0.45; P < .001). Patients assigned to EPS-guided therapy who were treated with only pharmacologic antiarrhythmics had a similar rate of death and cardiac arrest as those in the control group who had not been treated with antiarrhythmic therapy. These studies demonstrated that ICDs used in patients with previous MI and depressed EF and NSVT significantly reduce the risk of SCD and total mortality.¹⁷³

Subsequently, MADIT II hypothesized that patients with previous MI and markedly depressed left ventricular function (EF ≤30%)—regardless of the presence or absence of other risk stratifiers, including frequent ventricular ectopy and inducibility of sustained VT—will benefit from ICD therapy.¹⁷⁴ MADIT II enrolled 1232 patients with previous MI (742 randomized to ICD therapy and 490 to the non-ICD arm) and demonstrated that ICD therapy was associated with a significant 30% reduction in total mortality during a 20-month follow-up and a sustained 8-year survival benefit.¹⁷⁵ SCD-HeFT (with 52% of the patients having ischemic cardiomyopathy) confirmed the MADIT II findings, indicating substantial benefit from ICD therapy in patients with a low EF (<36%) and NYHA classes II and III. MADIT II and SCD-HeFT significantly changed the clinical approach to patients with previous MI and NSVT. In light of MADIT II, patients with previous MI and EF of 30% or less should undergo ICD therapy regardless of the presence or absence of NSVT. Based on SCD-HeFT, patients with previous MI and EF of 31% to 35% should undergo ICD implantation if they are in NYHA class II or III. Therefore, on the basis of the MUSTT findings, patients with previous MI and NSVT and EF of 36% to 40% should undergo EPS and, if inducible, they should be treated with ICDs.

Two trials have investigated the optimal timing of ICD in patients with previous MI and reduced left ventricular function and other risk factors. The Defibrillator in Acute Myocardial Infarction Trial (DINAMIT), a randomized trial, compared ICD therapy (in 332 patients) with no ICD therapy (in 342 patients) 6 to 40 days after MI in patients with LVEF 35% or less and impaired cardiac autonomic function (manifested as depressed HRV or an elevated average 24-hour heart rate on Holter monitoring).¹⁷⁶ Prophylactic ICD therapy did not reduce overall mortality during an approximately 3-year follow-up, although it was associated with a reduction in the rate of arrhythmic death. The Immediate Risk Stratification Improves Survival (IRIS) investigators randomized 898 patients with an LVEF of 40% or less and a heart rate of 90 or more beats/min on the first available ECG (602 patients), or NSVT (≥150 beats/min) during Holter monitoring (208 patients), or both criteria (88 patients), 5 to 31 days after MI, to treatment with an ICD (n = 445) and to medical therapy alone (n = 453).¹⁷⁷ During a mean follow-up of 37 months, prophylactic ICD therapy did not reduce overall mortality. Fewer SCDs occurred in the ICD group than in the control group (27 vs. 60; HR, 0.55; 95% CI, 0.31–1.00; P = .049), but the number of non-SCDs was higher (68 vs. 39; HR, 1.92; 95% CI, 1.29–2.84; P = .001). Thus, ICD after MI, when indicated, should be considered at least 40 days later than the event.

Current guidelines for ICDs include MUSTT-based class I indication, formulated as follows: “ICD therapy is indicated in patients with NSVT due to prior MI, LVEF <40%, and inducible VF or sustained VT at electrophysiological study (Evidence level B).”¹⁷⁸ However, this category of patients is very much limited to individuals with LVEF of 36% to 40%, since other (MADIT II and SCD-HeFT based) approved indications that do not require documented NSVT cover patients with an LVEF less than 35%.⁴

No data are available from clinical trials to indicate that NSVT in patients with previous MI and EF greater than 40% should be treated with ICDs. The role of EPS-guided therapy and ICDs in these patient populations remains to be determined.

Summary

NSVT can be recorded in an extremely wide range of conditions, from apparently healthy individuals to patients with significant heart disease. The prognostic significance of NSVT is strongly influenced by the type and severity of underlying heart disease. The current evidence-based therapy in patients with NSVT is summarized in Table 43-3. ICD therapy remains the mainstay of current antiarrhythmic regimen in high-risk conditions complicated by NSVT.

Table 43-3 Management and Evidence-Based Therapy in Patients with NSVT Depending on Underlying Conditions

NSVT SETTING	MANAGEMENT	EVIDENCE-BASED THERAPY
NONISCHEMIC CONDITIONS
Asymptomatic, no overt heart disease	Evaluate for ischemic heart disease and other disorders	No treatment necessary
Symptomatic with RVOT morphology of NSVT	EPS	β-Blockers, verapamil, adenosine Differentiate with ARVD Radiofrequency ablation, if needed
Hypertrophic cardiomyopathy	Evaluate additional risk factors: Previous cardiac arrest (although most are lethal) Unexplained syncope Massive left ventricular hypertrophy (≥30 mm) Hypotensive or attenuated blood pressure response to upright exercise	β-Blockers, CCBs (in nonobstructive form), septal myectomy/ablation ICD when frequent and prolonged (>10 beats) episodes of NSVT and additional risk factor
Nonischemic dilated cardiomyopathy	Value of EPS not established	Optimal CCB therapy (medical and CRT, if indicated) Ablation for bundle branch re-entry ICD for syncope or LVEF ≤30% to 35% and NYHA class II/III
ARVC	Value of EPS not established	ICD with sustained VT or VF or left ventricular involvement and/or one or more affected family members
LQTS	Genotype analysis useful	β-Blockers ICD if cardiac arrest with β-blockers (especially in LQT2 and LQT3)
CPVT	Value of EPS not established	β-Blockers ICD, if cardiac arrest on β-blockers
Brugada syndrome	Value of EPS disputed	ICD with syncope
ISCHEMIC CONDITIONS
Acute MI, NSVT <24 hours	Routine for acute MI	Primary angioplasty, thrombolysis
NSVT >24 hours until predischarge	Routine for acute MI	Optimal CAD therapy* Revascularization
Asymptomatic CAD without MI; or MI with EF >40%	EPS if EF <40%	No need for specific management
Syncope in CAD without MI; or MI with EF >40%	EPS	Optimal CAD therapy* If EPS-inducible: ICD† optimal CAD therapy
MI with EF of 31% to 40%	EPS	Optimal CAD therapy If EPS-inducible: ICD
MI with LVEF ≤35% and NYHA II/III	No further testing needed	Optimal CAD therapy ICD therapy
MI with EF ≤30%	No further testing needed	Optimal CAD therapy ICD therapy

ARVC, Arrhythmogenic right ventricular cardiomyopathy; ARVD, arrhythmogenic right ventricular dysplasia; CAD, coronary artery disease; CCB, calcium channel blocker; CPVT, catecholaminergic polymorphic ventricular tachycardia; EF, ejection fraction; EPS, electrophysiology study; ICD, implantable cardioverter-defibrillator; LQTS, long QT syndrome; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NSVT, nonsustained ventricular tachycardia; NYHA, New York Heart Association; RVOT, right ventricular outflow tract; VF, ventricular fibrillation; VT, ventricular tachycardia.