Felix Yang, Mintu P. Turakhia and Victor F. Froelicher

Chapter Outline

Exercise-Induced Atrial Arrhythmias

Exercise-induced atrial arrhythmias are less common than ventricular arrhythmias. In the Baltimore Longitudinal Study of Aging, 1383 asymptomatic volunteers aged 20 to 94 years underwent exercise testing.⁴ Exercise treadmill–induced supraventricular arrhythmia (ETISVA) was noted in 85 subjects (6%). An eightfold increase in the relative risk of developing lone atrial fibrillation (AF) was noted in subjects with exercise-induced ETISVA. In a 5.7-year follow-up, 10% of 85 subjects with ETISVA developed AF or paroxysmal supraventricular tachycardia (SVT). Therefore, ETISVA may be a marker for AF or paroxysmal SVT during follow-up.

The relationship between exercise and atrial fibrillation is particularly relevant to athletes. The overall risk for AF is significantly higher in athletes than in controls (odds ratio 5.29, 95% confidence interval [CI] 3.57 to 7.85, P = .0001).⁵ Endurance sports increase preload, which increases atrial pressure and therefore shortens atrial refractory periods and increases the dispersion of atrial refractoriness. Increased vagal tone in athletes, sympathetic surges during exercise, and fluid and electrolyte changes during exercise may also contribute to the development of atrial arrhythmias.⁶ Anatomically, athletes may have larger left atrial dimensions and fibrosis secondary to chronic systemic inflammation from excessive endurance exercise.⁷

In patients with no structural heart disease, treatment is generally targeted at addressing the trigger for the arrhythmia. A reduction in exercise intensity or duration is often highly effective in reducing arrhythmia burden.⁸ However, many patients, especially competitive athletes, may be unwilling or unable to reduce or refrain from exercise. In these cases, β-blockers, antiarrhythmics, and catheter ablation can be considered.

In a study of 5375 patients with known or suspected coronary artery disease (CAD), 24% of patients developed atrial ectopy, 3.4% developed SVT, and 0.8% developed AF upon treadmill testing.⁹ Exercise treadmill–induced supraventricular arrhythmias were not predictive of any end point.

Exercise-Induced Ventricular Arrhythmias

Outflow Tract Ventricular Tachycardia

Outflow tract VT should be considered in patients with a structurally normal heart and a QRS in VT that features a left bundle branch block morphology and an inferior axis. Most outflow tract VTs originate from the RVOT (80%), and the remainder originate from the left ventricular outflow tract (LVOT).²⁰ RVOT VT has a left bundle branch QRS morphology and an inferior axis, with an R/S transition typically in V3 or V4. LVOT VT may also have left bundle branch QRS morphology but with small R waves in V1 and an earlier R/S transition. Lerman and collegues have determined that outflow tract VTs are the product of triggered activity secondary to cyclic adenosine monophosphate–mediated delayed afterdepolarizations. ²¹ The VT is adrenergically mediated and is sensitive to perturbations that lower intracellular calcium such as adenosine and verapamil. The diagnosis of idiopathic VT is one of exclusion; therefore other causes of left bundle branch block (LBBB) pattern VT should be considered.

Clinically, outflow tract VT accounts for the vast majority of idiopathic VTs. The age of presentation is usually 30 to 50 years, and patients usually have a benign clinical course.²⁰ The most common complaint among patients is palpitations (48% to 80%), followed by presyncope or light-headedness (28% to 50%). Syncope is rare (<10%) and SCD is extremely rare. However, some patients may develop cardiomyopathy from incessant repetitive monomorphic VT or from a high burden of ventricular premature complexes (VPCs). Ablation of the focus usually normalizes left ventricular function in a few months.

The spectrum of outflow tract VT includes three clinical subtypes.²² Patients may have repetitive monomorphic VPCs, repetitive nonsustained monomorphic VT, or exercise-induced sustained VT. Patients may present with a predominance of one type; however, significant overlap has been noted, and it is believed that the subtypes share the same cellular mechanism. Generally, outflow tract tachycardias are provoked by exercise, and treadmill testing is useful in reproducing the clinical VT. Approximately 70% of patients who present with sustained VT will have VT induced by exercise testing.²² However, in patients who present with monomorphic nonsustained ventricular tachycardia (NSVT) or VPCs on monitoring, exercise testing may induce sustained VT in only 10%. Overall, exercise testing reproduces VT in less than 50% of patients with clinical VT. As a result, exercise testing may not be a reliable indicator of β-blocker or antiarrhythmic efficacy, and ambulatory monitoring would be an appropriate adjunct.

Two responses of outflow tract VT to exercise testing have been reported. In the first case, VT occurs during acceleration of the heart rate with exercise. A progression from VPCs to salvos of NSVT to sustained VT may be observed. In contrast, patients with repetitive monomorphic VT may have suppression of their VT during exercise and development of VT during the recovery phase of exercise.²³ These responses indicate that a critical window of heart rates is required for VT initiation. This cycle length dependence of ventricular ectopy may also be observed on ambulatory monitoring. ^23,24

In general, patients with exercise-induced outflow tract VTs have no structural heart disease. In contrast, patients with post-infarction septal VTs will have a history of coronary disease and myocardial infarction. Bundle branch reentry VT is usually seen in the setting of structural heart disease, most commonly a dilated cardiomyopathy.²⁵ Patients with antidromic atrioventricular reciprocating tachycardia (AVRT) using an atriofascicular bypass tract might also demonstrate an LBBB morphology VT, although the axis is usually leftward.²⁶ The triggered activity of outflow tract VT also differs from the reentry mechanisms of post-infarction VT, bundle branch reentry VT, and antidromic AVRT using an atriofascicular bypass tract. Although they characteristically have exercise-induced VT, patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) will have polymorphic ventricular ectopy and will manifest bidirectional VT. Last, outflow tract morphology VTs may be a manifestation of arrhythmogenic right ventricular dysplasia (ARVD), although the morphology of VT is often varied in ARVD.

In addition to exercise, ventricular ectopy, including sustained VT, can be provoked by emotional stress. High levels of sympathetic tone contribute to arrhythmogenicity. This is also illustrated in the circadian variations in episodes of VT, ventricular runs (2 to 4 beats), and VPCs. Hayashi et al. demonstrated that peaks for these ventricular arrhythmias occurred around 7 AM and 6 PM.²⁷ β-Blockers completely eliminated VT episodes and blunted ventricular runs; however rates of single VPCs were similar to those before β-blockade therapy.

Idiopathic Left Ventricular Tachycardia

Approximately 10% of idiopathic VTs originate from the fascicles of the left ventricle. These arrhythmias are referred to as fascicular VT or verapamil-sensitive VT.²⁸ This condition should be considered in the differential diagnosis of right bundle branch block (RBBB) with left anterior fascicular block pattern VT. Less commonly, a left posterior block pattern may be seen (5% to 10%).²⁸ The usual age of presentation is between 15 and 40 years, and patients usually have normal resting electrocardiogram (ECG) and left ventricular function.²⁹ Although verapamil-sensitive VT was originally described at rest, VT is sensitive to exercise or emotional stress, is frequently precipitated by exercise, and may be seen during or after exertion.

This reentrant arrhythmia is believed to involve the posterior Purkinje system with the left posterior fascicle as one limb and abnormal Purkinje tissue with slow, decremental conduction as the other limb.³⁰ In the small percentage of patients with RBBB and a right inferior axis VT (left posterior block pattern), the left anterior fascicle is thought to be the involved Purkinje system and the site of ventricular exit.³¹ The circuit is sensitive to catecholamines as evidenced by induction by exercise, and induction during electrophysiological testing is facilitated by isoproterenol infusion. Whereas adenosine has no effect on the arrhythmia, administration of verapamil slows the VT rate and then terminates it.³²

Patients suspected to have verapamil-sensitive VT should undergo an evaluation to exclude structural heart disease. An echocardiogram, a stress test, and/or cardiac catheterization may be indicated depending on the clinical suspicion for coronary disease. Medical treatment for verapamil-sensitive VT involves verapamil; however patients with severe or recurrent symptoms can undergo catheter-based ablation with high rates of success.³³

Arrhythmogenic Right Ventricular Dysplasia

Patchy replacement of right ventricular myocardium by fibrofatty tissue is the hallmark of arrhythmogenic right ventricular dysplasia (ARVD) and provides a substrate for reentrant ventricular arrhythmias. Generally, this fibrofatty replacement preferentially affects the free wall of the right ventricle; however, the disorder can affect the outflow tract, left ventricle, and septum. ARVD is more common in males and predominantly affects young adults, with a mean age of diagnosis around 30 years.

Ventricular arrhythmias can occur during exercise, and SCD is thought to be due to acceleration of VT with degeneration into ventricular fibrillation. The most common arrhythmia is sustained or nonsustained monomorphic VT from the right ventricle, therefore manifesting a left bundle branch pattern. Usually the VT seen in ARVD will be of left bundle branch morphology with a superior rather than inferior axis. However, preferential or isolated outflow tract involvement has been described. Exercise testing may demonstrate monomorphic VT in up to 50% to 60% of patients. Exercise is thought to impart increased stress on the right ventricle and may increase right ventricular dilatation and worsen the manifestations of ARVD. Accordingly, patients with ARVD should not engage in competitive sports or endurance training and should not participate in any activities that cause palpitations, presyncope, or syncope.³⁴

The diagnosis of ARVD consists of the fulfillment of multiple criteria.³⁵ ECG findings suggestive of ARVD include the presence of right ventricular (RV) conduction delay, precordial T wave inversions, and epsilon waves.^35,36 The presence of notching in the QRS complex of the LBBB VT may also suggest ARVD.³⁷ Treadmill exercise testing may be used to elicit the characteristic LBBB morphology of ventricular tachycardia of ARVD. Nonsustained or sustained VT of LBBB morphology with a superior axis fulfills a major criterion for the diagnosis of ARVD, whereas an inferior axis fulfills a minor criterion.³⁵ Other corroborative data are needed for the diagnosis of ARVD, and the usual diagnostic work-up for ARVD consists of a signal-averaged ECG, echocardiogram, cardiac magnetic resonance imaging (MRI), a detailed family history, and, if needed, invasive electroanatomic mapping of the right ventricle.

In addition to exercise restriction, treatment for ARVD involves implantation of an implantable cardioverter-defibrillator (ICD) in patients deemed at high risk for arrhythmic events and for secondary prevention of SCD.³⁸ Medical management with antiarrhythmics or sotalol may be used in those who are not candidates for ICD therapy and in those with frequent shocks. Radiofrequency ablation also plays a role in patients with recurrent ventricular arrhythmias.

Hypertrophic Cardiomyopathy

Described in further detail in Chapter 86, hypertrophic cardiomyopathy (HCM) is a disease of left ventricular hypertrophy with a spectrum of clinical manifestations and hemodynamic abnormalities that are most often caused by mutations in one of several sarcomere genes. The mechanism of SCD in HCM patients is likely multifactorial but ultimately results from ventricular tachyarrhythmias. The arrhythmia is thought to result from electrical instability and distorted electrophysiological propagation from the disorganized arrangement of cardiac muscle cells of HCM. Findings of increased SCD during the afternoon hours in athletes support an exercise-induced mechanism.³⁴ This is also supported by findings of sinus tachycardia preceding VT/VF events in stored ICD events, which suggest that high sympathetic drive is proarrhythmic when a susceptible substrate is present.³⁹

Risk stratification for SCD involves an assessment of family history of SCD, a personal history of syncope, determination of left ventricular wall thickness, assessment of the blood pressure response and outflow tract gradient to treadmill exercise, and NSVT on Holter monitoring.

Although NSVT during Holter monitoring has been demonstrated to be a useful prognostic factor, ventricular arrhythmias induced during exercise testing have not been well established as a prognostic indicator of SCD. In a study of 263 patients with HCM who underwent exercise testing, 3.0% of patients had new nonsustained atrial arrhythmias and 4.2% had nonsustained ventricular arrhythmias.⁴⁰ In a larger series by Gimeno et al. of 1380 patients referred to a cardiomyopathy clinic, only 27 (2.0%) had NSVT (defined as 3 or more consecutive beats at a rate of ≥120 beats/min) or VF during exercise testing.⁴¹ Although NSVT was not frequent, researchers found that the hazard ratio for exercise-induced NSVT/VF (HR = 3.14) in predicting SCD or appropriate ICD discharge was higher than that of all other predictors (HR = 2.57 for NSVT on Holter; HR = 1.79 for family history of SCD). High rates of SCD or ICD discharge in patients with exercise-induced ventricular arrhythmia suggest that treadmill exercise may be a useful tool for assessing SCD risk in HCM.

Prevention of ventricular tachyarrhythmias and prevention of SCD involve the use of ICDs.⁴² The risk of SCD may also be reduced with septal myectomy in patients with symptomatic LVOT obstruction, although septal ablation has not been found to yield similar results.⁴³ Pharmacologic agents such as antiarrhythmic drugs or negative inotropes have little impact on the incidence of SCD. Last, because of the potential risk of SCD associated with exercise in HCM patients, activity restriction is advised.³⁴

Long QT Syndrome

Detailed discussion of long QT syndrome (LQTS) is found in other chapters; however, we will discuss here some of the distinguishing features of LQT-1 that pertain to exercise. LQT-4 and LQT-7 will be discussed in the following section, given some overlapping features with CPVT. The most common LQTS is LQT-1, which is the type whose events are most often triggered by adrenergic stimuli and exercise. Events in LQT-2 patients are less often triggered by adrenergic stimulation, and events in LQT-3 patients usually occur during rest or sleep.⁴⁴ LQT-1 should be considered in patients who have a prolonged QTc and a history of syncope with stress. The T wave morphology in LQT-1 is typically broad-based and high in amplitude. This contrasts with the precordial biphasic T wave pattern of LQT-2 and the long isoelectrical ST-T segment of LQT-3.

Arrhythmic events in LQT-1 generally occur at relatively elevated heart rates. Tan et al. observed an average sinus heart rate of 98 beats/min before torsades de pointes for LQT-1 in contrast to an average of 73 beats/min for LQT-2.⁴⁵ The preceding TdP in LQT-1 is not pause dependent, unlike that in LQT-2 patients.⁴⁶

The defect in LQT-1 is a mutation in KCNQ1, resulting in loss-of-function in I_Ks.⁴⁷ At fast heart rates, I_Ks is the most important current that shortens the action potential.⁴⁸ As a result, the dysfunctional I_Ks in LQT-1 patients results in an inability to appropriately shorten QTc during exercise.⁴⁷ This particular response to exercise and adrenergic stimulation is of particular interest in exercise stress testing and epinephrine QT stress testing.

Observation of a paradoxical prolongation of the uncorrected QT interval by >30 ms during infusion of low-dose epinephrine suggests a diagnosis of LQT-1.⁴⁹ Epinephrine QT stress testing has been demonstrated to have a positive predictive value of 76% and a negative predictive value of 96% for LQT-1, even when the baseline ECG has a normal QTc.⁴⁹

Ackerman and associates analyzed 243 treadmill tests of patients studied for LQTS and reported good diagnostic accuracy of treadmill testing for the diagnosis of LQT-1.⁵⁰ During exercise, QTc decreases in LQT-2, LQT-3, and control patients. In contrast, LQT-1 patients essentially have unchanged QTc durations. Additionally, the QTc of concealed LQT-1 patients actually increased at peak exercise (Figure 63-1). Investigators found that an absolute QTc ≥460 ms during the recovery phase or a paradoxical increase in QTc, which was defined as (QTc at 3 minutes of recovery) − (QTc baseline) ≥30 ms, reliably distinguished patients with manifest or concealed LQT-1 from those with LQT-2 and LQT-3.

Clinically, 40% of LQT-1 patients will become symptomatic by age 10, and very few will develop symptoms for the first time after the age of 20. As a result, asymptomatic adults who are diagnosed in adulthood may be at low risk for events. Regardless, β-blockers are the treatment of choice and are extremely effective in reducing symptoms and lethal events. Patients who have recurrences despite maximal β-blocker therapy may be considered for ICD implantation or left stellate ganglion ablation.

Catecholaminergic Polymorphic Ventricular Tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited syndrome that is characterized by adrenergically induced supraventricular and ventricular arrhythmias in structurally normal hearts and is associated with syncope and sudden death. It typically manifests in children and adolescents and provokes symptoms in up to 80% of patients younger than 40 years of age.⁵¹ SCD is often the first manifestation of the disease, which carries a 30% to 40% overall mortality by age 40.⁵¹

The basis for the overwhelming majority of cases of CPVT is a mutation in the cardiac ryanodine receptor RyR2, which is inherited in an autosomal dominant fashion.⁵² Mutations in the ryanodine receptor are implicated in the uncontrolled release of calcium from the sarcoplasmic reticulum in cardiomyocytes during electrical diastole, which produces delayed afterdepolarizations and cardiac arrhythmias.⁵³ Genetic screening allows successful genotyping of CPVT in approximately 50% to 60% of patients with a definitive clinical diagnosis of CPVT.

Exercise testing is particularly useful in the evaluation of patients with CPVT. One of the diagnostic findings in CPVT is the progressive increase in supraventricular and ventricular arrhythmias that parallels increases in exercise workload. Ectopic supraventricular beats and polymorphic PVCs usually begin at a heart rate of approximately 100 to 110 beats/min. Supraventricular arrhythmias include isolated atrial ectopic beats and can progress to nonsustained SVT or even short runs of atrial fibrillation. Ventricular ectopic beats also progress during exercise into bigeminy, couplets, and runs of bidirectional VT. Continuation of exercise may result in faster and more disorganized VT, which could degenerate into VF. During the recovery phase, these arrhythmias gradually diminish.

The hallmark of CPVT is bidirectional ventricular tachycardia, where the beat-to-beat axis rotates 180 degrees each beat (see Figure 63-1). This contrasts with torsades de pointes, where the QRS axis gradually and chaotically rotates around the baseline. However, a small minority of CPVT patients have been noted to show irregular polymorphic VT. The vast majority of the initiating beat of VT has been localized to the RVOT.⁵⁴ The second most common source was the LVOT. The morphology of the initiating beat of bidirectional VT is generally reproducible in 80% of patients with multiple episodes of VT.

In general, CPVT patients have a normal ECG at baseline but may demonstrate prominent U waves and slower resting heart rates. A normal QT interval is useful in distinguishing CPVT from long QT patients. However, some long QT patients exhibit borderline QT prolongation, and a couple of long QT syndromes share CPVT-type phenotypes. Adrenergically triggered bidirectional VT is also seen in long QT-4 (a mutation in the ANK2 gene, which codes for cardiac ankyrin-B) and long QT-7, otherwise known as Andersen-Tawil syndrome (a mutation in KCNJ2, which codes for a potassium channel). LQT-4 is associated with mild QTc prolongation, AF, sinus bradycardia, sinus node dysfunction, and polyphasic U waves. Andersen-Tawil syndrome is characterized by QT prolongation, prominent U waves, facial dysmorphisms, and periodic paralysis. The bidirectional VT rate in Anderson-Tawil syndrome has been reported to be much slower than in CPVT.⁵⁵ Additional features of these syndromes, along with genetic testing, help distinguish them from CPVT.

A definitive diagnosis of CPVT depends on the finding of bidirectional VT in exercise ECG, Holter monitoring, or isoproterenol infusion, with a family or personal history of syncope during exercise or emotional stress.⁵⁵ Infusion of isoproterenol can also be used to elicit the characteristic arrhythmias, although exercise testing is preferred. Monomorphic or polymorphic PVCs are insufficient for a diagnosis of CPVT, and further testing or monitoring is required for a diagnosis.

The main and most effective therapy for CPVT is β-blockade.³⁸ Follow-up exercise testing is advised as a method of assessing the adequacy of β-blocker dosage. Compelling evidence indicates that the addition of flecainide at doses of 150 to 200 mg/day is also effective in suppressing ventricular arrhythmias in CPVT.⁵⁶ Implantation of an ICD is indicated in patients who have survived cardiac arrest and who have ventricular arrhythmias despite maximally tolerated β-blockade. Finally, left cervical sympathetic denervation should be considered for patients in whom β-blockers and ICDs are insufficient.⁵⁷ Patients with CPVT are advised against competitive exercise, high-stress occupations, and substances that would increase sympathetic tone.

Antiarrhythmics and Exercise-Induced Ventricular Arrhythmias

Class I sodium channel blocking antiarrhythmic drugs, such as flecainide and propafenone, can cause ventricular reentry through a use-dependent mechanism. QRS duration increases progressively with increasing levels of exercise while taking flecainide.⁵⁸ A QRS increase of approximately 15% to 20% is consistent with pharmacologic effect; however further increases in QRS duration would warrant dose reduction or discontinuation of the drug. Provocation of ventricular tachycardia, preceded by excessive QRS widening, has been documented on treadmill exercise testing.⁵⁹ Guidelines recommend that the QRS duration should not prolong by more than 50% from baseline and that a QRS duration of <120 ms should be maintained.⁶⁰ To ensure that the QRS duration does not exceed these parameters at higher heart rates, treadmill testing may be employed to determine the degree of maximal QRS prolongation during exercise after the patient is fully loaded with flecainide or propafenone.

Conclusion

Multiple mechanisms have been identified for exercise-induced arrhythmias. We have provided a brief overview of the various causes. Although most of the arrhythmias encountered during exercise are benign, familiarity with the differential diagnosis allows an assessment of prognosis and appropriate treatment. Further pathophysiological and clinical details for each topic are explored in the other chapters of this book.

References