Premature Ventricular Contractions: Reassure Or Refer?

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REVIEW CME EDUCATIONAL OBJECTIVE: Readers will perform the initial assessment and treatment of ventricular contractions, CREDIT referring appropriate patients to a cardiologist BARIS AKDEMIR, MD HIRAD YARMOHAMMADI, MD, MPH M. CHADI ALRAIES, MD, FACP WAYNE O. ADKISSON, MD, FHRS, FACC Cardiovascular Division, Cardiovascular Division, University of Minnesota Cardiovascular Division, Cardiovascular Division, University of Minnesota University of Minnesota Medical School, Minneapolis University of Minnesota Medical School, Medical School, Minneapolis Medical School, Minneapolis Minneapolis

Premature ventricular contractions: Reassure or refer?

ABSTRACT octor, my heart ______.” Fill in the blank D with: skips, flip-flops, hiccups, stops, beats When patients present with palpitations, the primary care in my throat or chest, or any of the various physician can perform the initial evaluation and treat- ways patients describe palpitations. One can- ment for premature ventricular contractions (PVCs). Many not practice clinical medicine and not see pa- patients need only reassurance and do not need to see a tients with some variation of this chief com- cardiologist. plaint.1–3 Not every patient who complains of palpitations will be found to have premature KEY POINTS ventricular contractions (PVCs), but PVCs The focus of the initial evaluation is to determine wheth- are often part of the clinical problem. This review focuses on the initial evalua- er there is underlying structural heart disease. If there is, tion and management of PVCs in the primary early referral to a specialist is probably warranted. care setting (Figure 1). It is not intended to be a comprehensive review of the pathophysi- Idiopathic PVCs (in which there is no structural heart ology, electrophysiology, or localization and disease) have a benign prognosis. ablation of PVCs. We will discuss approaches to the initial therapy of symptomatic PVCs. Treatment of PVCs is indicated for relief of symptoms if We will not discuss catheter-based therapy in reassurance is not sufficient. detail except for which patients might benefit from referral to a clinical cardiac electrophysiologist. Patients who have a high PVC burden (> 10% of total Findings that should prompt consideration heartbeats, though this is a subject of debate) should for referral to a specialist (“red flags”) are sum- have an evaluation of their systolic function. If it is marized at the end of each section. The type of normal at baseline, periodic follow-up echocardiograms specialist depends to a degree on the cardiolo- should be considered. gy practice available to the referring physician. In our practice, such patients are typically seen Patients with a very high burden (> 20%) are at high risk by an electrophysiologist. In other practices, a of arrhythmia-induced cardiomyopathy. In these patients, general cardiologist might see such patients initially. referral is prudent, as some patients may opt for more aggressive treatment of their PVCs. ■■ INITIAL EVALUATION A primary concern of any patient presenting In patients with severe symptoms for whom medical with a new symptom is whether the symptom management has failed, referral for consideration of is a marker of serious risk to health or life. In a catheter ablation is reasonable. patient with palpitations, the answer depends in large part on whether he or she has underlying structural heart disease—and that is the doi:10.3949/ccjm.83a.15090 focus of the initial evaluation.

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Palpitations demonstrated to be due to PVCs

History of heart disease or surgery? Or Evidence of heart disease on examination or testing? Yes No Consider referral Symptoms for evaluation of heart disease and treatment Moderate or severe None or mild of PVCs

Beta-blocker Reassurance or nondihydropyridine calcium channel antagonist

Consider referral No Adequate response? Yes High PVC burden?a for treatment of PVCs Yes

Periodic assessment of left ventricular function

a The definition of “high” is unsettled. For very high PVC burdens (> 20%), referral is reasonable (see text for details).

FIGURE 1. Algorithm for managing premature ventricular complexes (PVCs). Any patient who has a History: Information to ascertain ter? If they occur at rest, does activity make • When did the patient first notice the pal- them better or worse? new symptom pitations? • Are there symptoms of heart failure, such wants to know • Had there been any significant life events, as dyspnea on exertion, early fatigue, decline either illness or emotional stress, at the time in exercise or exertional capacity, orthopnea, whether it is the palpitations began? or paroxysmal nocturnal dyspnea? a marker • Does the patient have a known history of • Are there symptoms suggesting cardiac of serious risk heart disease (myocardial infarction, heart ischemia, such as substernal chest pain or dis- surgery, valvular heart disease, heart failure)? comfort, chest pain or discomfort brought on to health or life • What medications is the patient taking? by or made worse by exertion, or chest pain • Does the patient take any dietary or health relieved with rest or sublingual nitroglycerin? supplements? Ask specifically about any sup- • Have the palpitations ever been associated plements taken to help with weight loss or with syncope? Keep in mind that syncope is increase energy levels. Almost all of them transient loss of consciousness that spontane- contain caffeine or other “natural” sympatho- ously resolves with no features to suggest sei- mimetic agents. Also ask specifically about il- zures.4 Thus, a patient who reports he or she licit drug use. If the patient is accompanied by “blacks out” with the palpitations but never a parent or partner, this question can be chal- falls or slumps has not had loss of conscious- lenging. ness and therefore has not had syncope.5 • When do the palpitations occur? At random? • Is there any history of unexplained death At rest? With exercise? Time of day? In relation in the family, especially in younger people? to the menstrual cycle? (More about this later.) Is there a history of unexplained accidental • Does anything make the palpitations bet- death in young family members?

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Red flags obtained from the history ■■ FURTHER EVALUATION: • Syncope related to palpitations EXTENDED MONITORING • Palpitations triggered by activity or exer- With luck, the patient’s typical palpitations tion will occur during ECG, in which case the • Known significant heart disease, congeni- palpitations can reasonably be attributed to tal heart disease, or history of heart surgery PVCs. If not, monitoring is required to estab- • Family history of premature unexplained lish the cause of the patient’s symptoms. sudden death in a first-degree relative. The type of monitoring to order depends Physical examination on the frequency of the palpitations. If the The physical examination should focus on de- patient reports several episodes per day, then tecting any signs of underlying heart or vascu- a 24- or 48-hour Holter monitor should both lar disease, eg: allow for a diagnosis and document the PVC • Significant murmurs burden (ie, the percent of the patient’s heart- • Abnormal S3 or S4 beats that are PVCs), or the burden of what- • Displaced and diffuse point of maximal im- ever is the cause of the patient’s palpitations. pulse or precordial heave If the palpitations are less frequent, a • Signs of right or left heart failure, or both, 14-to-30-day monitor should be considered. A eg, peripheral edema, elevation of jugular standard event recorder can confirm that the venous pulse, rales, S3, S4. palpitations are due to PVCs but does not tell you the PVC burden. For that, a system ca- Electrocardiography pable of mobile outpatient cardiac telemetry We consider 12-lead electrocardiography is needed. Several such systems are commer- (ECG) a part of the initial examination and cially available. assessment, not an ancillary test. One cannot A Holter monitor or other monitoring evaluate a patient’s complaint of palpitations system is useful in determining whether the without ECG. Ideally, ECG should include PVCs are unifocal (all look the same) or mul- In a patient a long 12-lead rhythm strip. The clinician tifocal (have more than one morphology) and should look for any evidence of underlying whether, in addition to PVCs, the patient has with structural heart disease, eg: nonsustained ventricular tachycardia or sus- palpitations, • Pathologic Q waves tained ventricular tachycardia (by definition 12-lead ECG • Long QT interval lasting longer than 30 seconds or associated • ST-segment elevation in leads V1 and V2 with symptoms of hemodynamic compromise is part of consistent with a Brugada pattern such as near-syncope). Even if the patient has the initial • Epsilon waves (seen in right ventricular ar- nonsustained ventricular tachycardia, if the rhythmogenic cardiomyopathy). heart is structurally normal the prognosis re- assessment, Examples of the above can be found at mains excellent. not ancillary sites such as ecgpedia.org. Given the importance of knowing wheth- testing er the patient has structural heart disease, we Red flags in the physical examination have a low threshold for ordering echocar- and ECG diography, especially if nonsustained ventric- Any of the above findings on physical exami- ular tachycardia has been documented. The nation or ECG should prompt consideration finding of significant systolic dysfunction on of early referral, even though we have yet echocardiography should prompt a cardiology to establish that the palpitations are due to consultation even if the physical examination PVCs. Early consultation is suggested not for is normal. In patients who have a high PVC treatment of the palpitations but for further burden, echocardiography is used to monitor evaluation of structural heart disease. for arrhythmia-induced cardiomyopathy.6 Assuming the history, physical examina- If the patient’s symptoms occur with activ- tion, and electrocardiography do not demon- ity, an exercise study can be helpful. It is impor- strate any reasons for early cardiology or elec- tant to either supervise the study oneself or, at trophysiology consultation, what’s next? the least, alert the exercise laboratory staff that

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the study is being performed to evaluate for ceived increase in palpitations is in fact due to exercise-induced arrhythmias. If the exercise an increase in the number of PVCs.10 study induces sustained ventricular tachycar- If the patient’s PVCs have not been cap- dia, the patient is almost invariably admitted tured on 12-lead ECG (ie, if it is not seen in to the hospital and inpatient consultation with all 12 leads), 12-lead Holter monitoring, if an electrophysiologist is obtained. available, can be helpful. Examination of the morphology of the PVC on 12-lead ECG is Red flags on extended monitoring extremely helpful. Outflow tract PVCs are the • Multifocal PVCs or nonsustained ventric- most common cause of idiopathic PVCs and ular tachycardia nonsustained ventricular tachycardia and are • Polymorphic nonsustained ventricular easily recognizable with 12-lead ECG. tachycardia • Sustained ventricular tachycardia; this still ECG points to the origin of the PVCs may be idiopathic and have a benign prog- A PVC arising on the right side of the heart nosis but generally should prompt referral. will activate the right ventricle first and then If at this point no red flags have been un- the left ventricle. This is analogous to the se- covered, monitoring has established the pa- quence of ventricular activation in a patient tient’s symptoms are due to PVCs, and our with left bundle-branch block. Not surprising- examination and ancillary testing have estab- ly, on ECG a right-sided PVC looks similar to lished the patient has a structurally normal the QRS complex seen in left bundle-branch heart, what is the next step? block—similar, but not identical. When describing PVCs or the morphol- ■■ IDIOPATHIC PVCs ogy of nonsustained ventricular tachycardia, PVCs in a patient with a structurally normal the terms “left bundle-branch block pattern” heart are called “idiopathic.” Often, these pa- and “right bundle-branch block pattern” refer tients will also be found to have nonsustained to lead V1. If the PVC is negative (or mostly ventricular tachycardia, and may also be clas- negative) in V1, the PVC has a left bundle- sified as having “idiopathic ventricular tachy- branch block pattern. A PVC that is positive A PVC arising in V is said to have a right bundle-branch cardia.” Regardless of whether the patient has 1 on the right PVCs, nonsustained ventricular tachycardia, block pattern and by implication arises from or both, the management approach is the the left side of the heart. side of the same. A PVC originating from the top of the heart heart activates Roughly 60% to 80% of idiopathic PVCs will move from top to bottom. The electrical originate from the right ventricle, in particu- axis of the PVC will be directed inferiorly. This the right lar the right ventricular outflow tract.7 Pa- means the PVC will be strongly positive in the ventricle first inferior leads, ie, II, aVF, and III. tients with outflow tract PVCs typically pres- and then the ent between the ages of 30 and 50 but range The electrocardiogram shown in Figure 2 from adolescents to elders. More women than demonstrates the typical appearance of a right left ventricle men are affected. ventricular outflow tract PVC. Outflow tract PVCs often occur only, or If the PVC arises from the left ventricular at much greater frequency, within a range outflow tract, the axis will still be inferiorly of heart rates.8 Individual patients may have directed. However, the further to the left the different ranges of heart rates at which their origin of the PVC, the earlier the precordial PVCs are more frequent. Patients may com- transition will occur (the point at which the plain that their palpitations are more frequent PVC is more positive than negative in the at rest, early in exercise, at a peak of exercise, precordial leads). A PVC origin far enough or early in recovery from exercise. It is not to the left will result in a right bundle-branch unusual for patients with outflow tract PVCs block pattern PVC. to report that activity reduces the frequency Not all idiopathic PVCs arise from the of their palpitations. Women might note an outflow tracts. A right bundle branch block increase in their symptoms during menstrua- pattern PVC does not imply the presence of tion.9 It is not clear, however, that this per- underlying structural heart disease. PVCs may

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FIGURE 2. Typical configuration of right outflow tract premature ventricular complexes (PVCs) in the 12-lead electrocardiogram. The PVCs exhibit a tall R wave in the inferior leads (arrows) and a left bundle-branch block pattern. arise from both the tricuspid and mitral valve right ventricular size and function is reassur- annuli, the left ventricular fascicles, or from ing, and if echocardiography is not conclusive, the epicardium. cardiovascular magnetic resonance imaging Multiple methods have been proposed to may provide additional diagnostic and prog- locate the origin of the PVC. For example, nostic data, especially when arrhythmogenic What Park et al reviewed the use of surface ECG in cardiomyopathy, cardiac sarcoidosis, or car- 6 constitutes locating the site of origin of ventricular tachy- diac amyloidosis is suspected. cardia.11 All such algorithms should be applied Recently, magnetic resonance imaging a ‘high’ PVC with care, and with awareness of the caveats has been used most for infiltrative diseases burden remains associated with their use. as the imaging modality of choice due to its superior tissue characterization and noninva- a matter Arrhythmogenic right ventricular sive morphological and functional evaluation. of debate cardiomyopathy is not benign Magnetic resonance imaging findings in pa- Arrhythmogenic right ventricular cardiomy- tients with arrhythmogenic cardiomyopathy opathy may give rise to PVCs or nonsustained correlate well with those of endomyocardial ventricular tachycardia with morphologies biopsy, angiography, and echocardiography similar to those of right ventricular outflow and have been associated with incremental tract PVCs and ventricular tachycardia. The arrhythmic risk in the setting of electrical ab- ventricular tachycardia complicating arrhyth- normalities. The increasing use of magnetic mogenic cardiomyopathy is, like PVCs arising resonance imaging is leading to the recogni- from the right ventricular outflow tract, com- tion that left ventricular involvement (left- monly associated with exercise or activity. dominant arrhythmogenic right ventricular Unlike right ventricular outflow tract cardiomyopathy) is more common than pre- tachycardia, ventricular tachycardia related viously recognized, with some suggesting that to arrhythmogenic cardiomyopathy is not be- arrhythmogenic right ventricular cardiomyop- nign.12 Distinguishing right ventricular out- athy should be simply called “arrhythmogenic flow tract tachycardia from tachycardia sec- cardiomyopathy.” ondary to arrhythmogenic cardiomyopathy is Although endomyocardial biopsy can es- therefore critical. tablish the diagnosis of arrhythmogenic right Good-quality ECG demonstrating normal ventricular cardiomyopathy, it is rarely per-

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formed because it has a high false-negative What is rare? There is no defined standard, rate owing to the patchy, epicardial nature of but a PVC burden less than 1% is reasonable. this disorder.13 Treatment of the PVCs may be indicated in patients with systolic heart failure receiving Red flags for cardiomyopathy cardiac resynchronization therapy, ie, a biven- • Multifocal PVCs, or nonsustained ventricular pacemaker. For cardiac resynchroniza- tricular tachycardia of more than one mor- tion therapy to be clinically beneficial, close phology on monitoring to 100% of heartbeats need to be paced, and • Syncope associated with active exercise frequent PVCs, even at a burden less than • Abnormal imaging findings that are con- 10%, may undermine its effectiveness.16 sistent with arrhythmogenic right ventricular cardiomyopathy, cardiac sarcoidosis, ■■ HOW TO INTERVENE? or amyloidosis. Beta-blockers and nondihydropyridine cal- ■■ WHEN TO TREAT IDIOPATHIC PVCs cium channel blockers have both been used to treat symptomatic PVCs. If the patient is In our practice we explain to patients that there are two primary indications for treating found to have systolic dysfunction as part of idiopathic PVCs: (1) to relieve symptoms or the evaluation, a beta-blocker is indicated, (2) in asymptomatic patients with presumed irrespective of any desire to treat the PVCs. arrhythmia-induced cardiomyopathy, to try Beta-blockers and calcium channel blockers to reverse the cardiomyopathy by eliminating both have low adverse effect profiles. They are the PVCs. available in once-a-day formulations and are Some patients report severe symptoms due inexpensive. Their efficacy is variable. The to their PVCs. Other patients appear to have use of these medications is well within the no symptoms whatsoever, while still others purview of the primary care physician. are not overly bothered by the PVCs but are Selective beta-blockers are the first choice concerned that they may indicate they are at in treatment, and metoprolol is commonly increased risk of cardiac events. In this last used in clinical practice. We start with a low No drugs are dose and increase it based on symptom relief. group, an evaluation such as outlined above approved that discloses no evidence of structural heart As noted, only nondihydropyridine calci- disease and reassurance by the physician may um channel blockers should be used for treat- for treating be all the treatment needed. ment of PVCs. As with beta-blockers, we start PVCs or Even if they have no symptoms or only at a low dose and increase as needed based on minimal symptoms, patients with a high the response to therapy. nonsustained PVC burden require follow-up because of the Antiarrhythymic drugs are classified ac- ventricular cording to the Vaughan-Williams system. The association between frequent PVCs and ar- tachycardia rhythmia-induced cardiomyopathy.14,15 What ones most frequently used for PVCs are the constitutes a “high” PVC burden remains a class Ic drugs propafenone and flecainide and matter of debate. Left ventricular dysfunc- the class III drugs sotalol, amiodarone, and tion has generally been reported at PVC bur- dofetalide. However, in our experience, if first- dens above 15% to 25% of the total cardiac line agents (ie, beta-blockers and nondihydro- beats, though this percentage can be as low as pyridine calcium channel blockers) are unsuc- 10%.14 cessful in controlling the patient’s symptoms, Eliminating the high burden of PVCs in most primary care physicians are uncomfort- patients with left ventricular dysfunction may able prescribing class Ic and class III drugs. significantly improve left ventricular systolic Failure of a beta-blocker, a calcium channel function.15 It is likely, however, that more blocker, or both often results in referral to a than PVC burden alone contributes to the de- cardiologist or electrophysiologist. velopment of the cardiomyopathy.14 The consultation should include a careful Given these complexities, it is reasonable discussion with the patient regarding the risk to request an electrophysiology consultation of treatment with a type I or a type III drug for patients who have more than rare PVCs. vs catheter ablation. Treatment with class I

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or class III antiarrhythmic drugs always en- of ventricular arrhythmias are labeled as being tails a small risk of proarrhythmia. The choice indicated for “sustained” or “life-threatening” between drug therapy or ablation therapy is ventricular arrhythmias. The use of drugs for highly individualized. However, if elimination the treatment of PVCs or nonsustained ven- of the PVCs is of paramount importance, such tricular tachycardia represents off-label usage. as in cases of arrhythmia-induced cardiomy- Referral to discuss catheter ablation of the opathy, ablation therapy is more effective at PVCs6 should be considered for patients who: eliminating the PVCs, although at the cost of • Have undergone unsuccessful attempts at an invasive procedure. Fortunately, the risk of drug therapy for either symptoms or PVC- complications with ablation therapy is quite related cardiomyopathy low. • Refuse drug therapy but have severe symp- No drugs are approved by the US Food toms, or and Drug Administration for treating PVCs • Do not respond to cardiac resynchroniza- or nonsustained ventricular tachycardia. The tion therapy due to suboptimal pacing due drugs that do have an indication for treatment to PVCs. ■

■■ REFERENCES 9. Marchlinski FE, Deely MP, Zado ES. Sex-specific triggers 1. Kennedy HL, Underhill SJ. Frequent or complex ventricu- for right ventricular outflow tract tachycardia. Am Heart lar ectopy in apparently healthy subjects: a clinical study J 2000; 139:1009–1013. of 25 cases. Am J Cardiol 1976; 38:141–148. 10. Fuenmayor AJ, Araujo X, Fuenmayor AM. Cardiac ar- 2. Brodsky M, Wu D, Denes P, Kanakis C, Rosen KM. Ar- rhythmias during two different stages of the menstrual rhythmias documented by 24 hour continuous electro- cycle. Int J Cardiol 1998; 63:267–270. 11. Park KM, Kim YH, Marchlinski FE. Using the surface cardiographic monitoring in 50 male medical students electrocardiogram to localize the origin of idiopathic without apparent heart disease. Am J Cardiol 1977; ventricular tachycardia. Pacing Clin Electrophysiol 2012; 39:390–395. 35:1516–1527. 3. Sobotka PA, Mayer JH, Bauernfeind RA, Kanakis C Jr, 12. Te Riele AS, Hauer RN. Arrhythmogenic right ventricu- Rosen KM. Arrhythmias documented by 24-hour continu- lar dysplasia/cardiomyopathy: clinical challenges in a ous ambulatory electrocardiographic monitoring in changing disease spectrum. Trends Cardiovasc Med 2015; young women without apparent heart disease. Am Heart 25:191–198. J 1981; 101:753–759. 13. Philips B, Cheng A. 2015 update on the diagnosis and 4. Sheldon RS, Grubb BP 2nd, Olshansky B, et al. 2015 management of arrhythmogenic right ventricular cardio- Heart Rhythm Society expert consensus statement on myopathy. Curr Opin Cardiol 2016; 31:46–56. the diagnosis and treatment of postural tachycardia syn- 14. Del Carpio Munoz F, Syed FF, Noheria A, et al. Character- drome, inappropriate sinus tachycardia, and vasovagal istics of premature ventricular complexes as correlates syncope. Heart Rhythm 2015;12:e41–e63. of reduced left ventricular systolic function: study of the 5. Benditt DG, Adkisson WO. Approach to the patient with burden, duration, coupling interval, morphology and syncope: venues, presentations, diagnoses. Cardiol Clin site of origin of PVCs. J Cardiovasc Electrophysiol 2011; 2013; 31:9–25. 22:791–798. 6. Pedersen CT, Kay GN, Kalman J, et al. EHRA/HRS/APHRS 15. Yarlagadda RK, Iwai S, Stein KM, et al. Reversal of car- expert consensus on ventricular arrhythmias. Heart diomyopathy in patients with repetitive monomorphic Rhythm 2014; 11:e166–e196. ventricular ectopy originating from the right ventricular 7. Iwai S, Cantillon DJ, Kim RJ, et al. Right and left ventricu- outflow tract. Circulation 2005; 112:1092–1097. lar outflow tract tachycardias: evidence for a common 16. Zhang Q, Zhou Y, Yu CM. Incidence, definition, diagnosis, electrophysiologic mechanism. Cardiovasc Electrophysiol and management of the cardiac resynchronization 2006; 17:1052–1058. therapy nonresponder. Curr Opin Cardiol 2015; 30:40–49. 8. Buxton AE, Waxman HL, Marchlinski FE, Simson MB, Cassidy D, Josephson ME. Right ventricular tachycardia: ADDRESS: Baris Akdemir MD, Cardiovascular Division, clinical and electrophysiologic characteristics. Circulation University of Minnesota Medical School, Mail Code 508, 420 1983; 68:917–927. Delaware St SE, Minneapolis, MN 55455; [email protected]

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