Review Article
Frequent Premature Ventricular Contractions An Electrical Link to Cardiomyopathy Paul L. Eugenio, MD
Abstract: Heart failure is common and is associated with significant morbidity and mortality. Identifying potentially modifiable risk factors for the development of ventricular dysfunction is important in both the prevention and the treatment of this condition. Arrhythmia disorders are increasingly recognized as contributory to the development of ventricular failure. Poorly controlled supraventricular tachyarrhythmias, altered left ventricular activation due to left bundle branch block or right ventricular pacing, and frequent premature ventricular contractions (PVCs) constitute the main subtypes of arrhythmia disorders that are associated with the development of ventricular dysfunction. PVCs are common and are considered benign in the absence of structural heart disease. Frequent PVCs, defined as greater than 20% of all QRS complexes on standard 24-hour Holter monitoring, are associated with the presence or subsequent development of left ventricular dilatation and dysfunction. Catheter ablation of frequent PVCs has been demonstrated to be effective at PVC suppression and is associated with improvement or normalization of ventricular function; thus defining a specific, reversible form of ventricular dysfunction termed PVC cardiomyopathy. In patients presenting with high burden PVCs, an assessment for symptoms and associated cardiomyopathy is warranted and, in the appropriate clinical setting, PVC catheter ablation may be a reasonable treatment option. Key Words: premature ventricular contractions, PVC cardiomyopathy, PVC ablation (Cardiology in Review 2015;23: 168–172)
H
eart failure (HF) is a common condition. From an epidemiological perspective, the diagnosis of HF has demonstrated a perpetual increase in annual prevalence due in large part to therapeutic advances that reduce mortality, and thereby enhance longevity of an ever-aging population. Despite these advances, HF remains a diagnosis that negatively impacts the quality and quantity of life while progressively burdening the economics of health care.
HF—EPIDEMIOLOGY HF generates formidable health care statistics.1,2 Nationally, the prevalence is approximately 5.1 million with 650,000 new cases diagnosed annually. Incidence increases with age. Among those aged 60–65 years, the incidence is 20 of 1000 persons per year. The incidence increases fourfold among those aged >85 years. The mortality associated with HF is substantial with an overall 5-year mortality rate of 50%. The strongest risk factor driving this poor prognosis is the presence and severity of clinical symptoms. Indeed, among those with an American College of Cardiology Foundation/American Heart Association Stage B profile, 5-year survival is 96% compared Division of Cardiology, Westchester Medical Center, Valhalla, NY. Disclosure: The authors have no conflicts of interest to report. Correspondence: Paul L Eugenio, MD, Division of Cardiology, Westchester Medical Center, Macy Pavilion, 100 Woods Road, Valhalla, NY 10595. E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 1061-5377/15/2304-0168 DOI: 10.1097/CRD.0000000000000063
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with Stage D at 20%. The cost of the disease upon the health care system is equally formidable. Annually, in the United States, there are approximately 1 million hospital admissions with an early readmission rate of 25%. The annual cost is estimated at $30 billion. There are numerous risk factors for the subsequent development of HF. Hypertension deserves special mention as the largest modifiable risk factor.2 Identification of such modifiable risk factors is important at a population-based level as interventions that positively alter such risk factors may profoundly impact the subsequent development of disease.
ARRHYTHMIA DISORDERS AS A RISK FACTOR FOR VENTRICULAR DYSFUNCTION Arrhythmia disorders have been increasingly recognized as a potentially modifiable risk factor for the subsequent development of ventricular dysfunction and, as a consequence, clinical HF. Table 1 summarizes the main subtypes. Tachyarrhythmias are the most well described. The classic example is the permanent junctional reciprocating tachycardia (PJRT), a particular subclassification of supraventricular tachycardia more commonly diagnosed in the pediatric population. This arrhythmia utilizes a slowly conducting posteroseptal accessory pathway and is characteristically associated with a high daily burden of tachycardia. Patients with PJRT are at risk of tachycardia-mediated ventricular dysfunction. A recently published retrospective case series of patients with PJRT reported left ventricular (LV) dysfunction in 18% of cases.3 The mechanism of this arrhythmia, utilizing an accessory pathway, renders it highly amenable to curative catheter ablation and expectant improvement or normalization of ventricular function after restoration of durable sinus rhythm. The recognition that poorly controlled tachyarrhythmias can directly result in ventricular dysfunction is the basis for the diagnosis of tachycardia-induced cardiomyopathy. Any poorly controlled tachyarrhythmia can cause tachycardia-induced cardiomyopathy including various subtypes of supraventricular tachycardia, atrial flutter, and importantly given its high prevalence, atrial fibrillation. Altered LV activation, in the form of right ventricular pacing or left bundle branch block, is associated with a decline in LV performance.4,5 Altered LV activation may be the primary causative process or may exacerbate a separate underlying cardiomyopathy. Dyssynchronous LV activation can cause a myopathic process because of a number of hypothesized mechanisms including altered sarcomeric protein expression, abnormal ion channel expression, abnormalities in regional myocardial blood flow, and changes in local myocardial sympathetic tone.6,7 Cardiac resynchronization therapy is an effective treatment for cardiomyopathy in the setting of altered LV activation and in selected patients can improve LV function and reduce morbidity and mortality.8–12
PREMATURE VENTRICULAR CONTRACTIONS Premature ventricular contractions (PVCs) are common and seen routinely in everyday clinical practice. PVCs are the electrocardiographic manifestation of independent, focal depolarization of a discrete region of ventricular myocardium due most often to enhanced automaticity or triggered activity. Such ectopic impulses can originate Cardiology in Review • Volume 23, Number 4, July/August 2015
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Cardiology in Review • Volume 23, Number 4, July/August 2015
TABLE 1. Arrhythmia Disorders Associated With the Development of Ventricular Dysfunction Condition Untreated/under-treated tachyarrhythmias Altered left ventricular activation Frequent premature ventricular contractions
Comment Supraventricular tachycardia, atrial flutter, atrial fibrillation Right ventricular pacing, left bundle branch block >20% daily burden
from any site within the ventricular myocardium though more commonly are noted to arise from zones of anatomic transition (perivalvular in the vicinity of the right and left ventricular outflow tracts or the perimitral/tricuspid regions, papillary muscles, within or near the specialized conduction system or in border zones of myocardial scar). PVCs may be a stand-alone entity without structural heart disease or can coexist with various concomitant cardiac disease states including ischemic myocardial disease, valvular heart disease, and ischemic and nonischemic forms of cardiomyopathy with or without manifest HF. PVCs are seen in 40% of 24-hour ambulatory electrocardiogram (ECG) recordings and in 75% of 48-hour recordings among the general population referred for ambulatory ECG monitoring.6 Prevalence increases with age with less than 1% of ambulatory ECG recordings demonstrating PVCs in those younger than 11 years of age compared with more than 69% in those aged older than 75 years.6 Data from the Framingham Heart Study suggest that complex or frequent ventricular ectopy, defined as more than 30 PVCs per hour or PVCs of multiple morphologies, confer a 2.3-fold increase in the relative risk of all cause mortality; this association was, however, limited to men without clinically evident coronary artery disease.13 Clinical evidence suggests that frequent PVCs (variably defined in the literature) are more strongly associated with concomitant cardiac disease. The Framingham study illustrated this association by demonstrating that frequent ventricular ectopy (defined as >30 PVCs per hour) or complex ventricular ectopy (multiple PVC morphologies) was more strongly associated with presence of clinically evident coronary artery disease in both men and women.13
Frequent PVCs and Ventricular Dysfunction More recent literature further supports the link between structural heart disease and frequent ventricular ectopy. A study by Baman et al14 evaluated a group of patients referred for PVC ablation. Among this cohort, patients with baseline LV systolic dysfunction demonstrated an average PVC daily burden of 33% ± 13% compared with 13% ± 12% among those with a preserved LV ejection fraction (LVEF), P < 0.001, suggesting that a high PVC burden is correlated with the presence of a myopathic ventricle. Niwano et al published results on a prospective cohort study following a group of patients with frequent PVCs (defined as >1000 per 24-hour period) and normal baseline LV systolic function followed over a period of more than 4 years. This cohort, at baseline, demonstrated preserved LV systolic function. A high ventricular ectopic burden (>20,000 PVCs per 24-hour period) was correlated with the subsequent development of LV dilatation and a decrement in LV systolic function over a 4–5.6-year follow-up period.15 This prospective study suggests that frequent PVCs may not only be associated with the presence of a cardiomyopathy but may have a direct deleterious effect on LV performance, thus giving rise to the term PVC-mediated cardiomyopathy. Animal data further support this notion. Huizar et al published an elegant study in 2011 involving a canine model of PVC-mediated cardiomyopathy. Thirteen dogs with baseline normal LV function were implanted with a pacemaker and randomized to deliver single © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Frequent Premature Ventricular Contractions
ventricular paced beats following each intrinsically conducted sinus beat (mimicking spontaneous ventricular bigeminy) or no pacing. The dogs were followed for 12 weeks. Twenty-four-hour PVC burden was, as expected, approximately 50% in the pacing arm. At follow-up, average LV systolic function in the pacing group was significantly lower compared with the nonpaced group (39.7% ± 5.4% vs 60.7% ± 3.8%, P < 0.0001). Within the paced group, ventricular function normalized 4 weeks after discontinuation of the pacing protocol. Of interest, histopathologic examination of sampled myocardium from dogs in the paced group who demonstrated a decrement in LV systolic function revealed no evidence of myocardial fibrosis, apoptosis, or mitochondrial abnormalities.16 Though frequent PVCs may correlate to a decline in LV function, the common nature with which PVCs are seen in clinical practice gives rise to important clinical queries: is there a threshold PVC burden that is more closely associated with the ultimate development of cardiomyopathy? In addition, are there clinical characteristics attributable to the PVC that may identify individuals who are more likely to demonstrate LV dysfunction? Such information would be useful in clinical practice for the initial evaluation and prospective follow-up of patients referred for frequent ventricular ectopy. The previously referenced study by Baman et al14 studying a cohort of patients referred for PVC ablation suggests that a cutoff PVC burden of 24%, as assessed by 24-hour ambulatory ECG monitoring before ablation, best differentiated those patients with concomitant LV dysfunction from those with preserved function with a sensitivity of 79% and a specificity of 78%. Furthermore, the study by Niwano et al15 suggested that the correlation between PVC burden and subsequent decline in LV systolic function was limited to patients who demonstrated a high daily PVC burden defined as greater than 20,000 PVCs per 24-hour period (20% daily PVC burden based on an average heart rate of 70 beats per minute). On the basis of available clinical data, it would seem prudent to consider a 24-hour PVC burden of greater than 20% as more strongly associated with the presence or subsequent development of LV dysfunction, thus identifying a subgroup of patients who, at a minimum, require closer surveillance.
PVC Characteristics and Risk of Cardiomyopathy Among patients with frequent PVCs, other characteristics attributable to the PVC may correlate with the risk of developing LV dysfunction. A study by Yokokawa et al assessed the relationship between PVC QRS duration and the presence of concomitant reversible LV dysfunction. Wide PVC QRS duration more than 150 ms was independently associated with the presence of a cardiomyopathy that was often reversible with catheter ablation.17 This was further supported by a study from Carballeira-Pol et al18 whereby a PVC QRS duration more than 153 ms best predicted patients with baseline frequent PVCs who would ultimately develop LV dysfunction. Of interest in this study was the observation that patients with frequent PVCs who ultimately develop LV dysfunction also manifest a wider QRS duration in sinus rhythm, suggesting intrinsic myocyte uncoupling and intramyocardial fibrosis. This suggests a possible multicomponent mechanism underpinning PVC cardiomyopathy whereby a smoldering intrinsic myopathic process combined with PVC-mediated dyssynchrony combines synergistically to generate the PVC cardiomyopathy phenotype. This hypothesis suggests that there may be a “point of no return” with respect to the extent of the abnormal myocardial substrate and frequent ventricular complexes. A study by Deyell et al assessed a population of patients with frequent PVCs and baseline LV dysfunction who underwent PVC catheter ablation. A “very-wide” PVC QRS duration of > 173 ms, suggesting more diffuse and widespread myocardial disease, identified a subgroup of www.cardiologyinreview.com | 169
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patients more likely to demonstrate persistent LV dysfunction despite successful PVC ablation.19 The PVC coupling interval has been variably reported to correlate with LV dysfunction. A study by Sun et al.20 reported that, in a pediatric population, a PVC coupling interval of less than 600 ms was associated with a mean lower LVEF compared with a coupling interval more than 600 ms. Other studies have not corroborated these findings.21 It is plausible that closely coupled, high burden PVCs more closely mimic poorly controlled atrial tachyarrhythmias. In addition, the post-PVC “pause” often seen in ventricular bigeminal rhythms may, at a cellular level, lead to postextrasystolic elevated intracellular calcium and increased myocardial oxygen demand. This derangement, over time, may be deleterious to ventricular function.16
Anatomic Origin of PVCs In addition to Holter monitoring to assess overall PVC burden, the 12-lead ECG is essential in the initial assessment and ultimate counseling of patients who are considered for an ablative approach. Ectopic impulses can originate from any location within the myocardium, though, as is a common theme in therapeutic electrophysiology, more often originate from sites of anatomic transition. The most well-studied site in this regard over the past decade has been the sleeves of myocardial fascicles at the pulmonary vein–left atrial junction in the initiation of paroxysmal atrial fibrillation. In the ventricle, ectopic impulse formation in the form of isolated ectopy (PVCs) or repetitive impulse formation (idiopathic ventricular tachycardia) are also frequently encountered at zones of anatomic transition. The “usual suspects” with regard to common sites of origin are the right and left ventricular outflow tracts (often in close proximity to the pulmonic and aortic valve cusps). Indeed, these sites represent the site of origin of idiopathic PVCs in two-thirds of patients referred for PVC ablation.21 Other sites within the ventricles include the periatrioventricular valvular regions (peritricuspid, perimitral), intracavitary structures (papillary muscles), the specialized conduction system (His-Purkinje tissue), and certain epicardial sites (in the vicinity of the epicardial venous system). The surface ECG can provide insight as to the site of origin with a reasonable degree of accuracy. In general terms, left bundle branch-like morphology in precordial leads V1 and V2 together with an inferior frontal plane axis identify sites of origin from the right or left ventricular outflow tracts—the most common site with respect to idiopathic PVCs. Morphology, as previously highlighted, can also provide insight into the myocardial substrate. PVCs demonstrating a wide QRS duration (>150 ms) along with slurring and notching of the initial QRS deflection may indicate either an epicardial site of origin or myocyte uncoupling and interstitial fibrosis suggesting a baseline cardiomyopathic process. The conducted QRS complex (ie, non-PVC complexes) may add additional information with respect to baseline His-Purkinje disease (right or left bundle branch block), prior infarct (pathologic Q waves) or ventricular hypertrophy (prominent QRS voltage and secondary repolarization abnormalities). Such information is clinically useful in assessing the status of underlying heart disease and planning an ablative approach.
Etiology of PVCs and Pathophysiologic Link to LV Dysfunction The etiology of PVCs, at a fundamental level, is not known beyond the observation that PVCs represent abnormal impulse formation from the ventricular myocardium. In general, abnormal impulse formation arises from (1) increased intrinsic automaticity, (2) triggered activity due to afterpotentials, and (3) reentry.22 The clinical observation that PVCs or idiopathic forms of ventricular tachycardia often originate from “zones of myocardial transition,” such as the ventricular outflow tracts, suggest that there may be an 170 | www.cardiologyinreview.com
anatomic-physiologic link whereby zones of fiber disruption are more likely to exhibit abnormal impulse formation. How frequent PVCs may be deleterious to ventricular function is also not understood. It would seem plausible that frequent, closely coupled PVCs, exceeding 20% of all ventricular systoles, would mimic a poorly controlled atrial tachyarrhythmia. Furthermore, the pattern of myocardial contraction in response to a PVC is dyssynchronous and similar to left bundle branch block or ventricular pacing. Thus, the combination of high burden, closely coupled PVCs with resultant dyssynchronous myocardial contraction does provide an empiric link to the ultimate deleterious effects on ventricular function. Speculative cellular mechanisms linking frequent PVCs to ventricular dysfunction include asymmetric hypertrophy in late activated regions of the ventricle, altered myocardial oxygen consumption, altered regional myocardial blood flow, altered sarcomeric protein expression leading to myofibrillar disarray, altered ion channel expression, and changes in myocardial autonomic tone.6
The Patient With Frequent PVCs—Clinical Evaluation The clinical evaluation of a patient referred for frequent PVCs is centered on the history, physical exam, standard 12 lead ECG, 24-hour Holter, resting transthoracic echocardiogram and, as necessary, stress testing and/or advanced cardiac imaging. History taking is of paramount importance. Patients may present with palpitations (especially at night when lying supine), fatigue, lightheadedness, neck fullness due to loss of AV synchrony, exertional intolerance, dyspnea, or chest pain. If concomitant ventricular dysfunction is present, symptoms of HF may be evident. Commonly, patients will present with no symptoms, with ectopy detected by an irregular pulse or prior ECG obtained for other clinical reasons. Establishing that the PVCs are symptomatic is important with regard to clinical decision making when considering a therapeutic approach of PVC suppression. A family history should be obtained to assess for such entities as early onset coronary artery disease, inherited cardiomyopathies and sudden cardiac death. Physical examination is often normal though may be notable for an irregular pulse, intermittent cannon “a” waves on jugular venous examination, or classic findings of a failing ventricle (jugular venous distension, displaced point of maximum impulse, S3 gallop). As previously stated, close inspection of the 12 lead ECG is important to establish the baseline rhythm, assess diagnostic criteria for His-Purkinje disease, hypertrophy, prior infarct, or classic morphologic changes of less common processes, such as arrhythmogenic right ventricular cardiomyopathy (ARVC). A signal averaged ECG, though of limited utility, can be considered in the evaluation of suspected ARVC. It is extremely helpful to capture the “suspect” PVC on the 12 lead ECG examination as this will aid in localization of the site of origin—invaluable when considering an ablative strategy. Ambulatory ECG monitoring in the format of 24-hour (or more extended) Holter monitoring provides such data as PVC pleomorphism (ie, number of dominant PVC morphologies), burden as assessed by percentage of all QRS complexes during a 24-hour monitoring period, format of ectopy (predominantly single PVCs vs periods of nonsustained ventricular tachycardia), PVC behavior with exertion versus rest, and associated symptoms. Laboratory analysis is most commonly unrevealing, though basic assessments of blood counts, chemistries, and renal, hepatic, and thyroid function are indicated. In the appropriate clinical context, measurement of b-type natriuretic peptide may provide insight into the neurohormonal status of a patient with a history and exam consistent with clinical HF. Cardiac imaging, most commonly transthoracic echocardiography, provides important structural information. Of particular importance in the evaluation of patients with frequent PVCs includes © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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LV end diastolic dimension/volume, global left and right ventricular systolic function, regional LV wall motion abnormalities, ventricular hypertrophy, valvular heart disease, and estimated pulmonary artery systolic pressure. Exercise stress testing is helpful in assessing for myocardial ischemia in the appropriate clinical context, though is also useful in evaluating the behavior of the ectopy to elevated sympathetic tone. PVCs may be suppressed with exercise or, conversely, may be more prevalent, even manifesting as frank ventricular tachycardia; such a response may be helpful in planning an ablative strategy. Advanced cardiac imaging, most commonly cardiac magnetic resonance imaging, should be pursued when there is a clinical suspicion of a myopathic process not easily accessed by echocardiography (ARVC, cardiac sarcoidosis, apical variant hypertrophy, ventricular noncompaction, and amyloidosis).
Frequent PVCs—When and How to Treat The decision to treat frequent PVCs, either pharmacologically or via catheter ablation, should be predicated on two factors: symptoms and associated LV dysfunction. As a general rule, PVCs are considered a benign condition in the absence of concomitant structural heart disease or myocardial ischemia. Indeed, the previously referenced study by Niwano et al15 following a cohort of 239 patients with frequent PVCs in the absence of structural heart disease demonstrated no adverse cardiac events during the entirety of the follow up period (4–5.6 years). Frequent PVCs are often asymptomatic though, conversely, may be associated with significant clinical symptoms (palpitations, lightheadedness, dyspnea, chest discomfort, effort intolerance). In addition, patients with frequent PVCs can demonstrate a diminished quality of life based on standardized testing that improves after treatment via catheter ablation.23 Thus, establishing symptoms that correlate to ventricular ectopy is important when considering suppressive therapy. A second factor to consider is the status of ventricular function. As has been previously described, high burden ventricular ectopy (>20% burden as assessed by 24 hour Holter monitoring) is associated with the presence of LV dilatation and dysfunction. If LV dysfunction or LV remodeling (ie, LV dilatation) is demonstrated, primary PVC cardiomyopathy or PVC “aggravated” preexisting cardiomyopathy should be considered as should suppressive therapy, including catheter ablation. Suppressive therapy for frequent PVCs includes either a pharmacologic or ablative approach. Duffee et al. first described successful suppression of frequent ventricular ectopy using amiodarone in patients with idiopathic dilated cardiomyopathy. Of interest in this small study was the observation that successful PVC suppression was associated with subsequent improvement in LVEF.24 Pharmacologic options include beta receptor antagonists (beta blockers) or non-dihydropyridine calcium receptor antagonists (calcium channel blockers) as typical first line therapies with antiarrhythmic drugs as second-line options. Beta blockers have been shown in a randomized trial to decrease PVC burden though they are limited by intolerance and variable effectiveness.25 Antiarrhythmics are of variable potency and can effectively reduce PVC burden. Selection of an appropriate antiarrhythmic drug should involve assessment of concomitant structural heart disease, sinus node function, integrity of AV conduction, the QT interval, and renal and hepatic function. Flecainide has been demonstrated to be particularly effective at PVC suppression though it should be reserved for those patients with structurally normal hearts and the absence of coronary artery disease.26 Amiodarone is generally the agent of choice with concomitant LV dysfunction though it is limited by potential organ toxicity.
PVC Catheter Ablation Catheter ablation of frequent PVCs has evolved into a safe and effective therapeutic option for patients with symptomatic frequent © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Frequent Premature Ventricular Contractions
TABLE 2. Treatment Decision Matrix in Patients With High Burden/Frequent PVCs LV size and systolic function
Symptoms −
Normal
Observe/surveillance
Abnormal
Treat—consider ablation first line
+ Treat—consider medical therapy first line Treat—consider ablation first line
PVCs and in those with suspected PVC cardiomyopathy or PVC “aggravated” preexisting cardiomyopathy. Over the past 10 years, multiple single center studies have demonstrated that PVC catheter ablation substantially reduces PVC burden, reduces or eliminates symptoms, enhances quality of life, and in those with suspected PVC cardiomyopathy or PVC “aggravated” preexisting cardiomyopathy, can result in improvement or reversal of LV dilatation or dysfunction post procedure.14,23,27–29 Zhong et al recently published a large single-center retrospective study of 512 patients treated over a 5-year period in a nonrandomized fashion with either pharmacotherapy or catheter ablation for frequent ventricular ectopy. In this trial, 60% were treated with drug therapy and 40% with catheter ablation. Mean reduction in PVC burden was significantly greater in the ablation group compared with the drug therapy group (−21,779 per 24-hour mean PVC reduction in the ablation group compared with −8376 per 24-hour in the drug therapy group, P < 0.001). Among the 121 patients with preexisting LV dysfunction, LV systolic function was restored in 25 of 53 patients (47%) in the ablation group compared with 14 of 68 patients (21%) in the drug therapy group, P = 0.003. Procedure related complications were 5.3% in the ablation group with no procedure related mortalities.29 The decision to pursue pharmacotherapy versus catheter ablation is dependent on multiple patient-specific factors. After assessing symptoms and evaluating for the presence or absence of a possible PVC-mediated cardiomyopathy, other clinical variables to consider when planning a therapeutic approach including patient age, comorbidities including adequacy of vascular access, previous trials of pharmacotherapy, anticipated site of origin of the suspect PVC as assessed by the 12 lead ECG (right versus left ventricular outflow tract origin, LV endocavitary vs epicardial origin, etc.), anticipated tolerance of drug therapy, and, importantly, the patient’s preferences. Table 2 illustrates a simplified 2 × 2 matrix for clinical decision making whereby symptoms and structural heart disease are the main variables. In summary, among patient with frequent PVCs: in the absence of both symptoms and structural heart disease, observation is appropriate; in the patient with symptoms and no structural heart disease, medical therapy (predominantly beta blocker therapy) is appropriate as first line therapy; and in the patient with structural heart disease with or without symptoms, catheter ablation is appropriate for consideration as first line therapy in patients deemed suitable for an invasive procedure. An important corollary to the patient with no symptoms and the absence of structural heart disease is the necessity for ongoing longitudinal follow-up to detect PVCmediated cardiomyopathy, especially among patients demonstrating a high daily PVC burden of >20% by Holter monitoring.
CONCLUSIONS Arrhythmia disorders are an increasingly recognized and potentially reversible risk factor for the development of LV systolic dysfunction. Poorly controlled supraventricular tachyarrhythmias, altered LV activation, and frequent PVCs constitute the main, potentially modifiable arrhythmia-mediated conditions that may directly www.cardiologyinreview.com | 171
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contribute to a failing ventricle. Frequent PVCs, though often clinically benign, may cause clinically significant symptoms and, in certain patients with a high daily burden, may be directly deleterious to ventricular function. Suppressive therapy for frequent PVCs, including PVC catheter ablation, is an effective treatment for this condition and should be considered in the appropriate clinical context. REFERENCES 1. Curtis LH, Whellan DJ, Hammill BG, et al. Incidence and prevalence of heart failure in elderly persons, 1994–2003. Arch Intern Med. 2008;168:418–424. 2. Yancy CW, Jessup M, Bozkurt B, et al; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62:e147–e239. 3. Kang KT, Potts JE, Radbill AE, et al. Permanent junctional reciprocating tachycardia in children: a multicenter experience. Heart Rhythm. 2014;11:1426–1432. 4. Sweeney MO, Hellkamp AS, Ellenbogen KA, et al; Mode Selection Trial Investigators. Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction. Circulation. 2003;107:2932–2937. 5. Grines CL, Bashore TM, Boudoulas H, et al. Functional abnormalities in isolated left bundle branch block. The effect of interventricular asynchrony. Circulation. 1989;79:845–853. 6. Cha Y, Lee GK, Klarich KW, et al. Premature ventricular contractioninduced cardiomyopathy: a treatable condition. Circ Arrhythm Electrophysiol. 2012;5:229–236. 7. Smith ML, Hamdan MH, Wasmund SL, et al. High-frequency ventricular ectopy can increase sympathetic neural activity in humans. Heart Rhythm. 2010;7:497–503. 8. Bristow MR, Saxon LA, Boehmer J, et al; Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004;350:2140–2150. 9. Cleland JG, Daubert JC, Erdmann E, et al; Cardiac ResynchronizationHeart Failure (CARE-HF) Study Investigators. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005;352:1539–1549. 10. Moss AJ, Hall WJ, Cannom DS, et al; MADIT-CRT Trial Investigators. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med. 2009;361:1329–1338. 11. Tang ASL, Wells GA, Talajic M, et al. Cardiac resynchronization therapy for mild to moderate heart failure. N Engl J Med. 2010;363:2386–2395. 12. Guglin M, Barold SS. The role of biventricular pacing in the preven tion and therapy of pacemaker-induced cardiomyopathy. Ann Noninvasive Electrocardiol. 2015;20:224–239. 13. Bikkina M, Larson MG, Levy D. Prognostic implications of asymptom atic ventricular arrhythmias: the Framingham heart study. Ann Intern Med. 1992;117:990–996.
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14. Baman TS, Lange DC, Ilg KJ, et al. Relationship between burden of premature ventricular complexes and left ventricular function. Heart Rhythm. 2010;7:865–869. 15. Niwano S, Wakisaka Y, Niwano H, et al. Prognostic significance of frequent premature ventricular contractions originating from the ventricular outflow tract in patients with normal left ventricular function. Heart. 2009;95:1230–1237. 16. Huizar JF, Kaszala K, Potfay J, et al. Left ventricular systolic dysfunc tion induced by ventricular ectopy: a novel model for premature ventricular contraction-induced cardiomyopathy. Circ Arrhythm Electrophysiol. 2011;4:543–549. 17. Yokokawa M, Kim HM, Good E, et al. Impact of QRS duration of frequent premature ventricular complexes on the development of cardiomyopathy. Heart Rhythm. 2012;9:1460–1464. 18. Carballeira Pol L, Deyell MW, Frankel DS, et al. Ventricular premature depolarization QRS duration as a new marker of risk for the development of ventricular premature depolarization-induced cardiomyopathy. Heart Rhythm. 2014;11:299–306. 19. Deyell MW, Park KM, Han Y, et al. Predictors of recovery of left ventricular dysfunction after ablation of frequent ventricular premature depolarizations. Heart Rhythm. 2012;9:1465–1472. 20. Sun Y, Blom NA, Yu Y, et al. The influence of premature ventricular contractions on left ventricular function in asymptomatic children without structural heart disease: an echocardiographic evaluation. Int J Cardiovasc Imaging. 2003;19:295–299. 21. Del Carpio Munoz F, Syed FF, Noheria A, et al. Characteristics of premature ventricular complexes as correlates of reduced left ventricular systolic function: study of the burden, duration, coupling interval, morphology and site of origin of PVCs. J Cardiovasc Electrophysiol. 2011;22:791–798. 22. Huang SKS, Wood MA. Catheter Ablation of Cardiac Arrhythmias. 2nd ed. Philadelphia: Elsevier Saunders; 2011. 23. Huang CX, Liang JJ, Yang B, et al. Quality of life and cost for patients with premature ventricular contractions by radiofrequency catheter ablation. Pacing Clin Electrophysiol. 2006;29:343–350. 24. Duffee DF, Shen WK, Smith HC. Suppression of frequent premature ventricular contractions and improvement of left ventricular function in patients with presumed idiopathic dilated cardiomyopathy. Mayo Clin Proc. 1998;73:430–433. 25. Krittayaphong R, Bhuripanyo K, Punlee K, et al. Effect of atenolol on symptomatic ventricular arrhythmia without structural heart disease: a randomized placebo-controlled study. Am Heart J. 2002;144:e10. 26. Capucci A, Di Pasquale G, Boriani G, et al. A double-blind crossover comparison of flecainide and slow-release mexiletine in the treatment of stable premature ventricular complexes. Int J Clin Pharmacol Res. 1991;11:23–33. 27. Takemoto M, Yoshimura H, Ohba Y, et al. Radiofrequency catheter ablation of premature ventricular complexes from right ventricular outflow tract improves left ventricular dilation and clinical status in patients without structural heart disease. J Am Coll Cardiol. 2005;45:1259–1265. 28. Yarlagadda RK, Iwai S, Stein KM, et al. Reversal of cardiomyopathy in patients with repetitive monomorphic ventricular ectopy originating from the right ventricular outflow tract. Circulation. 2005;112:1092–1097. 29. Zhong L, Lee YH, Huang XM, et al. Relative efficacy of catheter ablation vs antiarrhythmic drugs in treating premature ventricular contractions: a singlecenter retrospective study. Heart Rhythm. 2014;11:187–193.
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Frequent Premature Ventricular Contractions An Electrical Link to Cardiomyopathy Paul L. Eugenio, MD
Abstract: Heart failure is common and is associated with significant morbidity and mortality. Identifying potentially modifiable risk factors for the development of ventricular dysfunction is important in both the prevention and the treatment of this condition. Arrhythmia disorders are increasingly recognized as contributory to the development of ventricular failure. Poorly controlled supraventricular tachyarrhythmias, altered left ventricular activation due to left bundle branch block or right ventricular pacing, and frequent premature ventricular contractions (PVCs) constitute the main subtypes of arrhythmia disorders that are associated with the development of ventricular dysfunction. PVCs are common and are considered benign in the absence of structural heart disease. Frequent PVCs, defined as greater than 20% of all QRS complexes on standard 24-hour Holter monitoring, are associated with the presence or subsequent development of left ventricular dilatation and dysfunction. Catheter ablation of frequent PVCs has been demonstrated to be effective at PVC suppression and is associated with improvement or normalization of ventricular function; thus defining a specific, reversible form of ventricular dysfunction termed PVC cardiomyopathy. In patients presenting with high burden PVCs, an assessment for symptoms and associated cardiomyopathy is warranted and, in the appropriate clinical setting, PVC catheter ablation may be a reasonable treatment option. Key Words: premature ventricular contractions, PVC cardiomyopathy, PVC ablation (Cardiology in Review 2015;23: 168–172)
H
eart failure (HF) is a common condition. From an epidemiological perspective, the diagnosis of HF has demonstrated a perpetual increase in annual prevalence due in large part to therapeutic advances that reduce mortality, and thereby enhance longevity of an ever-aging population. Despite these advances, HF remains a diagnosis that negatively impacts the quality and quantity of life while progressively burdening the economics of health care.
HF—EPIDEMIOLOGY HF generates formidable health care statistics.1,2 Nationally, the prevalence is approximately 5.1 million with 650,000 new cases diagnosed annually. Incidence increases with age. Among those aged 60–65 years, the incidence is 20 of 1000 persons per year. The incidence increases fourfold among those aged >85 years. The mortality associated with HF is substantial with an overall 5-year mortality rate of 50%. The strongest risk factor driving this poor prognosis is the presence and severity of clinical symptoms. Indeed, among those with an American College of Cardiology Foundation/American Heart Association Stage B profile, 5-year survival is 96% compared Division of Cardiology, Westchester Medical Center, Valhalla, NY. Disclosure: The authors have no conflicts of interest to report. Correspondence: Paul L Eugenio, MD, Division of Cardiology, Westchester Medical Center, Macy Pavilion, 100 Woods Road, Valhalla, NY 10595. E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 1061-5377/15/2304-0168 DOI: 10.1097/CRD.0000000000000063
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with Stage D at 20%. The cost of the disease upon the health care system is equally formidable. Annually, in the United States, there are approximately 1 million hospital admissions with an early readmission rate of 25%. The annual cost is estimated at $30 billion. There are numerous risk factors for the subsequent development of HF. Hypertension deserves special mention as the largest modifiable risk factor.2 Identification of such modifiable risk factors is important at a population-based level as interventions that positively alter such risk factors may profoundly impact the subsequent development of disease.
ARRHYTHMIA DISORDERS AS A RISK FACTOR FOR VENTRICULAR DYSFUNCTION Arrhythmia disorders have been increasingly recognized as a potentially modifiable risk factor for the subsequent development of ventricular dysfunction and, as a consequence, clinical HF. Table 1 summarizes the main subtypes. Tachyarrhythmias are the most well described. The classic example is the permanent junctional reciprocating tachycardia (PJRT), a particular subclassification of supraventricular tachycardia more commonly diagnosed in the pediatric population. This arrhythmia utilizes a slowly conducting posteroseptal accessory pathway and is characteristically associated with a high daily burden of tachycardia. Patients with PJRT are at risk of tachycardia-mediated ventricular dysfunction. A recently published retrospective case series of patients with PJRT reported left ventricular (LV) dysfunction in 18% of cases.3 The mechanism of this arrhythmia, utilizing an accessory pathway, renders it highly amenable to curative catheter ablation and expectant improvement or normalization of ventricular function after restoration of durable sinus rhythm. The recognition that poorly controlled tachyarrhythmias can directly result in ventricular dysfunction is the basis for the diagnosis of tachycardia-induced cardiomyopathy. Any poorly controlled tachyarrhythmia can cause tachycardia-induced cardiomyopathy including various subtypes of supraventricular tachycardia, atrial flutter, and importantly given its high prevalence, atrial fibrillation. Altered LV activation, in the form of right ventricular pacing or left bundle branch block, is associated with a decline in LV performance.4,5 Altered LV activation may be the primary causative process or may exacerbate a separate underlying cardiomyopathy. Dyssynchronous LV activation can cause a myopathic process because of a number of hypothesized mechanisms including altered sarcomeric protein expression, abnormal ion channel expression, abnormalities in regional myocardial blood flow, and changes in local myocardial sympathetic tone.6,7 Cardiac resynchronization therapy is an effective treatment for cardiomyopathy in the setting of altered LV activation and in selected patients can improve LV function and reduce morbidity and mortality.8–12
PREMATURE VENTRICULAR CONTRACTIONS Premature ventricular contractions (PVCs) are common and seen routinely in everyday clinical practice. PVCs are the electrocardiographic manifestation of independent, focal depolarization of a discrete region of ventricular myocardium due most often to enhanced automaticity or triggered activity. Such ectopic impulses can originate Cardiology in Review • Volume 23, Number 4, July/August 2015
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Cardiology in Review • Volume 23, Number 4, July/August 2015
TABLE 1. Arrhythmia Disorders Associated With the Development of Ventricular Dysfunction Condition Untreated/under-treated tachyarrhythmias Altered left ventricular activation Frequent premature ventricular contractions
Comment Supraventricular tachycardia, atrial flutter, atrial fibrillation Right ventricular pacing, left bundle branch block >20% daily burden
from any site within the ventricular myocardium though more commonly are noted to arise from zones of anatomic transition (perivalvular in the vicinity of the right and left ventricular outflow tracts or the perimitral/tricuspid regions, papillary muscles, within or near the specialized conduction system or in border zones of myocardial scar). PVCs may be a stand-alone entity without structural heart disease or can coexist with various concomitant cardiac disease states including ischemic myocardial disease, valvular heart disease, and ischemic and nonischemic forms of cardiomyopathy with or without manifest HF. PVCs are seen in 40% of 24-hour ambulatory electrocardiogram (ECG) recordings and in 75% of 48-hour recordings among the general population referred for ambulatory ECG monitoring.6 Prevalence increases with age with less than 1% of ambulatory ECG recordings demonstrating PVCs in those younger than 11 years of age compared with more than 69% in those aged older than 75 years.6 Data from the Framingham Heart Study suggest that complex or frequent ventricular ectopy, defined as more than 30 PVCs per hour or PVCs of multiple morphologies, confer a 2.3-fold increase in the relative risk of all cause mortality; this association was, however, limited to men without clinically evident coronary artery disease.13 Clinical evidence suggests that frequent PVCs (variably defined in the literature) are more strongly associated with concomitant cardiac disease. The Framingham study illustrated this association by demonstrating that frequent ventricular ectopy (defined as >30 PVCs per hour) or complex ventricular ectopy (multiple PVC morphologies) was more strongly associated with presence of clinically evident coronary artery disease in both men and women.13
Frequent PVCs and Ventricular Dysfunction More recent literature further supports the link between structural heart disease and frequent ventricular ectopy. A study by Baman et al14 evaluated a group of patients referred for PVC ablation. Among this cohort, patients with baseline LV systolic dysfunction demonstrated an average PVC daily burden of 33% ± 13% compared with 13% ± 12% among those with a preserved LV ejection fraction (LVEF), P < 0.001, suggesting that a high PVC burden is correlated with the presence of a myopathic ventricle. Niwano et al published results on a prospective cohort study following a group of patients with frequent PVCs (defined as >1000 per 24-hour period) and normal baseline LV systolic function followed over a period of more than 4 years. This cohort, at baseline, demonstrated preserved LV systolic function. A high ventricular ectopic burden (>20,000 PVCs per 24-hour period) was correlated with the subsequent development of LV dilatation and a decrement in LV systolic function over a 4–5.6-year follow-up period.15 This prospective study suggests that frequent PVCs may not only be associated with the presence of a cardiomyopathy but may have a direct deleterious effect on LV performance, thus giving rise to the term PVC-mediated cardiomyopathy. Animal data further support this notion. Huizar et al published an elegant study in 2011 involving a canine model of PVC-mediated cardiomyopathy. Thirteen dogs with baseline normal LV function were implanted with a pacemaker and randomized to deliver single © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Frequent Premature Ventricular Contractions
ventricular paced beats following each intrinsically conducted sinus beat (mimicking spontaneous ventricular bigeminy) or no pacing. The dogs were followed for 12 weeks. Twenty-four-hour PVC burden was, as expected, approximately 50% in the pacing arm. At follow-up, average LV systolic function in the pacing group was significantly lower compared with the nonpaced group (39.7% ± 5.4% vs 60.7% ± 3.8%, P < 0.0001). Within the paced group, ventricular function normalized 4 weeks after discontinuation of the pacing protocol. Of interest, histopathologic examination of sampled myocardium from dogs in the paced group who demonstrated a decrement in LV systolic function revealed no evidence of myocardial fibrosis, apoptosis, or mitochondrial abnormalities.16 Though frequent PVCs may correlate to a decline in LV function, the common nature with which PVCs are seen in clinical practice gives rise to important clinical queries: is there a threshold PVC burden that is more closely associated with the ultimate development of cardiomyopathy? In addition, are there clinical characteristics attributable to the PVC that may identify individuals who are more likely to demonstrate LV dysfunction? Such information would be useful in clinical practice for the initial evaluation and prospective follow-up of patients referred for frequent ventricular ectopy. The previously referenced study by Baman et al14 studying a cohort of patients referred for PVC ablation suggests that a cutoff PVC burden of 24%, as assessed by 24-hour ambulatory ECG monitoring before ablation, best differentiated those patients with concomitant LV dysfunction from those with preserved function with a sensitivity of 79% and a specificity of 78%. Furthermore, the study by Niwano et al15 suggested that the correlation between PVC burden and subsequent decline in LV systolic function was limited to patients who demonstrated a high daily PVC burden defined as greater than 20,000 PVCs per 24-hour period (20% daily PVC burden based on an average heart rate of 70 beats per minute). On the basis of available clinical data, it would seem prudent to consider a 24-hour PVC burden of greater than 20% as more strongly associated with the presence or subsequent development of LV dysfunction, thus identifying a subgroup of patients who, at a minimum, require closer surveillance.
PVC Characteristics and Risk of Cardiomyopathy Among patients with frequent PVCs, other characteristics attributable to the PVC may correlate with the risk of developing LV dysfunction. A study by Yokokawa et al assessed the relationship between PVC QRS duration and the presence of concomitant reversible LV dysfunction. Wide PVC QRS duration more than 150 ms was independently associated with the presence of a cardiomyopathy that was often reversible with catheter ablation.17 This was further supported by a study from Carballeira-Pol et al18 whereby a PVC QRS duration more than 153 ms best predicted patients with baseline frequent PVCs who would ultimately develop LV dysfunction. Of interest in this study was the observation that patients with frequent PVCs who ultimately develop LV dysfunction also manifest a wider QRS duration in sinus rhythm, suggesting intrinsic myocyte uncoupling and intramyocardial fibrosis. This suggests a possible multicomponent mechanism underpinning PVC cardiomyopathy whereby a smoldering intrinsic myopathic process combined with PVC-mediated dyssynchrony combines synergistically to generate the PVC cardiomyopathy phenotype. This hypothesis suggests that there may be a “point of no return” with respect to the extent of the abnormal myocardial substrate and frequent ventricular complexes. A study by Deyell et al assessed a population of patients with frequent PVCs and baseline LV dysfunction who underwent PVC catheter ablation. A “very-wide” PVC QRS duration of > 173 ms, suggesting more diffuse and widespread myocardial disease, identified a subgroup of www.cardiologyinreview.com | 169
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patients more likely to demonstrate persistent LV dysfunction despite successful PVC ablation.19 The PVC coupling interval has been variably reported to correlate with LV dysfunction. A study by Sun et al.20 reported that, in a pediatric population, a PVC coupling interval of less than 600 ms was associated with a mean lower LVEF compared with a coupling interval more than 600 ms. Other studies have not corroborated these findings.21 It is plausible that closely coupled, high burden PVCs more closely mimic poorly controlled atrial tachyarrhythmias. In addition, the post-PVC “pause” often seen in ventricular bigeminal rhythms may, at a cellular level, lead to postextrasystolic elevated intracellular calcium and increased myocardial oxygen demand. This derangement, over time, may be deleterious to ventricular function.16
Anatomic Origin of PVCs In addition to Holter monitoring to assess overall PVC burden, the 12-lead ECG is essential in the initial assessment and ultimate counseling of patients who are considered for an ablative approach. Ectopic impulses can originate from any location within the myocardium, though, as is a common theme in therapeutic electrophysiology, more often originate from sites of anatomic transition. The most well-studied site in this regard over the past decade has been the sleeves of myocardial fascicles at the pulmonary vein–left atrial junction in the initiation of paroxysmal atrial fibrillation. In the ventricle, ectopic impulse formation in the form of isolated ectopy (PVCs) or repetitive impulse formation (idiopathic ventricular tachycardia) are also frequently encountered at zones of anatomic transition. The “usual suspects” with regard to common sites of origin are the right and left ventricular outflow tracts (often in close proximity to the pulmonic and aortic valve cusps). Indeed, these sites represent the site of origin of idiopathic PVCs in two-thirds of patients referred for PVC ablation.21 Other sites within the ventricles include the periatrioventricular valvular regions (peritricuspid, perimitral), intracavitary structures (papillary muscles), the specialized conduction system (His-Purkinje tissue), and certain epicardial sites (in the vicinity of the epicardial venous system). The surface ECG can provide insight as to the site of origin with a reasonable degree of accuracy. In general terms, left bundle branch-like morphology in precordial leads V1 and V2 together with an inferior frontal plane axis identify sites of origin from the right or left ventricular outflow tracts—the most common site with respect to idiopathic PVCs. Morphology, as previously highlighted, can also provide insight into the myocardial substrate. PVCs demonstrating a wide QRS duration (>150 ms) along with slurring and notching of the initial QRS deflection may indicate either an epicardial site of origin or myocyte uncoupling and interstitial fibrosis suggesting a baseline cardiomyopathic process. The conducted QRS complex (ie, non-PVC complexes) may add additional information with respect to baseline His-Purkinje disease (right or left bundle branch block), prior infarct (pathologic Q waves) or ventricular hypertrophy (prominent QRS voltage and secondary repolarization abnormalities). Such information is clinically useful in assessing the status of underlying heart disease and planning an ablative approach.
Etiology of PVCs and Pathophysiologic Link to LV Dysfunction The etiology of PVCs, at a fundamental level, is not known beyond the observation that PVCs represent abnormal impulse formation from the ventricular myocardium. In general, abnormal impulse formation arises from (1) increased intrinsic automaticity, (2) triggered activity due to afterpotentials, and (3) reentry.22 The clinical observation that PVCs or idiopathic forms of ventricular tachycardia often originate from “zones of myocardial transition,” such as the ventricular outflow tracts, suggest that there may be an 170 | www.cardiologyinreview.com
anatomic-physiologic link whereby zones of fiber disruption are more likely to exhibit abnormal impulse formation. How frequent PVCs may be deleterious to ventricular function is also not understood. It would seem plausible that frequent, closely coupled PVCs, exceeding 20% of all ventricular systoles, would mimic a poorly controlled atrial tachyarrhythmia. Furthermore, the pattern of myocardial contraction in response to a PVC is dyssynchronous and similar to left bundle branch block or ventricular pacing. Thus, the combination of high burden, closely coupled PVCs with resultant dyssynchronous myocardial contraction does provide an empiric link to the ultimate deleterious effects on ventricular function. Speculative cellular mechanisms linking frequent PVCs to ventricular dysfunction include asymmetric hypertrophy in late activated regions of the ventricle, altered myocardial oxygen consumption, altered regional myocardial blood flow, altered sarcomeric protein expression leading to myofibrillar disarray, altered ion channel expression, and changes in myocardial autonomic tone.6
The Patient With Frequent PVCs—Clinical Evaluation The clinical evaluation of a patient referred for frequent PVCs is centered on the history, physical exam, standard 12 lead ECG, 24-hour Holter, resting transthoracic echocardiogram and, as necessary, stress testing and/or advanced cardiac imaging. History taking is of paramount importance. Patients may present with palpitations (especially at night when lying supine), fatigue, lightheadedness, neck fullness due to loss of AV synchrony, exertional intolerance, dyspnea, or chest pain. If concomitant ventricular dysfunction is present, symptoms of HF may be evident. Commonly, patients will present with no symptoms, with ectopy detected by an irregular pulse or prior ECG obtained for other clinical reasons. Establishing that the PVCs are symptomatic is important with regard to clinical decision making when considering a therapeutic approach of PVC suppression. A family history should be obtained to assess for such entities as early onset coronary artery disease, inherited cardiomyopathies and sudden cardiac death. Physical examination is often normal though may be notable for an irregular pulse, intermittent cannon “a” waves on jugular venous examination, or classic findings of a failing ventricle (jugular venous distension, displaced point of maximum impulse, S3 gallop). As previously stated, close inspection of the 12 lead ECG is important to establish the baseline rhythm, assess diagnostic criteria for His-Purkinje disease, hypertrophy, prior infarct, or classic morphologic changes of less common processes, such as arrhythmogenic right ventricular cardiomyopathy (ARVC). A signal averaged ECG, though of limited utility, can be considered in the evaluation of suspected ARVC. It is extremely helpful to capture the “suspect” PVC on the 12 lead ECG examination as this will aid in localization of the site of origin—invaluable when considering an ablative strategy. Ambulatory ECG monitoring in the format of 24-hour (or more extended) Holter monitoring provides such data as PVC pleomorphism (ie, number of dominant PVC morphologies), burden as assessed by percentage of all QRS complexes during a 24-hour monitoring period, format of ectopy (predominantly single PVCs vs periods of nonsustained ventricular tachycardia), PVC behavior with exertion versus rest, and associated symptoms. Laboratory analysis is most commonly unrevealing, though basic assessments of blood counts, chemistries, and renal, hepatic, and thyroid function are indicated. In the appropriate clinical context, measurement of b-type natriuretic peptide may provide insight into the neurohormonal status of a patient with a history and exam consistent with clinical HF. Cardiac imaging, most commonly transthoracic echocardiography, provides important structural information. Of particular importance in the evaluation of patients with frequent PVCs includes © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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Cardiology in Review • Volume 23, Number 4, July/August 2015
LV end diastolic dimension/volume, global left and right ventricular systolic function, regional LV wall motion abnormalities, ventricular hypertrophy, valvular heart disease, and estimated pulmonary artery systolic pressure. Exercise stress testing is helpful in assessing for myocardial ischemia in the appropriate clinical context, though is also useful in evaluating the behavior of the ectopy to elevated sympathetic tone. PVCs may be suppressed with exercise or, conversely, may be more prevalent, even manifesting as frank ventricular tachycardia; such a response may be helpful in planning an ablative strategy. Advanced cardiac imaging, most commonly cardiac magnetic resonance imaging, should be pursued when there is a clinical suspicion of a myopathic process not easily accessed by echocardiography (ARVC, cardiac sarcoidosis, apical variant hypertrophy, ventricular noncompaction, and amyloidosis).
Frequent PVCs—When and How to Treat The decision to treat frequent PVCs, either pharmacologically or via catheter ablation, should be predicated on two factors: symptoms and associated LV dysfunction. As a general rule, PVCs are considered a benign condition in the absence of concomitant structural heart disease or myocardial ischemia. Indeed, the previously referenced study by Niwano et al15 following a cohort of 239 patients with frequent PVCs in the absence of structural heart disease demonstrated no adverse cardiac events during the entirety of the follow up period (4–5.6 years). Frequent PVCs are often asymptomatic though, conversely, may be associated with significant clinical symptoms (palpitations, lightheadedness, dyspnea, chest discomfort, effort intolerance). In addition, patients with frequent PVCs can demonstrate a diminished quality of life based on standardized testing that improves after treatment via catheter ablation.23 Thus, establishing symptoms that correlate to ventricular ectopy is important when considering suppressive therapy. A second factor to consider is the status of ventricular function. As has been previously described, high burden ventricular ectopy (>20% burden as assessed by 24 hour Holter monitoring) is associated with the presence of LV dilatation and dysfunction. If LV dysfunction or LV remodeling (ie, LV dilatation) is demonstrated, primary PVC cardiomyopathy or PVC “aggravated” preexisting cardiomyopathy should be considered as should suppressive therapy, including catheter ablation. Suppressive therapy for frequent PVCs includes either a pharmacologic or ablative approach. Duffee et al. first described successful suppression of frequent ventricular ectopy using amiodarone in patients with idiopathic dilated cardiomyopathy. Of interest in this small study was the observation that successful PVC suppression was associated with subsequent improvement in LVEF.24 Pharmacologic options include beta receptor antagonists (beta blockers) or non-dihydropyridine calcium receptor antagonists (calcium channel blockers) as typical first line therapies with antiarrhythmic drugs as second-line options. Beta blockers have been shown in a randomized trial to decrease PVC burden though they are limited by intolerance and variable effectiveness.25 Antiarrhythmics are of variable potency and can effectively reduce PVC burden. Selection of an appropriate antiarrhythmic drug should involve assessment of concomitant structural heart disease, sinus node function, integrity of AV conduction, the QT interval, and renal and hepatic function. Flecainide has been demonstrated to be particularly effective at PVC suppression though it should be reserved for those patients with structurally normal hearts and the absence of coronary artery disease.26 Amiodarone is generally the agent of choice with concomitant LV dysfunction though it is limited by potential organ toxicity.
PVC Catheter Ablation Catheter ablation of frequent PVCs has evolved into a safe and effective therapeutic option for patients with symptomatic frequent © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Frequent Premature Ventricular Contractions
TABLE 2. Treatment Decision Matrix in Patients With High Burden/Frequent PVCs LV size and systolic function
Symptoms −
Normal
Observe/surveillance
Abnormal
Treat—consider ablation first line
+ Treat—consider medical therapy first line Treat—consider ablation first line
PVCs and in those with suspected PVC cardiomyopathy or PVC “aggravated” preexisting cardiomyopathy. Over the past 10 years, multiple single center studies have demonstrated that PVC catheter ablation substantially reduces PVC burden, reduces or eliminates symptoms, enhances quality of life, and in those with suspected PVC cardiomyopathy or PVC “aggravated” preexisting cardiomyopathy, can result in improvement or reversal of LV dilatation or dysfunction post procedure.14,23,27–29 Zhong et al recently published a large single-center retrospective study of 512 patients treated over a 5-year period in a nonrandomized fashion with either pharmacotherapy or catheter ablation for frequent ventricular ectopy. In this trial, 60% were treated with drug therapy and 40% with catheter ablation. Mean reduction in PVC burden was significantly greater in the ablation group compared with the drug therapy group (−21,779 per 24-hour mean PVC reduction in the ablation group compared with −8376 per 24-hour in the drug therapy group, P < 0.001). Among the 121 patients with preexisting LV dysfunction, LV systolic function was restored in 25 of 53 patients (47%) in the ablation group compared with 14 of 68 patients (21%) in the drug therapy group, P = 0.003. Procedure related complications were 5.3% in the ablation group with no procedure related mortalities.29 The decision to pursue pharmacotherapy versus catheter ablation is dependent on multiple patient-specific factors. After assessing symptoms and evaluating for the presence or absence of a possible PVC-mediated cardiomyopathy, other clinical variables to consider when planning a therapeutic approach including patient age, comorbidities including adequacy of vascular access, previous trials of pharmacotherapy, anticipated site of origin of the suspect PVC as assessed by the 12 lead ECG (right versus left ventricular outflow tract origin, LV endocavitary vs epicardial origin, etc.), anticipated tolerance of drug therapy, and, importantly, the patient’s preferences. Table 2 illustrates a simplified 2 × 2 matrix for clinical decision making whereby symptoms and structural heart disease are the main variables. In summary, among patient with frequent PVCs: in the absence of both symptoms and structural heart disease, observation is appropriate; in the patient with symptoms and no structural heart disease, medical therapy (predominantly beta blocker therapy) is appropriate as first line therapy; and in the patient with structural heart disease with or without symptoms, catheter ablation is appropriate for consideration as first line therapy in patients deemed suitable for an invasive procedure. An important corollary to the patient with no symptoms and the absence of structural heart disease is the necessity for ongoing longitudinal follow-up to detect PVCmediated cardiomyopathy, especially among patients demonstrating a high daily PVC burden of >20% by Holter monitoring.
CONCLUSIONS Arrhythmia disorders are an increasingly recognized and potentially reversible risk factor for the development of LV systolic dysfunction. Poorly controlled supraventricular tachyarrhythmias, altered LV activation, and frequent PVCs constitute the main, potentially modifiable arrhythmia-mediated conditions that may directly www.cardiologyinreview.com | 171
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contribute to a failing ventricle. Frequent PVCs, though often clinically benign, may cause clinically significant symptoms and, in certain patients with a high daily burden, may be directly deleterious to ventricular function. Suppressive therapy for frequent PVCs, including PVC catheter ablation, is an effective treatment for this condition and should be considered in the appropriate clinical context. REFERENCES 1. Curtis LH, Whellan DJ, Hammill BG, et al. Incidence and prevalence of heart failure in elderly persons, 1994–2003. Arch Intern Med. 2008;168:418–424. 2. Yancy CW, Jessup M, Bozkurt B, et al; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62:e147–e239. 3. Kang KT, Potts JE, Radbill AE, et al. Permanent junctional reciprocating tachycardia in children: a multicenter experience. Heart Rhythm. 2014;11:1426–1432. 4. Sweeney MO, Hellkamp AS, Ellenbogen KA, et al; Mode Selection Trial Investigators. Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction. Circulation. 2003;107:2932–2937. 5. Grines CL, Bashore TM, Boudoulas H, et al. Functional abnormalities in isolated left bundle branch block. The effect of interventricular asynchrony. Circulation. 1989;79:845–853. 6. Cha Y, Lee GK, Klarich KW, et al. Premature ventricular contractioninduced cardiomyopathy: a treatable condition. Circ Arrhythm Electrophysiol. 2012;5:229–236. 7. Smith ML, Hamdan MH, Wasmund SL, et al. High-frequency ventricular ectopy can increase sympathetic neural activity in humans. Heart Rhythm. 2010;7:497–503. 8. Bristow MR, Saxon LA, Boehmer J, et al; Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004;350:2140–2150. 9. Cleland JG, Daubert JC, Erdmann E, et al; Cardiac ResynchronizationHeart Failure (CARE-HF) Study Investigators. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005;352:1539–1549. 10. Moss AJ, Hall WJ, Cannom DS, et al; MADIT-CRT Trial Investigators. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med. 2009;361:1329–1338. 11. Tang ASL, Wells GA, Talajic M, et al. Cardiac resynchronization therapy for mild to moderate heart failure. N Engl J Med. 2010;363:2386–2395. 12. Guglin M, Barold SS. The role of biventricular pacing in the preven tion and therapy of pacemaker-induced cardiomyopathy. Ann Noninvasive Electrocardiol. 2015;20:224–239. 13. Bikkina M, Larson MG, Levy D. Prognostic implications of asymptom atic ventricular arrhythmias: the Framingham heart study. Ann Intern Med. 1992;117:990–996.
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14. Baman TS, Lange DC, Ilg KJ, et al. Relationship between burden of premature ventricular complexes and left ventricular function. Heart Rhythm. 2010;7:865–869. 15. Niwano S, Wakisaka Y, Niwano H, et al. Prognostic significance of frequent premature ventricular contractions originating from the ventricular outflow tract in patients with normal left ventricular function. Heart. 2009;95:1230–1237. 16. Huizar JF, Kaszala K, Potfay J, et al. Left ventricular systolic dysfunc tion induced by ventricular ectopy: a novel model for premature ventricular contraction-induced cardiomyopathy. Circ Arrhythm Electrophysiol. 2011;4:543–549. 17. Yokokawa M, Kim HM, Good E, et al. Impact of QRS duration of frequent premature ventricular complexes on the development of cardiomyopathy. Heart Rhythm. 2012;9:1460–1464. 18. Carballeira Pol L, Deyell MW, Frankel DS, et al. Ventricular premature depolarization QRS duration as a new marker of risk for the development of ventricular premature depolarization-induced cardiomyopathy. Heart Rhythm. 2014;11:299–306. 19. Deyell MW, Park KM, Han Y, et al. Predictors of recovery of left ventricular dysfunction after ablation of frequent ventricular premature depolarizations. Heart Rhythm. 2012;9:1465–1472. 20. Sun Y, Blom NA, Yu Y, et al. The influence of premature ventricular contractions on left ventricular function in asymptomatic children without structural heart disease: an echocardiographic evaluation. Int J Cardiovasc Imaging. 2003;19:295–299. 21. Del Carpio Munoz F, Syed FF, Noheria A, et al. Characteristics of premature ventricular complexes as correlates of reduced left ventricular systolic function: study of the burden, duration, coupling interval, morphology and site of origin of PVCs. J Cardiovasc Electrophysiol. 2011;22:791–798. 22. Huang SKS, Wood MA. Catheter Ablation of Cardiac Arrhythmias. 2nd ed. Philadelphia: Elsevier Saunders; 2011. 23. Huang CX, Liang JJ, Yang B, et al. Quality of life and cost for patients with premature ventricular contractions by radiofrequency catheter ablation. Pacing Clin Electrophysiol. 2006;29:343–350. 24. Duffee DF, Shen WK, Smith HC. Suppression of frequent premature ventricular contractions and improvement of left ventricular function in patients with presumed idiopathic dilated cardiomyopathy. Mayo Clin Proc. 1998;73:430–433. 25. Krittayaphong R, Bhuripanyo K, Punlee K, et al. Effect of atenolol on symptomatic ventricular arrhythmia without structural heart disease: a randomized placebo-controlled study. Am Heart J. 2002;144:e10. 26. Capucci A, Di Pasquale G, Boriani G, et al. A double-blind crossover comparison of flecainide and slow-release mexiletine in the treatment of stable premature ventricular complexes. Int J Clin Pharmacol Res. 1991;11:23–33. 27. Takemoto M, Yoshimura H, Ohba Y, et al. Radiofrequency catheter ablation of premature ventricular complexes from right ventricular outflow tract improves left ventricular dilation and clinical status in patients without structural heart disease. J Am Coll Cardiol. 2005;45:1259–1265. 28. Yarlagadda RK, Iwai S, Stein KM, et al. Reversal of cardiomyopathy in patients with repetitive monomorphic ventricular ectopy originating from the right ventricular outflow tract. Circulation. 2005;112:1092–1097. 29. Zhong L, Lee YH, Huang XM, et al. Relative efficacy of catheter ablation vs antiarrhythmic drugs in treating premature ventricular contractions: a singlecenter retrospective study. Heart Rhythm. 2014;11:187–193.
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