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Premature Ventricular
Contraction-Induced Cardiomyopathy
A Treatable Condition
Yong-Mei Cha, MD; Glenn K. Lee, MBBS; Kyle W. Klarich, MD; Martha Grogan, MD
Received March 8, 2011; final revision received October 26, 2011; accepted October 31, 2011.
From the Division of Cardiovascular Diseases (Y.-M.C., K.W.K., M.G.), Mayo Clinic, Rochester, MN; and the Department of Medicine (G.K.L.),
National University Health System, Singapore.
Guest Editor for this article was Kenneth A. Ellenbogen, MD.
Correspondence to Yong-Mei Cha, MD, Division of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail
ycha@mayo.edu
(Circ Arrhythm Electrophysiol. 2012;5:229-236.)
© 2011 American Heart Association, Inc.
Circ Arrhythm Electrophysiol is available at http://circep.ahajournals.org DOI: 10.1161/CIRCEP.111.963348
genic mechanisms. Ventricular dyssynchrony results in com- interact with PVC frequency to influence the risk of cardio-
promised global cardiac mechanical efficiency, asymmetri- myopathy.47 The putative mechanisms of PVC-induced car-
cally increased wall thickness in the late-activated regions, diomyopathy are summarized in Figure 2.
altered myocardial blood flow, and local changes in myocar-
dial protein expression.28 The ventricular dyssynchrony asso- Clinical Evaluation
ciated with PVCs, particularly when the PVC burden is high, In many patients, the onset of frequent PVCs relative to the
may contribute to LV dilation and impaired function in a onset of LV dysfunction is unknown.47 It is particularly
fashion previously described for patients with left bundle important to identify the primary disorder because of the
branch block or chronic right ventricular pacing.25–29 Right potential reversibility of PVC-induced cardiomyopathy.48,49
ventricular pacing is notably associated with dyssynchronous Patients can present with debilitating symptoms, particularly
ventricular contraction,39 changes in cardiac sympathetic palpitations, or other symptoms such as chest pain, presyn-
activity, histopathology as well as ion channel expression and cope, syncope, or heart failure manifested by decreased effort
function40; animal models have shown that right ventricular tolerance, possibly as a result of decreased effective cardiac
pacing induces asymmetrical myocardial hypertrophy, myo- output.3 The vast majority of these patients are healthy with
fibrillar disarray, and increased catecholamine concentrations no known structural heart disease,4 but a detailed family
in the myocardium.41– 43 Although clinical studies describe history is required to help exclude familial dilated cardiomy-
LV dysfunction developing over reasonably long periods of opathy. The physical examination findings are often normal
time (⬎4 years in the series of Niwano et al13), in canine except irregular heart rhythm when PVCs are frequent. The
models, LV dysfunction occurred within 4 to 12 weeks of electrocardiography may indicate the presence and morphol-
induced ventricular ectopy.44,45 However, this PVC-induced ogy of PVCs, but PVC burden should be assessed by
cardiomyopathy animal model in a 3-month duration demon- continuous Holter monitoring for at least 24 hours. Because a
strated the lack of myocardial fibrosis and absence of changes single 24-hour recording may not reflect the true PVC load
in apoptosis and mitochondrial function, which support a due to day-to-day variability, a strong suspicion that frequent
functional rather than structural mechanism. Smith et al46 PVCs may be the cause of LV dysfunction may warrant
observed sympathoexcitation evoked by acutely high rates of extended Holter recordings of 48 to 72 hours or several
ventricular ectopy using programmed ventricular extrastimuli 24-hour Holter recordings.20 Echocardiography is useful to
after every 4, 2, and 1 spontaneous sinus beats in patients with exclude valvular pathology, regional wall motion abnormal-
a history of supraventricular tachycardia. This inappropriate ities, cardiomyopathies, or myocardial abnormalities such as
sympathetic activation could potentially impair LV function noncompaction, all of which could be a cause for frequent
in the long-term, yet although animal models are crucial in PVCs. Echocardiographic features in PVC-induced cardio-
helping us understand a variety of pathophysiological aspects myopathy include decreased LVEF, increased LV systolic
that are difficult or unable to explore in human subjects, and and diastolic dimensions, wall motion abnormalities, which
give us an impression of the relationship between the onset are often global as opposed to regional,20 as well as mitral
and burden of PVCs to the development of systolic dysfunc- regurgitation (typically due to mitral annular dilatation).14
tion, the limited comparability between animal and human Two-dimensional speckle tracking strain imaging has shown
studies has to be taken into account. Patient-specific factors altered LV contractility, whereas the LVEF remains pre-
such as genetic predispositions determining myocardial pro- served.50 –54 Whether the abnormal findings from speckle
tein expression in response to PVC-induced stress may tracking imaging predict the reduction of LVEF in patients
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232 Circ Arrhythm Electrophysiol February 2012
with PVCs remains to be studied. Cardiac MRI may be ⬎10% of total heart beats18,19,22 over 24 hours) if the clinical
warranted in detecting arrhythmogenic right ventricular car- suspicion for PVC-induced cardiomyopathy is high. The
diomyopathy with LV involvement and infiltrative disease patient should be followed up over 3 to 12 months to assess
when clinically suspected. Coronary angiography should be posttreatment PVC frequency as well as LV size and func-
performed in every patient with reduced LV systolic function tion. The workup, treatment, and follow-up of patients with
to exclude significant coronary artery disease except for those frequent PVCs are summarized in Figure 3.
with a low cardiovascular risk. Appropriate workup should
also be performed to exclude other causes of cardiomyopathy, Pharmacological Therapy
including those related to drugs/toxins, infectious diseases, Because the long-term prognosis of frequent PVCs is generally
and endocrinopathies. considered to be benign and the majority of patients presenting
It should be noted that PVC-induced cardiomyopathy with frequent PVCs have a preserved LVEF,4,9,12,13,15 the pre-
remains a diagnosis of exclusion; underlying structural dis- ferred treatment is usually reassurance and counseling of the
ease causing frequent PVCs must be ruled out. Given the patient with close follow-up if the patient is asymptomatic. In
reciprocal causal association between PVCs and cardiomy- the presence of symptoms, pharmacotherapy such as a
opathy where either 1 can lead to the other, it may be difficult -blocker or a nondihydropyridine calcium channel blocker
to isolate the primary disorder.49,55 In many patients, the onset may be the first-line therapy.56 Krittayaphong et al57 showed,
of frequent PVCs relative to the onset of LV dysfunction is in a randomized placebo-controlled study, that atenolol sig-
unknown.47 It is particularly important to identify the primary nificantly decreased symptom frequency and PVC count.
disorder because of the potential reversibility of PVC- Antiarrhythmics such as flecainide or sotalol may be consid-
induced cardiomyopathy.48,49 ered when -blockers or calcium channel blockers are inef-
fective.58 Capucci et al59 demonstrated that 91% of patients
Therapeutic Modalities taking flecainide and 55% of patients on mexiletine had a
A therapeutic medical trial or catheter ablation may be PVC reduction of ⱖ70%. In the presence of overt LV
considered in patients with LV dysfunction and frequent dysfunction, Class IA or IC drugs such as flecainide or
PVCs (a generally accepted range of ⬎10 000 –20 00013,17 or propafenone are not recommended given their side effect
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Cha et al Premature Ventricular Contractions 233
profiles, including the propensity for proarrhythmic effects induced cardiomyopathy. However, randomized clinical trials
and adverse impact on survival.3,60 Careful consideration in are needed to determine a comparative efficacy and outcome
regard to the baseline renal and hepatic function is also of modern medical against ablative approaches for those with
necessary when initiating an antiarrhythmic agent to avoid frequent PVCs that are likely to be the cause of
inadvertent drug toxicity. Amiodarone and dofetilide are cardiomyopathy.
preferred in view of their favorable cardiac safety profile.61– 63
A randomized, double-blind, placebo-controlled trial con- Future Perspectives
ducted by Singh et al11 showed that amiodarone was signif- Knowledge of the molecular, cellular, and hemodynamic
icantly more effective in suppressing PVCs with concomitant mechanisms of LV dysfunction in PVC-induced cardiomy-
improvement in LVEF in patients with congestive heart opathy is limited. Despite the limited comparability between
failure and asymptomatic ventricular arrhythmia. animal models and human subjects, animal models enable us
to study the effects of PVCs and to understand the pathogen-
Catheter Ablation esis of PVC-induced cardiomyopathy. Development of better
Catheter-based ablative approaches represent an emerging
imaging techniques such as 2-dimensional speckle tracking
effective and alternative therapy to pharmacological treat-
strain imaging and cardiac MRI aimed at assessing early LV
ment and have been increasingly reported over the past
dysfunction and excluding occult structural heart disease
decade. Many studies have documented the improvement in
allows the possibility of earlier detection of the disease. There
LV function after catheter ablation of frequent PVCs (Ta-
is at present little evidence to recommend the routine use of
ble).10 –12,14,16,18,21,54 Yarlagadda et al12 noted a significant
such imaging techniques in the workup of PVC-induced
improvement in LVEF to near 60% in all patients with LV
cardiomyopathy. Although the suppression of PVCs is indi-
dysfunction who underwent successful catheter ablation of
cated for symptomatic patients with frequent PVCs and those
their frequent PVCs. Bogun et al15 documented the normal-
with overt LV dysfunction, there is at present no evidence for
ization of LVEF in 82% of patients who underwent catheter
the treatment of asymptomatic patients with normal LVEF to
ablation for frequent PVCs and LV systolic dysfunction.
Improvement of LVEF was also documented by Sarrazin et prevent PVC-induced cardiomyopathy. Further research is
al10 after catheter ablation of frequent PVCs in the setting of needed to identify the risk predictors for developing PVC-
prior myocardial infarction. Other studies also found signif- induced cardiomyopathy and to make a recommendation on
icant reduction in LV end-diastolic dimensions of between 2 the need and frequency of echocardiographic follow-up in
and 8 mm, mitral regurgitation by 75%, and New York Heart this group of patients. In patients with a diagnosis of
Association functional class by nearly 1 class.14,15,21 Wijn- nonischemic cardiomyopathy and frequent PVCs with uncer-
maalen et al54 described a significant improvement in radial, tainty as to the former being the cause or consequence of the
circumferential, and longitudinal strain after catheter ablation latter, the plausibility of suppressing PVCs with medical or
in patients with frequent PVCs and preserved LVEF. How- interventional therapy before placement of an implantable
ever, like with any invasive intervention, the risks of catheter cardioverter– defibrillator (if current guidelines for its inser-
ablation (whether endocardial or epicardial) must be balanced tion are met) requires further study, bearing in mind that the
against any potential benefits.56 Major complications occur in cardiomyopathy is potentially reversible. In patients with
approximately 3% of cases, including death, stroke, myocar- decreased LVEF, a follow-up period of 3 to 12 months after
dial infarction, atrioventricular block necessitating permanent initiation of antiarrhythmic therapy or catheter ablation is
pacemaker placement, cardiac perforation with or without suggested to allow for recovery of LV function and to avoid
pericardial tamponade, pericardial effusion, and blood vessel unnecessary implantable cardioverter– defibrillator insertions
dissection or stenosis.64 Nevertheless, catheter ablation for in a potentially reversible condition.11,14,15,18 Where reduced
PVCs is associated with a high success rate and few LVEF persists despite diminished PVC burden, the decision
complications.12,14,15,21,58 as to the need for implantable cardioverter– defibrillator
Advancements and innovations in catheter ablation tech- insertion should be governed by current guidelines.69 Fre-
nology have favorably altered the efficacy–safety profile of quent PVCs might be a factor responsible for the lack of
ablation therapy. Our ability to predict the site of origin of the response to medical therapy or cardiac resynchronization
PVCs on surface electrocardiography65 and to safely access therapy. Suppression or elimination of PVCs may improve
the right ventricular outflow tract and left ventricle (including response to cardiac resynchronization therapy.
the pericardium and the aortic cusp region)66,67 and the use of
advanced 3-dimensional mapping tools allows us to precisely Conclusions
localize the PVC foci. Short-term ablation success rates of PVCs are a common occurrence within the general popula-
between 70% and 90% have been reported10,21,22,54; however, tion. In the absence of structural heart disease, they typically
the long-term ablative outcomes remain to be studied. Alter- carry a good prognosis. However, they may present with
native energy sources such as cryoablation may help improve debilitating symptoms. PVCs have been implicated in the
the efficacy–safety profile as compared with traditional development of LV dysfunction and cardiomyopathy, but the
radiofrequency-based techniques.68 Given the favorable effi- risk factors and pathogenic mechanisms are incompletely
cacy–safety profile of current catheter ablation techniques, understood. The suppression of PVCs using either antiar-
we believe that catheter ablation is an increasingly appealing rhythmic pharmacological agents or emerging catheter abla-
therapy for management of patients with suspected PVC- tion techniques appears to reverse the LV dysfunction.
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234 Circ Arrhythm Electrophysiol February 2012
38. Takada H, Takeuchi S, Ando K, Kaito A, Yoshida S. Experimental 57. Krittayaphong R, Bhuripanyo K, Punlee K, Kangkagate C, Chaithiraphan
studies on myocardial contractility and hemodynamics in extrasystoles. S. Effect of atenolol on symptomatic ventricular arrhythmia without
Jpn Circ J. 1970;34:419 – 430. structural heart disease: a randomized placebo-controlled study. Am
39. Kass DA. Pathophysiology of physiologic cardiac pacing: advantages of Heart J. 2002;144:e10.
leaving well enough alone. JAMA. 2002;288:3159 –3161. 58. Zhu DW, Maloney JD, Simmons TW, Nitta J, Fitzgerald DM, Trohman
40. Goldberger JJ, Kadish AH. Cardiac memory. Pacing Clin Electrophysiol. RG, Khoury DS, Saliba W, Belco KM, Rizo-Patron C, Pinski SL. Radio-
1999;22:1672–1679. frequency catheter ablation for management of symptomatic ventricular
41. Adomian GE, Beazell J. Myofibrillar disarray produced in normal hearts ectopic activity. J Am Coll Cardiol. 1995;26:843– 849.
by chronic electrical pacing. Am Heart J. 1986;112:79 – 83. 59. Capucci A, Di Pasquale G, Boriani G, Carini G, Balducelli M, Frabetti L,
42. Lee MA, Dae MW, Langberg JJ, Griffin JC, Chin MC, Finkbeiner WE, Carozzi A, Finzi A, Pinelli G, Magnani B. A double-blind crossover
O’Connell JW, Botvinick E, Scheinman MM, Rosenqvist M. Effects of comparison of flecainide and slow-release mexiletine in the treatment of
long-term right ventricular apical pacing on left ventricular perfusion, stable premature ventricular complexes. Int J Clin Pharmacol Res. 1991;
innervation, function and histology. J Am Coll Cardiol. 1994;24: 11:23–33.
225–232. 60. Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker
43. van Oosterhout MF, Prinzen FW, Arts T, Schreuder JJ, Vanagt WY, AH, Arensberg D, Baker A, Friedman L, Greene HL, Huther ML, Rich-
Cleutjens JP, Reneman RS. Asynchronous electrical activation induces ardson DW. Mortality and morbidity in patients receiving encainide,
asymmetrical hypertrophy of the left ventricular wall. Circulation. 1998; flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl
98:588 –595. J Med. 1991;324:781–788.
44. Akoum NW, Daccarett M, Wasmund SL, Hamdan MH. An animal model 61. Effect of prophylactic amiodarone on mortality after acute myocardial
for ectopy-induced cardiomyopathy. Pacing Clin Electrophysiol. 2011; infarction and in congestive heart failure: meta-analysis of individual data
34:291–295. from 6500 patients in randomised trials. Amiodarone Trials Meta-Anal-
ysis Investigators. Lancet. 1997;350:1417–1424.
45. Huizar JF, Kaszala K, Potfay J, Minisi AJ, Lesnefsky EJ, Abbate A,
62. Vorperian VR, Havighurst TC, Miller S, January CT. Adverse effects of
Mezzaroma E, Chen Q, Kukreja RC, Hoke NN, Thacker LR II,
low dose amiodarone: a meta-analysis. J Am Coll Cardiol. 1997;30:
Ellenbogen KA, Wood MA. Left ventricular systolic dysfunction induced
791–798.
by ventricular ectopy: a novel model for premature ventricular
63. Torp-Pedersen C, Moller M, Bloch-Thomsen PE, Kober L, Sandoe E,
contraction-induced cardiomyopathy. Circ Arrhythm Electrophysiol.
Egstrup K, Agner E, Carlsen J, Videbaek J, Marchant B, Camm AJ.
2011;4:543–549.
Dofetilide in patients with congestive heart failure and left ventricular
46. Smith ML, Hamdan MH, Wasmund SL, Kneip CF, Joglar JA, Page RL.
dysfunction. Danish Investigations of Arrhythmia and Mortality on
High-frequency ventricular ectopy can increase sympathetic neural
Dofetilide Study Group. N Engl J Med. 1999;341:857– 865.
activity in humans. Heart Rhythm. 2010;7:497–503. 64. Wellens HJ. Catheter ablation of cardiac arrhythmias: usually cure, but
47. Wilber DJ. Ventricular ectopic beats: not so benign. Heart. 2009;95: complications may occur. Circulation. 1999;99:195–197.
1209 –1210. 65. Dixit S, Gerstenfeld EP, Callans DJ, Marchlinski FE. Electrocardio-
48. Tikkanen JT, Anttonen O, Junttila MJ, Aro AL, Kerola T, Rissanen HA, graphic patterns of superior right ventricular outflow tract tachycardias:
Reunanen A, Huikuri HV. Long-term outcome associated with early distinguishing septal and free-wall sites of origin. J Cardiovasc Electro-
repolarization on electrocardiography. N Engl J Med. 2009;361: physiol. 2003;14:1–7.
2529 –2537. 66. Daniels DV, Lu YY, Morton JB, Santucci PA, Akar JG, Green A, Wilber
49. Bhushan M, Asirvatham SJ. The conundrum of ventricular arrhythmia DJ. Idiopathic epicardial left ventricular tachycardia originating remote
and cardiomyopathy: which abnormality came first? Curr Heart Fail Rep. from the sinus of Valsalva: electrophysiological characteristics, catheter
2009;6:7–13. ablation, and identification from the 12-lead electrocardiogram. Circu-
50. Delgado V, Ypenburg C, van Bommel RJ, Tops LF, Mollema SA, Marsan lation. 2006;113:1659 –1666.
NA, Bleeker GB, Schalij MJ, Bax JJ. Assessment of left ventricular 67. Ouyang F, Fotuhi P, Ho SY, Hebe J, Volkmer M, Goya M, Burns M, Antz
dyssynchrony by speckle tracking strain imaging comparison between M, Ernst S, Cappato R, Kuck KH. Repetitive monomorphic ventricular
longitudinal, circumferential, and radial strain in cardiac resynchroni- tachycardia originating from the aortic sinus cusp: electrocardiographic
zation therapy. J Am Coll Cardiol. 2008;51:1944 –1952. characterization for guiding catheter ablation. J Am Coll Cardiol. 2002;
51. Edvardsen T, Helle-Valle T, Smiseth OA. Systolic dysfunction in heart 39:500 –508.
failure with normal ejection fraction: speckle-tracking echocardiography. 68. Kurzidim K, Schneider HJ, Kuniss M, Sperzel J, Greiss H, Berkowitsch
Prog Cardiovasc Dis. 2006;49:207–214. A, Pitschner HF. Cryocatheter ablation of right ventricular outflow tract
52. Leitman M, Lysyansky P, Sidenko S, Shir V, Peleg E, Binenbaum M, tachycardia. J Cardiovasc Electrophysiol. 2005;16:366 –369.
Kaluski E, Krakover R, Vered Z. Two-dimensional strain-a novel 69. Epstein AE, DiMarco JP, Ellenbogen KA, Estes NA III, Freedman RA,
software for real-time quantitative echocardiographic assessment of myo- Gettes LS, Gillinov AM, Gregoratos G, Hammill SC, Hayes DL, Hlatky
cardial function. J Am Soc Echocardiogr. 2004;17:1021–1029. MA, Newby LK, Page RL, Schoenfeld MH, Silka MJ, Stevenson LW,
53. Reisner SA, Lysyansky P, Agmon Y, Mutlak D, Lessick J, Friedman Z. Sweeney MO, Smith SC Jr, Jacobs AK, Adams CD, Anderson JL, Buller
Global longitudinal strain: a novel index of left ventricular systolic CE, Creager MA, Ettinger SM, Faxon DP, Halperin JL, Hiratzka LF,
function. J Am Soc Echocardiogr. 2004;17:630 – 633. Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura RA, Ornato
54. Wijnmaalen AP, Delgado V, Schalij MJ, van Huls van Taxis CF, Holman JP, Riegel B, Tarkington LG, Yancy CW. ACC/AHA/HRS 2008
ER, Bax JJ, Zeppenfeld K. Beneficial effects of catheter ablation on left Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities:
ventricular and right ventricular function in patients with frequent pre- a report of the American College of Cardiology/American Heart Asso-
mature ventricular contractions and preserved ejection fraction. Heart. ciation Task Force on Practice Guidelines (Writing Committee to Revise
2010;96:1275–1280. the ACC/AHA/NASPE 2002 Guideline Update for Implantation of
55. Abdalla IS, Prineas RJ, Neaton JD, Jacobs DR Jr, Crow RS. Relation Cardiac Pacemakers and Antiarrhythmia Devices): developed in collab-
between ventricular premature complexes and sudden cardiac death in oration with the American Association for Thoracic Surgery and Society
apparently healthy men. Am J Cardiol. 1987;60:1036 –1042. of Thoracic Surgeons. Circulation. 2008;117:e350 – 408.
56. Ezzat VA, Liew R, Ward DE. Catheter ablation of premature ventricular
contraction-induced cardiomyopathy. Nat Clin Pract Cardiovasc Med. KEY WORDS: arrhythmia 䡲 cardiomyopathy 䡲 heart failure 䡲 premature
2008;5:289 –293. ventricular contractions 䡲 ventricular arrhythmia
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Glenn K. Lee, MBBS; Kyle W. Klarich, MD; Martha Grogan, MD; Yong-Mei Cha, MD
Reference
1. Cha Y-M, Lee GK, Klarich KW, Grogan M. Premature ventricular contraction-induced cardiomyopathy: a treatable
condition. Circ Arrhythm Electrophysiol. 2012;5:229 —236.
e62