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Arrhythmia-Induced Cardiomyopathy JACC State-of-the-Art Review
Arrhythmia-Induced Cardiomyopathy JACC State-of-the-Art Review
18, 2019
Arrhythmia-Induced Cardiomyopathy
JACC State-of-the-Art Review
Jose F. Huizar, MD,a,b Kenneth A. Ellenbogen, MD,a Alex Y. Tan, MD,a,b Karoly Kaszala, MD, PHDa,b
ABSTRACT
Arrhythmias coexist in patients with heart failure (HF) and left ventricular (LV) dysfunction. Tachycardias, atrial
fibrillation, and premature ventricular contractions are known to trigger a reversible dilated cardiomyopathy referred as
arrhythmia-induced cardiomyopathy (AiCM). It remains unclear why some patients are more prone to develop AiCM
despite similar arrhythmia burdens. The challenge is to determine whether arrhythmias are fully, partially, or at all
responsible for an observed LV dysfunction. AiCM should be suspected in patients with mean heart rate >100 beats/min,
atrial fibrillation, and/or premature ventricular contractions burden $10%. Reversal of cardiomyopathy by elimination of
the arrhythmia confirms AiCM. Therapeutic choice depends on the culprit arrhythmia, patient comorbidities, and
preferences. Following recovery of LV function, patients require continued follow-up if an abnormal myocardial substrate
is present. Appropriate diagnosis and treatment of AiCM is likely to improve quality of life and clinical outcomes and to
reduce hospital admission and health care spending. (J Am Coll Cardiol 2019;73:2328–44) Published by Elsevier on
behalf of the American College of Cardiology Foundation.
tachyarrhythmias
While T-CM was first described in a patient with AF
at the beginning of the 20th century, PVC-CM was
only recognized 9 decades later in 1998 (5-7). Signif-
icant skepticism remained on the cause-relationship
alone can result or trigger a reversible nonischemic between arrhythmias and cardiomyopathies until
CM. Most recently, atrial fibrillation (AF) despite experimental animal models developed in 1962 and
adequate rate control as well as premature ventricular 2011 (8,9), respectively, proved that these sustained
contractions (PVCs) have been recognized as a unique arrhythmias could result in LV dysfunction in struc-
etiology of nonischemic dilated cardiomyopathy (1–3). turally normal hearts. This review presents an update
Since the recognition of other arrhythmias besides of the current understanding of AiCM.
tachycardia as a cause of CM, a more inclusive term
of arrhythmia-induced cardiomyopathy (AiCM) has TACHYCARDIA-INDUCED CM
emerged to include tachycardia-induced cardiomyop-
athy (T-CM), AF-CM, and PVC-CM (Central Illustration). DEFINITION AND PREVALENCE. T-CM refers to the
However, this term does not include recently presence of a reversible LV dysfunction solely due to
recognized CM due to conduction abnormalities/ increase in ventricular rates, regardless of tachy-
dyssynchrony, such as chronic RV pacing, left bundle cardia origin. The risk of developing T-CM depends
branch block, and pre-excitation (1,4). not only on the type, but also the duration and rate of
Listen to this manuscript’s
audio summary by
Editor-in-Chief
Dr. Valentin Fuster on From the aVirginia Commonwealth University/Pauley Heart Center, Richmond, Virginia; and the bHunter Holmes McGuire
JACC.org. Veterans Affairs Medical Center, Richmond, Virginia. Dr. Huizar has received funding from the National Institutes of Health as a
Principal Investigator (1R01HL139874-01 and 5R34HL138110-02). Dr. Ellenbogen has served as a consultant, on the Data Safety
Monitoring Board, and as a lecturer for Medtronic and Boston Scientific; has performed talks for and received lecture fees from
Biotronik; and has served as a consultant for and received lecture fees from Abbott and Biosense Webster. All other authors have
reported that they have no relationships relevant to the contents of this paper to disclose.
Manuscript received November 1, 2018; revised manuscript received February 13, 2019, accepted February 18, 2019.
patients without an obvious etiology. Similar to humans, animals exposed to AT = atrial tachycardia
Reversal of CM by elimination of tation, decrease in LV dP/dtmax and myocar- RFA = radiofrequency ablation
arrhythmia not only confirms the dial blood flow, and increase in LV wall stress T-CM = tachycardia-induced
AV conduction with rates >150 beats/min. A recent present. Thus, an ambulatory ECG monitor for at least
clinical study found a more severe LV dysfunction a 2-week period is key to confirm or exclude T-CM.
(LVEF 29.3 6.6%) in T-CM when compared with Echocardiogram or cardiac magnetic resonance can
dilated and inflammatory CM (32.1 10.2% and 41.9 assist in excluding other etiologies. T-CM is charac-
12.9%, respectively; p < 0.001) (18). terized by a dilated CM (increased LV end-diastolic
Major reported symptoms include palpitations dimension and area) with moderate to severe biven-
(29%), HF class III to IV (47%), and syncope/pre- tricular systolic dysfunction and normal LV septal
syncope (12%), while the remaining may have no and posterior wall thickness (lack of hypertrophy).
symptoms (10). Sudden cardiac death is uncommon Mitral insufficiency may be present due to LV and
but has been reported in up to 8% to 12% despite mitral annular dilatation with lack of leaflet coapta-
treatment and resolution of cardiomyopathy (14,20). tion (16).
T-CM should be suspected in patients with LV Neurohormonal markers such as brain natriuretic
dysfunction and a prior or persistent or frequent peptide (BNP) and pro-BNP are commonly elevated
paroxysmal tachycardia without obvious etiology depending on the degree of heart failure and CM
(Table 2). A superimposed T-CM should be considered (14,21). Moreover, a sudden drop of pro-BNP within a
despite underlying secondary CM (ischemic, infiltra- week of elimination of tachycardia is supportive of
tive, or toxic/drug-related) if the tachycardia is T-CM (21). However, the final diagnosis of T-CM can
JACC VOL. 73, NO. 18, 2019 Huizar et al. 2331
MAY 14, 2019:2328–44 Arrhythmia-Induced Cardiomyopathy
In the presence of superimposed T-CM, full Ion Currents Y ICa Y ICa and Cav1.2
Y Ito and Kv4.3
reversibility of LV function is unlikely after treatment Y IKr
of tachyarrhythmia. Nevertheless, treatment should Ca2þ Transient / SR release Decreased Decreased
not be discouraged as it may have small yet signifi- SR Ca2þ-uptake (SERCA2a) Decreased Decreased
premise that AF alone can lead to CM despite appro- frequently required. In contrast, AADs have an overall
priate rate control. 30% to 50% success rate to maintain sinus rhythm
AF-CM is defined as LV systolic dysfunction in with frequent discontinuation due to side effects
patients with paroxysmal or persistent AF despite (2,26). Further evidence suggests that AF ablation
appropriate rate control. Thus, an ambulatory Holter may be superior to AADs in AF-CM (2). Landmark AF
monitor is key to rule out poor rate control and T-CM. trials with AADs have failed to demonstrate outcome
Despite AF being the most prevalent arrhythmia, the benefits including HF admissions in patients with and
prevalence and factors that predispose or prevent AF- without HF or CM (2,27,28). This is in contrast to
CM are unknown. A frequent clinical challenge is to randomized clinical studies comparing AF ablation as
recognize whether the AF is due to HF and cardio- a rhythm control versus rate control strategy, which
The mechanism of AF-CM is unknown (Central 60% to 70% in patients with AF and CM randomized
Illustration). It is believed that AF-CM is triggered in to ablation (2,13,23,29). The only trial comparing
part due to: 1) heart rate irregularity with calcium rhythm control strategies (ablation vs. amiodarone)
mishandling (24); and 2) loss of atrial contraction/ in patients with AF and CM demonstrated ablation to
emptying associated with sympathetic activation be superior by improving freedom of AF (70% vs.
contributing to limited ventricular filling and 34%), quality of life, HF admissions (31% vs. 57%) and
increased filling pressures, functional mitral mortality (8% vs. 18%) after 2-year follow-up (26).
regurgitation, and diastolic dysfunction (2,25). Un- Last, the CAMERA-MRI (Catheter Ablation Versus
fortunately, no AF-CM animal models exist to better Medical Rate Control in Atrial Fibrillation and Systolic
understand the causality, risk factors, and/or mech- Dysfunction) study supports the use of cardiac mag-
PVC burden >5%, a PVC burden $10% is often dyssynchrony, and increased heart rate (Table 4)
considered high and significant enough to trigger (41,50–54). Furthermore, it is unclear if and how these
PVC-CM. triggers, by altering hemodynamics and autonomic
EPIDEMIOLOGY OF PVCs AND PVC-CM. The inci- nervous system, contribute to the development of
dence of PVCs in a 10-s 12-lead ECG is estimated be- PVC-CM (55,56).
tween 1% to 4% of patients without heart disease Post-extrasystolic potentiation together with heart
(30,31). However, the prevalence of PVCs is signifi- rate irregularity, LV dyssynchrony, AV dissociation,
cantly higher during ambulatory ECG recordings and alteration in autonomic nervous system are
(40% and 75% of participants on 24- to 48-h ambu- possible triggers of PVC-CM. However, differences in
latory Holter monitoring) (31). This can be explained cellular and electrical remodeling between PVC- and
by a significant variability of PVC frequency with time T-CM (Table 1) reinforce the argument that tachy-
(32,33). cardia is unlikely to be the sole trigger for PVC-CM.
Prevalence of PVCs is also age-dependent The role of post-extrasystolic potentiation and
with, <1% in children younger than age 11 years and heart rate irregularity could be addressed by evalu-
near 70% in subjects age 75 years and older (30,31). ating the chronic effects of frequent PACs, which lack
PVCs are more frequently associated with post- LV dyssynchrony. Although Pacchia et al. (57)
myocardial infarction, coronary heart disease, and demonstrated that CM could be induced by atrial
dilated CM and HF (30,34). Furthermore, almost one- bigeminy, this has not been observed clinically and in
half of patients with HF class II and III had frequent other animal models (58–60). These findings suggest
PVCs (>1,000 PVCs/day) (34). that heart rate irregularity and post-extrasystolic
Clinical studies have found high PVC burden potentiation play a limited role, if any, in the patho-
associated with LV dysfunction, increased risk of physiology of PVC-CM.
systolic HF (hazard ratio [HR]: 1.48 to 1.8) and mor- Finally, Gerstenfeld’s group demonstrated in a
tality (HR: 1.31) (35–41) even after adjusting for age bigeminy PVC swine model that LV dysfunction is
and other ECG abnormalities (30). Surprisingly, a more pronounced in PVCs from LV epicardium as they
6-fold increased risk (HR: 6.5) of systolic HF has demonstrate a higher degree of dyssynchrony when
been reported in subjects age <65 years with PVCs compared with endocardial RV free wall (59). This is
without other cardiovascular risk factors (42) and also consistent with clinical studies where epicardial
a higher mortality risk for those with heart rate PVCs and QRS >150 ms were predictors of PVC-CM
>100 beats/min (30). Last, a significant increased risk (61,62).
of incident stroke (HR: 1.71; 95% confidence interval POTENTIAL MECHANISM(S) OF PVC-CM. In contrast
[CI]: 1.14 to 2.59) has been reported on a secondary to T-CM, the cellular mechanism of PVC-CM has not
analysis of the ARIC (Atherosclerosis Risk In Com- been extensively studied. Yet, it is clear that there
munities) study, which the investigators attribute to are distinct differences in histopathological and
possible atrioventricular remodeling (43). cellular features compared with other HF models
The prevalence of PVC-CM has been reported at 7% including T-CM (Central Illustration, Table 1)
among patients with frequent PVC burden >10% (44). (8,9,15,16,18,19,59,63,64).
Nevertheless, PVC-CM is likely underestimated (31). The primary cause of contractile dysfunction in
Clinical studies have reported a diagnosis of PVC-CM PVC-CM appears to be disorders of the calcium-
in 9% to 30% of patients referred for RFA of PVC induced calcium release mechanism itself, with al-
(35,38,45–47). Similarly, a secondary analysis of the terations of dyad (L-type Ca channel and Ryanodine
CHF-STAT (Survival Trial of Antiarrhythmic Therapy receptor) function proposed as a potential mecha-
in Congestive Heart Failure) (48) (>10 PVCs/h and nism. Similar to other cardiomyopathies, this PVC-CM
LVEF <40%) demonstrated an estimated rate of PVC- model has revealed electrophysiological remodeling
CM of 40% in all patients with CM and up to 66% in (Table 1). Histopathological abnormalities are distinct
nonischemic CM (49). This data supports frequent without evidence of increased inflammation or
PVCs as a significant and modifiable risk factor for apoptosis and minimal or no fibrosis. Mitochondrial
systolic HF and increased mortality. studies have demonstrated no changes in oxidative
ACUTE EFFECTS OF PVCs AND POTENTIAL phosphorylation (8). These findings are supported
TRIGGERS OF PVC-CM. PVCs have acute intrinsic clinically by the lack of scar on cardiac magnetic
effects that are innate to their ectopic and premature resonance imaging of patients with PVC-CM (38).
origin, including heart rate irregularity and post- These findings further confirm a primary functional
extrasystolic potentiation, LV dyssynchrony, AV abnormality as a primary mechanism of this
2334 Huizar et al. JACC VOL. 73, NO. 18, 2019
Representative examples of patients with atrial fibrillation (AF) with late gadolinium enhancement (LGE) in a patient without (A) and with AF-cardiomyopathy (CM) (B).
(Top) The presence (A, arrows) and absence (B) of scar in cardiac magnetic resonance with LGE in a patient without and with AF-CM, respectively. (C) Change in left
ventricular ejection fraction (LVEF) from baseline stratified by the presence or absence of scar and (D) correlation between % of scar (LGE) and change in LVEF from
baseline after catheter ablation for AF. Reprinted with permission from Prabhu et al. (23).
JACC VOL. 73, NO. 18, 2019 Huizar et al. 2335
MAY 14, 2019:2328–44 Arrhythmia-Induced Cardiomyopathy
Post-extrasystolic potentiation
Increase in contractility that follows either an atrial or ventricular extrasystole, associated with Ca2þ overload (54).
Has an inverse relationship to PVC coupling interval (prematurity): shorter PVC coupling intervals (early PVCs) have a greater intracellular Ca2þ and
post-extrasystolic potentiation (54).
Increase in O2 consumption with little change in cardiac output despite reduction of LVEDP (mean 13 mm Hg) and increase in coronary flow (54).
LV dyssynchrony
Uncoordinated contraction of the LV segments.
Cause disruption and progression of dyssynergic LV wall motion resulting in LV dysfunction (41,85,100).
Directly proportional to the PVC coupling interval: longer PVC coupling intervals (late PVCs) demonstrate a greater LV dyssynchrony (52).
Tachycardia
Mean heart rate in ambulatory ECG Holters in PVC-CM is frequently normal, likely due to compensatory pauses.
Clinical and animal studies have not found any difference in mean heart rate between PVC-CM and other etiologies (41,50,65).
AV dyssynchrony
Occurs when atrial contraction takes place against a closed AV valve during PVC, demonstrated as a prominent “a-wave in the PCWP tracing.
PVC-PCWP augmentation (defined as prominent a-wave >15 mm Hg) was associated with a lower LVEF (52 9% vs. 62 10%; p < 0.01) and
shorter coupling interval (432 41 ms vs. 522 54 ms; p < 0.0001) compared with those without PVC-PCWP augmentation despite having
similar PVC burden (53).
Autonomic nervous system
PVCs alone have shown to acutely increase sympathetic nerve activity not only at a cardiac level but also peripherally (56)
PVCs elicit a greater neuronal response than other stimuli such as aortic or inferior vena cava occlusion (55)
PVCs with variable prematurity had the greatest neuronal response (convergent, sympathetic, and parasympathetic input) when compared to early
and late PVCs (55)
AV ¼ atrioventricular; CM ¼ cardiomyopathy; ECG ¼ electrocardiogram; LV ¼ left ventricular; LVEDP ¼ left ventricular end-diastolic pressure; LVEF ¼ left ventricular ejection
fraction; PCWP ¼ pulmonary capillary wedge pressure; PVC ¼ premature ventricular contraction.
reversible CM (8,38,59,63,64). Whether all the cellular other patients’ characteristics and/or PVC features
and molecular changes are in response to the CM play a role in the pathophysiology of PVC-CM. Some
rather than the cause of the CM remains unclear. other PVC features have been found to be indepen-
PREDICTORS OF PVC-CM. Clinical evaluation of un- dent predictors for PVC-CM such as male sex (74),
derlying effects of frequent PVCs have limitations due lack of symptoms (adjusted OR: 13.1; 95% CI: 4.1 to
to a variability of PVC features (origin, prematurity, 37.0) or duration of palpitations >30 months, vari-
frequency, QRS width), presence of confounding pa- ability of PVC coupling interval (OR: 1.04; 95% CI:
tient comorbidities, and small sample population. 1.03 to 1.07 [39]), QRS duration of PVC >150 ms,
PVC burden has been shown to be a major predictor and epicardial origin (37,44,45,61,62,65,67,74,75)
of PVC-CM (odds ratio [OR]: 1.25 per each percent (Figure 2). Other less frequently reported indepen-
increase in PVC burden; 95% CI: 1.10 to 1.42) dent predictors are body mass index >30 kg/m 2
(35,45,62,65–67). Two main studies have shown that (OR: 3.03; 95% CI: 1.2 to 7.7) (39), less variability in
PVC burden >16% and 24% best identifies patients circadian PVC distribution (OR: 16.3; 95% CI: 1.7 to
with a diagnosis of PVC-CM (sensitivity and speci- 155.0) (76), and presence of retrograde P-wave (OR:
ficity of 79% to 100% and 78% to 87%, respectively) 2.79; 95% CI: 1.08 to 7.19) (67). AV dyssynchrony
(35,44). Although these and other studies suggest that during PVCs could potentially be a predictor, but
a PVC burden of at least 10% is required to induce yet remains to be studied (53,67). Except for PVC
PVC-CM (35,44,68–70), other studies question this burden, most predictors have been variably reported
minimal PVC threshold, because they have shown reflecting the heterogeneity of different populations.
improvement in LV function with PVC burden as low Although further validation is required, a PVC-CM
as 6% to 8% (48,51,66,71–73). The length of ambula- index, including PVC burden, PVC-QRS width,
tory ECG monitoring has important implications, and epicardial origin, has been developed in an
because increasing the duration from a 24-h to a 7-day attempt to identify patients with high probability of
ambulatory Holter monitor can doubled the number PVC-CM (62).
of patients who reach the 10% threshold (33). Although short PVC coupling intervals have been
Nevertheless, some patients do not develop a CM associated with idiopathic ventricular fibrillation (77),
even with high PVC burden. Thus, it is likely that most studies have not found a clear relationship
2336 Huizar et al. JACC VOL. 73, NO. 18, 2019
Representative cases of patients with similar high premature ventricular contraction (PVC) burden from left coronary cusp without (A) and with (B) associated CM (LVEF
40%). PVC-CM has a wider PVC QRS duration (172 ms) when compared with preserved LV function (150 ms). Reprinted with permission from Carballeira et al. (75). (C)
Representative case of PVC-CM with dispersion of CI of 144 ms (cutoff of CI dispersion >99 ms best identified patients with and without PVC-CM). Reprinted with
permission from Kawamura et al. (39). Abbreviations as in Figure 1.
JACC VOL. 73, NO. 18, 2019 Huizar et al. 2337
MAY 14, 2019:2328–44 Arrhythmia-Induced Cardiomyopathy
develop PVC-CM (68,78), but others reported that Patient characteristics Older with known heart Healthy otherwise
disease
PVC coupling interval variability (dispersion) is
Comorbidities CAD, myocarditis, RV No prior cardiac hx
associated with not only a higher risk of PVC-CM, but dysplasia
also cardiovascular mortality (39,79,80). A potential Echocardiogram Segmental hypokinesis, Global hypokinesis,
LVEF <25% LVEF 37 10%
explanation (demonstrated in animal data) is the
Cardiac magnetic resonance Significant scar Absence or minimal scar
large cardiac neuronal disturbance demonstrated in imaging (late-gadolinium burden (#9 g)
PVCs with variable coupling interval, beyond what is enhancement)
PVC frequency <5,000/24 h (<5%) $10,000/24 h ($10%)
seen in short or long coupling intervals (55). Animal
PVC pattern Multifocal Monomorphic
studies are currently underway to investigate the ef-
QRS morphology Nonspecific RVOT/LVOT/epicardial
fects of PVC coupling interval on LVEF. Response to PVC suppression No change in LV function Improvement of LV function
PVC locations other than epicardial origin have not
shown to be predictors of PVC-CM (45,68). One of the CAD ¼ coronary artery disease; RV ¼ right ventricular; RVOT ¼ right ventricular outflow tract; other abbrevia-
tions as in Table 4.
largest series have found that PVC-CM have a PVC
origin from coronary sinus (epicardial) in 24%, RV
outflow in 21%, LV outflow tract in 28%, mitral
bystanders” in patients with CM. Even if PVCs are the
annulus (endocardial) in 7%, RV/LV septum in 5%,
result of CM, these PVCs, if frequent, may contribute
and RV/LV apex in 4% (65).
to and further worsen CM and HF symptoms; this is
Last, genetic predisposition could explain why
referred to as “superimposed” PVC-CM (73,83). In
some patients are prone to develop PVC-CM while
selected cases, echocardiographic and PVC features
others do not despite similar PVC burden. For
can help identify these patients (Table 5) (1).
instance, R222Q missense variant of the Nav1.5 sub-
Even though the ECG is important, a prolonged
unit of sodium channel, resulting in a greater and
ambulatory ECG monitor is essential to improve the
earlier sodium current, has been attributed to a rate-
diagnostic yield of high PVC burden. As noted by
dependent ectopy of Purkinje and associated with a
Loring et al. (33), a minimum of 6 days is required to
CM reversible upon treatment with amiodarone or
detect an individual’s maximum PVC burden. In
flecainide (81).
LV Ejection Fraction
First Author, Baseline PVC-CM Suppression Successful Pre-PVC Post-PVC Follow-Up Notes/ Outcome/
Year (Ref. #) N PVC Burden Rate Strategy CM Suppression Suppression Suppression (Months) Predictors (P)
Singh et al., 1995 336 >10 PVC/h 40% Amiodarone vs. I þ NI 72% (Amio) A: 24.9 8% A: 33.7 11% 45 *15% pts in placebo had
(48,49) placebo (RC)* 12% (placebo) P: 25.7 8% P: 29.2 11% LVEF improvement
(delta EF $10%)
despite PVC
suppression <80%
Duffee et al., 1998 (6) 5 >20,000/day — AADs NI 35% 27 10% 49 17% 63
Yarlagadda et al., 8 17,541/day — RFA NI* 87% 39 6% 62 6% 3 *Included PVC from RVOT
2005 (71) only
Bogun et al., 18 37 13% 82% RFA NI 80% 34 13% 59 7% 46
2007 (36)
Taieb et al., 2007 (101) 6 17,717/day — RFA NI ? 42 2.5% 57 3.7% 6
Sarrazin et al., 12 22 12% 66% RFA I* 100% 38 11% 51 0.1 14 13 *Included pts with remote
2009 (73) hx of MI referred for IC
& PVC $5%; NYHA
improved after RFA
Baman et al., 2010 57 33 13% 81% RFA NI* 84% 35 9% 54 10% 48 *Excluded CAD only;
(35) Burden (P)
Hasdemir et al., 2011 17 29 9% — RFA NI* 75% 38 7% 53 7% 4 *Excluded prior cardiac or
(44) ischemic disease
Mountantonakis et al., 69 29 13% — RFA NI 78% 35 9% 48 10%* 11 6 LVEF improvement
2011 (91) correlated with ablation
outcome and decline in
PVC burden.
Lu et al., 2012 (46) 24 15 6% 58% RFA I þ NI ? 32 15% 43 14% 8
Ban et al., 2013 (67) 28 26 10% 75% RFA NI 91% 44 5% 55 6% 19 17 Burden (P), retrograde
P waves (P)
Yokokawa et al., 87 26 11% 86% RFA NI 86% 39 10% 59 4% 5 to 45 32% with delayed recovery
2013 (47) of LVEF (5–45 months).
Epicardial origin
predicted delayed
recovery.
Zhong et al., 2014 (68) 121 25% (RFA) 32% RFA vs. I þ NI 86% (RFA) 42% 55%* 6.3 2.4 *EF restored 47% (RFA) vs.
22% (AAD) AAD (NR) 49% (AAD) 21% (AAD); PVC
CI <450 ms (P)
El Kadri et al., 30 23 8.8% 50% RFA NI* 60% 34 15% 45 17% 30 28 *Included pts with scar or
2015 (83) prior CM; NYHA
improved after RFA
Penela et al., 2015 (70) 66 21 12% 26% RFA I þ NI 76% 28 4% 42 12% 12 Included only LVEF <35%
referred for ICD
Latchamsetty et al., 245 27 13% 67% RFA NI 71% 38% 50% 20 22 Burden (P), Male sex (P),
2015 (45) epicardial origin (P)
Sadron Blaye-Felice 96 26 12% — RFA NI* 80% 38 10% 50 13% 24 21 *39% had HD (ischemic,
et al., 2016 (65) HTN < valvular) with
high suspicious of PVC–
CM; Burden (P),
epicardial origin (P) and
lack of palpitations (P)
Hamon et al., 2016 58 23 12% 54% RFA I þ NI þ 91% 38 9% 55 9% 22 15 Burden (P), epicardial origin
(62) SHD (P), PVC–QRS duration
(P), SHD (P)
Lee et al., 2018 (66) 54 28% (19–44) 61% RFA I þ NI 73% 40% 52% (45–56) 7 (median) Burden (P), Male sex (P)
(30–46)
All studies were observational except the CHF-STAT study (48), which was a randomized controlled trial. PVC-CM rate refers to the percentage of patients with improvement of LV function (LVEF normalize
or absolute increase $10% to 15%) after PVC suppression. *See column “notes.”
I ¼ ischemic cardiomyopathy; NI ¼ nonischemic cardiomyopathy; NYHA ¼ New York Heart Association functional class; SHD ¼ structural heart disease (including valvular heart disease, ischemic,
hypertensive, and dilated cardiomyopathy); P ¼ predictors of PVC-CM only by multivariate analysis; pts ¼ patients; RFA ¼ radiofrequency ablation; other abbreviations as in Tables 3, 4, and 5.
contrast, a 24-h Holter identified only 53% of patients PVC-CM is characterized by mild to moderate LV
with a PVC burden >10%, which would likely miss systolic dysfunction, LV dilatation, mild mitral
almost one-half (47%) of patients with potential PVC- regurgitation, and LA enlargement, which resolved
CM diagnosis (33). within 2 to 12 weeks after elimination of PVCs
JACC VOL. 73, NO. 18, 2019 Huizar et al. 2339
MAY 14, 2019:2328–44 Arrhythmia-Induced Cardiomyopathy
(8,41,50). Cardiac imaging is key to identify LV epicardium, or nearby critical structures such as cor-
dysfunction and prompt suspicion of PVC-CM in pa- onary arteries and conduction system (40,45,68).
tients with high PVC burden ($10%) (Table 5). Cardiac Thus, antiarrhythmic therapy may be necessary in
magnetic resonance with late-gadolinium enhance- about 5% to 15% of patients after RFA (68). PVC
ment has the advantage of identifying scar and suppression strategies (RFA or AADs) carry an overall
quantifying scar burden, which in turn potentially low risk. While the complication rates of RFA have
predicts the response to PVC suppression (84). Few been reported between 5% to 8%, antiarrhythmics
clinical and animal studies have also demonstrated have a discontinuation rate of near 10% due to short-
diastolic dysfunction after 12 weeks of chronic ven- and long-term side effects (45,68,84,91,92) in addi-
tricular bigeminy (50,85). Interestingly, a subclinical tion to potentially decreased efficacy overtime (93).
form of PVC-CM (LVEF $50%) has been reported us- Randomized clinical studies of AADs have only
ing speckle tracking by a decrease in radial, circum- been performed prior to the recognition of PVC-CM
ferential, and longitudinal strain that can reverse as a unique entity. Whereas the CAST (Cardiac
after RFA (86,87). This is further supported by Arrhythmia Suppression Trial) trial demonstrated an
translational studies demonstrating a mild and linear increase mortality with class IC agents in patients
decrease of LV systolic function with 7%, 14%, and with frequent ectopy after MI, the GESICA (Grupo de
25% PVC burden (Figure 3) (50). Estudio de la Sobrevida en la Insuficiencia Cardiaca
Most recently, myocarditis has been implicated as en Argentina), CAMIAT (Canadian Amiodarone
a potential trigger for frequent PVCs and CM (88), Myocardial Infarction Arrhythmia Trial), and CHF-
while elevated hs-CRP has been reported to be an STAT trials demonstrated at least a trend toward a
independent predictor of PVCs in a Chinese popula- decrease in mortality after MI and in nonischemic CM
tion study (89). Thus, it may be clinically challenging with the use of amiodarone (48,94). No randomized-
to determine a causal versus bystander role of PVCs in prospective studies have compared the efficacy and
an inflammatory process. outcomes between RFA and AAD therapy. A contem-
porary retrospective study has shown that PVC
TREATMENT. Currently, a PVC suppression strategy reduction was greater with RFA than antiarrhythmics
with RFA or AADs is a widely accepted intervention to (mean reduction: RFA 15.5 1.3% vs. AADs 4.8
treat a CM that might be caused or exacerbated by 0.8; p < 0.001) (68). Although RFA and antiar-
frequent PVCs (1). However, the treatment of rhythmic drugs can successfully suppress high PVC
frequent PVCs ($10% burden) without LV dysfunc- burdens, a single retrospective study suggests that
tion (LVEF $50%), symptoms, or idiopathic ventric- RFA may be more effective in patients with lower PVC
ular fibrillation is less clear. Due to the lack of data burdens (68).
and potential risk of developing PVC-CM, these pa- PVC suppression in PVC-CM has been shown to
tients require close monitoring every 6 to 12 months improve LV function, LV dilatation, mitral regurgita-
or more closely if HF symptoms develop. Echocar- tion, and BNP levels (1,70). The mean improvement of
diogram should be repeated to confirm normal LV LVEF after RFA in most studies is between 10% and
function, while a prolonged ambulatory ECG monitor 15% (Table 6) (45,65,68,70,91,92) even in super-
should be considered to reassess PVC burden. imposed PVC-CM. A recent multicenter retrospective
Although spontaneous resolution of frequent PVCs study of 245 patients with nonischemic CM and
has not been evaluated, data from the CHF-STAT trial frequent PVCs (mean PVC burden 20 13%) demon-
demonstrated that 12% of patients on placebo had strated improvement of LV function in 67% of
spontaneous and significant decrease in PVC burden patients after RFA (45). Similarly, a prospective
at 6 months (49). study demonstrated a significant decrease in BNP
PVC suppression is considered successful if burden levels while primary prophylaxis ICD implantation
is decreased by >80% of baseline PVCs, as it likely was avoided in 80% of all patients with PVC burden
represents a true effect of treatment rather than >13% due to significant improvement of LVEF after
spontaneous PVC variability (90). However, this cri- successful RFA (95). Interestingly, another study
terion was based on 24-h Holter data and it is unclear (40) found that 81% of patients (n ¼ 36) with
if this is different nowadays with extended 2- or even abnormal baseline estimated glomerular filtration
4-week ambulatory monitors. Current therapies, rate (<60 ml/min/1.73 m 2) had significant improve-
RFA and AADs, have similar long-term PVC ment in renal function (estimated glomerular filtra-
suppression success rate between 70% and 80% tion rate 51 to 57 ml/min/1.73 m 2) after RFA of PVCs.
(45,48,62,68,70,91). Successful RFA may be limited in Successful ablation (OR: 15.7; 95% CI: 1.4 to 180.0),
patients with PVCs originating from papillary muscle, myocardial scar mass <9 g (OR: 0.9; 95% CI: 0.81
2340 Huizar et al. JACC VOL. 73, NO. 18, 2019
A 53-year-old man with 21% PVC burden and LVEF of 40% underwent PVC ablation. Successful ablation was achieved at the midseptal right ventricular outflow tract
(RVOT) just above the pulmonary valve with a PVC burden of 1.5% after radiofrequency ablation. (A) 12-lead electrocardiogram of representative PVC. (B) Baseline
cardiac magnetic resonance demonstrates absence of scar with late-gadolinium enhancement. LVEF normalized to 55% after 3 months, diagnostic of PVC-CM.
Abbreviations as in Figures 1 and 2.
to 0.99), and reduction of mean PVC burden LVEF (92). Recently, post-extrasystolic potentiation
(OR: 1.09; 95% CI: 1.01 to 1.16) have been shown to be assessed by invasive blood pressure monitoring has
independent predictors of response to RFA (84,91). been described as a predictor of LV function recovery
This supports assessment of scar burden using after radiofrequency ablation (96).
cardiac magnetic resonance with late-gadolinium Clinical studies have consistently demonstrated a
enhancement to predict responders versus non- significant increase in LV function after PVC sup-
responders to PVC suppression (Figure 4). However, if pression with antiarrhythmic agents, ranging from
significant PVC burden reduction (>20%) is achieved, 10% to 13% (48,68). Because the CAST trial included
the presence of myocardial scar seems to be less patients with ischemic CM, the guidelines discourage
relevant to predict response (84). In contrast, PVC the use of Class IC antiarrhythmic agents not only in
location does not appear to predict improvement of ischemic but also in nonischemic CM patients. Most
JACC VOL. 73, NO. 18, 2019 Huizar et al. 2341
MAY 14, 2019:2328–44 Arrhythmia-Induced Cardiomyopathy
LV dysfunction/Cardiomyopathy
No No
Tachyarrhythmias / AF PVC burden ≥10% Optimize HF Med Rx
Yes Yes
Normalization
Improvement No Change
of LVEF
of LVEF
*Consider following the algorithm even if coronary artery disease (CAD) is documented or worsening of prior CM is noted (superimposed arrhythmia-induced
cardiomyopathy [AiCM]). †Two-week ambulatory Holter is preferred as it increases the diagnosis yield of high PVC burden ($10%). ‡Consider cardiac magnetic
resonance to assess scar burden and predict response to PVC suppression. Short-term observation is reasonable for PVC-CM as 15% of cases may improve without PVC
suppression strategy (49). §Continue close surveillance and HF med Rx in those with abnormal LV dimensions and presence of scar (cardiac magnetic resonance
imaging). Abbreviations as in Figures 1 and 2.
recently, a small retrospective study (93) demon- study, PAPS: Pilot (Prospective Assessment of PVC
strated that flecainide and propafenone (Class IC) can Suppression in Cardiomyopathy: A pilot study), is
also improve LV function (LVEF from 37.4 2.0% to ongoing to better understand the prevalence
49.0 1.9%), even without an 80% PVC suppression of frequent PVCs and CM and prove the feasibility
(PVC burden from 36.2 3.5% to 10.0 2.4%) without of a large-scale randomized clinical trial
an increase in ventricular arrhythmias and/or death (NCT03228823). Focused studies to understand the
(93). prevalence of PVC-CM are key to provide a better
Although the current published data supports perspective of the magnitude of this clinical entity
improvement of LV function and symptoms by elim- and its potential impact in the HF population.
ination of PVCs, there is limited data that PVC sup-
pression will subsequently modify the risk of CLINICAL SIGNIFICANCE OF AiCM
cardiovascular events including HF and death
(97,98). Over the past few years it has become clear Tachycardia, AF, and PVCs are highly prevalent in
that comparative effectiveness trials are needed to patients with CM and HF, and they must be
understand how to best treat patients with frequent considered as a potential cause of an HF and CM
PVCs and CM (95,97). Currently, a pilot multicenter (Figure 5). While it is unclear why some patients
2342 Huizar et al. JACC VOL. 73, NO. 18, 2019
with high arrhythmia burden (frequent heart rate with an obvious etiology (Figure 5). T-CM should be
>100 beats/min and/or PVC burden $10%) do not strongly considered in patients with paroxysmal or
develop CM, these patients are at risk and should persistent SVTs, primarily AF/atrial flutter, atrial
undergo close monitoring every 6 to 12 months or tachycardia, and persistent junctional reciprocating
sooner if symptoms develop. The risk factors for tachycardia with heart rates above 100 beats/min. AF-
developing PVC-CM include male sex, lack of CM should be suspected in patients with nonischemic
symptoms, and PVCs with QRS duration >150 ms, CM and paroxysmal, persistent, or permanent AF,
epicardial origin, and/or variable coupling interval. even with appropriate rate control, whereas PVC-CM
As any other CM, AiCM can lead to HF admissions should be considered in patients with nonischemic
and implantation of defibrillators and resynchroni- CM and PVC burden $10%. Appropriate diagnosis and
zation devices (51,73,95,99). Thus, AiCM carries a treatment of AiCM not only will reverse LV dysfunc-
significant financial burden if untreated, which tion with its associated morbidity, mortality, and
makes diagnosis and treatment paramount to health care spending, but most importantly, will
improve morbidity and potentially decrease health improve quality of life and long-term prognosis.
care costs. A better understanding of the mechanism Future clinical studies are needed to compare stan-
of tachycardia and PVC-CM could lead to novel dard treatment strategies and identify best long-term
therapies to prevent and improve outcomes, espe- PVC suppression and prevention of recurrence of
cially when antiarrhythmic agents or RFA are not PVC-CM.
feasible or unsuccessful.
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