JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
18, 2019
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VOL. 73, NO.
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THE PRESENT AND FUTURE
JACC STATE-OF-THE-ART REVIEW
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.
A rrhythmias have been long
part of the clinical presentation of heart
failure (HF) and cardiomyopathy (CM). Yet,
supraventricular or ventricular
considered
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
From the aVirginia Commonwealth University/Pauley Heart Center, Richmond, Virginia; and the bHunter Holmes McGuire
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.
ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2019.02.045
JACC VOL. 73, NO. 18, 2019
MAY 14, 2019:2328–44
HIGHLIGHTS

Tachycardias, AF, and PVCs are known to
trigger a reversible dilated CM.

AiCM should be highly suspected in
patients without an obvious etiology.

Ambulatory ECG monitors are key to
screen and properly diagnose AiCM.

Reversal of CM by elimination of
arrhythmia not only confirms the
diagnosis but may significantly
improve outcomes.
tachycardia. The overall prevalence and incidence of
T-CM is unclear and is likely underestimated.
A study reported T-CM in 2.7% patients referred for
radiofrequency ablation (RFA); however, it also
included patients referred for PVC ablation (10). T-CM
has been reported in 10% of patients with atrial
tachycardia (AT) (11), and as high as 37% of patients
with incessant AT. Moreover, permanent junctional
reciprocating tachycardia appears to have the highest
association with T-CM (20% to 50%) as it frequently
presents as an incessant supraventricular tachycardia
(SVT) (12). Despite AF being the most prevalent
arrhythmia, there is no clear data on the prevalence of
T-CM in this population. Only a single study reported
T-CM in 4% of patients referred for pulmonary vein
isolation (13); however, this data is confounded by
selection and referral biases. Children are also prone
to T-CM resulting most frequently from AT (59%),
permanent junctional reciprocating tachycardia
(23%), and ventricular tachycardia (7%) (12).
CAUSES. T-CM can manifest in the setting of either
an incessant or paroxysmal tachycardia and it should
be suspected if no other cause of LV dysfunction is
identified. A frequent challenge is to identify a
superimposed T-CM when tachycardia worsens a
known CM. T-CM has been reported to present weeks,
months, or years after the onset of tachycardia (14).
Supraventricular arrhythmias are the most com-
mon etiology, namely AF and atrial flutter with rapid
ventricular response. Although rare, other arrhyth-
mias, such as incessant or very frequent paroxysmal
AT, persistent atrioventricular (AV) reciprocating
tachycardia and AV nodal re-entrant tachycardia,
sustained sinus tachycardia, frequent ventricular
tachycardias (idiopathic, bundle branch, and fascic-
ular) and pacemaker-mediated tachycardia can also
be responsible (11,14). In general, it is suspected that
faster tachycardia rates and ventricular arrhythmias
Huizar et al. 2329
Arrhythmia-Induced Cardiomyopathy
cause a more severe T-CM, although no ABBREVIATIONS
AND ACRONYMS
studies exist to support this hypothesis (1).
PATHOPHYSIOLOGY AND MECHANISM. An- AADs = antiarrhythmic drugs
imal models have been key to understand the AiCM = arrhythmia-induced
pathophysiology and mechanism of T-CM. cardiomyopathy
Similar to humans, animals exposed to AT = atrial tachycardia
persistent tachycardia using a continuous CM = cardiomyopathy
rapid atrial or ventricular pacing develop HF PVC = premature ventricular
symptoms, LV systolic dysfunction and dila- contraction
tation, decrease in LV dP/dtmax and myocar- RFA = radiofrequency ablation
dial blood flow, and increase in LV wall stress T-CM = tachycardia-induced
and end-diastolic pressure and volume cardiomyopathy
(9,15,16). Dilatation tends to be biventricular with
mild thinning or no associated hypertrophy or change
in heart mass (9,15). The progression of these physi-
ological changes include a decrease in systemic blood
pressure and increase in LV and pulmonary artery
pressure, which plateaus at 1 week, while cardiac
output, ejection fraction, and volumes continue to
deteriorate the following 4 weeks with development
of symptomatic HF within 2 to 3 weeks (9).
T-CM is characterized by structural and functional
myocardial changes (Table 1, Central Illustration).
Similar to human studies, T-CM models have also
demonstrated electrical remodeling and abnormal
Ca homeostasis thought to be responsible for
impaired excitation-contraction coupling and dia-
stolic dysfunction (9,16–18). Only total Ca cycling, Ca-
channel inhibition, and basal ATPase activity have
demonstrated a statistical correlation with decrease
in left ventricular ejection fraction (LVEF) (17).
Cessation of tachy-pacing results in normalization
of right atrial and arterial pressure with significant
recovery of LVEF and cardiac output by 48 h, and full
normalization after 1 to 2 weeks (9). However, a week
after resolution of tachycardia, LV mass increases by
26% and LV remains dilated and myocytes continue
to demonstrate contractile dysfunction (15). More-
over, only Ca cycling (sum of Ca uptake and Ca
release), Ca-uptake, and CK activity significantly
normalized (17) 4 weeks after cessation of tachy-
pacing. Importantly, some changes such as fibrosis
appear to persist despite elimination of the tachy-
cardia and normalization of LV function (16,19).
CLINICAL PRESENTATION, DIAGNOSIS, AND
IMAGING FEATURES. Clinical studies have found a
variable time from onset of arrhythmia symptoms to
development of T-CM, ranging from 3 to 120 days
with an overall LVEF of 32% (14). Regardless of
tachyarrhythmia, HF symptoms will manifest earlier
at higher tachycardia rates (1,9,16), such as patients
with persistent atrial flutter or tachycardia with 2:1
2330 Huizar et al.
Arrhythmia-Induced Cardiomyopathy
C E NT R AL IL L U STR AT IO N Arrhythmia-Induced Cardiomyopathies: Possible Triggers, Mediators, Effect,
and Recovery
Huizar, J.F. et al. J Am Coll Cardiol. 2019;73(18):2328–44.
AV ¼ atrioventricular; HR ¼ hazard ratio; LVEF ¼ left ventricular ejection fraction.
AV conduction with rates >150 beats/min. A recent
clinical study found a more severe LV dysfunction
(LVEF 29.3  6.6%) in T-CM when compared with
dilated and inflammatory CM (32.1  10.2% and 41.9 
12.9%, respectively; p < 0.001) (18).
Major reported symptoms include palpitations
(29%), HF class III to IV (47%), and syncope/pre-
syncope (12%), while the remaining may have no
symptoms (10). Sudden cardiac death is uncommon
but has been reported in up to 8% to 12% despite
treatment and resolution of cardiomyopathy (14,20).
T-CM should be suspected in patients with LV
dysfunction and a prior or persistent or frequent
paroxysmal tachycardia without obvious etiology
(Table 2). A superimposed T-CM should be considered
despite underlying secondary CM (ischemic, infiltra-
tive, or toxic/drug-related) if the tachycardia is
JACC VOL. 73, NO. 18, 2019
MAY 14, 2019:2328–44
present. Thus, an ambulatory ECG monitor for at least
a 2-week period is key to confirm or exclude T-CM.
Echocardiogram or cardiac magnetic resonance can
assist in excluding other etiologies. T-CM is charac-
terized by a dilated CM (increased LV end-diastolic
dimension and area) with moderate to severe biven-
tricular systolic dysfunction and normal LV septal
and posterior wall thickness (lack of hypertrophy).
Mitral insufficiency may be present due to LV and
mitral annular dilatation with lack of leaflet coapta-
tion (16).
Neurohormonal markers such as brain natriuretic
peptide (BNP) and pro-BNP are commonly elevated
depending on the degree of heart failure and CM
(14,21). Moreover, a sudden drop of pro-BNP within a
week of elimination of tachycardia is supportive of
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

be only confirmed after recovery or improvement of

T A B L E 1 Summary of Abnormalities Found in T-CM and PVC-CM Based in Human and
LV systolic function within 1 to 6 months after elim- Animal Models
ination of the tachyarrhythmia.
Feature (Ref. #) T-CM PVC- CM

Tissue remodeling (8,9,16,18,19,59)

TREATMENT. A major feature of T-CM is its revers-
Myocardial blood flow Decreased ??
ibility once tachycardia is eliminated. Thus, the
Fibrosis Mild Absent or mild/[
mainstay treatment consists of suppression of collagen type I
tachycardia based on the culprit arrhythmia (Table 3) Extracellular matrix and myocyte Disarray ??
basal membrane
with antiarrhythmics (AADs) and/or RFA. Neverthe-
Myocyte misalignment Present ??
less, the initial treatment of T-CM should include
Inflammation Macrophage-dominated Absent
initiation and optimization of medical therapy for [[ MHC-class II; [ MMP-9)
heart failure and LV systolic dysfunction (beta- [ CD68 macrophages
Myocyte remodeling (8,16,18,64)
blockers, angiotensin-converting enzyme inhibitors
Myocyte loss Present ??
or angiotensin receptor blockers, diuretic agents, and
Apoptosis Increased Unchanged
aldosterone blockers) to optimize reverse T-tubules Depletion Depletion
remodeling. Sarcomere Loss and change in sarcomere ??
Elimination of tachyarrhythmia not only resolves Mitochondria Abnormal size, architecture and Normal oxidative
function phosphorylation
LV function within 4 to 12 weeks, but also improves
[ Number at intercalated disc
heart failure symptoms by at least 1 New York Heart [ MPC1
Association functional class in most patients ATP and Na-K ATPase Reduced ??

(9,14,16). Multivariate analysis demonstrated that b-adrenergic receptors Y Number of b-receptors ??

Y G stimulator protein density and
age, tachycardia rate, and baseline LVEF and LVEDD adenylate cyclase activity
were predictors of recovery in a pediatric population [ G inhibitory protein density
Oxidative stress Increased ??
(12). Unfortunately, the recovery of T-CM is not al-
Glucose metabolism Impaired ??
ways complete. Histopathological abnormalities,
Electrical remodeling (8,16,17,24,59,63,64)
diastolic dysfunction, and ventricular dilatation with
Action potential duration Prolonged Prolonged
a hypertrophic response may persist despite normal- (heterogeneity)
ization of LVEF (15,16,18,19). VERP Increased Increased

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

cant benefits. CaMKII-alpha Increased Increased

TACHYCARDIA RECURRENCE IN PRIOR HISTORY OF
T-CM. Studies have documented that recurrence of
T-CM and HF symptoms upon arrhythmia is faster
and with at least the same severity compared with the
initial presentation (14,20). It is speculated that
persistence of underlying histopathological abnor-
malities from initial presentation are likely respon-
sible for a more rapid and severe presentation if
arrhythmia recurs (16,19). Yet, LV dysfunction re-
covers to prior or normal levels with elimination of
new or recurrent tachycardia. Thus, a permanent
treatment such as ablation therapy should be espe-
cially considered in arrhythmias with a high success
or cure rate such as atrial flutter, AV nodal re-entrant
tachycardia, AV reciprocating tachycardia, and AT.
AF-INDUCED CM
AF is frequently considered a primary cause for T-CM.
Limited evidence suggests that ventricular rate dur-
ing AF does not predict reversibility of CM (22). This
SR Ca2þ store Decreased Unchanged
SR Ca2þ leak Decreased Unchanged
Naþ/Ca2þ exchanger (NCX) - Cai Increased Unclear
extrusion (contradictory data)
Dyad remodeling ?? Y JPH-2 and BIN-1
?? ¼ unknown; [ ¼ increased; Y ¼ decreased; BIN-1 ¼ a key protein involved in Cav1.2 targeting to T-tubules;
CaMKII-alpha ¼ Ca2þ/calmodulin-dependent protein kinase II; Cav1.2 ¼ L-type Ca2þ channel pore-forming
subunit; ICa ¼ L-type Ca2þ current; IKr ¼ rapid delay potassium current; Ito ¼ potassium transient outward
current; JPH-2 ¼ junctophilin-2 (a dyad scaffolding protein); MHC-class II ¼ major histocompatibility complex
Class II; MMP-9 ¼ anti-matrix metallopeptidase; MPC1 ¼ mitochondrial pyruvate carrier; PVC-CM ¼ premature
ventricular contraction induced cardiomyopathy; SERCA2a ¼ sarcoplasmic/endoplasmic reticulum Ca2þ ATPase-
2a; SR ¼ sarcoplasmic reticulum; T-CM ¼ tachycardia-induced cardiomyopathy; VERP ¼ ventricular effective
refractory period.
has raised the question of whether AF duration
and/or irregularity predicts LV dysfunction rather
than ventricular rate. More recently, AF ablation trials
in HF have questioned current recommendations that
rate control alone is appropriate in patients with
paroxysmal/persistent AF and associated CM/HF
(3,23). This is in light of the significant improvement
of LV function and HF symptoms after AF ablation
when compared with medical therapy, supporting the
2332 Huizar et al. JACC VOL. 73, NO. 18, 2019

Arrhythmia-Induced Cardiomyopathy MAY 14, 2019:2328–44

AF-CM is a diagnosis of exclusion and should be

T A B L E 2 Reversible and Irreversible Causes of Cardiomyopathy
Reversible
Transient ischemia/post-cardiac arrest
Subacute valvular heart disease
Uncontrolled hypertension
LBBB – cardiomyopathy
Pacing-induced cardiomyopathy
Drug or alcohol abuse
Endocrine (severe hypothyroidism)
PVC-induced cardiomyopathy
Stress-induced cardiomyopathy
Peripartum cardiomyopathy
Inflammatory/infectious
(e.g., myocarditis, sepsis)
LBBB ¼ left bundle branch block; PVC ¼ premature ventricular contraction.
Irreversible
Extensive/multiple myocardial infarctions
Hypertrophic cardiomyopathy
Cardiac sarcoidosis
End-stage valvular heart disease
Infectious (e.g., Chagas disease)
primarily suspected in patients with nonischemic CM
and persistent AF that do not improve after appro-
priate medical therapy and rate control. Due to the
overlap with T-CM and lack of animal models, it is
unclear how the time course and clinical, laboratory,
or imaging features differ between AF- and T-CM. A
final AF-CM diagnosis can only be corroborated if LV
systolic function improves or normalizes after elimi-
nation of AF.
Restoration of sinus rhythm should be considered
if AF-CM is suspected. AF ablation has been reported
to achieve sinus rhythm from 50% to 88% in both
paroxysmal and persistent AF patients with HF and
CM (2,3,23,26). Although the complication rate of AF
ablation is low (2% to 3%), a second ablation is

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

myopathy or vice versa. reported an 8% to 18% absolute increase in LVEF in

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-

anism involved in its pathogenesis. netic resonance imaging with late-gadolinium

enhancement as a screening tool to predict CM
reversibility before ablation. The absence of ventric-
ular scar or scar burden <10% predicted reversibility
T A B L E 3 Treatment Options of T-CM Based on Tachyarrhythmia
of AF-CM (Figure 1) (23).
Arrhythmia Treatment

Sinus tachycardia/thyrotoxicosis BB þ treatment of underlying disease

PVC-CARDIOMYOPATHY
Atrial fibrillation with RVR Rhythm (PVI  AADs) vs. rate
control vs. AVJ
Atrial flutter with RVR Radiofrequency ablation Due to its unique features and lack of tachycardia,
Atrial tachycardia Radiofrequency ablation vs. AADs PVC-CM is now recognized as a distinct clinical entity
AV reciprocating tachycardia/AV nodal Radiofrequency ablation by the most recent 2016 AHA Scientific Statement of
re-entrant tachycardia
dilated cardiomyopathies (1). PVC-CM is defined as
Rapid atrial/ventricular pacing Reprogram pacemaker
(pacemaker-mediated tachycardia) the development of LV dysfunction caused solely by
Sustained ventricular tachycardia Radiofrequency ablation  AADs frequent PVCs. Moreover, superimposed PVC-CM can
be defined as worsening of LVEF by at least 10% due
AADs ¼ antiarrhythmic drugs; AV ¼ atrioventricular; AVJ ¼ atrioventricular nodal ablation; BB ¼ beta-blockers;
PVI ¼ pulmonary vein isolation; T-CM ¼ tachycardia-induced cardiomyopathy; RVR ¼ rapid ventricular response.
to frequent PVCs in a previously known CM. Even
though frequent PVCs are commonly referred to as
JACC VOL. 73, NO. 18, 2019
MAY 14, 2019:2328–44
PVC burden >5%, a PVC burden $10% is often
considered high and significant enough to trigger
PVC-CM.
EPIDEMIOLOGY OF PVCs AND PVC-CM. The inci-
dence of PVCs in a 10-s 12-lead ECG is estimated be-
tween 1% to 4% of patients without heart disease
(30,31). However, the prevalence of PVCs is signifi-
cantly higher during ambulatory ECG recordings
(40% and 75% of participants on 24- to 48-h ambu-
latory Holter monitoring) (31). This can be explained
by a significant variability of PVC frequency with time
(32,33).
Prevalence of PVCs is also age-dependent
with, <1% in children younger than age 11 years and
near 70% in subjects age 75 years and older (30,31).
PVCs are more frequently associated with post-
myocardial infarction, coronary heart disease, and
dilated CM and HF (30,34). Furthermore, almost one-
half of patients with HF class II and III had frequent
PVCs (>1,000 PVCs/day) (34).
Clinical studies have found high PVC burden
associated with LV dysfunction, increased risk of
systolic HF (hazard ratio [HR]: 1.48 to 1.8) and mor-
tality (HR: 1.31) (35–41) even after adjusting for age
and other ECG abnormalities (30). Surprisingly, a
6-fold increased risk (HR: 6.5) of systolic HF has
been reported in subjects age <65 years with PVCs
without other cardiovascular risk factors (42) and
a higher mortality risk for those with heart rate
>100 beats/min (30). Last, a significant increased risk
of incident stroke (HR: 1.71; 95% confidence interval
[CI]: 1.14 to 2.59) has been reported on a secondary
analysis of the ARIC (Atherosclerosis Risk In Com-
munities) study, which the investigators attribute to
possible atrioventricular remodeling (43).
The prevalence of PVC-CM has been reported at 7%
among patients with frequent PVC burden >10% (44).
Nevertheless, PVC-CM is likely underestimated (31).
Clinical studies have reported a diagnosis of PVC-CM
in 9% to 30% of patients referred for RFA of PVC
(35,38,45–47). Similarly, a secondary analysis of the
CHF-STAT (Survival Trial of Antiarrhythmic Therapy
in Congestive Heart Failure) (48) (>10 PVCs/h and
LVEF <40%) demonstrated an estimated rate of PVC-
CM of 40% in all patients with CM and up to 66% in
nonischemic CM (49). This data supports frequent
PVCs as a significant and modifiable risk factor for
systolic HF and increased mortality.
ACUTE EFFECTS OF PVCs AND POTENTIAL
TRIGGERS OF PVC-CM. PVCs have acute intrinsic
effects that are innate to their ectopic and premature
origin, including heart rate irregularity and post-
extrasystolic potentiation, LV dyssynchrony, AV
Huizar et al. 2333
Arrhythmia-Induced Cardiomyopathy
dyssynchrony, and increased heart rate (Table 4)
(41,50–54). Furthermore, it is unclear if and how these
triggers, by altering hemodynamics and autonomic
nervous system, contribute to the development of
PVC-CM (55,56).
Post-extrasystolic potentiation together with heart
rate irregularity, LV dyssynchrony, AV dissociation,
and alteration in autonomic nervous system are
possible triggers of PVC-CM. However, differences in
cellular and electrical remodeling between PVC- and
T-CM (Table 1) reinforce the argument that tachy-
cardia is unlikely to be the sole trigger for PVC-CM.
The role of post-extrasystolic potentiation and
heart rate irregularity could be addressed by evalu-
ating the chronic effects of frequent PACs, which lack
LV dyssynchrony. Although Pacchia et al. (57)
demonstrated that CM could be induced by atrial
bigeminy, this has not been observed clinically and in
other animal models (58–60). These findings suggest
that heart rate irregularity and post-extrasystolic
potentiation play a limited role, if any, in the patho-
physiology of PVC-CM.
Finally, Gerstenfeld’s group demonstrated in a
bigeminy PVC swine model that LV dysfunction is
more pronounced in PVCs from LV epicardium as they
demonstrate a higher degree of dyssynchrony when
compared with endocardial RV free wall (59). This is
also consistent with clinical studies where epicardial
PVCs and QRS >150 ms were predictors of PVC-CM
(61,62).
POTENTIAL MECHANISM(S) OF PVC-CM. In contrast
to T-CM, the cellular mechanism of PVC-CM has not
been extensively studied. Yet, it is clear that there
are distinct differences in histopathological and
cellular features compared with other HF models
including T-CM (Central Illustration, Table 1)
(8,9,15,16,18,19,59,63,64).
The primary cause of contractile dysfunction in
PVC-CM appears to be disorders of the calcium-
induced calcium release mechanism itself, with al-
terations of dyad (L-type Ca channel and Ryanodine
receptor) function proposed as a potential mecha-
nism. Similar to other cardiomyopathies, this PVC-CM
model has revealed electrophysiological remodeling
(Table 1). Histopathological abnormalities are distinct
without evidence of increased inflammation or
apoptosis and minimal or no fibrosis. Mitochondrial
studies have demonstrated no changes in oxidative
phosphorylation (8). These findings are supported
clinically by the lack of scar on cardiac magnetic
resonance imaging of patients with PVC-CM (38).
These findings further confirm a primary functional
abnormality as a primary mechanism of this
2334 Huizar et al. JACC VOL. 73, NO. 18, 2019

Arrhythmia-Induced Cardiomyopathy MAY 14, 2019:2328–44

F I G U R E 1 Cardiac Magnetic Resonance Imaging With Late-Gadolinium Enhancement to Identify AF-CM

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

T A B L E 4 Acute Effects and Potential Triggers of PVC-CM

Intrinsic PVC Effects/Triggers

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
and molecular changes are in response to the CM
rather than the cause of the CM remains unclear.
PREDICTORS OF PVC-CM. Clinical evaluation of un-
derlying effects of frequent PVCs have limitations due
to a variability of PVC features (origin, prematurity,
frequency, QRS width), presence of confounding pa-
tient comorbidities, and small sample population.
PVC burden has been shown to be a major predictor
of PVC-CM (odds ratio [OR]: 1.25 per each percent
increase in PVC burden; 95% CI: 1.10 to 1.42)
(35,45,62,65–67). Two main studies have shown that
PVC burden >16% and 24% best identifies patients
with a diagnosis of PVC-CM (sensitivity and speci-
ficity of 79% to 100% and 78% to 87%, respectively)
(35,44). Although these and other studies suggest that
a PVC burden of at least 10% is required to induce
PVC-CM (35,44,68–70), other studies question this
minimal PVC threshold, because they have shown
improvement in LV function with PVC burden as low
as 6% to 8% (48,51,66,71–73). The length of ambula-
tory ECG monitoring has important implications,
because increasing the duration from a 24-h to a 7-day
ambulatory Holter monitor can doubled the number
of patients who reach the 10% threshold (33).
Nevertheless, some patients do not develop a CM
even with high PVC burden. Thus, it is likely that
other patients’ characteristics and/or PVC features
play a role in the pathophysiology of PVC-CM. Some
other PVC features have been found to be indepen-
dent predictors for PVC-CM such as male sex (74),
lack of symptoms (adjusted OR: 13.1; 95% CI: 4.1 to
37.0) or duration of palpitations >30 months, vari-
ability of PVC coupling interval (OR: 1.04; 95% CI:
1.03 to 1.07 [39]), QRS duration of PVC >150 ms,
and epicardial origin (37,44,45,61,62,65,67,74,75)
(Figure 2). Other less frequently reported indepen-
dent predictors are body mass index >30 kg/m 2
(OR: 3.03; 95% CI: 1.2 to 7.7) (39), less variability in
circadian PVC distribution (OR: 16.3; 95% CI: 1.7 to
155.0) (76), and presence of retrograde P-wave (OR:
2.79; 95% CI: 1.08 to 7.19) (67). AV dyssynchrony
during PVCs could potentially be a predictor, but
yet remains to be studied (53,67). Except for PVC
burden, most predictors have been variably reported
reflecting the heterogeneity of different populations.
Although further validation is required, a PVC-CM
index, including PVC burden, PVC-QRS width,
and epicardial origin, has been developed in an
attempt to identify patients with high probability of
PVC-CM (62).
Although short PVC coupling intervals have been
associated with idiopathic ventricular fibrillation (77),
most studies have not found a clear relationship
2336 Huizar et al. JACC VOL. 73, NO. 18, 2019

Arrhythmia-Induced Cardiomyopathy MAY 14, 2019:2328–44

F I G U R E 2 QRS Duration and Variability of Coupling Interval of PVCs as Predictors of PVC-CM

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

between PVC coupling interval and CM (37). Some

T A B L E 5 Clinical and PVC Features to Identify PVC-CM
studies have reported that interpolated PVCs or
coupling interval <450 ms may be predictors to CM Resulting in PVCs PVCs Causing CM

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).

CLINICAL PRESENTATION, DIAGNOSIS, AND

IMAGING FEATURES. The time course for the devel- F I G U R E 3 Linear Decrease of LV Ejection Fraction With Sequential Increase in PVC
Burden in an Experimental Model
opment of PVC-CM is unclear, but it is estimated to
occur within months up to several years (62,67,75).
65
Although animal studies with persistent high PVC
burden (33% to 50%) develop CM within 4 weeks 60
LV Ejection Fraction (%)

(8,50), human studies are not consistent in part due

55
to the unclear onset and variability of PVCs.
PVC-CM may have a wide range of presentations, 50
from asymptomatic or vague symptomatology to
45
heart failure and even syncope. It is unclear why
some patients have symptoms related to PVCs while 40
others do not, but a PVC coupling interval ratio <0.5
35
(PVC CI ratio: PVC coupling interval/Sinus coupling
interval) has been proposed as an important marker 30
0 4 4 8 4 8 4 8 4 8 4 8 Weeks
of symptoms (82). A careful history and pertinent
Baseline 7% 14% 25% 33% 50%
testing should be obtained to rule out other causes of
PVC Burden
CM (Table 2), while physical examination is
frequently normal with the exception of irregular
heart sounds and mild signs of HF. Progression of LV ejection fraction in a large animal PVC model after 4 and 8 weeks of a
progressive incremental PVC burden starting from 0% (baseline) to 7%, 14%, 24%,
PVC-CM is a diagnosis of exclusion, to be suspected
33%, and 50% (p < 0.0001, 1-way analysis of variance). Although PVC-CM is not seen
in patients with frequent PVCs >10%, especially in until PVC burden of 33%, a decline in LVEF can be noted at lower PVC burdens.
nonischemic CM. A challenge is to identify when Reprinted with permission from Tan et al. (50). Abbreviations as in Figures 1 and 2.
PVCs are the etiology of a CM or just “innocent
2338 Huizar et al. JACC VOL. 73, NO. 18, 2019

Arrhythmia-Induced Cardiomyopathy MAY 14, 2019:2328–44

T A B L E 6 Summary of Studies of PVC-CM

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
MAY 14, 2019:2328–44
(8,41,50). Cardiac imaging is key to identify LV
dysfunction and prompt suspicion of PVC-CM in pa-
tients with high PVC burden ($10%) (Table 5). Cardiac
magnetic resonance with late-gadolinium enhance-
ment has the advantage of identifying scar and
quantifying scar burden, which in turn potentially
predicts the response to PVC suppression (84). Few
clinical and animal studies have also demonstrated
diastolic dysfunction after 12 weeks of chronic ven-
tricular bigeminy (50,85). Interestingly, a subclinical
form of PVC-CM (LVEF $50%) has been reported us-
ing speckle tracking by a decrease in radial, circum-
ferential, and longitudinal strain that can reverse
after RFA (86,87). This is further supported by
translational studies demonstrating a mild and linear
decrease of LV systolic function with 7%, 14%, and
25% PVC burden (Figure 3) (50).
Most recently, myocarditis has been implicated as
a potential trigger for frequent PVCs and CM (88),
while elevated hs-CRP has been reported to be an
independent predictor of PVCs in a Chinese popula-
tion study (89). Thus, it may be clinically challenging
to determine a causal versus bystander role of PVCs in
an inflammatory process.
TREATMENT. Currently, a PVC suppression strategy
with RFA or AADs is a widely accepted intervention to
treat a CM that might be caused or exacerbated by
frequent PVCs (1). However, the treatment
frequent PVCs ($10% burden) without LV dysfunc-
tion (LVEF $50%), symptoms, or idiopathic ventric-
ular fibrillation is less clear. Due to the lack of data
and potential risk of developing PVC-CM, these pa-
tients require close monitoring every 6 to 12 months
or more closely if HF symptoms develop. Echocar-
diogram should be repeated to confirm normal LV
function, while a prolonged ambulatory ECG monitor
should be considered to reassess PVC burden.
Although spontaneous resolution of frequent PVCs
has not been evaluated, data from the CHF-STAT trial
demonstrated that 12% of patients on placebo had
spontaneous and significant decrease in PVC burden
at 6 months (49).
PVC suppression is considered successful if burden
is decreased by >80% of baseline PVCs, as it likely
represents a true effect of treatment rather than
spontaneous PVC variability (90). However, this cri-
terion was based on 24-h Holter data and it is unclear
if this is different nowadays with extended 2- or even
4-week ambulatory monitors. Current therapies,
RFA and AADs, have similar long-term
suppression success rate between 70% and 80%
(45,48,62,68,70,91). Successful RFA may be limited in
patients with PVCs originating from papillary muscle,
Huizar et al. 2339
Arrhythmia-Induced Cardiomyopathy
epicardium, or nearby critical structures such as cor-
onary arteries and conduction system (40,45,68).
Thus, antiarrhythmic therapy may be necessary in
about 5% to 15% of patients after RFA (68). PVC
suppression strategies (RFA or AADs) carry an overall
low risk. While the complication rates of RFA have
been reported between 5% to 8%, antiarrhythmics
have a discontinuation rate of near 10% due to short-
and long-term side effects (45,68,84,91,92) in addi-
tion to potentially decreased efficacy overtime (93).
Randomized clinical studies of AADs have only
been performed prior to the recognition of PVC-CM
as a unique entity. Whereas the CAST (Cardiac
Arrhythmia Suppression Trial) trial demonstrated an
increase mortality with class IC agents in patients
with frequent ectopy after MI, the GESICA (Grupo de
Estudio de la Sobrevida en la Insuficiencia Cardiaca
en Argentina), CAMIAT (Canadian Amiodarone
Myocardial Infarction Arrhythmia Trial), and CHF-
STAT trials demonstrated at least a trend toward a
decrease in mortality after MI and in nonischemic CM
with the use of amiodarone (48,94). No randomized-
prospective studies have compared the efficacy and
outcomes between RFA and AAD therapy. A contem-
porary retrospective study has shown that PVC
reduction was greater with RFA than antiarrhythmics
(mean reduction: RFA 15.5  1.3% vs. AADs 4.8 
0.8; p < 0.001) (68). Although RFA and antiar-
of rhythmic drugs can successfully suppress high PVC
burdens, a single retrospective study suggests that
RFA may be more effective in patients with lower PVC
burdens (68).
PVC suppression in PVC-CM has been shown to
improve LV function, LV dilatation, mitral regurgita-
tion, and BNP levels (1,70). The mean improvement of
LVEF after RFA in most studies is between 10% and
15% (Table 6) (45,65,68,70,91,92) even in super-
imposed PVC-CM. A recent multicenter retrospective
study of 245 patients with nonischemic CM and
frequent PVCs (mean PVC burden 20  13%) demon-
strated improvement of LV function in 67% of
patients after RFA (45). Similarly, a prospective
study demonstrated a significant decrease in BNP
levels while primary prophylaxis ICD implantation
was avoided in 80% of all patients with PVC burden
>13% due to significant improvement of LVEF after
successful RFA (95). Interestingly, another study
(40) found that 81% of patients (n ¼ 36) with
abnormal baseline estimated glomerular filtration
rate (<60 ml/min/1.73 m 2) had significant improve-
PVC ment in renal function (estimated glomerular filtra-
tion rate 51 to 57 ml/min/1.73 m 2) after RFA of PVCs.
Successful ablation (OR: 15.7; 95% CI: 1.4 to 180.0),
myocardial scar mass <9 g (OR: 0.9; 95% CI: 0.81
2340 Huizar et al. JACC VOL. 73, NO. 18, 2019

Arrhythmia-Induced Cardiomyopathy MAY 14, 2019:2328–44

F I G U R E 4 Representative PVC Cardiomyopathy

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
(OR: 1.09; 95% CI: 1.01 to 1.16) have been shown to be
independent predictors of response to RFA (84,91).
This supports assessment of scar burden using
cardiac magnetic resonance with late-gadolinium
enhancement to predict responders versus non-
responders to PVC suppression (Figure 4). However, if
significant PVC burden reduction (>20%) is achieved,
the presence of myocardial scar seems to be less
relevant to predict response (84). In contrast, PVC
location does not appear to predict improvement of
LVEF (92). Recently, post-extrasystolic potentiation
assessed by invasive blood pressure monitoring has
been described as a predictor of LV function recovery
after radiofrequency ablation (96).
Clinical studies have consistently demonstrated a
significant increase in LV function after PVC sup-
pression with antiarrhythmic agents, ranging from
10% to 13% (48,68). Because the CAST trial included
patients with ischemic CM, the guidelines discourage
the use of Class IC antiarrhythmic agents not only in
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

F I G U R E 5 Proposed Management of Potential Arrhythmia-Induced CM

LV dysfunction/Cardiomyopathy

Assess/treat CAD or other secondary causes

Nonischemic dilated CM*

2–14 day ECG monitor† + Initiate HF Med Rx

No No
Tachyarrhythmias / AF PVC burden ≥10% Optimize HF Med Rx

Yes Yes

Ablation vs. antiarrhythmics‡

Normalization
Improvement No Change
of LVEF
of LVEF

AiCM§ Superimposed AiCM Nonischemic CM

*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

Arrhythmia-Induced Cardiomyopathy MAY 14, 2019:2328–44

with high arrhythmia burden (frequent heart rate
>100 beats/min and/or PVC burden $10%) do not
develop CM, these patients are at risk and should
undergo close monitoring every 6 to 12 months or
sooner if symptoms develop. The risk factors for
developing PVC-CM include male
symptoms, and PVCs with QRS duration >150 ms,
epicardial origin, and/or variable coupling interval.
As any other CM, AiCM can lead to HF admissions
and implantation of defibrillators and resynchroni-
zation devices (51,73,95,99). Thus, AiCM carries a
significant financial burden if untreated, which
makes diagnosis and treatment
improve morbidity and potentially decrease health
care costs. A better understanding of the mechanism
of tachycardia and PVC-CM could lead to novel
therapies to prevent and improve outcomes, espe-
cially when antiarrhythmic agents or RFA are not
feasible or unsuccessful.
with an obvious etiology (Figure 5). T-CM should be
strongly considered in patients with paroxysmal or
persistent SVTs, primarily AF/atrial flutter, atrial
tachycardia, and persistent junctional reciprocating
tachycardia with heart rates above 100 beats/min. AF-
sex, lack of CM should be suspected in patients with nonischemic
CM and paroxysmal, persistent, or permanent AF,
even with appropriate rate control, whereas PVC-CM
should be considered in patients with nonischemic
CM and PVC burden $10%. Appropriate diagnosis and
treatment of AiCM not only will reverse LV dysfunc-
tion with its associated morbidity, mortality, and
paramount to health care spending, but most importantly, will
improve quality of life and long-term prognosis.
Future clinical studies are needed to compare stan-
dard treatment strategies and identify best long-term
PVC suppression and prevention of recurrence of
PVC-CM.

CONCLUSIONS ADDRESS FOR CORRESPONDENCE: Dr. Jose F.

Huizar, Virginia Commonwealth University/Pauley
AiCM, a reversible CM, has a significant variety of Heart Center, Hunter Holmes McGuire VA Medical
presentations from asymptomatic to severe HF Center, 1201 Broad Rock Boulevard, Suite 4A-100,
symptoms. Clinicians should have a high index of Richmond, Virginia 23249. E-mail: jfhuizar@gmail.com.
suspicion of superimposed AiCM even in patients OR Jose.Huizar2@va.gov. Twitter: @VCUHealth.

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KEY WORDS arrhythmia, cardiomyopathy,
heart failure, left ventricular dysfunction,
premature ventricular contractions,
supraventricular tachycardia