![(A) 36-year old woman presenting with frequent premature ventricular contractions, with right bundle branch block inferior axis morphology and (B,C) evidence on cardiac magnetic resonance of a patchy area of subepicardial late gadolinium enhancement, involving the basal anterolateral left ventricular segment (arrows). Reproduced with permission from Muser et al. [50].](https://www.researchgate.net/publication/355139852/figure/fig2/AS:1076866886705154@1633756481998/A-36-year-old-woman-presenting-with-frequent-premature-ventricular-contractions-with_Q320.jpg)
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Diagnostics 2021, 11, 1840. https://doi.org/10.3390/diagnostics11101840 www.mdpi.com/journal/diagnostics
Review
Diagnosis and Treatment of Idiopathic Premature Ventricular
Contractions: A Stepwise Approach Based on the Site of Origin
Daniele Muser 1,†, Massimo Tritto 2,†, Marco Valerio Mariani 3,†, Antonio Di Monaco 4,5,†, Paolo Compagnucci 6,†,
Michele Accogli 7, Roberto De Ponti 8 and Fabrizio Guarracini 9,*,†
1 Cardiothoracic Department, University Hospital of Udine, 33100 Udine, Italy; daniele.muser@gmail.com
2 Electrophysiology and Cardiac Pacing Unit, Humanitas Mater Domini Hospital, 21053 Castellanza, Italy;
m.tritto@libero.it
3 Department of Cardiovascular, Respiratory, Nephrology, Anaesthesiology and Geriatric Sciences, Sapienza
University of Rome, 00161 Rome, Italy; marcoval.mariani@gmail.com
4 Cardiology Department, General Regional Hospital F. Miulli, 70021 Acquaviva delle Fonti, Italy;
a.dimonaco@gmail.com
5 Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy
6 Cardiology and Arrhythmology Clinic, University Hospital Ospedali Riuniti Umberto I-Lancisi-Salesi,
60126 Ancona, Italy; paolocompagnucci1@gmail.com
7 Cardiology Unit, “Card. G. Panico” Hospital, 73039 Tricase, Italy; accogli.michele@libero.it
8 Department of Heart and Vessels, Ospedale di Circolo & Macchi Foundation, University of Insubria,
21100 Varese, Italy; roberto.deponti@uninsubria.it
9 Department of Cardiology, S. Chiara Hospital, 38122 Trento, Italy
* Correspondence: fabrizioguarracini@yahoo.it; Tel.: +39-0461-903-121
† Membership of the Task Force on Catheter Ablation of Ventricular Tachycardia—Italian Association of
Arrhythmias and Cardiac Pacing (AIAC).
Abstract: Premature ventricular contractions in the absence of structural heart disease are among
the most common arrhythmias in clinical practice, with well-defined sites of origin in the right
and left ventricle. In this review, starting from the electrocardiographic localization of premature
ventricular contractions, we investigated the mechanisms, prevalence in the general population,
diagnostic work-up, prognosis and treatment of premature ventricular contractions, according to
current scientific evidence.
Keywords: premature ventricular contractions; transcatheter ablation; antiarrhythmic drugs
1. Introduction
Premature ventricular contractions (PVCs) in the absence of structural heart
disease (SHD), or inherited ion channelopathies, are referred to as idiopathic and are
among the most common arrhythmias encountered in everyday clinical practice. They
have a focal mechanism and usually originate from specific endocardial or epicardial
sites, the right and left ventricular outflow tracts (RV/LV-OT) being the most frequent
sites of origin (SOO). Even if isolated PVCs are the predominant clinical manifestation,
less frequently they can be accompanied by non-sustained ventricular tachycardia
(NSVT) or even sustained ventricular tachycardia (VT) with the same ECG
morphology. They generally have a favorable prognosis and can be effectively treated
with radiofrequency catheter ablation (CA). A careful analysis of ECG features can help
to predict the SOO and plan the procedure. This review aims to present an overview on
the current approach to PVCs, starting from the twelve-lead ECG analysis to clinical
manifestations and prognosis, and therapeutic strategies including CA.
Citation:
Muser, D.; Tritto, M.; Mariani, M.V.;
Monaco, A.D.; Compagnucci, P.; Accogli, M.;
De Ponti, R.; Guarracini,
F.; on behalf of the
Task Force on Catheter
Ablation of
Ventricular Tachycardia
—Italian Association
of Arrhythmias and Cardiac Pacing (AIAC)
Diagnosis and Treatment of Idi opathic
Premature Ventricular Contractions: A
Stepwise Approach
Based on the Site of
Origin.
Diagnostics 2021, 11, 1840. https://
doi.org/10.3390/diagnostics11101840
Academic Editor
: Ernesto Di Cesar e
Received:
5 August 2021
Accepted: 29 September 2021
Published:
5 October 2021
Publisher’s Note:
MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional
affiliations.
C
opyright: © 2021 by the authors. Licensee
MDPI, Basel, Switzerland. This article is an
open access article distributed under the
terms and conditions of the Creative
Commons Attribution (CC BY) license
(http://creativecommons.org/licenses/by/4.0/).
Diagnostics 2021, 11, 1840 2 of 19
2. Prevalence and Mechanism
Idiopathic PVCs originate, in almost 70% of cases, from the right and left ventricular
OT, and they account for 10% of all ventricular arrhythmias (VAs) referred for CA [1]. In
particular, the RVOT is the most common SOO, harboring 80% of OT-PVCs, whereas up
to 20% of OT-PVCs originate from the LVOT and near structures, including the LV
summit and intramural foci in the basal interventricular septum [2]. Within the RVOT, its
septal or posterior aspect represents the main source of PVC, accounting for
three-quarters of RVOT PVCs, while the remaining originate from the RVOT free wall or
anterior aspect and the proximal pulmonary artery. Within the LVOT, the most common
SOO are the aortic cusps, with a reported prevalence in large series of cases as high as
15% [3]. However, LVOT PVCs may arise from other near structures, such as the
aortic-mitral continuity (AMC), the endocardial aspect of the LVOT and the LV summit,
with a cumulative prevalence up to 20% [4]. The remaining 30% of PVCs originate from
non-OT structures including the left and right papillary muscles (5–15%), mitral annulus
(5%), tricuspid annulus (8–10%), left bundle branch fascicles (10%), cardiac crux and
moderator band (Table 1) [2–5].
Table 1. Idiopathic ventricular arrhythmia prevalence, procedural success and risk of
complications according to the site of origin as reported in larger series. AFT: anterior fascicular
tachycardia; LV: left ventricular; LVOT: left ventricular outflow tract; PFT: posterior fascicular
tachycardia; RVOT: right ventricular outflow tract.
Site of Origin
Acute Procedural
Success Rate, %
Complications, %
Pericardial Effusion
(40%)
Thromboembolism
(3%)
Vascular Access
Complications (8%)
Coronary Arteries
Injury (5%)
RVOT (60%)
97%
<1%
LVOT (10%)
94%
5%
LV summit (3%)
70%
5%
Right Ventricle intracavitary structures (14%)
93%
1%
Left Ventricle intracavitary structures (10%)
91%
9%
Mitral and Tricuspid Annular Region (5–10%)
90%
3%
Left bundle fascicles (10%)
90%
3%
Epicardial Foci (3–5%)
80%
8%
Sometimes frequent PVCs can present together with NSVT, or even SVT, which is
encountered in about one third of the patients [6,7]. Those manifestations are generally
benign while malign PVC-induced ventricular fibrillation (VF) is only rarely seen.
In a population-based study including incident cases between 2005 and 2013,
Sirichand at al. found an overall age- and sex-adjusted incidence of idiopathic ventricular
arrhythmias among individuals ≥ 18 years of 51.9 per 100,000, with an increasing
incidence with aging [6]. Moreover, although the rate of idiopathic VT was similar across
sexes, the age-adjusted incidence of symptomatic PVC was higher in females than males
(46.2 per 100,000 vs. 20.5 per 100,000, p < 0.001) [6]. In an analysis of gender and age
differences in patients undergoing CA of PVCs, the RVOT SOO was 1.5 times more
frequent in women than men, while LVOT-PVCs were more common in men and their
prevalence increased with aging, as compared to RVOT-idiopathic Vas [7]. Taken
Diagnostics 2021, 11, 1840 3 of 19
together, these observational studies suggest that RVOT and PVCs may be the most
frequent SOO and clinical arrhythmia in females.
Frequent PVCs may sometimes lead to PVCs-induced cardiomyopathy (CMP),
which is characterized by otherwise unexplained progressive LV dysfunction and heart
failure [3,6,8–10].
From a mechanistic perspective, idiopathic PVCs are focal arrhythmias related to
delayed afterdepolarizations (DADs) and triggered activity during phase 4 of action
potential [11]. These arrhythmias are usually adrenergically mediated, so that sinus
tachycardia facilitates their initiation and are frequently triggered by stress or exertion.
The adrenergic stimulus leads to an increased adenylyl-cyclase activity with increased
levels of intracellular cyclic adenosine monophosphate (cAMP). cAMP activates the
cAMP-dependent protein kinase (protein kinase A, PKA) that phosphorylates the L-type
sarcolemmal calcium channels, ryanodine receptor (RyR2) and phospholamban. All these
processes lead to increased intracellular calcium concentrations by spontaneous diastolic
calcium release from the sarcoplasmic reticulum, known as calcium sparks [11].
Eventually, through the activation of electrogenic sodium–calcium exchanger, a transient
sodium inward current enters the cell and produces a DAD, which, if repetitive, may
generate VT. This mechanism explains some peculiar characteristics of idiopathic VAs,
such as termination by adenosine by lowering cAMP in the ventricular myocardium via
an inhibitory G-protein cascade.
Considered the cAMP-mediated mechanism, it is comprehensible that the
pharmacological therapy of idiopathic PVCs is dependent on agents or maneuvers that
reduce cAMP levels. Examples include activation of the M2 muscarinic receptor with
vagal maneuvers, calcium channel blockers, -blockers and adenosine (through the
activation of the A1-adenosine receptor) [12].
3. Twelve Leads Electrocardiographic Localization of Premature Ventricular
Contractions
Twelve-leads surface ECG characteristics, such as frontal plane axis, bundle branch
block pattern, precordial transition and QRS width, can be used to predict the most likely
SOO. Knowledge of the 3D-anatomy of the heart, its orientation within the chest and the
relationship between different cardiac structures is crucial to understand ECG findings.
However, it has always to be kept in mind that general rules may have significant
variations related to body type, lead placement and relative orientation of the heart to the
chest wall. A schematic representation of principal SOO of idiopathic PVCs and their
ECG characteristics is presented in Figure 1.
Diagnostics 2021, 11, 1840 4 of 19
Figure 1. Schematic representation of the main sites of origin of idiopathic premature ventricular contractions and their
ECG features.
3.1. Outflow Tract Structures
The RVOT and LVOT are anatomically close, as such, PVCs arising from these
structures share some common ECG findings. Being located at the base of the heart
(superior within the chest) they all present with an inferiorly directed axis (positive in
leads II and III and negative in lead aVL and aVR) and they typically present a left bundle
branch block (LBBB) pattern in V1 with various precordial transition according to the
specific SOO. The proximal part of the RVOT begins at the superior margin of the
tricuspid valve annulus (TVA) and lies to the right of the LVOT, then the RVOT wraps
around and crosses the LVOT lying leftward and anteriorly to the aortic root so that the
pulmonary valve lies anteriorly, superiorly and to the left of the aortic valve, making the
RVOT free wall the most leftward and anterior outflow tract structure. As V1 is a
unipolar lead, structures closer to the chest wall show a LBBB pattern with a QS complex,
while more posterior structures show a progressive increase in the initial r wave
amplitude through a right bundle branch block (RBBB) pattern. As such, when the
precordial transition is ≥V4 the PVC are likely to originate from the RVOT. In particular,
when the SOO is the RVOT free wall, the precordial transition is typically very late
(V4–V5); as the SOO moves progressively more posterior and inferior to the RVOT
septum, right coronary cusp (RCC), left coronary cusp (LCC), AMC and lateral mitral
valve annulus (MVA), the precordial transition becomes progressively earlier till the V1
pattern transforms to a RBBB pattern. Consistently, there is also a progressive change in
the polarity of lead I from negative to positive, moving from structures located leftwards
to the chest midline, such as the most anterior part of the RVOT, the LCC, the AMC and
the lateral MVA (negative lead I), to structures located to the right of the midline such as
septal RVOT and the RCC (positive in lead I). The RVOT free wall and septum extend
both leftward and rightward as they curve around the aortic root, thus PVC arising from
either the anterior and septal aspect of the RVOT may appear positive, negative or
Diagnostics 2021, 11, 1840 5 of 19
biphasic in lead I. The RCC/LCC junction is typically very close to the midline and
therefore may have either a positive, a negative, or a biphasic QRS complex in lead I.
When the precordial transition is ≤V2, the SOO is very likely in the LVOT. The RCC is in
close proximity to the mid-septal RVOT, thus making it very difficult to differentiate
PVC coming from these structures. In general, the precordial transition in V3 represents
the most difficult scenario to differentiate RVOT from LVOT PVC, and different
algorithms have been proposed [13–17]. A PVC transition later than the transition of
sinus rhythm QRS complex is highly specific for an RVOT origin. A V2 transition ratio
(defined as the percentage of R wave during the PVC divided by the percentage of R
wave during sinus rhythm) ≥ 0.6, instead, predicts an LVOT origin with a high degree of
sensitivity and specificity [13]. A V2S/V3R index (defined as the S-wave amplitude in
lead V2 divided by the R-wave amplitude in lead V3) ≤ 1.5 is also able to predict an LVOT
origin with high accuracy [14]. Compared to PVC coming from the RCC, those coming
from the LCC, typically have a significant r wave in V1 due to the more posterior location
of the LCC, while RVOT and RCC PVC typically have a QS pattern in V1. Arrhythmias
arising from the LCC may also have a multiphasic “M” or “W” pattern in V1 while a QS
pattern with notching in downstroke is suggestive of RCC/LCC junction [18,19]. A qR
pattern in lead V1 is often seen in VAs from the AMC while a RBBB pattern in lead V1
with positive precordial concordance is suggestive of anterolateral MVA [20].
3.2. Left Ventricular Summit and Intramural Left Ventricular Outflow Tract
The left ventricular summit (LVS) is the most superior aspect of the left ventricular
ostium, delimited on its epicardial surface by the bifurcation of the left anterior
descending (LAD) and the left circumflex (LCx) coronary arteries and transected by the
great cardiac vein (GCV) at its junction with the anterior interventricular vein (AIV) [21].
The GCV divides the region into two main areas of clinical interest: (1) a medial and
superior region (above GCV), corresponding to the apex of the LVS, inaccessible to
catheter ablation (CA) because of its close proximity to the major coronary vessels
(inaccessible area); and (2) a lateral and inferior region (below GCV), which may be
suitable for CA (accessible area).
Ventricular arrhythmias originating from the LVS typically show a RBBB pattern
with a positive concordance throughout the precordial leads or a LBBB pattern with very
early precordial transition (≤V2). The axis is typically rightward and inferior. A dominant
R wave in V1 with a R/S ratio ≥ 2.5 is observed in up to 90% of cases and predicts an origin
from the accessible area [22]. Only PVC from the inaccessible area may present an LBBB
pattern [23]. A peculiar pattern is the “pattern break” in V2, characterized by an abrupt
loss of R wave in lead V2 compared to V1 and V3, suggesting an origin from the anterior
interventricular sulcus, which is located opposite to the unipolar lead V2, usually in close
proximity to the proximal LAD before the take-off of the first septal perforator branch
[24]. An epicardial origin is suspected when there is a slurring of the initial portion of the
QRS complex, reflecting delayed initial activation of the LV epicardium, which can be
quantified as (1) time to earliest rapid deflection in precordial leads (pseudo-delta wave)
≥ 34 ms; (2) interval to peak of R wave in lead V2 (intrinsicoid deflection time) ≥ 85 ms; (3)
shortest interval to maximal positive or negative deflection divided by QRS duration
(maximum deflection index) ≥ 0.55; and (4) time to earliest QRS nadir in precordial leads
(shortest RS complex) ≥ 121 ms [24–27].
3.3. Cardiac Crux
The cardiac crux is an epicardial region at the intersection of the atrioventricular
groove and the posterior interventricular groove near the junction of the coronary sinus
with the middle cardiac vein. Arrhythmias arising from this region typically have LBBB
with an early (V2) transition and a left superior axis with deep QS waves in the inferior
leads. They also present one or more of the aforementioned features, suggesting an
epicardial origin. The presence of a greater S wave than R wave in V6 is highly specific of
Diagnostics 2021, 11, 1840 6 of 19
an origin from the cardiac crux as the depolarization propagates epicardially from the
crux to the apex first, where it enters the Purkinje system in the endocardium and,
thereafter, rapidly moves away from V6 towards the base [28].
3.4. Mitral and Tricuspid Valve Annuli
Arrhythmias originating from the mitral valve (MV) annulus present with a RBBB
pattern and positive concordance throughout the precordium. The QRS axis is right
inferior in anterolateral MV PVCs with a negative QRS complex in leads I and aVL, while
lateral and inferolateral MA PVCs may exhibit a right superior axis with negative QRS
complexes in the inferior leads and positive in aVL. Sometimes, PVCs arising from the
inferolateral MV may exhibit an inferior lead discordance with negative II and positive
III. A notching in the downstroke of the Q wave or upstroke of the R wave in inferior
leads can be seen in the case of PVCs coming from the free wall of the mitral annulus,
representing the late activation of the RV [29].
All PVCs originating from the tricuspid valve (TV) annulus are characterized by a
LBBB pattern. Those coming from the lateral TV annulus present a late transition >V3 and
a left intermediate axis with a dominant R wave in lead I, a positive deflection in aVL and
a positive II/ negative III inferior lead discordance. Notching in the inferior leads can be
seen as a result of delayed LV activation. Arrhythmias originating from the septal aspect
of the TV annulus, show, instead, an earlier transition in V3 and a narrower QRS
duration. The majority of PVCs arising from the septal portion of the TV annulus, present
a QS in V1, while most PVCs from the free wall portion exhibit an rS pattern [30].
3.5. Para-Hisian
The main characteristic of para-hisian PVCs is the narrow QRS duration (typically <
130 ms) related to the involvement of the conduction system. Para-hisian PVCs may be
mapped from all the structures near to the His bundle region, including the LV septum
below the membranous septum, the RCC and the NCC. Generally, they show an LBBB
pattern with QS in V1 and a left inferior axis with a dominant R wave in lead I. A peculiar
characteristic is the presence of a positive deflection in aVL related to the more rightward
and inferior location, compared to the RVOT and RCC. For the same reason lead III can
be isoelectric or negative and, generally, there is a III/II R wave ratio < 1. Infrequently,
para-hisian PVCs from below the membranous septum may present an RBBB pattern
[31].
3.6. Left and Right Ventricular Papillary Muscles, Moderator Band and Left Bundle Branch
Fasciculi
Arrhythmias originating from the papillary muscles are characterized by a RBBB
pattern with a dominant R wave in V1, a late transition (V3–V5) and a wider QRS
(median QRS width of 150 ms). Those originating from the APM have a right inferior axis
and sometimes an inferior lead discordance with a negative QRS complex in lead II and a
positive one in lead III; while those originating from the posteromedial papillary muscle
(PPM) have a left superior axis [32,33].
Fascicular PVCs are characterized instead by a narrower QRS complex (<130 ms), an
rsR’ pattern in V1 resembling a typical RBBB and an initial q wave in lead I which are
almost never seen in papillary muscle arrhythmias. Left anterior fascicle PVCs have a
right inferior (left posterior fascicular block pattern), while those originating from the
posterior fascicle have a left superior axis (left anterior fascicular block pattern).
Arrhythmias originating from anterior and posterior RV papillary muscles, as well
as those originating from the moderator band, all show an LBBB pattern with late
transition (>V4) and a left superior axis[34].
Diagnostics 2021, 11, 1840 7 of 19
4. Diagnostic Work-Up
Initial patient evaluation should include detailed clinical history with focus on
inherited arrhythmic syndromes, cardiomyopathies and familiar history of SCD,
adrenergic substances consumption and metabolic disorders such as hyperthyroidism.
Beyond the prediction of the SOO, resting ECG may rise the suspicion of underlying SHD
in presence of depolarization or repolarization abnormalities including q waves, QRS
fragmentation and inverted T waves. Exercise stress test should always be part of the
initial diagnostic work-up, as exercise-induced PVCs or induction of SVT, as well as
frequent PVCs occurring during the recovery phase are all markers of increased risk,
even in the absence of myocardial ischemia [35,36]. Although PVCs commonly occur in
subjects with morphologically normal hearts, it is crucial to exclude an underlying SHD
due to its impact on the therapeutic approach and risk stratification. In this regard,
cardiac imaging plays a central role (Table 2) [37,38].
Table 2. Indications, merits, and limitations of imaging tests in patients with premature ventricular
contractions. 3D, three-dimensional; CAD, coronary artery disease; CIEDs, cardiac implantable
electronic devices; EF, ejection fraction; EMB, endomyocardial biopsy; LV, left ventricular; PCI,
percutaneous coronary intervention; PVCs, premature ventricular contractions; RV, right ventricle;
RVOT, right ventricular outflow tract; SCD, sudden cardiac death; VT, ventricular tachycardia.
Imaging Test
Indications
Advantages
Limitations
Echocardiogram
Potentially indicated in
each patient presenting
PVCs; may be omitted in
asymptomatic healthy
subjects with low PVC
burden and no family
history of SCD
- Widely
available
-
Lack of
contrast/radiat
ion exposure
-
May be
repeated over
time
-
Allows precise
measurement
of LV EF
-
Operator-dependent
-
Does not allow
myocardial tissue
characterization
-
Suboptimal
visualization of
complex 3D
structures,
including the RV
Cardiac magnetic
resonance
imaging
-
PVCs arising from
unusual locations
-
Sustained VT
-
Suspected structural
heart disease by
echocardiogram
-
Reduced LV EF
- Unlimited
number of
imaging
planes
-
Accurate
tissue
characterizatio
n
-
Gold-
standard
assessment of
ventricular
structure and
function (i.e.,
LV EF)
-
Gating
difficulties/artifacts
due to PVCs
-
False positive
detection of
intramyocardial fat
-
Difficult detection
of RV fibrosis
-
Patients with CIEDs
-
Gadolinium
exposure
Computed
tomographic
coronary
angiography
-
Reduced LV EF
-
Symptoms
indicating a possible
underlying CAD
-
low-to-intermediate
pre-test probability
of CAD
-
Non-invasive
assessment of
coronary
anatomy
-
Limited
radiation
exposure
-
Contrast and
radiation exposure
Diagnostics 2021, 11, 1840 8 of 19
- Possible
identification
of myocardial
fibrosis
Invasive coronary
angiography
- Reduced LV EF
-
Symptoms
indicating a possible
underlying CAD
-
intermediate-to-
high
pre-test probability
of CAD
-
Gold-
standard
assessment of
coronary
anatomy
-
PCI in the
same session
-
Invasive test
-
Contrast and
radiation exposure
Electroanatomical
mapping
-
Preliminary test for
catheter ablation or
EMB
-
Suspected
arrhythmogenic
cardiomyopathy
- Accurate
assessment of
the
myocardial
substrate
-
Enhances
diagnostic
yield of EMB
-
Invasive test
-
Operator and tissue
contact-dependent
Transthoracic echocardiogram (TTE) represents the first line diagnostic test, and its
main role is to detect a reduced left ventricular ejection fraction (LVEF), which may either
point to an underlying SHD or be secondary to the high PVCs burden (as in PVCs-CMP)
[38,39]. LVEF is best measured in the sinus beat after the first post-extrasystolic beat or, in
case of bigeminy, by averaging measures taken during PVCs and sinus beats [40,41].
Besides LVEF, echocardiographic assessment should focus on PVCs’ presumed SOO,
especially is case of a suspected arrhythmogenic right ventricular cardiomyopathy
(ARVC): the presence of right ventricular wall motion abnormalities (akinesia,
dyskinesia, aneurysm, bulging), together with a disproportionate RVOT dilation,
represent diagnostic criteria for ARVC, and help to differentiate it from training-induced
RV re-modeling, which is commonly encountered in athletes [42–44]. In case of reduced
LVEF, symptoms, cardiovascular risk factors, or other elements suggestive of ischemic
heart disease (i.e., presence of abnormal q waves, repolarization abnormalities, regional
wall motion abnormalities) invasive or computed tomographic (CT), coronary
angiography should be considered to rule out a significant coronary artery disease, with
the latter reserved for younger patients, with a lower pre-test probability [45,46]. Cardiac
magnetic resonance (CMR) is currently the cornerstone for the assessment of cardiac
structure and function, as well as for myocardial tissue characterization. Concealed
myocardial structural abnormalities have been reported in up to 50% of patients with
unremarkable ECG and echocardiographic findings [47–50]. Generally, CMR is best
reserved for patients with PVCs not arising from the RVOT (i.e., RBBB pattern with
superior axis), in presence of multifocal PVCs, exercise induced PVCs, family history of
CMP or SCD, older age or when LVEF is reduced (Figure 2) [47,49,51,52].
Diagnostics 2021, 11, 1840 9 of 19
Figure 2. (A) 36-year old woman presenting with frequent premature ventricular contractions, with right bundle branch
block inferior axis morphology and (B,C) evidence on cardiac magnetic resonance of a patchy area of subepicardial late
gadolinium enhancement, involving the basal anterolateral left ventricular segment (arrows). Reproduced with
permission from Muser et al. [50].
The main advantage of CMR as compared to TTE lies in the unlimited number of
imaging planes, which allows optimal assessment of complex three-dimensional
structures, such as the RV [53]. Furthermore, CMR offers non-invasive myocardial
characterization capabilities, enabling the detection of fatty infiltration, fibrosis and
myocardial edema, which are key elements of the substrate underpinning PVCs in SHD.
In addition to diagnostic purposes, the identification and localization of myocardial
fibrosis is also important for proper planning of CA and carries significant prognostic
implications as the presence of CMR abnormalities has been correlated with increased
risk of malignant arrhythmic events during long-term follow-up [50,54,55]. Nonetheless,
CMR carries some limitations in patients with frequent PVCs, including gating
difficulties and motion artifacts due to the irregular rhythm [56,57]. Furthermore,
identification of fibro-fatty replacement of the right ventricular wall may be problematic
due to its thin structure [43]. Besides non-invasive diagnostic modalities,
electroanatomical mapping (EAM), which is pivotal during CA procedures as it allows
the precise localization of the arrhythmic focus by activation mapping, may also provide
important diagnostic and prognostic information [58,59]. Notably, EAM allows a very
accurate characterization of the myocardial substrate, identifying the presence of
abnormal myocardium (i.e., areas of scar or inflammation) as low voltage areas. Some
data indicate that EAM has a higher sensitivity than CMR for the detection of myocardial
structural abnormalities, even when they have a limited extent such as in early stages of
ARVC [60,61]. Furthermore, EAM may serve as a preliminary step for endomyocardial
biopsy (EMB), by disclosing diseased myocardial regions in many conditions
Diagnostics 2021, 11, 1840 10 of 19
characterized by a patchy myocardial involvement (i.e., myocarditis, ARVC, sarcoidosis),
thus allowing the direct sampling of the diseased myocardium and enhancing EMB’s
diagnostic yield [62,63]. The main limitation of EAM lies in its operator dependency, and
in the importance of ensuring an adequate tissue contact to avoid the spurious detection
of low-voltage areas; in this regard, the introduction of contact-force sensing catheters
helped to increase EAM’s accuracy, and to facilitate its standardization [62].
5. Prognosis
The available evidence on the prognostic impact of idiopathic PVCs in terms of risk
of death and heart failure is conflicting. Some studies have reported the prognosis of
asymptomatic patients with frequent PVCs superimposable to that of the general
population, while others have found an increased risk of heart failure and death
including SCD [64–66]. Two recent large metanalysis, including 11 and 8 large
population-based studies and almost 150000 healthy subjects, have found the presence of
PVCs (defined as any PVC occurring ≥1 time during a standard ECG recording or ≥30
times over a 1-h recording and as any PVC documented by a ≥12 s ECG recording,
respectively) associated with a 1.7-fold increase in the risk of major adverse cardiac
events (MACE) and a 2.64-fold increase in the risk of SCD [67,68]. These data should be
carefully interpreted as the major prognostic element in patients presenting with PVCs is
represented by the presence of underlying SHD, and the criteria used to define normal
heart in the vast majority of the included studies were simply the absence of clinical
history of heart disease, normal physical examination and normal resting ECG, with a
single study out of 19 having included the use of TTE. More recent data have
demonstrated that advanced imaging techniques such as CMR may identify concealed
SHD in a non-negligible proportion of patients presenting with apparently idiopathic
PVCs, on the basis of a normal resting ECG and TTE [50,53]. Several studies have
consistently reported an increased risk of adverse events when CMR abnormalities are
detected even in presence of normal LVEF (Figure 3) [50,54,55,69].
Figure 3. Forest plot showing the results of the principal studies investigating the prognostic role of cardiac magnetic
resonance abnormalities in patients with frequent premature ventricular contractions.
On the other hand, a prospective study including 239 patients with frequent
RVOT/LVOT PVCs and normal CMR did not show any MACE during a median
follow-up of 5.6 years [70]. When CMR abnormalities are detected, further refinement of
risk stratification should be considered, especially in patients with preserved LVEF. In
this regard, induction of SVT by programmed electrical stimulation has been associated
with a significant increased risk of malignant VA, compared to patients with CMR
abnormalities which are non-inducible [69].
Enthusiasm around the “PVCs hypothesis”, postulating that PVCs suppression with
antiarrhythmic drugs (AAD) could lead to a reduced risk of SCD among patients with
Diagnostics 2021, 11, 1840 11 of 19
recent myocardial infarction and asymptomatic PVCs, was suddenly stopped by the
publication of the Cardiac Arrhythmia Suppression Trial (CAST), in which a paradoxical
increase in the risk of death was reported in subjects receiving class IC AAD [71].
However, several lines of evidence have subsequently supported the notion that PVC
suppression with either AAD or CA may result in improved EF and heart failure
symptoms, and these treatments should be considered among patients at higher risk of
developing PVC-CMP, especially in cases of high PVC burden. The PVC burden
threshold at which AAD and/or CA should be considered is variably defined as >10%
(the threshold after which most cases of PVC-CMP occur), >16–24% (the statistically
optimal discriminatory cut-off value for PVC-CMP), or >6% (the threshold indicating a
potential benefit of CA) [38,41,66,72]. Apart from the PVC burden, other predictors of
PVC-CMP include wider PVC QRS duration and epicardial origin of PVCs as a result of a
higher degree of LV dyssynchrony during the PVC beat. Interpolated PVCs and PVCs
with variable coupling interval have been also associated with a higher risk of PVC-CMP
[38,42].
Finally, a history of syncope in a patient presenting with PVCs and a structurally
normal heart should be considered a red-flag, possibly pointing to a PVC-triggered
ventricular fibrillation/polymorphic ventricular tachycardia and requires a careful
assessment [73].
6. Medical Therapy and Catheter Ablation
No treatment other than reassurance is needed in patients with PVC without
underlying heart disease, or inherited arrhythmogenic disorder, who are asymptomatic
or mildly symptomatic [74].
In patients with symptomatic PVCs, β-blockers or non-dihydropyridine calcium
channel blockers are considered the first-line treatments [45]. These drugs have a long
track record of safety in structurally normal hearts, and β-blockers are useful in patients
with coronary artery disease or reduced LV function [45].
β-blockers can decrease the arrhythmic burden and improve symptoms and are
particularly effective for sympathetically mediated PVCs. In randomized controlled trials
the use of β-blockers resulted in a clinically significant reduction in OT-PVCs and
symptoms improvement by reducing the increase in contractility of the post PVC sinus
beat [75]. Similarly, non-dihydropyridine calcium channel blockers have demonstrated to
be effective in treating OT-PVCs and are considered particularly useful for fascicular VA
[76]. For these reasons, in patients with a structurally normal heart, it is reasonable to try
a calcium channel blocker if a β-blocker fails (and vice versa). Beta-blockers and calcium
channel blockers should be used at the lowest effective dose to relieve symptoms and
minimize side effects. The exception to this is patients with a prior myocardial infarction
or heart failure; then, doses should be titrated to the maximal tolerated. Failure of a drug
may occur because of either non-responsiveness or intolerance. With either type of drug,
patients may experience fatigue, hypotension, bradycardia or presyncope. β-blockers
may also cause depression and erectile dysfunction, and non-dihydropyridine calcium
channel blockers may result in gastrointestinal side effects, such as gastroesophageal
reflux and constipation, and can cause leg swelling [45].
For patients who have symptomatic PVCs that are unresponsive to a beta-blocker or
calcium channel blocker, or in whom those drugs are poorly tolerated and are not good
candidates for CA (because of frailty or multifocal PVCs), treatment with additional AAD
such as flecainide, propafenone, sotalol and amiodarone may be considered to reduce the
frequency of PVCs and improve symptoms [45,77–80]. Mexiletine is rarely used as its
effectiveness is inferior to either other AAD or CA [79].
Class IC AAD (flecainide and propafenone) are generally well-tolerated and highly
effective [77–79].These drugs are contraindicated in the presence of coronary artery
disease, severe left ventricular hypertrophy, or heart failure. Since the CAST
demonstrated an excess of mortality related to flecainide use in an attempt to suppress
Diagnostics 2021, 11, 1840 12 of 19
post myocardial infarction PVCs, class IC AAD became contraindicated in SHD due to
their propensity to facilitate re-entrant ventricular arrhythmias [71].
A number of studies have assessed the efficacy of sotalol for suppressing PVCs,
particularly in the presence of coronary artery disease. Sotalol is effective for reducing
PVC burden; however, it is associated with QT prolongation and torsades de pointes, a
risk that must be balanced with its efficacy for PVC suppression [80].
Amiodarone is highly effective and is one of the few AAD that can be safely
administered in patients with severely reduced systolic function; however, side-effects
associated with its long-term use make it substantially less preferable, especially in
younger patients [72].
For patients with PVC-induced cardiomyopathy, amiodarone is reasonable to
reduce the PVC burden, improve symptoms and left ventricular function [72]. Class IC
AAD have also been shown to be effective for PVC suppression and improving left
ventricular function in patients with PVC-induced cardiomyopathy [81]. However, in the
last two decades, with progressive improvement in mapping techniques and CA
outcomes, CA has become a first-line therapeutic option especially, when a PVC CMP is
suspected [82].
The recent expert consensus statement on catheter ablation of VAs reports some
recommendations for CA depending on the specific SOO of PVCs, considering its impact
on the choice of the initial approach between antiarrhythmic therapy and CA. This
consensus also states that patients with PVC who have characteristics that could lead to
tachycardia induced cardiomyopathy should be followed up with careful structured
clinical follow-up [82].
In a clinical scenario when it is suspected that a high PVCs burden (>15–25%) may
play a significant role in LV dysfunction, CA can help to improve LVEF [68,69]. In
patients who were non responders to cardiac resynchronization therapy (CRT) with a
PVC burden > 22%, Lakkireddy et al. demonstrated that CA of PVCs improved the
efficacy of CRT and consequently LVEF together with New York Heart Association
(NYHA) functional class [83].
Medical therapy should be considered as first-line therapy in patients in whom
ablation is more complex and leads to a higher risk of procedural complications, but in
general, CA has a strong recommendation in symptomatic patients who do not tolerate
or do not prefer long-term AAD [82,84].
The planning of the ablative procedure starts with the identification of the possible
SOO by careful evaluation of the 12-lead ECG, and this specific approach must be
tailored taking into account the anatomical structures that are in close proximity and
susceptible to injury. Activation mapping and pace mapping are the standard methods
used to define arrhythmia origin. Occasionally, activation mapping during spontaneous
arrhythmias is limited by infrequent PVCs. In these cases, VA induction may be
attempted with isoproterenol infusion and ventricular or atrial burst pacing.
Radiofrequency CA should be performed at the site where earliest activation (≥20 ms) is
recorded and, ideally, where the pace-map is also optimal (i.e., 12/12 leads) [82].
In case of OT PVCs, the RVOT is mapped first in patients presenting with LBBB and
transition ≥ V3, while the aortic cusps and the LVOT is mapped first in cases presenting
with RBBB or LBBB with an early transition (≤V2) [82]. When local activation times at
multiple adjacent sites (i.e., GCV/AIC, LCC, LV endocardium and RVOT in cases of OT
PVCs) have similar values, especially in the presence of suboptimal pacemaps, an
intramural origin of the arrhythmic focus should be suspected. For patients with
intramural PVCs, standard unipolar RF ablation may not be successful in eliminating the
arrhythmias, even if sequentially delivered from multiple adjacent sites. In these cases,
bipolar RF ablation, simultaneous unipolar RF ablation or the use of half-normal
saline/non-ionic irrigants have been shown to enhance success. Coronary angiography
should be performed before ablation from the great cardiac vein, epicardium and in
select cases of ablation within the aortic cusps and radiofrequency energy delivery
Diagnostics 2021, 11, 1840 13 of 19
should be deferred if the site is in close proximity (within 5 mm) to a major coronary
artery [82].
In case of RV OT PVCs, CA success rates are reported between 80–95%, with a low
complication rate [3,78,85]. Moreover, in symptomatic patients with frequent PVCs from
the RVOT, CA has demonstrated a higher rate of efficacy compared to medical therapy
with either metoprolol or propafenone in a randomized controlled trial. This study
enrolled 330 patients with PVCs from RVOT showing that during the one-year follow-up
period, PVCs recurrence was significantly lower in patients randomized to CA (19.4%)
vs. medical therapy (88.6%). In this scenario, the expert consensus statement favors CA as
a first line approach. However, some patients with PVCs from the RVOT and minimal or
tolerable symptoms might prefer medical therapy or no therapy [84].
In patients with recurrent ventricular fibrillation triggered by PVCs often the SOO
lies in the Purkinije network. In such cases, CA is a standardized approach to avoid
further malignant arrhythmic events [86].
Acute suppression of non-OT idiopathic PVCs with RV origin is over 90% (RV
papillary muscles, tricuspid annulus and moderator band) but the risk of recurrence
especially of PVCs from the parietal band is higher with the need for redo procedures
[5,34,87,88]. Compared to PVCs originating from the RVOT, ablation of PVCs originating
from the LVOT is more complex and can involve greater procedural risk due to nearby
anatomical structures such as coronary arteries or aortic valve cusps [89].
Left ventricular non-OT PVCs have several well-defined SOO, including papillary
muscles, MVA and LV summit.
In PVCs originating from intracavitary structures such as papillary muscles and
moderator band, the complex anatomy, its variability and the motion during the cardiac
cycle, make CA extremely challenging. In these cases, the use of intracardiac
echocardiography (ICE) is pivotal to allow real-time visualization and ensure proper
catheter contact. Cryoablation may also be an option to improve catheter stability [82].
In particular ablative treatment of PVCs originating from the papillary muscles
requires greater catheter stability, with the need for frequent use of the intracardiac echo
and a higher risk of recurrence with the necessity of redo procedures in about 30% of the
cases [90,91].
In cases of para-Hisian PVCs, cryoablation has been described as an option when
radiofrequency CA is deemed to be at high risk of collateral injury of the conduction
system or resulted to be ineffective [92].
A subxiphoid percutaneous epicardial approach may be pursued when an
epicardial origin is suspected on the basis of 12-lead ECG or after failure of an
endocardial approach [93].
7. Future Perspectives
Although basic and clinical research is constantly evolving, many aspects of
diagnosis and management of PVCs remain unknown. In particular, the identification of
patients at risk to develop PVC induced cardiomyopathy or malignant arrhythmic events
at follow-up is still largely debated, as well as the identification of patients who may
benefit from an advanced diagnostic workup, including CMR.
In terms of invasive management, even if current careful procedural planning based
on the twelve-lead morphology of PVCs and imaging evaluation has improved the
accuracy of identification of the SOO, and advanced technologies such as ICE or
cryoablation have improved procedural outcomes, the best approach for PVCs
originating from complex anatomical structures such as papillary muscles and
intramural foci remains to be defined.
Diagnostics 2021, 11, 1840 14 of 19
8. Conclusions
Idiopathic PVCs are among the most common ventricular arrhythmias in clinical
practice. They originate from well-defined and standardized sites of origin from the right
and left ventricle that can be predicted on the basis of specific twelve-leads ECG
characteristics [94]. In the absence of underlying structural heart disease PVCs have a
good long-term prognosis. In case of a transcatheter ablative treatment, an overall
evaluation of the patient is essential, starting from the morphology of the arrhythmia
ECG to plan the most effective approach.
Author Contributions: Conceptualization, D.M., F.G. and M.T.; writing—original draft
preparation, P.C., M.V.M., A.D.M., D.M. and F.G.; writing—review and editing, F.G., M.T. and
D.M.; supervision, F.G., M.A., R.D.P.; All authors have read and agreed to the published version of
the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: R. De Ponti has received honoraria for lectures from Biosense Webster, other
authors declare no conflict of interest.
Abbreviations
Premature ventricular contractions (PVCs); structural heart disease (SHD); right and
left ventricular outflow tracts (RV/LV-OT); sites of origin (SOO); nonsustained
ventricular tachycardia (NSVT); sustained ventricular tachycardia (VT); catheter ablation
(CA); ventricular arrhythmias (VAs); the aortic-mitral continuity (AMC); ventricular
fibrillation (VF); cardiomyopathy (CMP); delayed afterdepolarizations (DADs); cyclic
adenosine monophosphate (cAMP); protein kinase (protein kinase A, PKA); ryanodine
receptor (RyR2); left bundle branch block (LBBB); tricuspid valve annulus (TVA); right
bundle branch block (RBBB); right coronary cusp (RCC); left coronary cusp (LCC); mitral
valve annulus (MVA); left ventricular summit (LVS); left circumflex (LCx); anterior
interventricular vein (AIV); transthoracic echocardiogram (TTE); left ventricular ejection
fraction (LVEF); arrhythmogenic right ventricular cardiomyopathy (ARVC); computed
tomographic (CT); cardiac magnetic resonance (CMR); mitral valve (MV); tricuspid valve
(TV); electroanatomical mapping (EAM); endomyocardial biopsy (EMB); major adverse
cardiac events (MACE); antiarrhythmic drugs (AAD); Cardiac Arrhythmia Suppression
Trial (CAST); intracardiac echocardiography (ICE).
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