Coupling interval variability of premature ventricular contractions in patients with different underlying pathology: an insight into the arrhythmia mechanism
Journal of Interventional Cardiac Electrophysiology
Coupling interval variability of premature ventricular contractions in patients with different underlying pathology: an insight into the arrhythmia mechanism
Lennart J. de Vries 0 1 2 3
Tamas Szili-Torok 0 1 2 3
Mihran Martirosyan 0 1 2 3
Ron T. van Domburg 0 1 2 3
Sip A. Wijchers 0 1 2 3
Tamas Géczy 0 1 2 3
0 Ron T. van Domburg
1 Mihran Martirosyan
2 Lennart J. de Vries
3 Department of Epidemiology, Erasmus Medical Center , Rotterdam , The Netherlands
Purpose Coupling interval (CI) variability of premature ventricular contractions (PVCs) is influenced by the underlying arrhythmia mechanism. The aim of this study was to compare CI variability of PVCs in different myocardial disease entities, in order to gain insight into their arrhythmia mechanism. Methods Sixty-four patients with four underlying pathologies were included: idiopathic (n = 16), non-ischemic dilated cardiomyopathy (NIDCM) (n = 16), familial cardiomyopathy (PLN/LMNA) (n = 16), and post-MI (n = 16)-associated PVCs. The postMI group was included as a reference, on account of its known re-entry mechanism. On Holter registrations, the first 20 CIs of the dominant PVC morphology were measured manually after which median ΔCI and mean SD of CI/√R-R (= CI of PVC corrected for underlying heart rate) were obtained. Two observers independently measured PVC CIs on pre-selected Holter registrations in order to determine inter- and intra-observer reliability. Results The largest ΔCI was seen in the PLN/LMNA group (220 ms (120-295)), the lowest in the idiopathic group (120 ms (100-190)). The ΔCI in the PLN/LMNA group was significantly larger than the post-MI group (220 ms (120-295) vs 130 ms (105-155), p = 0.023). Mean SD of CI/√R-R in the PLN/LMNA group was also significantly higher than in the post-MI group (p = 0.044). Inter- and intra-observer reliability was good (ICC = 0.91 vs 0.86 and 0.96 vs 0.77, respectively). Conclusions Low ΔCI and SD of CI/√R-R of idiopathic and NIDCM PVCs suggest that the underlying arrhythmia mechanisms might be re-entry or triggered activity. Abnormal automaticity or modulated parasystole are unlikely mechanisms. High CI variability in PLN/LMNA patients suggests that the re-entry and triggered activity are less likely mechanisms in this group.
Coupling interval variability; Ventricular premature complexes; Idiopathic ventricular arrhythmia; Non-ischemic dilated cardiomyopathy; Familial cardiomyopathy; Arrhythmogenesis
Department of Cardiology, Electrophysiology, Erasmus Medical
Center, Rotterdam, The Netherlands
Premature ventricular contractions (PVCs) are common both
in patients with and without structural heart disease (SHD) [
Even in the population without apparent SHD, the incidence
of PVCs is estimated to lie between 4 and 50% [
Although the independent prognostic importance of the PVC
burden regarding adverse cardiac events (e.g., VT, sudden
cardiac death, and heart failure) has not been clarified
unambiguously, symptomatic PVCs can significantly reduce the
quality of life (QoL) in both patient populations, and frequent
PVCs can result in tachycardiomyopathy even in the absence
of overt SHD [
1, 6, 7
]. It is therefore important to emphasize
that the treatment of symptomatic and/or frequent PVCs can
lead to a significant improvement of the QoL  and to the
preservation/improvement of left ventricular function [
Catheter ablation (CA) has become a highly efficient
alternative to medical therapy and is now in many cases being
applied as a treatment of first choice [
]. However, a broad range
of success rates have been reported in the literature, varying
from 69% [
] to as high as 90% [
]. Incomplete understanding
of the main underlying mechanisms of these arrhythmias may
play a key role in this discrepancy.
One of the basic ECG characteristics of PVCs is the
coupling interval (CI), which is defined as the distance between
the onset of the preceding sinus QRS and that of the premature
beat. An important feature of PVCs described in the literature
is the variability of the CI. Although the determinants of CI
variability and their clinical implications are not completely
understood yet, early studies describe an association between
higher CI variability and the incidence of VT and SHD among
PVC patients [
]. In addition, a relation between CI
variability and the efficiency of anti-arrhythmic medical therapy
has also been implicated . Moreover, a recent publication
has shown that CI variability might be able to discriminate
between the precise anatomic origins of PVCs within the
outflow tracts in patients with idiopathic ventricular arrhythmias
Although the variability of CIs is influenced by several
factors (e.g., variation of the preceding cycle length, fluctuations in
rhythmic distribution patterns, intermittent parasystole, and
precipitancy of another ectopic source [
]), their major
determinant is believed to be the underlying arrhythmia
mechanism. When PVCs have fixed CIs, then re-entry and triggered
activity are among the most probable mechanisms. On the other
hand, when PVCs exhibit variable CIs, then increased/
abnormal automaticity or parasystole are more likely to be the
source of rhythm disturbances [
By describing the CI variability of PVCs in four distinct
pathophysiological groups of myocardial disease, this study
aims to shed more light on their underlying arrhythmia
mechanisms. As the arrhythmogenic substrate for PVCs in patients
with prior myocardial infarction (post-MI group) is
welldescribed as being scar-related re-entry with a fixed CI (in
cases of monomorphic PVC/VT,) this group of patients served
as a control in our analyses. The arrhythmogenic substrates in
structurally normal hearts and in non-ischemic myocardial
disorders are less well-understood; therefore, we assessed
the CI variability of PVCs in the following three groups: (i)
patients with idiopathic VAs (idiopathic group), who exhibited
PVCs in the absence of apparent SHD; (ii) patients with
nonischemic dilated cardiomyopathy (NIDCM group); and (iii)
patients with familial dilated cardiomyopathy due to
mutations in the genes encoding lamin A/C or phospholamban
A database containing all performed CAs in our center was
screened for patients undergoing VA ablation. Out of 345 VA
ablations performed in our center between 2007 and 2015, 16
consecutive idiopathic VA patients, 16 NIDCM patients, and
16 post-MI patients were selected based on availability of
Holter registrations. Sixteen PLN/LMNA cardiomyopathy
patients from the inherited channelopathy and cardiomyopathy
database were selected based on the same criteria. Selection of
Holter registrations was based on the amount of PVCs
recorded. A cutoff of 20 monomorphic PVCs of the dominant
morphology was applied for selection, or otherwise the recording
with the highest amount with a minimum of 4. All patient data
was acquired from medical records by a trained physician.
Pediatric patients were defined as younger than the age of
18 years. Arrhythmia origin was derived from
electrophysiological studies, when available. We distinguished right
ventricular outflow tract (RVOT), left ventricular outflow tract
(LVOT), which includes coronary cusps and aortomitral
continuity, and others (such as, ventricle walls, fascicular, or His
region). Demographic data are presented in Table 1. Data
collection was performed respecting the Health Insurance
Portability and Accountability Act 1996.
2.2 Measurement and determination of CIs
For every patient, PVC CIs were taken from a single 24-h
Holter recording. Individual rhythm strips (depicting a certain
time frame within the 24-h recording period, which usually
encompassed approximately 10–60 s) were selected by
designated Holter analyst, either manually or with the help of a
computer software that generates an automatic event
summary. These rhythm strips had been collected (and saved within
the electronic documentation of each patient) based on their
relevance with regard to the clinical inquiry posed by the
referring physician. For the purpose of our analysis, we
Descriptive statistics are presented as mean ± SD for continuous variables, if normally distributed, or otherwise by
median with (25th and 75th percentile). (*Not applicable: no ablation was done in this group of patients; therefore,
the exact origin of the PVCs was not determined by electroanatomical mapping; PVC characteristics, indicative of
PVC foci, are presented as a surrogate. #Not displayed: in case electroanatomical mapping is available, no PVC
characteristics are displayed.)
BMI body mass index, LBBB left bundle branch block, LVEF left ventricular ejection fraction, LVOT left
ventricular outflow tract, RBBB right bundle branch block, RVOT right ventricular outflow tract
selected PVCs (and corresponding R-R intervals) without
regard to the actual time periods these rhythm strips were
depicting (throughout the 24 h registration period); thereby,
ensuring that comparable numbers of day or nighttime
registrations have been included. The first 20 PVC CIs of the
dominant morphology were measured by hand with an accuracy of
20 ms. Additionally, the corresponding sinus R-R intervals
preceding the selected PVC CIs were measured in order to
correct the CIs for heart rate variability (as described below).
The dominant PVC morphology was established by reviewing
all the individual rhythm strips of the full 24-h Holter
registrations. Distinct morphologies were then identified and
grouped accordingly. Subsequently, the number of PVCs in
each distinct group was determined, and the morphology,
which belonged to the group with the highest PVC count
(thus, the most frequently occurring morphology) on the
anal y z e d r h y t h m s t r i p s , w a s c o n s i d e r e d t h e d o m i n a n t
VTs were not included in this study. Two methods were
used for assessing CI variability: (i) delta (Δ) CI (defined as
the maximum minus the minimum CI duration) was defined
for each patient, and the median and 25th and 75th percentiles
of ΔCIs were presented for each group; (ii) the SD of CI/√R-R
(the CI of each PVC corrected for the underlying heart rate)
for each patient was defined, after which the SD of CI/√R-R
per group was presented as mean with SD. The first step of the
latter methodology was analogous to Bazett’s formula, which
is used to correct the QT-interval by taking into consideration
the underlying heart rate [
]. In our calculations of CI/√R-R,
the R-R interval of the preceding sinus beat was used.
The monomorphic or polymorphic nature of PVCs and the
amount of each morphology were determined subsequently
(as described above). The monomorphic or polymorphic
nature of PVCs was defined as possessing only one morphology
or two or more morphologies on Holter, respectively.
2.3 Inter- and intra-observer reliability
To determine inter- and intra-observer reliability, agreement
and bias for CI measurements, the first two observers, both
physicians, independently measured the PVC CIs on
preselected Holter registrations from 32 patients (the idiopathic
and NIDCM groups). When there was a discrepancy in the
amount of CIs measured by the observers, this was discussed
and a consensus decision was made. After a good reliability of
Fig. 1 ΔCI compared to post-MI
group. Median ΔCI per patient
for post-MI group versus a
idiopathic PVCs, b NIDCM PVCs,
and c PLN/LMNA PVCs. The
median ΔCI with 25th and 75th
percentiles per group is shown in
the measurement method was established, one observer
analyzed the two remaining groups.
The normality of distribution was assessed using the
ShapiroWilk test. Descriptive statistics are presented as mean ± SD for
continuous variables if normally distributed, or otherwise as
median with 25th and 75th percentiles, where appropriate.
Data were compared by one-way ANOVA or median test, as
appropriate. The median test was used because equal
variances between the groups were not assumed. Categorical data
were expressed as percentages and compared with the
chisquared test. Intra-class correlation coefficients (ICC) were
used to describe inter- and intra-observer reliability.
Additionally, a Bland-Altman plot was used to assess the
agreement between the two observers and to detect any bias.
Statistical analysis was performed using SPSS version 21
(IBM Corp., Somers, NY). Statistical significance was
defined as p < 0.05 (two-tailed).
3.1 Patients and demographics
Patient demographics are presented in Table 1. Patients in the
post-MI group contained more men (93.8%, p = 0.028), they
were older (55 years (53–63), p = 0.042), and had a higher
BMI (28 ± 3, p = 0.026). Digoxin was used more often in the
PLN/LMNA group (37.5%, p = 0.006). Left ventricular
ejection fraction (LVEF) was significantly different among the
groups (p < 0.001): most patients (93.8%) in the idiopathic
group had a normal LVEF and most patients (50%) in the
PLN/LMNA group had severe LV dysfunction. All VAs in
the post-MI group originated in the LV and none of them in
the outflow tracts, whereas most of the VAs in the idiopathic
group originated in the RV (75%), predominantly in the
RVOT (75%). In the NIDCM group, the etiology was
unknown (idiopathic) in 68.7% of the patients. The remaining
etiologies included the following: SCN5A mutation, structural
congenital heart defects, and limb-girdle muscular dystrophy.
3.2 Coupling intervals
In four cases, there was a discrepancy in the amount of CIs
measured by the observers, which was discussed followed by
a consensus decision. Overall, the largest median ΔCI was
seen in the PLN/LMNA group (220 ms (120–295)) and the
lowest in the idiopathic group (120 ms (100–190)) (Fig. 1).
The ΔCI in the PLN/LMNA group was significantly larger
than in the post-MI group (220 ms (120–295) vs 130 ms (105–
155), p = 0.023) (Fig. 1). The mean SD of CI/√R-R was as
follows: post-MI 47 ± 15 ms; idiopathic, 47 ± 20 ms; NIDCM,
52 ± 25 ms; and PLN/LMNA, 65 ± 31 ms (Fig. 2). The mean
Fig. 2 Mean SD of CI/√R-R
compared to post-MI group.
Mean SD of CI/√R-R per patient
for post-MI group versus a
idiopathic PVCs, b NIDCM PVCs,
and c PLN/LMNA PVCs. The
mean SD of CI/√R-R with
standard deviation per group is shown
in panel d
SD of CI/√R-R in the PLN/LMNA group was significantly
higher compared to the post-MI group (p = 0.044) (Fig. 2).
The median amount of CIs measured was equal between the
groups (p = 0.485). In the idiopathic group, there were no
patients with polymorphic PVCs; in the PLN/LMNA, most
patients (94%) had polymorphic PVCs (p < 0.001) (Table 1).
3.3 Inter- and intra-observer reliability
The inter-observer reliability in a two-way mixed effect model
was very good for the idiopathic group (ICC = 0.91) and good
for the NIDCM group (ICC = 0.86) (Supplementary Fig. 1).
The Bland-Altman plots for both groups show the observers
were in good agreement regarding CI measurements
(Supplementary Fig. 1).
The intra-observer reliability in a one-way random effect
model was very good for the idiopathic group (ICC = 0.96)
and good for the NIDCM group (ICC = 0.77) (Supplementary
Fig. 2). The Bland-Altman plots for both groups show good
agreement and no bias regarding CI measurements
(Supplementary Fig. 2).
To the best of our knowledge, this is the first study in the
literature that analyzes the CI variability of PVCs in several
distinct subgroups of patients with VAs, in order to provide
further insights into the underlying mechanisms of
arrhythmogenesis related to different cardiac
pathophysiology. The main findings of this study are the following: (1)
although the underlying arrhythmia mechanisms might differ
between the post-MI population and the idiopathic VA
population (scar-related macro re-entry vs focal triggered activity),
the CI variability of these groups were essentially identical,
which indicates a similarly stable CI (fixed CI) for both
reentry and triggered activity within these pathophysiological
subgroups. (2) The majority of the patients in the NIDCM
group exhibited similar CI variability as the patients of the
post-MI and idiopathic VA groups, which suggests that
(despite a rather heterogeneous etiological background) the main
mechanisms for arrhythmogenesis might essentially be similar
to the ones of the previous groups, namely: scar-related micro/
macro re-entry or focal-triggered activity with fixed CIs. (3)
The patients of the familial dilated cardiomyopathy group
(PLN/LMNA mutation group) exhibited high CI variability,
which indicates that a mechanism different from re-entry or
triggered activity might be responsible for PVC generation in
this group. This mechanism may be abnormal automaticity,
parasystole, or another more complex mechanism. Since a
considerable portion of patients (10 out of 16) from this group
were on either digoxin or class III anti-arrhythmic drug
therapy, we additionally compared the CI variability of the
subgroup of patients on these AADs with their counterparts not
using these medications. We found no significant differences
between the CI variability of these subgroups of patients (data
not shown), implicating that although these AADs might be
able to alter the PVC frequency, they might not have any effect
on the underlying arrhythmia substrate (however, the numbers
in each subgroup were considerably small with regard to
statistical relevance; therefore, a firm conclusion from the results
cannot be drawn).
4.1 PVCs: General symptomatology and treatment
Symptomatic PVCs can present a considerable burden to
patients, even with a structurally normal heart [
]. In addition to
the significant impact of symptomatic PVCs on QoL, frequent
PVCs can cause LV dysfunction, and in a minority of patients,
they are also reported to initiate malignant VAs with a
potential to cause sudden cardiac death. These outcomes should not
be trivialized, especially when structural heart disease is
7, 8, 19, 20
Treatment of symptomatic and/or frequent PVCs can be
challenging. More often than not, medical drug therapy is
either inadequately effective, or its adverse side effects ensure
that the cure becomes worse than the disease [
Moreover, anti-arrhythmic drugs have not been demonstrated
to reduce all-cause mortality in patients with or without
structural heart disease . On the other hand, although
randomized trials of PVC suppression have not been
performed, multiple studies indicate the high efficacy of PVC
]. In addition, technological advancements, such
as magnetic navigation, have increased the safety of these
procedures significantly [
]. Abolishment of frequent PVCs
has been shown to reverse LV dysfunction in PVC-induced
cardiomyopathy and improve QoL in patients with
structurally normal heart [
]. CA of some specific VA entities (such
as idiopathic RVOT VAs or left posterior fascicular VAs) are
reported to have very high success rates (> 95%) , and CA
is increasingly being performed as a first choice therapy in
these select cases. However, CA of certain other VA etiologies
shows a much lower success rate in terms of arrhythmia
]. The relatively wide range of success rates
reported in the literature can at least be partially attributable to the
different sites of VA origin [
] (i.e., technically challenging
locations for the ablation procedure as, e.g., epicardial sites),
and/or they might also be influenced by publication bias. On
the other hand, incomplete understanding of the underlying
arrhythmia mechanisms of VAs occurring in the presence of
distinct cardiac diseases could represent another key
contributing factor to the failure of CA procedures.
4.2 Correlation of CI variability with arrhythmia mechanisms in different myocardial diseases
In order to further dissect the possible mechanisms that
generate PVCs in different myocardial disease states, we analyzed
the CI of PVCs in different patient populations. Although
there is limited data available in the literature about the
characteristics of CIs and their clinical significance, some reports
suggest a connection between short CI duration (< 300 ms), a
low prematurity index (< 0.73), and the potential of these
parameters to indicate an increased risk for malignant VAs
]. An earlier report of Komatsu et al. describes the
variability of CIs as a characteristic that might have the
potential to discriminate between groups of patients with low versus
high risk for VT [
]. Additionally, their report suggests that
higher CI variability has a tendency to occur in patients with
organic heart disease, whereas patients with frequent PVCs in
the absence of SHD tend to have a more fixed CI. Moreover,
they also describe a correlation between CI variability and the
efficacy of anti-arrhythmic drug therapy. Intriguingly, the
characteristics of fixed and variable CIs that we describe in
our study correspond well with the results of Komatsu et al.,
i.e., the mean SD of CI/√R-R of the post-MI group (47 ms),
the idiopathic VA group (47 ms), and that of the NIDCM
group (52 ms) all approach a range (35.4 ± 14.1 ms) that has
been identified in their report as fixed CI, and the mean SD of
CI/√R-R of the PLN/LMNA group (65 ms) fits well with the
measures of their variable group (74.1 ± 28.6 ms).
In general, the following underlying mechanisms have
been described in the literature to account for the
generation of VAs: re-entry, abnormal automaticity,
triggered activity, parasystole, and other more complex
mechanisms involving such entities as, e.g., an arrhythmogenic
milieu created by genetically defected ion channels and
abnormal regulatory protein functions. Although it is not
completely understood what determines the length and
variability of CIs, and there is limited data on their
association with the above mentioned basic arrhythmia
mechanisms, it is generally presumed that re-entry and
triggered activity have a rather fixed CI, whereas abnormal
automaticity, parasystole, and other more complex
mechanisms tend to result in CIs of higher variability [
Hence, analyzing these interval changes might give us a
good hint about the underlying mechanisms in different
From the four different disease entities included in our
study, the arrhythmogenic substrate for VAs is best described
and understood in post-MI patients. Unidirectional block and
slow conduction in areas within myocardial scar tissue
represent the pathological basis for the re-entry mechanism, which
then gives rise to PVCs with a fixed CI (in case PVCs with the
same morphology are taken into consideration, which of
course represent the same underlying re-entry circuit with an
identical exit site) [
]. Our results from the post-MI group
indeed demonstrated low CI variability; hence, this group
served as a control for the other three groups. One of them is
the idiopathic VA group (patients with VAs in the absence of
SHD). Most idiopathic VAs have their origin in one of the
outflow tracts. Focal mechanisms have been described to
account for this type of idiopathic VAs, which are usually
localized in the RVOT (other less common sites include the LVOT
and the aortic sinuses of Valsalva). Triggered activity
secondary to cAMP-mediated delayed afterdepolarization is believed
to be mainly responsible for this focal activity, but micro
reentry, abnormal automaticity, and modulated parasystole have
also been implicated to account for this focal activity [
Our results showed a relatively low CI variability in this group
(similar to post-MI patients), which in turn suggests that
triggered activity and/or micro re-entry are the most likely
mechanism for PVCs from the outflow tracts. However, as
demonstrated by the three Boutliers^ in this group with a ΔCI above
200 ms (Fig. 1a), it is conceivable that in a small subset of
patients different mechanisms might also play a role. A recent
report of Bradfield et al. identified a subset of patients with
outflow tract VAs, who exhibited more variable CIs than the
majority of patients in this group. They postulated that the
arrhythmia mechanism might be modulated parasystole in
these patients and that the occurrence of this rather unusual
mechanism might be related to the fact that the focal activity
originates in more unique anatomic locations within the
outflow tract (e.g., aortic sinus of Valsalva) [
]. However, we
did not observe such a correlation, as all three patients
exhibited PVCs with a common RVOT origin.
Since the patients in the NIDCM group represent a
population with heterogeneous etiological backgrounds (in most
cases, the underlying etiology remains unknown, other
etiologies include valvular heart disease, hypertension, and
sarcoidosis), a high CI variability would be expected in this group.
Intriguingly, our data shows the opposite: PVCs with fixed CIs.
In contrast to post-MI patients, the electrophysiological VA
substrate in this group is not clearly defined. Although
scarrelated macro re-entry seems to account for the majority of
monomorphic VTs, PVCs are believed to initiate primarily
from the subendocardium by a focal mechanism without
evidence of macro re-entry. The exact nature of the focal
mechanism remained unknown so far, but our results might suggest
that triggered activity and/or micro re-entry might be the most
likely candidates. However, similarly to the previous subgroup
of patients with idiopathic VAs, we identified several Boutliers^
in the NIDCM group ΔCI as well (see Fig. 1b), who exhibited
higher CI variability, which could indicate the presence of
different underlying arrhythmogenic substrates (abnormal
automaticity or modulated parasystole). Correlations between the
higher CI variability and clinical outcomes were beyond the
scope of our present study.
The last group of patients in our present study was the
group of familial dilated cardiomyopathy patients (PLN/
LMNA group) who had a genetic disorder affecting the genes
LMNA and PLN [
]. The LMNA gene encodes for two
splice variants of proteins: lamin A and C that are members
of the intermediate filament class of cytoskeletal proteins [
Phospholamban (gene product of PLN) is a
calciumregulating protein in the sarcoplasmic reticulum [
Intriguingly, we found that the CI of PVCs was highly
variable in this group of patients, unlike that of the other three
groups. This could suggest that common mechanisms such as
re-entry and triggered activity are not likely to play a role in
the genesis of VAs in this population. Other potential
mechanisms could involve abnormal automaticity or modulated
parasystole but more complex mechanisms cannot be
excluded either. Especially if we consider that phospholamban plays
an important role in intra-myocardial Ca2+-handling, it seems
plausible that the gene alteration of such a regulatory protein
might be able to create an arrhythmogenic milieu, which
enables the generation of PVCs. How the altered intra-cellular
ionic concentrations can specifically affect the mechanism of
arrhythmogenesis and result in PVCs with variable CIs
remains to be elucidated in future studies.
4.3 Outcome implications and clinical significance
In an optimal case scenario, the treatment strategy of VAs
should target the underlying arrhythmia mechanism. With
CA, this mechanism can be targeted directly. For instance, in
case of macro re-entry as the underlying mechanism (e.g.,
fascicular VAs), abolishment is accomplished simply by
interrupting the re-entry circuit [
]. For VAs with a triggered
activity-related mechanism (e.g., RVOT VAs), ablation of a
focal target is required [
], as it is the case for automaticity.
VAs precipitated by myocardial scar-related re-entry (e.g.,
postMI VAs) should be targeted by substrate-based ablation [
Therefore, it is of importance that the underlying mechanism of
the arrhythmia to be treated is clarified before deciding on a
therapeutic strategy. Determination of CI variability could be a
relatively easy and non-invasive method for aiding in the
identification process. A better understanding of the arrhythmia
mechanism could assist physicians in selecting optimal
patient-tailored care and to determine the appropriate medical
therapy. For instance, instead of beta-blockers, class III
antiarrhythmic drugs may be prescribed when the arrhythmia
mechanism is found to be re-entry. Interestingly, ranolazine
(originally intended as an anti-anginal drug) has recently been
shown to reduce triggered PVCs based on its suppression of
early or delayed afterdepolarizations [
studies are required to clarify whether this drug might be useful for
the treatment of VAs for which the underlying mechanism is
thought to be triggered activity.
4.4 Limitations of the study
Although we tried to minimize any form of bias through our
meticulous methodology, including (but not limited to) the
assessment of inter- and intra-observer reliability of the
measurement method, some limitations should be mentioned. Firstly, the
use of Holter registrations with a registration speed of 25 mm/s
for our CI measurements could introduce a minimal lack of
precision. Secondly, the amount of PVC CIs that were counted
per patient and the number of included patients were relatively
small. The total patient count per group was limited by the
amount of patients in the NIDCM group, upon which we
matched the amount of included patients in the other groups.
An automated CI measurement program counting PVC amounts
of above 1000 per patient would be ideal. Additionally, inter- and
intra-observer reliability was assessed with measurements from
patients in the idiopathic and NIDCM group and not from
patients in the two other groups. Finally, for patients from the PLN/
LMNA group, EP studies were not available to confirm the
clinical PVC origin or to invasively measure CIs. More basic
studies are needed to clarify arrhythmia mechanisms, in order
to improve our understanding of the different types of ventricular
arrhythmias and to optimize their treatment strategies.
Compliance with ethical standards
Conflicts of interest The authors declare that they have no conflict of
Ethical approval Data collection was performed respecting the Health
Insurance Portability and Accountability Act 1996.
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