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Systemic inflammation as a novel
QT-prolonging risk factor in patients with
torsades de pointes
Heart (British Cardiac Society)
Take-home message
•
In this study, 40 consecutive patients experiencing torsade de pointes (TdP) were
enrolled, and their levels of CRP and proinflammatory cytokines were compared
with those of patients with rheumatoid arthritis and healthy controls to determine
whether systemic inflammation may be an overlooked risk factor contributing to
TdP development. Of the patients with TdP, 80% had elevated CRP levels and
18 patients had identifiable inflammatory disease. These patients had IL-6 levels
approximately 15 to 20 times higher than levels in the control group. An additional
46 patients with inflammatory conditions and elevated CRP were enrolled. In these
patients, CRP reduction was associated with decreased IL-6 levels and significant
QTc shortening.
•
These results suggest that elevated IL-6 levels may represent a novel QT-prolonging
risk factor related to TdP occurrence, which may introduce new areas for
antiarrhythmic therapy.
Abstract
OBJECTIVE
Increasing evidence indicates sys-
temic inflammation as a new potential cause
of acquired long QT syndrome (LQTS), via
cytokine-mediated changes in cardiomyo-
cyte ion channels. Torsade de pointes (TdP)
is a life-threatening polymorphic ventricular
tachycardia occurring in patients with LQTS,
usually when multiple QT-prolonging factors
are simultaneously present. Since classical
risk factors cannot fully explain TdP events in
a number of patients, we hypothesised that
systemic inflammation may represent a currently
overlooked risk factor contributing to TdP devel-
opment in the general population.
METHODS
Forty consecutive patients who
experienced TdP (TdP cohort) were consecutively
enrolled and circulating levels of C-reactive
protein (CRP) and proinflammatory cytokines
(interleukin-6 [IL-6],tumour necrosis factor alpha
[TNFα], interleukin-1 [IL-1]) were compared with
patients with active rheumatoid arthritis (RA),
comorbidity or healthy controls. An additional 46
patients with different inflammatory conditions
(acute infections, n=31; immune-mediated
diseases, n=12; others, n=3) and elevated
CRP (inflammatory cohort) were prospectively
enrolled, and corrected QT (QTc) and cytokine
levels were measured during active disease
and after a CRP decrease of >75%subsequent
to therapy.
RESULTS
In the TdP cohort, 80% of patients
showed elevated CRP levels (median: ~3mg/
dL), with a definite inflammatory disease iden-
tifiable in 18/40 cases (acute infections, n=12;
immune-mediated diseases, n=5; others, n=1).
In these subjects, IL-6, but not TNFα and IL-1,
was ~15–20 times higher than in controls, and
comparable to RA patients. In the inflammatory
cohort, where QTc prolongation was common
(mean values: 456.6±30.9 ms), CRP reduction
was associated with IL-6 level decrease and
significant QTc shortening (-22.3 ms).
CONCLUSION
The data are first to show that sys-
temic inflammation via elevated IL-6 levels may
represent a novel QT-prolonging risk factor
contributing to TdP occurrence in the presence
of other classical risk factors. If confirmed, this
could open new avenues in antiarrhythmic
therapy.
Systemic inflammationas anovel QT-prolonging
risk factor in patients with Torsades de Pointes.
Heart
2017 May 10;[EPub Ahead of Print], PE
Lazzerini, F Laghi-Pasini, I Bertolozzi, et al.
COMMENT
By Marmar Vaseghi
MD, PhD
C
ardiac repolarization and the QT
interval are controlled by myriad
factors, ranging from cardiac ion
channel function to the cardiac autonomic
nervous system. Specifically, defects in
certain ion channels, including potas-
sium channels, are known to cause QT
prolongation, whereas sympathetic acti-
vation can also affect QT interval, cardiac
repolarization, and increase the risk of
ventricular arrhythmias. It is also known
that patients with systemic inflamma-
tion are at risk for cardiac disease and
arrhythmias, although much of this work
has previously focused on coronary artery
disease.
In this study by Lazzerini and colleagues,
patients who developed torsade de
pointes not only had prolonged QTc inter-
vals but also were more likely to have
elevated CRP and IL-6 levels, equivalent
to those in patients with active rheuma-
toid arthritis. Acute or chronic infection or
inflammation was observed in 45%. Fur-
thermore, CRP and IL-6 reduction were
associated with a significant reduction
in QTc interval. Interestingly, TNF-α and
IL-1 levels were not significantly elevated
in torsade de pointes patients and were
comparable to age-, gender-, and comor-
bidity-matched controls. Although this
study does not provide a causative link,
it is intriguing in that it points to additional
factors, including specific cytokines, which
may affect cardiac repolarization and con-
tribute to initiation of arrhythmias.
It’s also important to note that patients
with rheumatoid arthritis who had equiva-
lent CRP and IL-6 levels were not reported
to develop torsade de pointes in this
study, suggesting that multiple factors are
required for arrhythmia initiation. Whether
IL-6 can directly alter cardiac repolariza-
tion, and therefore QTc, or if it’s a surrogate
for other causative factors, remains to be
elucidated. This study should also be
interpreted in the broader context of sys-
temic inflammation and infection, which
are not only accompanied by sympathetic
activation affecting cardiac repolarization
and arrhythmia development, but also by
parasympathetic withdrawal, which, via
the cholinergic anti-inflammatory path-
way, can further amplify production of
inflammatory cytokines and affect cardiac
repolarization.
Dr Vaseghi is Assistant Professor of
Medicine and Director of Clinical and
Translational Research at UCLA Cardiac
Arrhythmia Center in California.
ARRHYTHMIAS/HEART RHYTHM DISORDERS
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