4. Discussion
Acquired LQTS is an often-overlooked entity that lacks better
understanding and study.
To the best of our knowledge, this is the first study that evaluated the
prevalence and characteristics of aLQTS in the ER. Our results show that
this syndrome is particularly common in this setting, even when
accounting only for patients with a severely prolonged QTc. Similarly to
other studies, we detected a that these were mainly older patients (73.7
years)[2,25]. Of note, the great majority of patients in this study
had no symptoms that could draw attention to LQTS. As such, careful
evaluation of the QT interval is key, even in asymptomatic patients, as
it may be the only sign detected before a dysrhythmic event and death.
Regarding drugs contributing to this syndrome, most interact with the
hERG gene and the IKr channel.[17] In this study,
and in contrast to previous studies where antiarrhythmics had the
spotlight,[2,25] diuretics (and in particular, furosemide) were the
drugs most commonly associated with LQTS in our emergency population. In
addition to contributing to ionic imbalance, furosemide may lead to QT
prolongation even when corrected for low serum levels of calcium and
potassium.[26] We hypothesize that the high prevalence of these
drugs in our population reflects the advanced age and the fact that
heart failure and hypertension are particularly frequent in the ER
setting.
The second most prescribed drug class in this population was proton pump
inhibitors, mainly pantoprazole. Its impact is mainly due to decreased
absorption of magnesium and consequent hypomagnesaemia and not by
directly prolonging QT.[27,28] This effect is particularly magnified
in the presence of diuretics.[27]
Psychotropic medication also plays a crucial role in a large subset of
patients. Antidepressants (SSRI but also tricyclic) are increasingly
prescribed and used chronically.[29] The main mechanism for QT
prolongation appears to be Na channel blockage in tricyclic agents and
inhibition of the IKr channel in SSRIs.[14] Their impact on the QT
interval demands a careful risk-benefit analysis prior to their
initiation and in every hospital appointment,[30,31] as excessive
dosage or co-administration with other drugs such as potassium channel
blockers may lead to a devastating effect.[14,32] Regarding
antipsychotics, their impact has been long studied and is mainly
mediated by hERG channel blockade.[33] Nearly all antipsychotics
cause QT prolongation[30] but particular attention needs to be given
to patients on haloperidol, thioridazine, pimozide, ziprasidone,
risperidone, melperone, quetiapine as they are known to prolong QT the
most.[32]
Also of note are antibiotics. Macrolides and fluoroquinolones are
increasingly utilized in clinical practice as beta-lactams resistance
surges. Similarly to SSRIs, blockade of the IKr channel is the main
contributor to QT prolongation.[14,34] In addition, CYP3A4
inhibition by macrolides can also increase half-life and concentration
of other QT prolonging drugs and dramatically increase of QTc.[14]
Classically regarded as the main culprits of prolonged QT,
antiarrhythmics were found in only a small proportion of our sample.
Nonetheless, the same channel blocking capabilities responsible for
their antiarrhythmic effect contribute to QT prolongation and
TdP.[14,35] As such, careful ECG monitoring, especially in class IA
(quinidine, procainamide and disopyramide) and class III agents (such as
amiodarone and sotalol), is needed in order to maintain a tight control
of the clinical status.[14]
Pertaining clinical risk factors, our study showed that CRP is a
frequent factor contributing to LQTS in the ER. Recent studies showed
that the inflammatory pathway affects the electrophysiological
properties of cardiomyocytes, contributing to changes in repolarization
and consequent QT prolongation.[36] Heart failure was also
particularly prevalent in our study population. Multiple mechanisms have
also been hypothesized as contributing to QT prolongation in heart
failure, including structural changes and heterogeneous depolarization,
in addition to the effect of drug iatrogenesis.[37,38] Hypokalemia
is also a determinant factor in prolonging QT. Its impact on the
functioning of the potassium channels leads to synergy with the
inhibiting properties of QT prolonging drugs and a marked increase of
the risk of VF and TdP.[39]
A QT interval greater than 500ms has been linked to an increased risk of
ventricular arrhythmias and complications.[3,24] Our study
demonstrated that female patients on antibiotics were at an increased
risk of severely prolonged QT interval. Other particularly relevant
contributors for this severely prolonged QTc were number of QT
prolonging drugs and of clinical risk factors, and use of antipsychotics
and antidepressants. Studies have shown that antipsychotics and
antidepressants are being prescribed at a particularly high and
increasing rate in the last years, particularly in elderly
patients.[40–42] In fact, most recent national studies found an
increasing trend for overall polypharmacy in the elderly, reaching in
some cases a general prevalence of 8-29%.[43–46] This fact leads
not only to increased direct costs in health care systems, but also
greater risk of drug and clinical factors interaction. Accordingly,
careful monitoring of baseline and follow-up ECG in this therapeutic
setting is crucial to avoid severe QT prolongation.
Despite the increased risk of TdP, direct correlation between QT
prolongation and clinical presentation remains to be fully
determined.[7,24] Our study showed no link between a severely
prolonged QT interval and symptoms.