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.