Unusual case of severe arrhythmia developed after acute intoxication with tosylchloramide
- Vincenzo Lariccia†1,
- Alessandra Moraca†2,
- Marco Marini2,
- Annamaria Assunta Nasti1,
- Ilaria Battistoni2,
- Salvatore Amoroso1Email author and
- Gian Piero Perna2
© Lariccia et al.; licensee BioMed Central Ltd. 2013
Received: 4 September 2012
Accepted: 21 January 2013
Published: 24 January 2013
Drugs not commonly considered to be cardioactive agents may cause prolongation of the QT interval with resultant torsades de pointes and ventricular fibrillation. This form of drug toxicity often causes cardiac arrest or sudden death.
After accidental ingestion of tosylchloramide a caucasian 77-year-old woman, with a family history of cardiovascular disease and hypertension, was admitted to the intensive care unit following episodes of torsades de pointes with a prolonged QT/QTc interval (640/542 ms). The patient received an implantable cardioverter-defibrillator, was discharged from the hospital with normal QT/QTc interval and did not experience additional ventricular arrhythmias during one year of follow-up.
This is the first report concerning an unusual case of torsades de pointes after accidental intoxication by ingestion of tosylchloramide. The pronounced impact of the oxidyzing agent tosylchloramide on the activity of some of the ion channels regulating the QT interval was identified as a probable cause of the arrhythmia.
KeywordsTosylchloramide Acute intoxication Arrhythmia Ventricular fibrillation Ion channels
Because of its high activity against fungi and bacteria, tosylchloramide is a widely used disinfectant agent for common applications such household cleaning and swimming pool disinfection. Many case reports describing tosylchloramide intoxication have been already published in the past showing that the chronic exposure to this compound may cause hypersensitivity reactions, such as asthma [1, 2], conjunctivitis , whereas toxic pneumonitis , cardiovascular collapse and myocardial damage may occur in acutely intoxicated patients . Here we report the first case of a severe arrhythmia developed in the context of acute oral intoxication with tosylchloramide.
The occurrence of TdP in our patient after tosylchloramide ingestion can be explained considering that this compound acts as a strong oxidant of methionines and cysteines residues in proteins . The activity of some of the ion channels regulating the duration of the QT interval is, indeed, strongly influenced by oxydation of critical methionine residues in channel proteins. In particular, voltage-dependent inactivation of NaV channels is significantly slowed down when methionine residues located in the so called IMF domain, which is responsible for voltage-dependent channel inactivation, are oxydized . Consistently, tosylchloramide, which has a strong preference in oxydizing methionine residues , is one of the most powerful oxydants affecting NaV channel inactivation [9, 10] and it has been used as a pharmacological tool to abolish voltage-dependent inactivation in studies aiming to determine its contribution in the activity of specific cardiovascular drugs . Tosylchloramide-induced slowing of NaV channel inactivation is a quite general phenomenon being observed in the brain, muscle and, importantly, cardiac isoform of these channels . Oxydant-induced impairment of NaV voltage-dependent inactivation may per se explain the appearance of TdP in our patient intoxicated with tosylchloramide since it causes a marked increase in persistent INa (INaP ) [12, 13], the inactivation-resistant Na+ current which persists in the presence of prolonged membrane depolarization . An increase in INaP is, indeed, a well documented mechanism of QT prolongation and arrhythmogenesis and a potentailly relevant target for treatment and prevention of arrhythmias [15, 16]. In addition, an increase in INaP is considered responsible for arrhythmogenesis in patients affected with the LQT3 syndrome which bear specific mutations in the NaV1.5 channel gene [17–19]. Confirming the involvement of INaP in oxydant-induced arrhythmogenesis, the INaP blocker ranolazine was effective in preventing QT prolongation and early afterdepolarzations induced by the strong oxydant agent H2O2 in cultured guinea pig cardiomyocytes . Therefore, it is tempting to speculate that, in our patient, tosylchloramide exposure recapitulated the pathophysiological mechanism of cardiac arrhythmia in LQT3 patients.
hERG is another oxydation-sensitive ion channel that could have been involved in the genesis of TdP in our patient. hERG is the main K+ current responsible for rapid repolarization of cardiac myocytes in phase III of cardiac action potential  and its loss of function is one of the best characterized mechanisms of drug-induced or congenital LQT syndrome . Specifically, mutations causing either loss of function or alterations in trafficking of hERG channels are responsible for the LQT2 syndrome [22, 23] whereas mutations in MiRP1, an accessory subunit that coassembles with hERG, have been found in LQT6 patients . Intriguingly, by oxydizing critical methionine residues, tosylchloramide causes an almost complete loss of hERG channel activity in vitro thus reproducing the effect of drugs or mutations known to cause TdP. Therefore, it is likely that hERG channel blockade could have played a role in the appearance of TdP in our patient.
Finally, it is worth to remind that several oxydants, including tosylchloramide, may also increase the activity of L-type voltage-gated Ca2+ channels (VGCC), even though, in this case, the specific inolvement of methionine residues has not been demonstrated [26, 27]. By increasing Ca2+ influx through L-type VGCC, tosylchloramide is expected to prolong the plateau phase of cardiac action potential thus delaying cardiomyocyte repolarization and promoting the appearance of TdP. Intriguingly, an increase in L-type VGCC activity represents the mechanistic base of arrhythmias in LQT8 patients [28–30] bearing the Timothy syndrome mutations which cause an impairment in voltage-dependent CaV1.2 channel inactivation .
Oxidative stress has been proposed as one of the upstream events provoking clinical relevant arrhythmic responses  and several drugs used in therapy exert antiarrhythmic effects in part via their antioxidative property [33, 34]. Here we suggest that severe arrhythmia may occur in the form of TdP after massive exposure to the oxidizing agent tosylchloramide. In fact, tosylchloramide has a pronounced impact on the activity of some of the ion channels regulating the QT interval. Since our patient exhibited no evidence of QT interval alteration after 12 and 24 months of follow-up, this strongly suggests a causal role of tosylchloramide intoxication for the ECG abnormalities occurred during observation in the ICU. Therefore, a strict electrocardiographic monitoring is advised in patients intoxicated with this compound.
Written informed consent was obtained from the patient prior to publication of this case report and any accompanying images. A copy of the written consent is available for review by the Series Editor of this journal.
Salvatore Amoroso and Gian Piero Perna equally contributed as senior authors.
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