ajmaline and Long-QT-Syndrome

Overlap syndromes of long QT 3 syndrome (LQT3) and the Brugada syndrome (BrS) have been reported. Identification of patients with an overlapping phenotype is crucial before initiation of Class I antiarrhythmic drugs for LQT3. Aim of the present study was to elucidate the yield of ajmaline challenge in unmasking the Brugada phenotype in patients with LQT3 caused by the most common mutation, SCN5A-E1784K.. Consecutive families in tertiary referral centres diagnosed with LQT3 caused by SCN5A-E1784K were included in the study. Besides routine clinical work-up, ajmaline challenge was performed after informed consent. A total of 23 subjects (11 female, mean age 27 ± 14 years) from 4 unrelated families with a family history of sudden cardiac death and familial diagnosis of the SCN5A-E1784K mutation underwent ajmaline challenge and genetic testing. Sixteen subjects (9 female) were found to be heterozygous carriers of SCN5A-E1784K. Ajmaline challenge was positive in 12 out of the 16 (75%) mutation carriers, but negative in all non-carriers. Following ajmaline, a significant shortening of the rate-corrected JT (JTc) interval was observed in mutation carriers. The baseline JTc interval was significantly longer in mutation carriers with a positive ajmaline challenge compared with those with a negative one.. Overlap of LQT3 and BrS in patients carrying the most common mutation is high. Therefore, ajmaline challenge represents an important step to rule out potential BrS overlap in these patients before starting sodium channel blockers for the beneficial effect of QT shortening in LQT3.

Topics: Action Potentials; Adolescent; Adult; Ajmaline; Anti-Arrhythmia Agents; Brugada Syndrome; Diagnosis, Differential; DNA Mutational Analysis; Electrocardiography; Female; Genetic Predisposition to Disease; Germany; Heart Rate; Humans; Long QT Syndrome; Male; Middle Aged; Mutation; NAV1.5 Voltage-Gated Sodium Channel; Phenotype; Predictive Value of Tests; Tertiary Care Centers; Time Factors; Voltage-Gated Sodium Channel Blockers; Young Adult

Sudden arrhythmic death syndrome defines a sudden unexpected and unexplained death despite comprehensive pathological and toxicological investigation. Previous studies have focused on evaluation of adult relatives. There is, however, a lack of data in children, leading to highly variable management. We sought to determine the clinical utility of cardiac evaluation in pediatric relatives of sudden arrhythmic death syndrome probands.. Retrospective review was undertaken of pediatric patients with a family history of sudden arrhythmic death syndrome assessed from 2010 to 2013 in 2 centers. Clinical history, cardiac, and genetic investigations were assessed, including diagnoses made after evaluation of adult relatives. A total of 112 pediatric relatives from 61 families were evaluated (median age at presentation, 8 years; range, 0.5-16 years). A probable diagnosis was made in 18 (29.5%) families: Brugada syndrome, 13/18 (72%); long QT syndrome, 3/18 (17%); and catecholaminergic polymorphic ventricular tachycardia, 2/18 (11%). Genetic testing identified mutations in 20% of Brugada syndrome (2/10) and 50% of long QT syndrome (1/2) and catecholaminergic polymorphic ventricular tachycardia families (1/2) who were tested. Pediatric evaluation diagnosed 6/112 relatives (5.4%), increasing to 7% (6/85) if only first-degree relatives were assessed. The only useful diagnostic tests were the 12-lead and exercise electrocardiograms and ajmaline provocation test. The median duration of follow-up was 2.1 years (range, 0.2-8.2 years) with no cardiac events.. The yield of evaluating pediatric relatives is significant and higher when focused on first-degree relatives and on conditions usually expressed in childhood. We propose a management pathway for these children.

Topics: Adolescent; Adult; Age Factors; Ajmaline; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Brugada Syndrome; Child; Child, Preschool; Death, Sudden, Cardiac; Electrocardiography; Female; Genetic Predisposition to Disease; Genetic Testing; Humans; Infant; London; Long QT Syndrome; Male; Middle Aged; Pedigree; Phenotype; Predictive Value of Tests; Prognosis; Retrospective Studies; Risk Factors; Tachycardia, Ventricular; Time Factors; Young Adult

The aim of the present study was to elucidate the molecular mechanism underlying the concomitant occurrence of cardiac conduction disease and long QT syndrome (LQT3), two SCN5A channelopathies that are explained by loss-of-function and gain-of-function, respectively, in the cardiac Na+ channel.. A Caucasian family with prolonged QT interval, intermittent bundle-branch block, sudden cardiac death, and syncope was investigated. Lidocaine (1 mg/kg i.v.) normalized the prolonged QT interval and rescued bundle-branch block. An SCN5A mutation analysis was performed that revealed a C-to-A mutation at position 4859 (exon 28), predicted to change a highly conserved threonine for a lysine at position 1620. Mutant channels were characterized both in Xenopus oocytes and HEK293 cells. The T1620K mutation remarkably altered the properties of Nav1.5 channels. In particular, the voltage-dependence of the current decay time constants was largely lost. As a consequence, mutant channels inactivated faster than wild-type channels at potentials negative to -30 mV, resulting in less Na+ inward current (loss-of-function), but significantly slower at potentials positive to -30 mV, resulting in an increased Na+ inward current (gain-of-function). Moreover, we found a hyperpolarized shift of steady-state activation and an accelerated recovery from inactivation (gain-of-function). At the same time, channel availability was significantly reduced at the resting membrane potential (loss-of-function).. We conclude that lysine at position 1620 leads to both loss-of-function and gain-of-function properties in hNav1.5 channels, which may consequently cause in the same individuals impaired impulse propagation in the conduction system and prolonged QTc intervals, respectively.

Topics: Action Potentials; Adolescent; Adult; Ajmaline; Animals; Anti-Arrhythmia Agents; Bundle-Branch Block; Cell Line; Child; Death, Sudden, Cardiac; DNA Mutational Analysis; Electrocardiography; Female; Gene Transfer Techniques; Genetic Predisposition to Disease; Humans; Kinetics; Lidocaine; Long QT Syndrome; Lysine; Male; Muscle Proteins; Mutation; Myocardium; NAV1.5 Voltage-Gated Sodium Channel; Patch-Clamp Techniques; Pedigree; Sodium; Sodium Channels; Syncope; Threonine; Xenopus laevis

We present a 56-year-old man who was admitted to an emergency service after receiving an electric shock. The ECG showed a J point and ST segment elevation of up to 5 mm in leads V1 to V3, which normalized in 24 hours. The ajmaline test caused elevation of the J point and of the ST segment up to 12 mm in leads V1 to V3, QTc lengthening, and QTc and T wave alternans. These results denoted alterations in the duration of myocardial action potentials, a common finding in patients with Brugada syndrome and long QT syndrome.

Topics: Ajmaline; Anti-Arrhythmia Agents; Electric Injuries; Electrocardiography; Humans; Long QT Syndrome; Male; Middle Aged; Syndrome

Ajmaline, a reserpine derivative, is an effective class I antiarrhythmic agent. Herein we report two cases of ajmaline-induced abnormal QT prolongation accompanied by polymorphic ventricular tachycardia of the torsade de pointes type. Since ajmaline is increasingly used for the acute termination of wide complex tachycardia and as a diagnostic tool after syncope and in patients with idiopathic ventricular tachyarrhythmias, our observations suggest that caution should be exercised with regard to the effects of the drug on the QT interval and its potency to induce proarrhythmia of the torsade de pointes type.

Topics: Ajmaline; Anti-Arrhythmia Agents; Atrial Flutter; Electrocardiography; Female; Humans; Long QT Syndrome; Male; Middle Aged; Tachycardia; Tachycardia, Ventricular; Torsades de Pointes