Long QT syndrome: novel insights into the mechanisms of cardiac arrhythmias

The congenital long QT syndrome is a rare disorder in which mutation carriers are at risk for polymorphic ventricular tachycardia and/or sudden cardiac death. Discovery and analysis of gene mutations associated with variants of this disorder have provided novel insight into mechanisms of cardiac arrhythmia and have raised the possibility of mutation-specific therapeutic intervention.     

Long QT syndrome

The long QT syndrome (LQTS) is characterized by prolongation of the QT interval, causing torsade de pointes and sudden cardiac death. This syndrome can be divided into idiopathic (congenital) and acquired forms. The idiopathic form is a familial disorder that can be associated with sensorineural deafness (Jervell and Lange--Nielsen syndrome, autosomal recessive) or normal hearing (Romano--Ward syndrome, autosomal dominant). The acquired form has a long QT interval caused by various drugs such as quinidine sotalol and dofetilide, also by noncardiovascular drugs such as antihistamine, antibiotics, antipsychotics and others. Also, the QT interval is prolonged by electrolyte abnormalities such as hypokalemia and hypomagnesemia, central nervous system lesions, significant bradyarrhythmias, cardiac ganglionitis, mitral valve prolapse and probucol. DNA variants appearing to predispose to drug-associated acquired long QT syndrome have been reported in congenital long QT.     

Mechanisms of cardiac arrhythmias and sudden death in transgenic rabbits with long QT syndrome

Long QT syndrome (LQTS) is a heritable disease associated with ECG QT interval prolongation, ventricular tachycardia, and sudden cardiac death in young patients. Among genotyped individuals, mutations in genes encoding repolarizing K+ channels (LQT1:KCNQ1; LQT2:KCNH2) are present in approximately 90% of affected individuals. Expression of pore mutants of the human genes KCNQ1 (KvLQT1-Y315S) and KCNH2 (HERG-G628S) in the rabbit heart produced transgenic rabbits with a long QT phenotype. Prolongations of QT intervals and action potential durations were due to the elimination of IKs and IKr currents in cardiomyocytes. LQT2 rabbits showed a high incidence of spontaneous sudden cardiac death (>50% at 1 year) due to polymorphic ventricular tachycardia. Optical mapping revealed increased spatial dispersion of repolarization underlying the arrhythmias. Both transgenes caused downregulation of the remaining complementary IKr and IKs without affecting the steady state levels of the native polypeptides. Thus, the elimination of 1 repolarizing current was associated with downregulation of the reciprocal repolarizing current rather than with the compensatory upregulation observed previously in LQTS mouse models. This suggests that mutant KvLQT1 and HERG interacted with the reciprocal wild-type alpha subunits of rabbit ERG and KvLQT1, respectively. These results have implications for understanding the nature and heterogeneity of cardiac arrhythmias and sudden cardiac death.     

Long QT syndrome and other repolarization-related dysrhythmias

Until recently, sudden cardiac death in a young person often remained an unexplained tragedy. However, in the last decade there have been dramatic advances in medical knowledge regarding inheritable dysrhythmias that increase the risk of SCD in otherwise healthy young individuals. The primary mechanism in this group of dysrhythmias appears to be an alteration of cardiac repolarization. In some diseases, the specific genes affected and even precise cellular mechanisms have been identified. The information about these diseases is often complex and rapidly evolving, challenging both healthcare providers and the families who must make important decisions based on emerging and incomplete information. The purpose of this article is to describe current understanding of the repolarization-related dysrhythmias and discuss the clinical implications for advanced practice nurses.     

Long QT Syndrome:

MILLER, R.F., et al .: Long QT Syndrome: First and Fatal Events Provoked by Hemodialysis. Long QT syndrome (LQTS) involves both congenital and acquired predispositions toward the characteristic torsades de pointes (TP) ventricular arrhythmia. Congenital long QT syndrome generally manifests with TP, syncope, or sudden death early in life. This is a documented case of previously undiagnosed congenital LQTS in a 48-year-old woman where the first and fatal episodes of TP were provoked by hemodialysis. (PACE 2003; 26[Pt. I]:103–104)     

Long QT syndrome induced by cordaron and quinidine

The article presents an observation of a 63-year-old female patient suffering from arterial hypertension, coronary artery disease complicated by a persistent form of atrial fibrillation during 1.5 months, and hereditary Minkowski-Chauffard hemolytic anemia. Treatment with cordaron proved to be ineffective, while oral administration of quinidin in a dose of 1 gr (0.2 gr five times a day) led to restoration of sinus rhythm. However, long QT interval syndrome complicated by ventricular tachycardic paroxysms of torsade de pointes type developed; later it transformed into ventricular fibrillation.     

Extreme QT prolongation during therapeutic hypothermia after cardiac arrest due to long QT syndrome

During therapeutic hypothermia, QT interval is prolonged. In patients with congenital long QT syndrome (LQTs), a longer QT interval was associated with significantly increased risk of cardiac arrest (CA). Therefore, therapeutic hypothermia may have proarrhythmic effects in survivors of CA due to congenital LQTs. A 27-year-old man was resuscitated from CA due to congenital LQTs type 3 and Brugada syndrome. Torsade de pointes (TdP) recurred spontaneously on admission (body temperature, 36.9°C). During mild hypothermia therapy, QTc increased from 499 (36.9°C) to 667 milliseconds (33.8°C), although TdP was not induced. A 13-year-old boy with congenital LQTs type 1 underwent therapeutic hypothermia after resuscitation. Short-acting β-blocker was administered intravenously during this treatment. The QTc increased from 534 (36.4°C) to 626 milliseconds (34.3°C). However, TdP did not recur during mild hypothermia therapy. In both patients, electrolyte abnormalities were checked frequently and corrected immediately. QT prolongation remained a couple of days after completion of rewarming. The withdrawal of sedative drugs and extubation were not pursued before QT shortening reached to a plateau. Both patients were fully recovered from neurologic damage. During therapeutic hypothermia, QT interval was extremely prolonged, although TdP did not recur in 2 patients with congenital LQTs. Therapeutic hypothermia may be beneficial for comatose survivors of CA due to LQTs.     

Long QT syndrome presenting as a seizure.

A 21-year-old woman was brought to the emergency department after being found unconscious in a hotel lobby. On presentation, she was awake but confused. The initial evaluation revealed no evidence of trauma, metabolic abnormality, drug ingestion, or intracranial process. The only abnormality noted was electrocardiographic, and included a long QT interval as well as occasional atrial and junctional beats within a normal sinus rhythm. While in the department the patient developed tonic-clonic activity and was concurrently noted to have developed ventricular tachycardia. A precordial thump was given with the simultaneous cessation of the arrythmia and the seizure. After definitive electrophysiologic study, the diagnosis of long QT syndrome was made. Treatment consisting of beta blockade and pacemaker insertion prevented further arrythmia or seizure activity. Long QT syndrome should be considered a possible etiology in any patient presenting with new onset seizures, especially in the young.     

Cardiac K+ channels and drug-acquired long QT syndrome

The hallmark of long QT syndromes (LQTS) is an abnormal ventricular repolarization characterized by a prolonged QT interval on the electrocardiogram and a propensity to the occurrence of syncopes resulting from polymorphic ventricular tachycardia, called torsades de pointes. They may degenerate to ventricular fibrillation, possibly causing sudden death. Congenital LQTS, which implicates at least six chromosomal loci, LQT1 to LQT6, three of them corresponding to mutations concerning the coding of K+ channel proteins, give useful information about the mechanism underlying the arrhythmia. One of the potassium channel genes implicated in congenital LQTS is HERG, which encodes the IKr current channel protein. This current has provided a relevant insight into the occurrence of drug-acquired LQTS, since all drugs associated with torsades, such as erythromycin, terfenadine, haloperidol, or cisapride, also block IKr.     

Strategy for cardiac arrhythmias in acute coronary syndrome

Acute coronary syndrome causes several types of arrhythmia because of its electrical instability and ischemia. The most important arrhythmia is ventricular tachycardia which degenerates to ventricular fibrillation. Prompt direct current cardioversion will be needed and prevention of ventricular tachyarrhythmia by potassium channel blocker became more popular in Japan. Nifekalant or amiodarone should be selected. Atrial fibrillation also occurred in the patients with acute coronary syndrome, and it may deteriorate hemodynamics condition. Therefore, termination and prevention of atrial fibrillation is another important issue in acute coronary syndrome. Aprindine, amiodarone, or bepridil will be the choice to prevent recurrent atrial fibrillation after direct current cardioversion.     

Long QT syndrome presenting as epileptic seizures in an adult

A 50 year old woman with a previous diagnosis of epilepsy presented to the emergency department with a generalised seizure. Her admission ECG showed QT prolongation secondary to bradycardia and a subsequent seizure in the department demonstrated that these events were secondary to cerebral hypoperfusion during episodes of torsades de pointes. This case illustrates how long QT syndrome can masquerade convincingly as epilepsy, delaying treatment and exposing the patient to a high risk of sudden cardiac death. Careful ECG analysis is recommended for all patients presenting with seizures.     

Long QT syndrome,Brugada syndrome,and conduction system disease are linked to a single sodium channel mutation

The function of the 12 positive charges in the 53-residue III/IV interdomain linker of the cardiac Na(+) channel is unclear. We have identified a four-generation family, including 17 gene carriers with long QT syndrome, Brugada syndrome, and conduction system disease with deletion of lysine 1500 (DeltaK1500) within the linker. Three family members died suddenly. We have examined the functional consequences of this mutation by measuring whole-cell and single-channel currents in 293-EBNA cells expressing the wild-type and DeltaK1500 mutant channel. The mutation shifted V(1/2)h( infinity ) to more negative membrane potentials and increased k(h) consistent with a reduction of inactivation valence of 1. The shift in h( infinity ) was the result of an increase in closed-state inactivation rate (11-fold at -100 mV). V(1/2)m was shifted to more positive potentials, and k(m) was doubled in the DeltaK1500 mutant. To determine whether the positive charge deletion was the basis for the gating changes, we performed the mutations K1500Q and K1500E (change in charge, -1 and -2, respectively). For both mutations, V(1/2)h was shifted back toward control; however, V(1/2)m shifted progressively to more positive potentials. The late component of Na(+) current was increased in the DeltaK1500 mutant channel. These changes can account for the complex phenotype in this kindred and point to an important role of the III/IV linker in channel activation.