Neonatal long QT syndrome due to a de novo dominant negative hERG mutation.

A 4-day-old girl with ventricular tachyarrhythmias, sinus bradycardia, and 2:1 atrioventricular block had prolongation of the QT interval. She was symptomatic with arching, gasping, and cyanosis presumably due to a life-threatening ventricular tachyarrhythmia such as torsades de pointes. Molecular genetic studies indicated a heterozygous, de novo, dominant negative mutation in hERG, a gene that encodes a protein in a potassium ion channel. The parents do not have the mutation. The patient's clinical scenario was produced by the convergence of 3 events: a de novo mutation occurred in hERG, the mutation was dominant negative, and the action of the mutation resulted in neonatal long QT syndrome. The child was treated aggressively and is doing well at age 6 years.     

Genetics and genomics of long QT syndrome

In the past decade, molecular genetics has revealed that some life-threatening arrhythmogenic disorders, such as long QT syndrome, are due to mutated genes encoding ion channels that generate the cardiac action potential. Great efforts made in various fields have partly solved problems caused by unforeseen genetic diversity of these congenital arrhythmogenic disorders, while the genetics of these disorders has recently proved to be applicable to very wide-ranging conditions associated with sudden cardiac death, and increased knowledge about the human genome will revolutionize researches into arrhythmic diseases in future. The purpose of this review is to outline the recent advances and problems in the molecular genetics in long QT syndrome.     

Genetics of acquired long QT syndrome

The QT interval is the electrocardiographic manifestation of ventricular repolarization, is variable under physiologic conditions, and is measurably prolonged by many drugs. Rarely, however, individuals with normal base-line intervals may display exaggerated QT interval prolongation, and the potentially fatal polymorphic ventricular tachycardia torsade de pointes, with drugs or other environmental stressors such as heart block or heart failure. This review summarizes the molecular and cellular mechanisms underlying this acquired or drug-induced form of long QT syndrome, describes approaches to the analysis of a role for DNA variants in the mediation of individual susceptibility, and proposes that these concepts may be generalizable to common acquired arrhythmias.     

Fetal and neonatal presentation of long QT syndrome

This report describes a fetus presenting with intrauterine tachycardia and hydrops fetalis. Soon after birth the neonate was noted to be in torsades de pointes that responded dramatically to medical management. Long QT syndrome (LQTS) was diagnosed on electrocardiogram obtained soon after birth. The prognosis is poor when LQTS presents in utero or during the first week of life. However, our infant did well with medical management and has remained free of arrhythmias at follow-up.     

Ibutilide-induced long QT syndrome and torsade de pointes

Ibutilide is a class III antiarrhythmic agent used for the termination of atrial fibrillation and atrial flutter. It mainly affects membrane potassium currents and prolongs the cardiac action potential. This effect is reflected as QT interval prolongation on the surface electrocardiogram. Like other drugs that affect potassium currents, ibutilide is prone to induce a malignant ventricular tachycardia, torsade de pointes. We report four cases of torsade de pointes after administration of ibutilide for pharmacologic cardioversion of atrial fibrillation and atrial flutter; three of these cases required direct current cardioversion for termination of torsade de pointes. All four patients were female. We discuss the risk factors for development of ibutilide-induced torsade de pointes.     

Genotype-specific clinical manifestation in long QT syndrome

The congenital form of long QT syndrome (LQTS) is characterized by QT prolongation in the electrocardiogram (ECG) and a polymorphic ventricular tachycardia, Torsade de Pointes (TdP) mainly as a result of an increased sympathetic tone during exercise or mental stress. Recent genetic studies have so far identified seven forms of congenital LQTS caused by mutations in genes of the potassium and sodium channels or membrane adapter located on chromosomes 3, 4, 7, 11, 17 and 21. It is of particular importance to examine the genotype–phenotype correlation, especially in the LQT1, LQT2 and LQT3 forms of LQTS, which make up more than 90% of genotyped patients with LQTS, because it would enable us to manage and treat genotyped patients more effectively.     

Genotype-specific clinical manifestation in long QT syndrome

The congenital form of long QT syndrome (LQTS) is characterized by QT prolongation in the electrocardiogram (ECG) and a polymorphic ventricular tachycardia, Torsade de Pointes (TdP) mainly as a result of an increased sympathetic tone during exercise or mental stress. Recent genetic studies have so far identified seven forms of congenital LQTS caused by mutations in genes of the potassium and sodium channels or membrane adapter located on chromosomes 3, 4, 7, 11, 17 and 21. It is of particular importance to examine the genotype-phenotype correlation, especially in the LQT1, LQT2 and LQT3 forms of LQTS, which make up more than 90% of genotyped patients with LQTS, because it would enable us to manage and treat genotyped patients more effectively.     

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.     

Depressive symptoms in the congenital long QT syndrome

Background. A proportion of patients with congenital long QT syndrome (LQTS) experience potentially life-threatening cardiac arrhythmias.

Aim. To examine whether depressive symptoms are related to arrhythmic events among symptomatic and asymptomatic LQTS patients, and syncope events among their relatives not carrying the family's LQTS-causing mutation.

Methods. The participants were 569 molecularly defined LQTS mutation carriers and 622 non-carrier relatives from the Finnish LQTS registry. Depressive symptoms were self-rated with a revised version of the Beck Depression Inventory.

Results. LQTS patients with arrhythmic events scored higher on depressive symptoms than those without (P=0.011) or the control group (P=0.005). In addition, in the binary logistic regression analysis including symptomatic and asymptomatic LQTS mutation carriers, depressive symptoms showed an age- and sex-adjusted association of odds ratio (OR) 1.40 (95% confidence interval (CI) 1.12–1.74) with symptomatic status of LQTS. In similar analysis including non-carriers of the LQTS mutation, there was no association between depressive symptoms and history of syncope events OR 1.23 (95% CI 0.99–1.53).

Conclusion. Our results from this relatively large genotyped LQTS patient cohort indicate that depressive symptoms are associated with arrhythmic events in LQTS patients. Whether depressive symptoms are causally related to arrhythmias in LQTS remains uncertain.     

Sudden arrhythmia death syndrome: importance of the long QT syndrome

In approximately 5 percent of sudden cardiac deaths, no demonstrable anatomic abnormality is found. Some cases are caused by sudden arrhythmia death syndrome. A prolonged QT interval is a common thread among the various entities associated with sudden arrhythmia death syndrome. A number of drugs are known to cause QT prolongation (e.g., terfenadine), as are hypokalemia, hypomagnesemia, myocarditis, and endocrine and nutritional disorders. Recently, attention has focused on a group of inherited gene mutations in cardiac ion channels that cause long QT syndrome and carry an increased risk for sudden death. Some of the highest rates of inherited long QT syndrome occur in Southeast Asian and Pacific Rim countries. The median age of persons who die of long QT syndrome is 32 years; men are predominately affected. In addition to a prolonged QT interval, which occurs in some but not all persons with long QT syndrome, another characteristic electrocardiographic abnormality is the so-called Brugada sign (an upward deflection of the terminal portion of the QRS complex). Most cardiac events are precipitated by vigorous exercise or emotional stress, but they also can occur during sleep. Torsades de pointes and ventricular fibrillation are the usual fatal arrhythmias. Long QT syndrome should be suspected in patients with recurrent syncope during exertion and those with family histories of sudden, unexpected death. Unfortunately, not all persons with long QT syndrome have premonitory symptoms or identifiable electrocardiographic abnormalities, and they may first present with sudden death. Beta blockers, potassium supplements, and implantable defibrillators have been used for treatment of long QT syndrome. Identifying the specific gene mutation in a given patient with long QT syndrome can help guide prophylactic therapy.     

Genetics,molecular mechanisms and management of long QT syndrome

Cardiac arrhythmias cause more than 300 000 sudden deaths each year in the USA alone. Long QT syndrome (LQT) is a cardiac disorder that causes sudden death from ventricular tachyarrhythmias, specifically torsade de pointes. Four LQT genes have been identified: KVLQT1 (LQT1) on chromosome llpl5.5, HERG (LQT2) on chromosome 7q35–36, SCNSA (LQT3) on chromosome 3p21–24, and MinK (LQT5) on chromosome 21q22. SCNSA encodes the cardiac sodium channel, and LQT-causing mutations in SCNSA lead to the generation of a late phase of inactivation-resistant whole-cell inward currents. Mexiletine, a sodium channel blocker, is effective in shortening the QT interval corrected for heart rate (QTc) of patients with SCNSA mutations. HERG encodes the cardiac I potassium channel. Mutations in HERG act by a dominant-negative mechanism or by a loss-of-function mechanism. Raising the serum potassium concentration can increase outward HERG potassium current and is effective in shortening the QTc of patients with HERG mutations. KVLQT1 is a cardiac potassium channel protein that interacts with another small potassium channel MinK to form the cardiac I potassium channel. Like HERG mutations, mutations in KVLQT1 and MinK can act by a dominant-negative mechanism or a loss-of-function mechanism. An effective treatment for LQT patients with KVLQT1 or MinK mutations is expected to be developed based on the functional characterization of the I_Ks potassium channel. Genetic testing is now available for some patients with LQT.     

Locus heterogeneity of autosomal dominant long QT syndrome.

Autosomal dominant long QT syndrome (LQT) is an inherited disorder that causes syncope and sudden death from cardiac arrhythmias. In genetic linkage studies of seven unrelated families we mapped a gene for LQT to the short arm of chromosome 11 (11p15.5), near the Harvey ras-1 gene (H ras-1). To determine if the same locus was responsible for LQT in additional families, we performed linkage studies with DNA markers from this region (H ras-1 and MUC2). Pairwise linkage analyses resulted in logarithm of odds scores of -2.64 and -5.54 for kindreds 1977 and 1756, respectively. To exclude the possibility that rare recombination events might account for these results, we performed multipoint linkage analyses using additional markers from chromosome 11p15.5 (tyrosine hydroxylase and D11S860). Multipoint analyses excluded approximately 25.5 centiMorgans of chromosome 11p15.5 in K1756 and approximately 13 centiMorgans in K1977. These data demonstrate that the LQT gene in these kindreds is not linked to H ras-1 and suggest that mutations in at least two genes can cause LQT. While the identification of locus heterogeneity of LQT will complicate genetic diagnosis, characterization of additional LQT loci will enhance our understanding of this disorder.     

Electrical alternans in long QT syndrome resembling a Brugada syndrome pattern

Isolated T wave alternans (repolarization alternans) is frequently associated with long QT syndrome. However, electrical alternans involving the P wave, QRS complex, ST segment (depolarization alternans), and the T wave is a rare finding. This report describes a 62-year-old woman with long QT syndrome and an electrical alternans occurring after previous syncope. Alternating QRS complexes showed a prolonged PR interval, a Brugada syndrome resembling pattern of the QRS complexes (elevation and downslope of the ST segments), and a T wave alternans. A genetic basis for the long QT syndrome has been ruled out by sequencing of all coding areas of the LQT genes. Potential mechanisms for the electrical alternans are discussed.     

Inherited long QT syndrome revealed by antifungals drug-drug interaction

A 14-year-old Tahitian girl with acute myeloid leukaemia and a suspected mucormucosis infection was treated with intravenous voriconazole and caspofungin. Because of worsening of fungal infection, voriconazole was switched to posaconazole. During the switch, the patient presented with QT interval prolongation with 'torsades de pointes' and reversible cardiac arrest. Voriconazole plasma level measured 15 h after the last administration was 7 mg/L. Genotyping suggested that the patient was an extensive metabolizer with respect to CYP2C9 and CYP2C19. The association of antifungal agents with pro-arrhythmogenic drugs and other risk factors led to torsades de pointes and the revealing of inherited QT syndrome.     

Acquired long QT syndrome secondary to cesium chloride supplement

The use of complementary medication is on the rise worldwide. More often than not, the treating physicians are unaware of this and also unfamiliar with the potential benefit or toxicity of the agents. Here, we present the case of a 39-year-old woman who presented with new onset of syncope as a result of acquired long QT syndrome secondary to taking a cesium chloride supplement. A brief discussion of the pathophysiology of this agent follows the case presentation.