Heikki Swan

Arrhythmic disorder mapped to chromosome 1q42–q43 causes malignant polymorphic ventricular tachycardia in structurally normal hearts

OBJECTIVES The purpose of this study was to provide clinical and anatomical characteristics as well as genetic background of a malignant arrhythmogenic disorder. BACKGROUND An inherited autosomally dominant cardiac syndrome causing stress-induced polymorphic ventricular tachycardia and syncope in the absence of structural myocardial changes was detected in two families. METHODS Two unrelated families with six victims of sudden death and 51 living members were evaluated. Resting and exercise electrocardiograms (ECG), echocardiography, magnetic resonance imaging (MRI), cineangiography, microscopic examination of endomyocardial biopsies and a drug testing with a class IC antiarrhythmic agent flecainide were performed. A genetic linkage analysis was carried out to map the gene locus. RESULTS Of the 24 affected individuals, 10 had succumbed with six cases of sudden death, and 14 survivors showed evidence of disease. Exercise stress test induced ventricular bigeminy or polymorphic ventricular tachycardia in affected individuals. Three children initially examined before 10 years of age developed arrhythmias during a four-year follow-up. Resting ECGs were normal in affected subjects except a slight prolongation of the QT intervals adjusted for heart rate (QTc) (430 +/- 18 vs. 409 +/- 19 ms, affected vs. nonaffected, p < 0.01). Administration of flecainide did not induce ECG abnormalities encountered in familial idiopathic ventricular fibrillation. Ventricular volumes, contractility and wall measurements were normal by echocardiography, right ventricular cineangiography and MRI. Histopathological examination showed no fibrosis or fatty infiltration. The cumulative cardiac mortality by the age of 30 years was 31%. The disease locus was assigned to chromosome 1q42-q43, with a maximal pairwise lod score of 4.74 in the two families combined. Only one heterozygous carrier was clinically unaffected suggesting high disease penetrance in adulthood. CONCLUSIONS A distinct cardiac disorder linked to chromosome 1q42-q43 causes exercise-induced polymorphic ventricular tachycardia in structurally normal hearts and is highly malignant. Delayed clinical manifestation necessitates repeated exercise electrocardiography to assure diagnosis in young individuals of the families.

Model for long QT syndrome type 2 using human iPS cells demonstrates arrhythmogenic characteristics in cell culture

SUMMARY Long QT syndrome (LQTS) is caused by functional alterations in cardiac ion channels and is associated with prolonged cardiac repolarization time and increased risk of ventricular arrhythmias. Inherited type 2 LQTS (LQT2) and drug-induced LQTS both result from altered function of the hERG channel. We investigated whether the electrophysiological characteristics of LQT2 can be recapitulated in vitro using induced pluripotent stem cell (iPSC) technology. Spontaneously beating cardiomyocytes were differentiated from two iPSC lines derived from an individual with LQT2 carrying the R176W mutation in the KCNH2 (HERG) gene. The individual had been asymptomatic except for occasional palpitations, but his sister and father had died suddenly at an early age. Electrophysiological properties of LQT2-specific cardiomyocytes were studied using microelectrode array and patch-clamp, and were compared with those of cardiomyocytes derived from control cells. The action potential duration of LQT2-specific cardiomyocytes was significantly longer than that of control cardiomyocytes, and the rapid delayed potassium channel (IKr) density of the LQT2 cardiomyocytes was significantly reduced. Additionally, LQT2-derived cardiac cells were more sensitive than controls to potentially arrhythmogenic drugs, including sotalol, and demonstrated arrhythmogenic electrical activity. Consistent with clinical observations, the LQT2 cardiomyocytes demonstrated a more pronounced inverse correlation between the beating rate and repolarization time compared with control cells. Prolonged action potential is present in LQT2-specific cardiomyocytes derived from a mutation carrier and arrhythmias can be triggered by a commonly used drug. Thus, the iPSC-derived, disease-specific cardiomyocytes could serve as an important platform to study pathophysiological mechanisms and drug sensitivity in LQT2.

High Efficacy of β-Blockers in Long-QT Syndrome Type 1 Contribution of Noncompliance and QT-Prolonging Drugs to the Occurrence of β-Blocker Treatment “Failures”

Background— β-Blocker efficacy in long-QT syndrome type 1 is good but variably reported, and the causes of cardiac events despite β-blocker therapy have not been ascertained. Methods and Results— This was a retrospective study of the details surrounding cardiac events in 216 genotyped long-QT syndrome type 1 patients treated with β-blocker and followed up for a median time of 10 years. Before β-blocker, cardiac events occurred in 157 patients (73%) at a median age of 9 years, with cardiac arrest (CA) in 26 (12%). QT-prolonging drugs were used by 17 patients; 9 of 17 (53%) had CA compared with 17 of 199 nonusers (8.5%; odds ratio, 12.0; 95% confidence interval, 4.1 to 35.3; P<0.001). After β-blocker, 75% were asymptomatic, and cardiac events were significantly reduced (P<0.001), with a median event count (quartile 1 to 3) per person of 0 (0 to 1). Twelve patients (5.5%) suffered CA/sudden death, but 11 of 12 (92%) were noncompliant (n=8), were on a QT-prolonging drug (n=2), or both (n=1) at the time of the event. The risk for CA/sudden death in compliant patients not taking QT-prolonging drugs was dramatically less compared with noncompliant patients on QT-prolonging drugs (odds ratio, 0.03; 95% confidence interval, 0.003 to 0.22; P=0.001). None of the 26 patients with CA before β-blocker had CA/sudden death on β-blockers. Conclusions— β-Blockers are extremely effective in long-QT syndrome type 1 and should be administered at diagnosis and ideally before the preteen years. β-Blocker noncompliance and use of QT-prolonging drug are responsible for almost all life-threatening “β-blocker failures.” β-Blockers are appropriate therapy for asymptomatic patients and those who have never had a CA or β-blocker therapy. Routine implantation of cardiac defibrillators in such patients does not appear justified.

Sinus node function and ventricular repolarization during exercise stress test in long QT syndrome patients with KVLQT1 and HERG potassium channel defects

OBJECTIVES This study was performed to evaluate the QT interval and heart rate responses to exercise and recovery in gene and mutation type-specific subgroups of long QT syndrome (LQTS) patients. BACKGROUND Reduced heart rate and repolarization abnormalities are encountered among long QT syndrome (LQTS) patients. The most common types of LQTS are LQT1 and LQT2. METHODS An exercise stress test was performed in 23 patients with a pore region mutation and in 22 patients with a C-terminal end mutation of the cardiac potassium channel gene causing LQT1 type of long QT syndrome (KVLQT1 gene), as well as in 20 patients with mutations of the cardiac potassium channel gene causing LQT2 type of long QT syndrome (HERG gene) and in 33 healthy relatives. The QT intervals were measured on electrocardiograms at rest and during and after exercise. QT intervals were compared at similar heart rates, and rate adaptation of QT was studied as QT/heart rate slopes. RESULTS In contrast to the LQT2 patients, achieved maximum heart rate was decreased in both LQT1 patient groups, being only 76 +/- 5% of predicted in patients with pore region mutation of KvLQT1. The QT/heart rate slopes were significantly steeper in LQT2 patients than in controls during exercise. During recovery, the QT/heart rate slopes were steeper in all LQTS groups than in controls, signifying that QT intervals lengthened excessively when heart rate decreased. At heart rates of 110 or 100 beats/min during recovery, all LQT1 patients and 89% of LQT2 patients had QT intervals longer than any of the controls. CONCLUSIONS LQT1 is associated with diminished chronotropic response and exaggerated prolongation of QT interval after exercise. LQT2 patients differ from LQT1 patients by having marked QT interval shortening and normal heart rate response to exercise. Observing QT duration during recovery enhances the clinical diagnosis of these LQTS types.

The Common Long-QT Syndrome Mutation KCNQ1/A341V Causes Unusually Severe Clinical Manifestations in Patients With Different Ethnic Backgrounds Toward a Mutation-Specific Risk Stratification

Background— The impressive clinical heterogeneity of the long-QT syndrome (LQTS) remains partially unexplained. In a South African (SA) founder population, we identified a common LQTS type 1 (LQT1)–causing mutation (KCNQ1-A341V) associated with high clinical severity. We tested whether the arrhythmic risk was caused directly by A341V or by its presence in the specific ethnic setting of the SA families. Methods and Results— Seventy-eight patients, all with a single KCNQ1-A341V mutation, from 21 families and 8 countries were compared with 166 SA patients with A341V and with 205 non-A341V LQT1 patients. In the 2 A341V populations (SA and non-SA), the probability of a first event through 40 years of age was similar (76% and 82%), and the QTc was 484±42 versus 485±45 ms (P=NS). Compared with the 205 non-A341V patients with the same median follow-up (30 versus 32 years), the 244 A341V patients were more likely to have cardiac events (75% versus 24%), were younger at first event (6 versus 11 years), and had a longer QTc (485±43 versus 465±38 ms) (all P<0.001). Arrhythmic risk remained higher (P<0.0001) even when the A341V patients were compared with non-A341V patients with mutations either localized to transmembrane domains or exhibiting a dominant-negative effect. A341V patients had more events despite β-blocker therapy. Conclusions— The hot spot KCNQ1-A341V predicts high clinical severity independently of the ethnic origin of the families. This higher risk of cardiac events also persists when compared with LQT1 patients with either transmembrane or dominant-negative mutations. The identification of this high-risk mutation and possibly others may improve the risk stratification and management of LQTS.

A founder mutation of the potassium channel KCNQ1 in long QT syndrome ☆: Implications for estimation of disease prevalence and molecular diagnostics

OBJECTIVES We took advantage of the genetic isolate of Finns to characterize a common long QT syndrome (LQTS) mutation, and to estimate the prevalence of LQTS. BACKGROUND The LQTS is caused by mutations in different ion channel genes, which vary in their molecular nature from family to family. METHODS The potassium channel gene KCNQ1 was sequenced in two unrelated Finnish patients with Jervell and Lange-Nielsen syndrome (JLNS), followed by genotyping of 114 LQTS probands and their available family members. The functional properties of the mutation were studied using a whole-cell patch-damp technique. RESULTS We identified a novel missense mutation (G589D or KCNQ1-Fin) in the C-terminus of the KCNQ1 subunit. The voltage threshold of activation for the KCNQ1-Fin channel was markedly increased compared to the wild-type channel. This mutation was present in homozygous form in two siblings with JLNS, and in heterozygous form in 34 of 114 probands with Romano-Ward syndrome (RWS) and 282 family members. The mean (+/- SD) rate-corrected QT intervals of the heterozygous subjects (n = 316) and noncarriers (n = 423) were 460 +/- 40 ms and 410 +/- 20 ms (p < 0.001), respectively. CONCLUSIONS A single missense mutation of the KCNQ1 gene accounts for 30% of Finnish cases with LQTS, and it may be associated with both the RWS and JLNS phenotypes of the syndrome. The relative enrichment of this mutation most likely represents a founder gene effect. These circumstances provide an excellent opportunity to examine how genetic and nongenetic factors modify the LQTS phenotype.

association between HERG K897T polymorphism and QT interval in middle-aged finnish women

OBJECTIVES The aim of this study was to test whether a recently reported polymorphism in the HERG gene coding for the rapidly activating delayed rectifier K+ channel has influence on myocardial repolarization. BACKGROUND The length of myocardial repolarization, measured as the QT interval, has a hereditary component, but no genes that would explain the variability of repolarization have been identified in healthy subjects. METHODS QT intervals were measured from the 12-lead electrocardiogram in a random middle-aged population (226 men/187 women). The longest QT interval at any of the 12 leads (QTmax), QTV(2), and the Tpeak-Tend interval were used as measures of repolarization. Deoxyribonucleic acid samples were genotyped for the nucleotide 2690A>C variation of the HERG gene, corresponding to the HERG K(lysine)897T(threonine) amino acid polymorphism. RESULTS The allele frequencies were 0.84 (A) and 0.16 (C). Females with the genotype AC or CC had longer QTcmax (477 +/- 99 ms) and Tpeak-Tend intervals (143 +/- 95 ms) than females with the genotype AA (441 +/- 69 ms and 116 +/- 65 ms, p = 0.005 and p = 0.025, respectively). In males, the QTcmax and the Tpeak-Tend intervals did not differ between the genotypes. After adjustment for echocardiographic and various laboratory variables, the HERG K897T polymorphism remained as an independent predictor of QTcmax (p = 0.009) and the Tpeak-Tend intervals (p = 0.026) in females. CONCLUSIONS; The common K897T polymorphism of the HERG channel is associated with the maximal duration and transmural dispersion of ventricular repolarization in middle-aged females.

Four potassium channel mutations account for 73% of the genetic spectrum underlying long-QT syndrome (LQTS) and provide evidence for a strong founder effect in Finland.

BACKGROUND. Mutations in five cardiac voltage‐gated ion channel genes, including KCNQ1, HERG, SCN5A, KCNE1 and KCNE2, constitute the principal cause of inherited long‐QT syndrome (LQTS). Typically, each family carries its own private mutation, and the disease manifests with varying phenotype and incomplete penetrance, even within particular families. We had previously identified 14 different LQTS‐causing mutations in 92 Finnish families. AIM. In order to complete the characterization of Finnish spectrum of LQTS genes, we conducted a systematic search for mutations in the five LQTS genes among 188 additional unrelated probands. METHODS. The screening was performed by denaturing high‐performance liquid chromatography (dHPLC) and DNA sequencing. RESULTS. Nineteen novel and 12 previously described mutations were identified. Collectively, these data extend the number of molecularly defined affected Finnish LQTS families and patients at present to 150 and 939, respectively. Four presumable founder mutations (KCNQ1 G589D and IVS7‐2A > G, HERG R176W and L552S) together account for as much as 73% of all established Finnish LQTS cases. CONCLUSIONS. The extent of genetic homogeneity underlying LQTS in Finland is unique in the whole world, providing a major advantage for screening and presymptomatic diagnosis of LQTS, and constituting an excellent basis to study the role of genetic and non‐genetic factors influencing phenotypic variability in this disease.

Cell Model of Catecholaminergic Polymorphic Ventricular Tachycardia Reveals Early and Delayed Afterdepolarizations

Background Induced pluripotent stem cells (iPSC) provide means to study the pathophysiology of genetic disorders. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a malignant inherited ion channel disorder predominantly caused by mutations in the cardiac ryanodine receptor (RyR2). In this study the cellular characteristics of CPVT are investigated and whether the electrophysiological features of this mutation can be mimicked using iPSC -derived cardiomyocytes (CM). Methodology/Principal Findings Spontaneously beating CMs were differentiated from iPSCs derived from a CPVT patient carrying a P2328S mutation in RyR2 and from two healthy controls. Calcium (Ca2+) cycling and electrophysiological properties were studied by Ca2+ imaging and patch-clamp techniques. Monophasic action potential (MAP) recordings and 24h-ECGs of CPVT-P2328S patients were analyzed for the presence of afterdepolarizations. We found defects in Ca2+ cycling and electrophysiology in CPVT CMs, reflecting the cardiac phenotype observed in the patients. Catecholaminergic stress led to abnormal Ca2+ signaling and induced arrhythmias in CPVT CMs. CPVT CMs also displayed reduced sarcoplasmic reticulum (SR) Ca2+ content, indicating leakage of Ca2+ from the SR. Patch-clamp recordings of CPVT CMs revealed both delayed afterdepolarizations (DADs) during spontaneous beating and in response to adrenaline and also early afterdepolarizations (EADs) during spontaneous beating, recapitulating the changes seen in MAP and 24h-ECG recordings of patients carrying the same mutation. Conclusions/Significance This cell model shows aberrant Ca2+ cycling characteristic of CPVT and in addition to DADs it displays EADs. This cell model for CPVT provides a platform to study basic pathology, to screen drugs, and to optimize drug therapy.

Evaluation of QT interval duration and dispersion and proposed clinical criteria in diagnosis of long QT syndrome in patients with a genetically uniform type of LQT1.

OBJECTIVES This study investigated the ability of QT duration, QT dispersion (QTD) and clinical diagnostic criteria to correctly identify genetically documented LQT1 type long QT syndrome (LQTS) patients, and to separate symptomatic and asymptomatic LQT1 patients. BACKGROUND Ventricular repolarization has played an essential role both in diagnosis and risk assessment of LQTS. Today, molecular genetic techniques permit unequivocal identification of many LQTS patients. METHODS QT interval and QTD in 12 symptomatic and 18 asymptomatic LQT1 patients and their 43 healthy relatives were evaluated. The sensitivity and specificity of upper normal limits of QT interval, two QT interval adjustment methods (Bazetts and Fridericias formulas), and the proposed clinical criteria for LQTS were assessed. Occurrence of a mutant (D188N) KVLQT1 gene was considered as the basis of classification into affected and nonaffected individuals. RESULTS Diagnostic sensitivity and specificity values were 90% and 88% using Bazetts formula, and 80% and 100% using Fridericias cubic root formula or upper normal limits for QT interval. Suggested diagnostic criteria for LQTS reached 100% specificity, but 47% of the DNA-documented LQT1 patients were classified into the category of low or intermediate probability of LQTS. QT interval and heart rate did not differ between symptomatic (464 +/- 47 ms, 70 +/- 9 min(-1)) and asymptomatic 460 +/- 41 ms, 65 +/- 13 min(-1)) LQT1 patients. QTD was increased in symptomatic LQT1 patients compared to unaffected relatives (66 +/- 48 vs. 37 +/- 15 ms, p = 0.02), but symptomatic patients LQT1 did not differ from asymptomatic (45 +/- 19 ms). CONCLUSIONS Not all LQT1 patients can be distinguished from healthy relatives by assessment of QT duration or clinical criteria. Presence of LQT1 gene can carry the risk of cardiac events even with no or only marginal prolongation of QT interval.