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Heikki Swan

Publications and source records attributed to Heikki Swan.

At least 19 recordsLinked to original sources
PubMed2006

Female predominance and transmission distortion in the long-QT syndrome.

BACKGROUND: Congenital long-QT syndrome is a disorder resulting in ventricular arrhythmias and sudden death. The most common forms of the long-QT syndrome, types 1 and 2, are caused by mutations in the potassium-channel genes KCNQ1 and KCNH2, respectively. Although inheritance of the long-QT syndrome is autosomal dominant, female predominance has often been observed and has been attributed to an increased susceptibility to cardiac arrhythmias in women. We investigated the possibility of an unbalanced transmission of the deleterious trait. METHODS: We investigated the distribution of alleles for the long-QT syndrome in 484 nuclear families with type 1 disease and 269 nuclear families with type 2 disease, all with fully genotyped offspring. The families were recruited in five European referral centers for the long-QT syndrome. Mutation segregation, sex ratio, and parental transmission were analyzed after correction for single ascertainment. RESULTS: Classic mendelian inheritance ratios were not observed in the offspring of either female carriers of the long-QT syndrome type 1 or male and female carriers of the long-QT syndrome type 2. Among the 1534 descendants, the proportion of genetically affected offspring was significantly greater than that expected according to mendelian inheritance: 870 were carriers of a mutation (57%), and 664 were noncarriers (43%, P<0.001). Among the 870 carriers, the allele for the long-QT syndrome was transmitted more often to female offspring (476 [55%]) than to male offspring (394 [45%], P=0.005). Increased maternal transmission of the long-QT syndrome mutations to daughters was also observed, possibly contributing to the excess of female patients with autosomal dominant long-QT syndrome. CONCLUSIONS: Positive selection of the mutated alleles that cause the long-QT syndrome leads to transmission distortion, with increased proportions of mutation carriers among the offspring of affected families. Alleles for the long-QT syndrome are more often transmitted to daughters than to sons.

Chi-Square Distribution↗
PubMed2006

Beta1-adrenergic receptor polymorphisms, QTc interval and occurrence of symptoms in type 1 of long QT syndrome.

BACKGROUND: The most prevalent LQT1 form of inherited long QT syndrome is caused by mutations of the KCNQ1 gene resulting repolarizing I(Ks) potassium current to decrease and the QT interval to prolong. As abrupt sympathetic activation triggers ventricular arrhythmias that may cause syncopal attacks and sudden death in LQT1 patients, we investigated whether two known beta1-adrenergic receptor polymorphisms were associated with the duration of QT interval or history of symptoms in LQT1. METHODS: We determined beta1-adrenergic receptor polymorphisms (Ser49Gly and Arg389Gly) in 168 LQT1 patients. We also reviewed each patient's clinical records on the history of long QT syndrome-related symptoms and measured QT intervals from baseline ECG in each subject and from an exercise test ECG in 55 LQT1 patients. RESULTS: Patients with the homozygous Arg389Arg genotype tended to have shorter and those with the Ser49Ser genotype longer QT intervals than patients with other genotypes, but neither polymorphism studied alone affected the risk of symptoms. In contrast, adjusted odds ratio for the history of symptoms was 4.9 (95% CI 1.18 to 20.3) in patients homozygous for both Ser49 and Arg389. These double homozygous patients showed similar QT intervals as the rest of the LQT1 cohort. CONCLUSIONS: In this relatively small study, double homozygosity for Arg389 and Ser49 of the human beta1-adrenergic receptor associated with the risk of symptoms in LQT1. The association between these beta1-adrenergic receptor polymorphisms and the symptom history in LQT1 is not mediated via QT interval duration.

Adolescent↗
PubMed2006

Effect of physical training on ventricular repolarization in type 1 long QT syndrome: a pilot study in asymptomatic carriers of the G589D KCNQ1 mutation.

AIMS: High-intensity physical exercise and competitive sports have been traditionally avoided in long QT syndrome. However, endurance training increases vagal activity and thus may improve cardiac electrical stability in healthy subjects. We hypothesized that controlled submaximal endurance training would not adversely affect ventricular repolarization in asymptomatic carriers of a KCNQ1 gene mutation of type 1 long QT syndrome (LQT1). METHODS AND RESULTS: Previously, sedentary carriers of a missense mutation of KCNQ1 gene (LQT1, n=7) and healthy controls (n=8) exercised on a bicycle ergometer 3-4 times a week, 30 min a day at 60-75% of maximal heart rate (HR) for a maximum of 3 months. Body surface potential mapping (BSPM) was recorded and QT intervals were determined automatically from 14 channels over the left chest area. Maximal work capacity increased by 4+/-1% in LQT1 and by 14+/-2% in controls (both P<0.05), and left ventricular (LV) mass by 8+/-1% and 9+/-1%, respectively (P<0.05). Resting corrected QT interval shortened by 10+/-1% (P<0.05) and QT interval dispersion by 25+/-9% (P<0.05) in LQT1, but not significantly in controls. QT intervals at specified HRs during workload and recovery phases were not changed in either group. CONCLUSION: In this pilot study of asymptomatic carriers of a KNCQ1 gene mutation, submaximal endurance training did not harmfully affect arrhythmia risk markers. Confirmatory studies in a broader spectrum of LQT1 genotypes are needed before any generalization can be made.

Adult↗
PubMed2006

Effects of beta-blocker therapy on ventricular repolarization documented by 24-h electrocardiography in patients with type 1 long-QT syndrome.

OBJECTIVES: We tested the hypothesis that in long-QT syndrome (LQT) type 1 (LQT1), beta-blocker therapy may decrease both the diurnal maximal T-wave peak to T-wave end interval (TPE) and the maximal ratio between late and early T-wave peak amplitude (T2/T1 ratio), which are electrocardiographic counterparts of transmural dispersion of repolarization (TDR) and early afterdepolarizations (EA), respectively. BACKGROUND: Ventricular repolarization duration and increased TDR and EAs are the three electrophysiological components generating the high risk of ventricular arrhythmias and sudden death in the inherited LQT. In the most prevalent LQT1 form of LQT, treatment with beta-blockers reduces serious arrhythmia events dramatically without a known influence on QT interval duration. In experimental LQT1 models, beta-blockers decrease TDR and prevent EAs. METHODS: We reviewed 24-h electrocardiographic recordings obtained before and during the treatment with beta-blockers from 24 genotyped LQT1 patients to record maximal TPE intervals and T2/T1 ratios as well as maximal and rate-adapted QT intervals using a computer-assisted program. RESULTS: Treatment with beta-blockers decreased the maximal diurnal T2/T1 amplitude ratio from 3.0+/- 1.0 to 2.2 +/- 0.6 (p = 0.002). Beta-blockers also decreased both maximal TPE intervals and abrupt maximal QT intervals at heart rates higher than 85 beats/min, whereas QT intervals measured at steady-state conditions remained unchanged. CONCLUSIONS: Prevention of abrupt increases of electrocardiographic TDR, EA, and ventricular repolarization duration at elevated heart rates may explain the favorable clinical effects of beta-blockers in LQT1.

Adolescent↗
PubMed2006

Molecular characterization of two founder mutations causing long QT syndrome and identification of compound heterozygous patients.

BACKGROUND: Mutations of at least six different genes have been found to cause long QT syndrome (LQTS), an inherited arrhythmic disorder characterized by a prolonged QT interval on the electrocardiogram (ECG), ventricular arrhythmias and risk of sudden death. AIM: The aims were to define the yet undetermined phenotypic characteristics of two founder mutations and to study clinical features in compound heterozygotes identified during the course of the study. METHODS: To maximize identification of the compound heterozygotes, we used an extended group of LQTS patients comprising 700 documented or suspected cases. Functional studies were carried out upon transient expression in COS-7 or HEK293 cells. RESULTS: The KCNQ1 IVS7-2A>G (KCNQ1-FinB) mutation associated with a mean QTc interval of 464 ms and a complete loss-of-channel function. The HERG R176W (HERG-FinB) mutation caused a reduction in current density as well as slight acceleration of the deactivation kinetics in vitro, and its carriers had a mean QTc of 448 ms. The HERG R176W mutation was also present in 3 (0.9%) out of 317 blood donors. A total of six compound heterozygotes were identified who had the HERG R176W mutation in combination with a previously reported LQTS mutation (KCNQ1 G589D or IVS7-2A>G). When present simultaneously with an apparent LQTS-causing mutation, the HERG R176W mutation may exert an additional in vivo phenotypic effect. CONCLUSIONS: The HERG R176W mutation represents a population-prevalent mutation predisposing to LQTS. Compound heterozygosity for mutant LQTS genes may modify the clinical picture in LQTS.

Adult↗
PubMed2006

Ventricular repolarization and heart rate responses during cardiovascular autonomic function testing in LQT1 subtype of long QT syndrome.

BACKGROUND: In the most prevalent LQT1 form of inherited long QT syndrome symptoms often occur during abrupt physical or emotional stress. Sympathetic stimulation aggravates repolarization abnormalities in experimental LQT1 models. We hypothesized that autonomic function tests might reveal the abnormal repolarization in asymptomatic LQT1 patients. METHODS: We measured heart rates (HRs) and QT intervals in nine asymptomatic carriers of a C-terminal KCNQ1 mutation and 8 unaffected healthy subjects using an approach of global QT values derived from 28 simultaneous electrocardiographic leads on beat-to-beat base during Valsalva maneuver, mental stress, sustained handgrip, and light supine exercise. RESULTS: LQT1 patients exhibited impaired shortening of both QTpeak and QTend intervals during autonomic interventions but exaggerated lengthening of the intervals--a QT overshoot--during the recovery phases. The number of tests with a QT overshoot was 2.4 +/- 1.7 in LQT1 patients and 0.8 +/- 0.7 in unaffected subjects (P = 0.02). Valsalva strain prolonged T wave peak to T wave end interval (TPE) in LQT1 but not in unaffected patients. LQT1 patients showed diminished HR acceleration in response to adrenergic challenge whereas HR responses to vagal stimuli were similar in both groups. CONCLUSIONS: Standard cardiovascular autonomic provocations induce a QT interval overshoot during recovery in asymptomatic KCNQ1 mutation carriers. Valsalva maneuver causes an exaggerated fluctuation of QT and TPE intervals partly explaining the occurrence of cardiac events during abrupt bursts of autonomic activity in LQT1 patients.

Adult↗
PubMed2006

Reproducibility of computerized measurements of QT interval from multiple leads at rest and during exercise.

BACKGROUND: Accurate measurement of the QT interval is important for diagnosing long QT syndrome (LQTS), and in research on determinants of ventricular repolarization time. We tested automatic analysis of QT intervals from multiple ECG leads on chest. METHODS: Eleven healthy volunteers and 10 genotyped LQTS patients were tested at rest and during exercise with a bicycle ergometer twice 1-31 months apart. Electrocardiograms were recorded with the body surface potential mapping system, and 12 precordial channels were selected for analysis. Averaged QT peak and QT end intervals were determined with an automated algorithm, and the difference QT end minus QT peak (Tp-e) was calculated. Repeatability was assessed by coefficient of variation (CV) between measurements. RESULTS: Within one test at rest the QT end intervals were highly repeatable with CV 0.6%. In repeated tests CV was 4.4% for QT end interval and 3.5% when the QT interval was corrected for heart rate. In exercise test at specified heart rates, mean CV was 3.0% for QT end and 2.9% for QT peak interval. The CV of Tp-e interval was 10.2% at rest, and 9.3% in exercise test. Reproducibility was comparable between healthy subjects and LQTS patients. CONCLUSIONS: The BSPM system with automated analysis produced accurate and highly repeatable QT interval measurements. Reproducibility was adequate also over prolonged time periods both at rest and in exercise stress test. The method can be applied in studying duration of ventricular repolarization time in different physiologic and pharmacologic interventions.

Adult↗
PubMed2005

Ratio of late to early T-wave peak amplitude in 24-h electrocardiographic recordings as indicator of symptom history in patients with long-QT Syndrome types 1 and 2.

UNLABELLED: We reviewed 24-h electrocardiographic recordings from 214 genotyped subjects--97 with long-QT syndrome type 1 (LQT1), 62 with LQT2, and 55 unaffected--to record maximal diurnal amplitude ratios between late and early T-wave peaks. Maximal amplitude ratios between late and early T-wave peaks were higher in symptomatic than in asymptomatic patients both in LQT1 (3.2 +/- 1.0 vs. 2.3 +/- 0.8; p < 0.001) and in LQT2 patients (2.6 +/- 1.0 vs. 1.7 +/- 0.5; p < 0.001). The maximal amplitude ratio between late and early T-wave peaks was independently associated with symptom history in both LQT1 and LQT2 patients. OBJECTIVES: We tested the hypothesis that in long-QT syndrome types 1 (LQT1) and 2 (LQT2), the diurnal maximal ratio between late and early T-wave peak amplitudes correlates with a history of symptoms better than QT interval durations. BACKGROUND: Genotype and phenotype studies have delineated clinical profiles of the most prevalent LQT1 and LQT2 subtypes of inherited LQT, but prediction of arrhythmia risk remains uncertain, the baseline QTc interval being the best predictor. In experimental long-QT syndrome models, the ratio between late and early T-wave peak amplitude predicts onset of torsade de pointes. METHODS: We reviewed 24-h electrocardiographic recordings from 214 genotyped subjects--97 with LQT1, 62 with LQT2, and 55 unaffected-to record maximal amplitude ratios between late and early T-wave peaks by use of a computer-assisted program. RESULTS: Maximal amplitude ratios between late and early T-wave peaks were higher in symptomatic than in asymptomatic patients both in LQT1 (3.2 +/- 1.0 vs. 2.3 +/- 0.8; p < 0.001) and LQT2 patients (2.6 +/- 1.0 vs. 1.7 +/- 0.5; p < 0.001). Although the QTc interval also was longer in symptomatic patients, only the maximal amplitude ratio between late and early T-wave peaks was independently associated with symptoms in both LQT1 and LQT2 patients. CONCLUSIONS: Maximal diurnal ratio between late and early T-wave peak amplitude improves noninvasive risk assessment both in LQT1 and LQT2 syndromes. We propose this new indicator in clinical evaluation of arrhythmia risk in LQT1 and LQT2.

Adult↗
PubMed2005

Catecholaminergic polymorphic ventricular tachycardia: recent mechanistic insights.

Cardiac excitation-contraction coupling occurs by a calcium ion-mediated mechanism in which the signal of action potential is converted into Ca2+ influx into the cardiomyocytes through the sarcolemmal L-type calcium channels. This is followed by Ca2+-induced release of additional Ca2+ ions from the lumen of the sarcoplasmic reticulum into the cytosol via type 2 ryanodine receptors (RyR2). RyR2 channels form large complexes with additional regulatory proteins, including FKBP12.6 and calsequestrin 2 (CASQ2). Catecholamines, released into the body fluids during emotional or physical stress, activate Ca2+-induced Ca2+ release by protein kinase A-mediated phosphorylation of RyR2. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an insidious, early-onset and highly malignant, inherited disorder characterized by effort-induced ventricular arrhythmias in the absence of structural alterations of the heart. At least some cases of sudden, unexplained death in young individuals may be ascribed to CPVT. Mutations of the RyR2 gene cause autosomal dominant CPVT, while mutations of the CASQ2 gene may cause an autosomal recessive or dominant form of CPVT. The steps of the molecular pathogenesis of CPVT are not entirely clear, but inappropriate "leakiness" of RyR2 channels is thought to play a role; the underlying mechanisms may involve an increase in the basal activity of the RyR2 channel, alterations in its phosphorylation status, a defective interaction of RyR2 with other molecules or ions, such as FKBP12.6, CASQ2, or Mg2+, or its abnormal activation by extra- or intraluminal Ca2+ ions. Beta-adrenergic antagonists have proven to be of value in prevention of arrhythmias in CPVT patients, but occasional treatment failures call for alternative measures. There is great interest at present for the development of novel antiarrhythmic drugs for CPVT, as the same approaches may be applied for treatment of more common forms of life-threatening arrhythmias, such as those arising during ischemia and heart failure.

Animals↗
PubMed2005

Calcium channel antagonism reduces exercise-induced ventricular arrhythmias in catecholaminergic polymorphic ventricular tachycardia patients with RyR2 mutations.

UNLABELLED: Calcium channel antagonism in RyR2 defects. INTRODUCTION: Recently, gain-of-function mutations of cardiac ryanodine receptor RyR2 gene have been identified as a cause of familial or catecholaminergic polymorphic ventricular tachycardia. We examined the influence of the calcium channel blockers, verapamil and magnesium, on exercise-induced ventricular arrhythmias in patients with RyR2 mutations. METHODS AND RESULTS: Six molecularly defined catecholaminergic polymorphic ventricular tachycardia patients, all carrying a RyR2 mutation and on beta-adrenergic blocker therapy, underwent exercise stress test four times: at baseline, after verapamil and magnesium sulphate infusions, and finally, without interventions. The number of isolated and successive premature ventricular complexes during exercise ranged from 40 to 374 beats (mean 165 beats) at baseline, and was reduced during verapamil by 76+/-17% (P<0.05). Premature ventricular complexes appeared later and at higher heart rate during verapamil than at baseline (119+/-21 vs. 127+/-27 min-1, P<0.05). Magnesium did not inhibit the arrhythmias. Results in the fourth exercise stress test without interventions were similar to those in the first baseline study. CONCLUSIONS: This study provides the first in vivo demonstration that a calcium channel antagonist, verapamil, can suppress premature ventricular complexes and nonsustained ventricular salvoes in catecholaminergic polymorphic ventricular tachycardia caused by RyR2 mutations. Modifying the abnormal calcium handling by calcium antagonists might have therapeutic value.

Calcium Channel Blockers↗
PubMed2005

Effects of epinephrine on right ventricular monophasic action potentials in the LQT1 versus LQT2 form of long QT syndrome: preferential enhancement of "triangulation" in LQT1.

AIMS: To explore effects of epinephrine and phenylephrine on the behavior of right ventricular monophasic action potentials (MAPs) in symptomatic LQT1 and LQT2 patients. METHODS AND RESULTS: We recorded endocardial MAPs from right interventricular septum at baseline and during epinephrine and phenylephrine infusions in six symptomatic DNA-verified LQT1 (QTc 528 +/- 83) and five LQT2 patients (QTc 527 +/- 72) and in five control patients (QTc 381 +/- 22). We measured MAP durations at 90% and at 50% levels of repolarization and their difference (MAP50 to MAP90, a measure of MAP morphologic "triangulation"), during atrial pacing to characterize rate dependence of MAPs and repolarization phase 3 durations, respectively. Restitution kinetics were determined during atrioventricular sequential pacing, using the approach of empirical restitution rate. Epinephrine prolonged MAP50-to-MAP90 duration and increased the rate dependence of MAP90 duration and increased restitution rate in type LQT1, but not in LQT2 patients nor in control subjects. Phenylephrine did not change MAP behavior. During epinephrine administration, both LQT1 and LQT2 patients had a ratio of the restitution rate of MAP to diastolic interval >1.0 at short diastolic intervals. CONCLUSION: Symptomatic LQT1 patients with prolonged baseline QTc intervals showed beta-adrenergic-induced changes in MAPs (triangulation) known to be arrhythmogenic, thus giving insight to the difference in clinical triggers of life-threatening arrhythmias between LQT1- and LQT2-affected individuals.

Action Potentials↗
PubMed2004

Temporal repolarization lability differences among genotyped patients with the long QT syndrome.

The investigators sought to test whether certain long QT syndrome (LQTS) mutations are associated with increased repolarization lability and whether repolarization lability (quantified by the QT variability index [QTVI]) is increased in patients with LQTS compared with controls. In 32 genotyped patients with LQTS type 1 (LQT1), 32 genotyped patients with LQTS type 2 (LQT2), and 32 controls, the QTVI was increased in patients with LQT2 (-0.973 +/- 0.394, p = 0.01 vs controls) and in patients with LQT1 with mutations other than KCNQ1-FIN (-0.942 +/- 0.264, p = 0.04 vs controls) but was similar between the KCNQ1-FIN group and controls.

Adult↗
PubMed2004

Sudden death in familial polymorphic ventricular tachycardia associated with calcium release channel (ryanodine receptor) leak.

BACKGROUND: Familial polymorphic ventricular tachycardia (FPVT) is characterized by exercise-induced arrhythmias and sudden cardiac death due to missense mutations in the cardiac ryanodine receptor (RyR2), an intracellular Ca2+ release channel required for excitation-contraction coupling in the heart. METHODS AND RESULTS: Three RyR2 missense mutations, P2328S, Q4201R, and V4653F, which occur in Finnish families, result in similar mortality rates of approximately 33% by age 35 years and a threshold heart rate of 130 bpm, above which exercise induces ventricular arrhythmias. Exercise activates the sympathetic nervous system, increasing cardiac performance as part of the fight-or-flight stress response. We simulated the effects of exercise on mutant RyR2 channels using protein kinase A (PKA) phosphorylation. All 3 RyR2 mutations exhibited decreased binding of calstabin2 (FKBP12.6), a subunit that stabilizes the closed state of the channel. After PKA phosphorylation, FPVT-mutant RyR2 channels showed a significant gain-of-function defect consistent with leaky Ca2+ release channels and a significant rightward shift in the half-maximal inhibitory Mg2+ concentration (IC50). Treatment with the experimental drug JTV519 enhanced binding of calstabin2 to RyR2 and normalized channel function. CONCLUSIONS: Sympathetic activation during exercise induces ventricular arrhythmias above a threshold heart rate in RyR2 mutation carriers. Simulating the downstream effects of the sympathetic activation by PKA phosphorylation of RyR2 channels containing these FPVT missense mutations produced a consistent gain-of-function defect. RyR2 function and calstabin2 depletion were rescued by JTV519, suggesting stabilization of the RyR2 channel complex may represent a molecular target for the treatment and prevention of exercise-induced arrhythmias and sudden death in these patients.

Adult↗
PubMed2004

Loss-of-function mutations of the K(+) channel gene KCNJ2 constitute a rare cause of long QT syndrome.

Mutations of the KCNJ2 gene encoding the potassium channel Kir2.1 were previously shown to cause Andersen's syndrome (AS), a multisystem disease manifesting with developmental abnormalities, cardiac arrhythmias and periodic paralyses. We conducted a search for KCNJ2 mutations among 188 unrelated patients suspected to have long QT syndrome (LQTS). The screening was performed by denaturing high-performance liquid chromatography (dHPLC) and DNA sequencing. Two novel mutations of the KCNJ2 gene were detected: a missense threonine to alanine mutation (T75A) in the N-terminal region (family 1) and an in-frame deletion of two amino acids (DeltaFQ163-164) in the M2 transmembrane region (family 2). In addition, a previously described silent polymorphism C1146T was detected. In family 1, some of the affected family members had a history of periodic muscle weakness characteristic of AS, but no dysmorphic features. The mean QTc interval of the affected members were 444 +/- 24 ms (family 1, n=7) and 456 +/- 8 ms (family 2, n=2). The mutations affect functionally important regions of the KCNJ2 channel protein: upon injection of the Xenopus oocytes with the wild type and mutant KCNJ2 constructs, the channel proteins were correctly synthesized and localized to the cell surface, but no measurable inward K(+) current could be detected for the mutant KCNJ2 constructs. In conclusion, we report two novel loss-of-function mutations of the KCNJ2 channel, affecting different domains of the channel protein. Mutations of the KCNJ2 gene should be considered in genetic subclassification of LQTS patients, even in the absence of overt manifestations of AS.

Amino Acid Sequence↗
PubMed2004

Genes, exercise and sudden death: molecular basis of familial catecholaminergic polymorphic ventricular tachycardia.

Familial catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare arrhythmogenic disease manifesting with exercise- or stress-induced ventricular arrhythmias, syncope, and even sudden death. CPVT is inherited as an autosomal dominant or autosomal recessive trait, usually with high penetrance. We characterized in detail the clinical, structural and electrocardiographic findings in this disorder and by use of genome-wide linkage analysis, mapped the disease-causing gene to chromosome 1q42-q43. Thereafter, we and others demonstrated point mutations of the cardiac ryanodine receptor gene (RyR2) to underlie this life-threatening disease. In addition, RyR2 mutations were identified in patients affected with a variant form of arrhythmogenic right ventricular dysplasia (ARVD2), a phenotypically distinct disease entity. Identification of the causal mutations has enabled molecular diagnosis in the affected families, which is of major importance in identifying individuals at risk of an arrhythmia. Recently, several groups have delineated the functional effects of the RyR2 mutations associated with CPVT and ARVD2. The results are slightly contradictory, and further studies are thus needed to clarify the exact molecular mechanisms leading to arrhythmia induction.

Catecholamines↗
PubMed2004

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 LOTS-causing mutations in 92 Finnish families. AIM: In order to complete the characterization of Finnish spectrum of LOTS genes, we conducted a systematic search for mutations in the five LOTS 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 LOTS 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 LOTS in Finland is unique in the whole world, providing a major advantage for screening and presymptomatic diagnosis of LOTS, and constituting an excellent basis to study the role of genetic and non-genetic factors influencing phenotypic variability in this disease.

Cation Transport Proteins↗
PubMed2004

Volatile anesthetics and succinylcholine in cardiac ryanodine receptor defects.

Familial polymorphic (catecholaminergic) ventricular tachycardia is an arrhythmogenic cardiac disorder caused by mutations of the myocardial isoform of the ryanodine receptor gene (RyR2). Mutations of the corresponding gene in the skeletal muscle (RyR1) predispose its carriers to malignant hyperthermia upon use of volatile anesthetics or succinylcholine, which further deteriorate the inherited intracellular calcium release disorder. We report a series of patients with cardiac RyR defects who underwent general anesthesia without complications. Succinylcholine and volatile anesthetics did not have a clinically significant effect on RyR2 defects.

Adolescent↗