Publications by authors named "Heikki Swan"

78 Publications

Genealogy and clinical course of catecholaminergic polymorphic ventricular tachycardia caused by the ryanodine receptor type 2 P2328S mutation.

PLoS One 2020 14;15(12):e0243649. Epub 2020 Dec 14.

University of Helsinki, Helsinki, Finland.

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe inherited arrhythmic disease associated with a risk of syncope and sudden cardiac death (SCD).

Aims: We aimed at identifying RYR2 P2328S founder mutation carriers and describing the clinical course associated with the mutation.

Methods: The study population was drawn from the Finnish Inherited Cardiac Disorder Research Registry, and from the present genealogical study. Kaplan-Meier graphs, log-rank test and Cox regression model were used to evaluate the clinical course.

Results: Genealogical study revealed a common ancestor couple living in the late 17th century. A total of 1837 living descendants were tested for RYR2 P2328S mutation unveiling 62 mutation carriers aged mean 39±23 years old. No arrhythmic deaths were documented among genotyped subjects, but 11 SCDs were detected in non-genotyped family members since 1970. Three genotyped patients (5%) suffered an aborted cardiac arrest (ACA), and 15 (25%) had a syncope triggered by exercise or stress. Rate of cardiac events was higher among patients who in exercise stress test showed a maximum rate of premature ventricular contractions >30/min (68% vs 17%, p<0.01; hazard ratio = 7.1, p = 0.02), in comparison to patients without the respective finding. A cardioverter-defibrillator (ICD) was implanted to 13 (22%) patients, with an appropriate ICD shock in four (31%) subjects. All ICD shocks, one ACA, and one syncope occurred during β-blocker medication.

Conclusions: Previously undiagnosed CPVT patients may be identified by well-conducted genealogical studies. The RYR2 P2328S mutation causes a potentially severe phenotype, but its expression is variable, thus calling for additional studies on modifying factors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243649PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735638PMC
January 2021

Heart Rate Recovery After Exercise Is Associated With Arrhythmic Events in Patients With Catecholaminergic Polymorphic Ventricular Tachycardia.

Circ Arrhythm Electrophysiol 2020 03 16;13(3):e007471. Epub 2020 Feb 16.

Department of Pediatrics, Children's Heart Centre, Division of Cardiology, British Columbia Children's Hospital, Vancouver, BC, Canada (T.M.R., S.S.).

Background: Risk stratification in catecholaminergic polymorphic ventricular tachycardia remains ill defined. Heart rate recovery (HRR) immediately after exercise is regulated by autonomic reflexes, particularly vagal tone, and may be associated with symptoms and ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. Our objective was to evaluate whether HRR after maximal exercise on the exercise stress test (EST) is associated with symptoms and ventricular arrhythmias.

Methods: In this retrospective observational study, we included patients ≤65 years of age with an EST without antiarrhythmic drugs who attained at least 80% of their age- and sex-predicted maximal HR. HRR in the recovery phase was calculated as the difference in heart rate (HR) at maximal exercise and at 1 minute in the recovery phase (ΔHRR1').

Results: We included 187 patients (median age, 36 years; 68 [36%] symptomatic before diagnosis). Pre-EST HR and maximal HR were equal among symptomatic and asymptomatic patients. Patients who were symptomatic before diagnosis had a greater ΔHRR1' after maximal exercise (43 [interquartile range, 25-58] versus 25 [interquartile range, 19-34] beats/min; <0.001). Corrected for age, sex, and relatedness, patients in the upper tertile for ΔHRR1' had an odds ratio of 3.4 (95% CI, 1.6-7.4) of being symptomatic before diagnosis (<0.001). In addition, ΔHRR1' was higher in patients with complex ventricular arrhythmias at EST off antiarrhythmic drugs (33 [interquartile range, 22-48] versus 27 [interquartile range, 20-36] beats/min; =0.01). After diagnosis, patients with a ΔHRR1' in the upper tertile of its distribution had significantly more arrhythmic events as compared with patients in the other tertiles (=0.045).

Conclusions: Catecholaminergic polymorphic ventricular tachycardia patients with a larger HRR following exercise are more likely to be symptomatic and have complex ventricular arrhythmias during the first EST off antiarrhythmic drug.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCEP.119.007471DOI Listing
March 2020

Mothers with long QT syndrome are at increased risk for fetal death: findings from a multicenter international study.

Am J Obstet Gynecol 2020 03 11;222(3):263.e1-263.e11. Epub 2019 Sep 11.

IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin, Milan, Italy.

Background: Most fetal deaths are unexplained. Long QT syndrome is a genetic disorder of cardiac ion channels. Affected individuals, including fetuses, are predisposed to sudden death. We sought to determine the risk of fetal death in familial long QT syndrome, in which the mother or father carries the long QT syndrome genotype. In addition, we assessed whether risk differed if the long QT syndrome genotype was inherited from the mother or father.

Objective: This was a retrospective review of pregnancies in families with the 3 most common heterozygous pathogenic long QT syndrome genotypes in KCNQ1 (LQT1), KCNH2 (LQT2), or SCN5A (LQT3), which occur in approximately 1 in 2000 individuals. The purpose of our study was to compare pregnancy and birth outcomes in familial long QT syndrome with the normal population and between maternal and paternal carriers of the long QT syndrome genotype. We hypothesized that fetal death before (miscarriage) and after (stillbirths) 20 weeks gestation would be increased in familial long QT syndrome compared with the normal population and that the parent of origin would not affect birth outcomes.

Study Design: Our study was a multicenter observational case series of 148 pregnancies from 103 families (80 mothers, 23 fathers) with familial long QT syndrome (60 with LQT1, 29 with LQT2, 14 with LQT3) who were recruited from 11 international centers with expertise in hereditary heart rhythm diseases, pediatric and/or adult electrophysiology, and high-risk pregnancies. Clinical databases from these sites were reviewed for long QT syndrome that occurred in men or women of childbearing age (18-40 years). Pregnancy outcomes (livebirth, stillbirth, and miscarriage), birthweights, and gestational age at delivery were compared among long QT syndrome genotypes and between maternal vs paternal long QT syndrome-affected status with the use of logistic regression analysis.

Results: Most offspring (80%; 118/148) were liveborn at term; 66% of offspring (73/110) had long QT syndrome. Newborn infants of mothers with long QT syndrome were delivered earlier and, when the data were controlled for gestational age, weighed less than newborn infants of long QT syndrome fathers. Fetal arrhythmias were observed rarely, but stillbirths (fetal death at >20 weeks gestation) were 8 times more frequent in long QT syndrome (4% vs approximately 0.5%); miscarriages (fetal death at ≤20 weeks gestation) were 2 times that of the general population (16% vs 8%). The likelihood of fetal death was significantly greater with maternal vs paternal long QT syndrome (24.4% vs 3.4%; P=.036). Only 10% of all fetal deaths underwent postmortem long QT syndrome testing; 2 of 3 cases were positive for the family long QT syndrome genotype.

Conclusion: This is the first report to demonstrate that mothers with long QT syndrome are at increased risk of fetal death and to uncover a previously unreported cause of stillbirth. Our results suggest that maternal effects of long QT syndrome channelopathy may cause placental or myometrial dysfunction that confers increased susceptibility to fetal death and growth restriction in newborn survivors, regardless of long QT syndrome status.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajog.2019.09.004DOI Listing
March 2020

An actionable KCNH2 Long QT Syndrome variant detected by sequence and haplotype analysis in a population research cohort.

Sci Rep 2019 07 29;9(1):10964. Epub 2019 Jul 29.

MRC Human Genetics Unit, University of Edinburgh, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK.

The Viking Health Study Shetland is a population-based research cohort of 2,122 volunteer participants with ancestry from the Shetland Isles in northern Scotland. The high kinship and detailed phenotype data support a range of approaches for associating rare genetic variants, enriched in this isolate population, with quantitative traits and diseases. As an exemplar, the c.1750G > A; p.Gly584Ser variant within the coding sequence of the KCNH2 gene implicated in Long QT Syndrome (LQTS), which occurred once in 500 whole genome sequences from this population, was investigated. Targeted sequencing of the KCNH2 gene in family members of the initial participant confirmed the presence of the sequence variant and identified two further members of the same family pedigree who shared the variant. Investigation of these three related participants for whom single nucleotide polymorphism (SNP) array genotypes were available allowed a unique shared haplotype of 1.22 Mb to be defined around this locus. Searching across the full cohort for this haplotype uncovered two additional apparently unrelated individuals with no known genealogical connection to the original kindred. All five participants with the defined haplotype were shown to share the rare variant by targeted Sanger sequencing. If this result were verified in a healthcare setting, it would be considered clinically actionable, and has been actioned in relatives ascertained independently through clinical presentation. The General Practitioners of four study participants with the rare variant were alerted to the research findings by letters outlining the phenotype (prolonged electrocardiographic QTc interval). A lack of detectable haplotype sharing between c.1750G > A; p.Gly584Ser chromosomes from previously reported individuals from Finland and those in this study from Shetland suggests that this mutation has arisen more than once in human history. This study showcases the potential value of isolate population-based research resources for genomic medicine. It also illustrates some challenges around communication of actionable findings in research participants in this context.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-47436-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662790PMC
July 2019

Heritability in genetic heart disease: the role of genetic background.

Open Heart 2019;6(1):e000929. Epub 2019 May 28.

Heart Center, Clinical and Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.

Background: Mutations in genes encoding ion channels or sarcomeric proteins are an important cause of hereditary cardiac disease. However, the severity of the resultant disease varies considerably even among those with an identical mutation. Such clinical variation is often thought to be explained largely by differences in genetic background or 'modifier genes'. We aimed to test the prediction that identical genetic backgrounds result in largely similar clinical expression of a cardiac disease causing mutation, by studying the clinical expression of mutations causing cardiac disease in monozygotic twins.

Methods: We compared first available clinical information on 46 monozygotic twin pairs and 59 control pairs that had either a hereditary cardiomyopathy or channelopathy.

Results: Despite limited power of this study, we found significant heritability for corrected QT interval (QTc) in long QT syndrome (LQTS). We could not detect significant heritability for structural traits, but found a significant environmental effect on thickness of the interventricular septum in hypertrophic cardiomyopathy.

Conclusions: Our study confirms previously found robust heritability for electrical traits like QTc in LQTS, and adds information on low or lacking heritability for structural traits in heritable cardiomyopathies. This may steer the search for genetic modifiers in heritable cardiac disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/openhrt-2018-000929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546190PMC
February 2021

Implantable cardioverter-defibrillators in previously undiagnosed patients with catecholaminergic polymorphic ventricular tachycardia resuscitated from sudden cardiac arrest.

Eur Heart J 2019 09;40(35):2953-2961

Department of Cardiology, Centre for Cardiological Innovation, Oslo University Hospital, Rikshospitalet, Sognsvannsveien 20, Oslo, Norway.

Aims: In patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), implantable cardioverter-defibrillator (ICD) shocks are sometimes ineffective and may even trigger fatal electrical storms. We assessed the efficacy and complications of ICDs placed in patients with CPVT who presented with a sentinel event of sudden cardiac arrest (SCA) while undiagnosed and therefore untreated.

Methods And Results: We analysed 136 patients who presented with SCA and in whom CPVT was diagnosed subsequently, leading to the initiation of guideline-directed therapy, including β-blockers, flecainide, and/or left cardiac sympathetic denervation. An ICD was implanted in 79 patients (58.1%). The primary outcome of the study was sudden cardiac death (SCD). The secondary outcomes were composite outcomes of SCD, SCA, appropriate ICD shocks, and syncope. After a median follow-up of 4.8 years, SCD had occurred in three patients (3.8%) with an ICD and none of the patients without an ICD (P = 0.1). SCD, SCA, or appropriate ICD shocks occurred in 37 patients (46.8%) with an ICD and 9 patients (15.8%) without an ICD (P < 0.0001). Inappropriate ICD shocks occurred in 19 patients (24.7%) and other device-related complications in 22 patients (28.9%).

Conclusion: In previously undiagnosed patients with CPVT who presented with SCA, an ICD was not associated with improved survival. Instead, the ICD was associated with both a high rate of appropriate ICD shocks and inappropriate ICD shocks along with other device-related complications. Strict adherence to guideline-directed therapy without an ICD may provide adequate protection in these patients without all the potential disadvantages of an ICD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurheartj/ehz309DOI Listing
September 2019

The Role of Mutations and Maternal Beta Blocker Use During Pregnancy in the Growth of Children With Long QT Syndrome.

Front Endocrinol (Lausanne) 2018 24;9:194. Epub 2018 Apr 24.

Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

Objective: Two missense mutations in , an imprinted gene that encodes the alpha subunit of the voltage-gated potassium channel Kv7.1, cause autosomal dominant growth hormone deficiency and maternally inherited gingival fibromatosis. We evaluated endocrine features, birth size, and subsequent somatic growth of patients with long QT syndrome 1 (LQT1) due to loss-of-function mutations in .

Design: Medical records of 104 patients with LQT1 in a single tertiary care center between 1995 and 2015 were retrospectively reviewed.

Methods: Clinical and endocrine data of the LQT1 patients were included in the analyses.

Results: At birth, patients with a maternally inherited mutation ( = 52) were shorter than those with paternal inheritance of the mutation ( = 29) (birth length, -0.70 ± 1.1 SDS vs. -0.2 ± 1.0 SDS,  < 0.05). Further analyses showed, however, that only newborns ( = 19) of mothers who had received beta blockers during pregnancy were shorter and lighter at birth than those with paternal inheritance of the mutation ( = 29) (-0.89 ± 1.0 SDS vs. -0.20 ± 1.0 SDS,  < 0.05; and 3,173 ± 469 vs. 3,515 ± 466 g,  < 0.05). Maternal beta blocker treatment during the pregnancy was also associated with lower cord blood TSH levels ( = 0.011) and significant catch-up growth during the first year of life (Δ0.08 SDS/month,  = 0.004). Later, childhood growth of the patients was unremarkable.

Conclusion: Loss-of-function mutations in are not associated with abnormalities in growth, whereas maternal beta blocker use during pregnancy seems to modify prenatal growth of LQT1 patients-a phenomenon followed by catch-up growth after birth.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fendo.2018.00194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5928157PMC
April 2018

Clinical and molecular genetic risk determinants in adult long QT syndrome type 1 and 2 patients : Koponen et al. Follow-up of adult LQTS patients.

BMC Med Genet 2018 04 5;19(1):56. Epub 2018 Apr 5.

Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland.

Background: Long QT syndrome (LQTS) is an inherited cardiac disorder predisposing to sudden cardiac death (SCD). We studied factors affecting the clinical course of genetically confirmed patients, in particular those not receiving β-blocker treatment. In addition, an attempt was made to associate risk of events to specific types of KCNQ1 and KCNH2 mutations.

Methods: A follow-up study covering a mean of 18.6 ± 6.1 years was conducted in 867 genetically confirmed LQT1 and LQT2 patients and 654 non-carrier relatives aged 18-40 years. Cox regression models were used to evaluate the contribution of clinical and genetic risk factors to cardiac events.

Results: In mutation carriers, risk factors for cardiac events before initiation of β-blocker included LQT2 genotype (hazard ratio [HR] = 2.1, p = 0.002), female gender (HR = 3.2, p < 0.001), a cardiac event before the age of 18 years (HR = 5.9, p < 0.001), and QTc ≥500 ms (vs < 470 ms, HR = 2.7, p = 0.001). LQT1 patients carrying the KCNQ1 D317N mutation were at higher risk (HR = 3.0-3.9, p < 0.001-0.03) compared to G589D, c.1129-2A > G and other KCNQ1 mutation carriers after adjusting for gender, QTc duration, and cardiac events before age 18. KCNH2 c.453delC, L552S and R176W mutations associated with lower risk (HR = 0.11-0.23, p < 0.001) than other KCNH2 mutations.

Conclusions: LQT2 (compared to LQT1), female gender, a cardiac event before age 18, and long QT interval increased the risk of cardiac events in LQTS patients aged 18 to 40 years. The nature of the underlying mutation may be associated with risk variation in both LQT1 and LQT2. The identification of high-risk and low-risk mutations may enhance risk stratification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12881-018-0574-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5887247PMC
April 2018

Type 1 long QT syndrome and psychological stress in a laboratory setting.

J Health Psychol 2020 08 22;25(9):1213-1221. Epub 2018 Jan 22.

University of Helsinki, Finland.

Trait-like sensitivity to stress in long QT syndrome patients has been documented previously. In addition, mental stress has been associated with symptomatic status of long QT syndrome. We examined whether the symptomatic type 1 long QT syndrome patients would be more sensitive to mental stress compared to asymptomatic patients and whether there would be differences in task-related physiological stress reactions between type 1 long QT syndrome patients and healthy individuals. The study population consisted of 21 symptomatic and 23 asymptomatic molecularly defined KCNQ1 mutation carriers, their 32 non-carrier relatives and 46 non-related healthy controls, with mean ages of 37, 39, 35 and 23 years, respectively. Electrocardiography was utilised to calculate inter-beat interval and high frequency and low frequency heart rate variability. Blood pressure was measured and mean arterial pressure and pulse pressure were calculated. Stress was induced using three different tasks: mental arithmetic, reaction time and public speech. Stress responses of symptomatic and asymptomatic type 1 long QT syndrome patients were not statistically different in any of the stress tasks. Short-term physiological stress reactivity of symptomatic type 1 long QT syndrome patients appears to be normal and does not enhance the risk assessment of asymptomatic mutation carriers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1359105317751617DOI Listing
August 2020

The genetics underlying idiopathic ventricular fibrillation: A special role for catecholaminergic polymorphic ventricular tachycardia?

Int J Cardiol 2018 Jan 5;250:139-145. Epub 2017 Oct 5.

Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy. Electronic address:

Background: Ventricular fibrillation (VF) is a major cause of sudden cardiac death. In some cases clinical investigations fail to identify the underlying cause and the event is classified as idiopathic (IVF). Since mutations in arrhythmia-associated genes frequently determine arrhythmia susceptibility, screening for disease-predisposing variants could improve IVF diagnostics.

Methods And Results: The study included 76 Finnish and Italian patients with a mean age of 31.2years at the time of the VF event, collected between the years 1996-2016 and diagnosed with idiopathic, out-of-hospital VF. Using whole-exome sequencing (WES) and next-generation sequencing (NGS) approaches, we aimed to identify genetic variants potentially contributing to the life-threatening arrhythmias of these patients. Combining the results from the two study populations, we identified pathogenic or likely pathogenic variants residing in the RYR2, CACNA1C and DSP genes in 7 patients (9%). Most of them (5, 71%) were found in the RYR2 gene, associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). These genetic findings prompted clinical investigations leading to disease reclassification. Additionally, in 9 patients (11.8%) we detected 10 novel or extremely rare (MAF<0.005%) variants that were classified as of unknown significance (VUS).

Conclusion: The results of our study suggest that a subset of patients originally diagnosed with IVF may carry clinically-relevant variants in genes associated with cardiac channelopathies and cardiomyopathies. Although misclassification of other cardiac channelopathies as IVF appears rare, our findings indicate that the possibility of CPVT as the underlying disease entity should be carefully evaluated in IVF patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcard.2017.10.016DOI Listing
January 2018

Is Symptomatic Long QT Syndrome Associated with Depression in Women and Men?

J Genet Couns 2017 Jun 23;26(3):491-500. Epub 2016 Aug 23.

Institute of Behavioral Sciences, University of Helsinki, Siltavuorenpenger 1 A, P.O. Box 9, 00014, Helsinki, Finland.

We examined whether long QT syndrome (LQTS) mutation carrier status or symptomatic LQTS are associated with depression, and whether there are sex differences in these potential relationships. The sample comprised 782 participants (252 men). Of the 369 genetically defined LQTS mutation carriers, 169 were symptomatic and 200 were asymptomatic. The control group consisted of 413 unaffected relatives. Depression was assessed using the Beck Depression Inventory-II (BDI-II). No association was found for LQTS mutation carrier status with depression. The multinomial logistic regression showed that LQTS mutation carrier men with arrhythmic events scored higher on depression compared with the control group, even when adjusting for age, β-blockers, antidepressants, and social support (OR = 1.09, 95 % CI [1.02, 1.15], p = .007). The binary logistic regression comparing symptomatic and asymptomatic LQTS mutation carriers showed that symptomatic LQTS was associated with depression in men (OR = 1.10, 95 % CI [1.03, 1.19], p = .009). The results were unchanged when additionally adjusted for education. These findings suggest that symptomatic LQTS is associated with depression in men but not in women. Overall, however, depression is more frequent in women than men. Thus, regular screening for depression in LQTS mutation carriers and their unaffected family members can be important.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10897-016-0004-4DOI Listing
June 2017

Genetic Modifiers for the Long-QT Syndrome: How Important Is the Role of Variants in the 3' Untranslated Region of KCNQ1?

Circ Cardiovasc Genet 2016 Aug;9(4):330-9

From the Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan (L.C., C.S., P.J.S.); Department of Molecular Medicine (L.C.) and Department of Public Health (M.C.M., C.M.), Unit of Biostatistics and Clinical Epidemiology, University of Pavia, Pavia; Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital IRCCS Istituto Auxologico Italiano, Milan, Italy (L.C., G.P.); Department of Medicine, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland (A.M.L., K.K.); Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany (E.M., P.L., T.M.); Department of Medicine and Surgery University of Milano-Bicocca, Milan, Italy (G.P.); Department of Internal Medicine, University of Stellenbosch, South Africa (M.H., A.G., P.A.B.); Institute of Human Genetics, Technische Universität München (T.M.); DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (T.M.); and Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland (H.S.).

Background: Long-QT syndrome is an inherited cardiac channelopathy characterized by delayed repolarization, risk of life-threatening arrhythmia, and significant clinical variability even within families. Three single-nucleotide polymorphisms (SNPs) in the 3' untranslated region of KCNQ1 were recently suggested to be associated with suppressed gene expression and hence decreased disease severity when located on the same haplotype with a disease-causing KCNQ1 mutation. We sought to replicate this finding in a larger and a genetically more homogeneous population of KCNQ1 mutation carriers.

Methods And Results: The 3 SNPs (rs2519184, rs8234, and rs10798) were genotyped in a total of 747 KCNQ1 mutation carriers with A341V, G589D, or IVS7-2A>G mutation. The SNP haplotypes were assigned based on family trees. The SNP allele frequencies and clinical severity differed between the 3 mutation groups. The different SNP haplotypes were neither associated with heart rate-corrected QT interval duration (QTc) nor cardiac events in any of the 3 mutation groups. When the mutation groups were combined, the derived SNP haplotype of rs8234 and rs10798 located on the same haplotype with the mutation was associated with a shorter QTc interval (P<0.05) and a reduced occurrence of cardiac events (P<0.01), consistent with the previous finding. However, when the population-specific mutation was controlled for, both associations were no longer evident.

Conclusions: 3' Untranslated region SNPs are not acting as genetic modifiers in a large group of LQT1 patients. The confounding effect of merging a genetically and clinically heterogeneous group of patients needs to be taken into account when studying disease modifiers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGENETICS.116.001419DOI Listing
August 2016

Effects of cardioactive drugs on human induced pluripotent stem cell derived long QT syndrome cardiomyocytes.

Springerplus 2016 29;5:234. Epub 2016 Feb 29.

BioMediTech, University of Tampere, Finn-Medi 5, Biokatu 12, 33014 Tampere, Finland.

Human induced pluripotent stem cells (hiPSC) have enabled a major step forward in pathophysiologic studies of inherited diseases and may also prove to be valuable in in vitro drug testing. Long QT syndrome (LQTS), characterized by prolonged cardiac repolarization and risk of sudden death, may be inherited or result from adverse drug effects. Using a microelectrode array platform, we investigated the effects of six different drugs on the electrophysiological characteristics of human embryonic stem cell-derived cardiomyocytes as well as hiPSC-derived cardiomyocytes from control subjects and from patients with type 1 (LQT1) and type 2 (LQT2) of LQTS. At baseline the repolarization time was significantly longer in LQTS cells compared to controls. Isoprenaline increased the beating rate of all cell lines by 10-73 % but did not show any arrhythmic effects in any cell type. Different QT-interval prolonging drugs caused prolongation of cardiac repolarization by 3-13 % (cisapride), 10-20 % (erythromycin), 8-23 % (sotalol), 16-42 % (quinidine) and 12-27 % (E-4031), but we did not find any systematic differences in sensitivity between the control, LQT1 and LQT2 cell lines. Sotalol, quinidine and E-4031 also caused arrhythmic beats and beating arrests in some cases. In summary, the drug effects on these patient-specific cardiomyocytes appear to recapitulate clinical observations and provide further evidence that these cells can be applied for in vitro drug testing to probe their vulnerability to arrhythmia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40064-016-1889-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4771667PMC
March 2016

Antiarrhythmic Action of Flecainide in Polymorphic Ventricular Arrhythmias Caused by a Gain-of-Function Mutation in the Nav 1.5 Sodium Channel.

Ann Noninvasive Electrocardiol 2016 Jul 7;21(4):343-51. Epub 2015 Oct 7.

Department of Clinical Research, University of Bern, Bern, Switzerland.

Background: The cardiac sodium channel Nav 1.5, encoded by the gene SCN5A, is associated with a wide spectrum of hereditary arrhythmias. The gain-of-function mutation p.I141V in SCN5A was identified in a large multigenerational family with exercise-induced polymorphic ventricular arrhythmias. The purpose of this study was to evaluate the molecular and clinical effects of flecainide administration on patients with this syndrome.

Methods: Eleven p.I141V carriers who exhibited frequent multiformic premature ventricular complexes (PVCs) during exercise were subjected to exercise stress tests, both before and after intravenous infusion of 2 mg/kg flecainide. The in vitro effects of flecainide were evaluated using the patch-clamp technique with HEK293 cells expressing the Nav 1.5 channel.

Results: The flecainide treatment significantly reduced the frequency of PVCs during and after exercise. Next, the sensitivity of the p.I141V mutant channel to flecainide was compared to that of the wild type channel. Perfusion of flecainide inhibited the peak and window currents in both groups.

Conclusion: The clinical investigations of the affected patients, as well as the molecular and pharmacological characterization of the SCN5A p.I141V mutation, provide new evidence supporting the association of this mutation with exercise-induced polymorphic ventricular arrhythmias. These data also demonstrate that flecainide may serve as an effective treatment for the defect in Nav 1.5 that leads to an increased sodium window current.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/anec.12312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6931835PMC
July 2016

Slowed depolarization and irregular repolarization in catecholaminergic polymorphic ventricular tachycardia: a study from cellular Ca2+ transients and action potentials to clinical monophasic action potentials and electrocardiography.

Europace 2016 Oct 24;18(10):1599-1607. Epub 2015 Dec 24.

Division of Cardiology, Heart and Lung Center HUS, Helsinki University Central Hospital, Helsinki, Finland.

Aims: Spontaneous Ca release leads to afterdepolarizations and triggered arrhythmia in catecholaminergic polymorphic ventricular tachycardia (CPVT). Irregular Ca release is hypothesized to manifest as slowed depolarization and irregular repolarization. Our goal was to study depolarization and repolarization abnormalities in CPVT, as they remain largely uninvestigated.

Methods And Results: We studied intracellular Ca handling and action potentials (APs) in an induced pluripotent stem cell (iPSC) model of CPVT. Induced pluripotent stem cell cardiomyocytes from a RyR2-P2328S patient showed increased non-alternating variability of Ca transients in response to isoproterenol. β-Agonists decreased AP upslope velocity in CPVT cells and in monophasic AP recordings of CPVT patients. We compared 24 h electrocardiograms (ECGs) of 19 CPVT patients carrying RyR2 mutations and 19 healthy controls. Short-term variability (STV) of the QT interval was 6.9 ± 0.5 ms in CPVT patients vs. 5.5 ± 0.4 ms in controls (P < 0.05) and associated with a history of arrhythmic events. Mean T-wave alternans (TWA) was 25 ± 1.4 µV in CPVT patients vs. 31 ± 2.0 µV in controls (P < 0.05). Older CPVT patients showed lower maximal upslope velocity of the ECG R-spike than control patients.

Conclusion: Catecholaminergic polymorphic ventricular tachycardia patients show higher STV of repolarization but lower TWA on the 24 h ECG than control patients, which is likely to reflect increased non-alternating variability of Ca release by mutant RyR2s as observed in vitro. β-Agonists slow depolarization in RyR2-mutant cells and in CPVT patients. These findings may constitute a marker of arrhythmogenicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/europace/euv380DOI Listing
October 2016

Follow-up of 316 molecularly defined pediatric long-QT syndrome patients: clinical course, treatments, and side effects.

Circ Arrhythm Electrophysiol 2015 Aug 10;8(4):815-23. Epub 2015 Jun 10.

From the Heart and Lung Center, Helsinki University Central Hospital (M.K., A.M., M.V., L.T., H.S.), Children's Hospital, Helsinki University Central Hospital (A.H., J.-M.H.), Department of Medicine, Helsinki University Central Hospital (A.M.L., K.K.), and Institute of Behavioural Sciences, Psychology (T.H.), University of Helsinki, Helsinki, Finland; and Department of Health, National Institute for Health and Welfare, Helsinki, Finland (A.S.H., V.S.).

Background: Inherited long-QT syndrome (LQTS) is associated with risk of sudden death. We assessed the clinical course and the fulfillment of current treatment strategies in molecularly defined pediatric LQTS type 1 and (LQT1) and type 2 (LQT2) patients.

Methods And Results: Follow-up data covering a mean of 12 years were collected for 316 genotyped LQT1 and LQT2 patients aged 0 to 18 years. No arrhythmic deaths occurred during the follow-up. Finnish KCNQ1 and KCNH2 founder mutations were associated with fewer cardiac events than other KCNQ1 and KCNH2 mutations (hazard ratio [HR], 0.33; P=0.03 and HR, 0.16; P=0.01, respectively). QTc interval ≥500 ms increased the risk of cardiac events compared with QTc <470 ms (HR, 3.32; P=0.001). Treatment with β-blocker medication was associated with reduced risk of first cardiac event (HR, 0.23; P=0.001). Noncompliant LQT2 patients were more often symptomatic than compliant LQT2 patients (18% and 0%, respectively; P=0.03). Treatment with implantable cardioverter defibrillator was rare (3%) and resulted in reinterventions in 44% of cases.

Conclusions: Severe cardiac events are uncommon in molecularly defined and appropriately treated pediatric LQTS mutation carriers. β-Blocker medication reduces the risk of cardiac events and is generally well tolerated in this age group of LQTS patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCEP.114.002654DOI Listing
August 2015

Antiarrhythmic Effects of Dantrolene in Patients with Catecholaminergic Polymorphic Ventricular Tachycardia and Replication of the Responses Using iPSC Models.

PLoS One 2015 8;10(5):e0125366. Epub 2015 May 8.

BioMediTech, University of Tampere, Tampere, Finland; School of Medicine, University of Tampere, Tampere, Finland; Heart Hospital, Tampere University Hospital, Tampere, Finland.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a highly malignant inherited arrhythmogenic disorder. Type 1 CPVT (CPVT1) is caused by cardiac ryanodine receptor (RyR2) gene mutations resulting in abnormal calcium release from sarcoplasmic reticulum. Dantrolene, an inhibitor of sarcoplasmic Ca(2+) release, has been shown to rescue this abnormal Ca(2+) release in vitro. We assessed the antiarrhythmic efficacy of dantrolene in six patients carrying various RyR2 mutations causing CPVT. The patients underwent exercise stress test before and after dantrolene infusion. Dantrolene reduced the number of premature ventricular complexes (PVCs) on average by 74% (range 33-97) in four patients with N-terminal or central mutations in the cytosolic region of the RyR2 protein, while dantrolene had no effect in two patients with mutations in or near the transmembrane domain. Induced pluripotent stem cells (iPSCs) were generated from all the patients and differentiated into spontaneously beating cardiomyocytes (CMs). The antiarrhythmic effect of dantrolene was studied in CMs after adrenaline stimulation by Ca(2+) imaging. In iPSC derived CMs with RyR2 mutations in the N-terminal or central region, dantrolene suppressed the Ca(2+) cycling abnormalities in 80% (range 65-97) of cells while with mutations in or near the transmembrane domain only in 23 or 32% of cells. In conclusion, we demonstrate that dantrolene given intravenously shows antiarrhythmic effects in a portion of CPVT1 patients and that iPSC derived CM models replicate these individual drug responses. These findings illustrate the potential of iPSC models to individualize drug therapy of inherited diseases.Trial Registration: EudraCT Clinical Trial Registry 2012-005292-14.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0125366PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425399PMC
February 2016

Distinct electrophysiological and mechanical beating phenotypes of long QT syndrome type 1-specific cardiomyocytes carrying different mutations.

Int J Cardiol Heart Vasc 2015 Sep 25;8:19-31. Epub 2015 Apr 25.

University of Tampere, BioMediTech, School of Medicine, Tampere, Finland.

Background: Long QT syndrome (LQTS) is associated with increased risk of ventricular arrhythmias and cardiac arrest. LQTS type 1 (LQT1), the most prevalent subtype of LQTS, is caused by defects of slow delayed rectifier potassium current (I) that lead to abnormal cardiac repolarization. Here we used pluripotent stem cell (iPSC)-technology to investigate both the electrophysiological and also for the first time the mechanical beating behavior of genetically defined, LQT1 specific cardiomyocytes (CMs) carrying different mutations.

Methods: We established models for LQT1 caused by two mutations (G589D or ivs7-2A>G). LQT1 specific CMs were derived from patient specific iPSCs and characterized for their electrophysiology using a current clamp and Ca-imaging. Their mechanical beating characteristics were analyzed with video-image analysis method.

Results And Conclusions: Both LQT1-CM-types showed prolonged repolarization, but only those with G589D presented early after-depolarizations at baseline. Increased amounts of abnormal Ca transients were detected in both types of LQT1-CMs. Surprisingly, also the mechanical beating behavior demonstrated clear abnormalities and additionally the abnormalities were different with the two mutations: prolonged contraction was seen in G589D-CMs while impaired relaxation was observed in ivs7-2A>G-CMs. The CMs carrying two different LQT1 specific mutations (G589D or ivs7-2A>G) presented clear differences in their electrical properties as well as in their mechanical beating behavior. Results from different methods correlated well with each other suggesting that simply mechanical beating behavior of CMs could be used for screening of diseased CMs and possibly for diagnostic purposes in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcha.2015.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5497295PMC
September 2015

Gain-of-function mutation of the SCN5A gene causes exercise-induced polymorphic ventricular arrhythmias.

Circ Cardiovasc Genet 2014 Dec 10;7(6):771-81. Epub 2014 Sep 10.

From the Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland (H.S., A.M., L.T.); Department of Clinical Research (M.Y.A., H.A), and Department of Physiology (J.P.K), University of Bern, Bern, Switzerland. and Institute for Molecular Medicine Finland (FIMM), University of Helsinki (J.L., A.P., E.W.), and Department of Medicine, University of Helsinki and Helsinki University Central Hospital (P.J.L.-F., A.M.L., K.K.), Helsinki, Finland.

Background: Over the past 15 years, a myriad of mutations in genes encoding cardiac ion channels and ion channel interacting proteins have been linked to a long list of inherited atrial and ventricular arrhythmias. The purpose of this study was to identify the genetic and functional determinants underlying exercise-induced polymorphic ventricular arrhythmia present in a large multigenerational family.

Methods And Results: A large 4-generation family presenting with exercise-induced polymorphic ventricular arrhythmia, which was followed for 10 years, was clinically characterized. A novel SCN5A mutation was identified via whole exome sequencing and further functionally evaluated by patch-clamp studies using human embryonic kidney 293 cells. Of 37 living family members, a total of 13 individuals demonstrated ≥50 multiformic premature ventricular complexes or ventricular tachycardia upon exercise stress tests when sinus rate exceeded 99±17 beats per minute. Sudden cardiac arrest occurred in 1 individual during follow-up. Exome sequencing identified a novel missense mutation (p.I141V) in a highly conserved region of the SCN5A gene, encoding the Nav1.5 sodium channel protein that cosegregated with the arrhythmia phenotype. The mutation p.I141V shifted the activation curve toward more negative potentials and increased the window current, whereas action potential simulations suggested that it lowered the excitability threshold of cardiac cells.

Conclusions: Gain-of-function of Nav1.5 may cause familial forms of exercise-induced polymorphic ventricular arrhythmias.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGENETICS.114.000703DOI Listing
December 2014

Stressful life events and depressive symptoms among symptomatic long QT syndrome patients.

J Health Psychol 2016 Apr 24;21(4):505-12. Epub 2014 Apr 24.

IBS, Psychology, University of Helsinki, Finland.

We examined whether long QT syndrome status moderates the association between stressful life events and depressive symptoms. Participants were 562 (n= 246 symptomatic) long QT syndrome mutation carriers. Depressive symptoms were measured with a modified version of the Beck's Depression Inventory. There was an interaction between long QT syndrome status and stressful life events on depressive symptoms. In the symptomatic long QT syndrome patients, stressful life events were associated with depressive symptoms (B= 0.24, p< 0.001). In the asymptomatic long QT syndrome mutation carriers, this association was 62.5 percent weaker (B= 0.09, p= 0.057). Compared to asymptomatic long QT syndrome mutation carriers, symptomatic long QT syndrome patients are more sensitive to the depressive effects of stressful life events.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1359105314530450DOI Listing
April 2016

Brief report: Emotional distress and recent stressful life events in long QT syndrome mutation carriers.

J Health Psychol 2015 Nov 11;20(11):1445-50. Epub 2013 Dec 11.

University of Helsinki, Finland.

To study emotional distress in symptomatic and asymptomatic long QT syndrome mutation carriers who had experienced a recent stressful life event. The participants were 209 symptomatic and 279 asymptomatic long QT syndrome mutation carriers. Emotional distress was assessed with the Cope questionnaire and stressful life events with the Social Readjustment Rating Scale. Symptomatic long QT syndrome mutation carriers with burdening recent stressful life events reported a higher emotional distress (β = 0.35, p < 0.001), while the asymptomatic did not show such difference (β = 0.13, p = 0.393). Symptomatic long QT syndrome mutation carriers who have experienced stressful life events recently report an increased emotional distress.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1359105313513049DOI Listing
November 2015

Identification of a KCNQ1 polymorphism acting as a protective modifier against arrhythmic risk in long-QT syndrome.

Circ Cardiovasc Genet 2013 Aug 15;6(4):354-61. Epub 2013 Jul 15.

INSERM, UMR S956, Paris, France.

Background: Long-QT syndrome (LQTS) is characterized by such striking clinical heterogeneity that, even among family members carrying the same mutation, clinical outcome can range between sudden death and no symptoms. We investigated the role of genetic variants as modifiers of risk for cardiac events in patients with LQTS.

Methods And Results: In a matched case-control study including 112 patient duos with LQTS from France, Italy, and Japan, 25 polymorphisms were genotyped based on either their association with QTc duration in healthy populations or on their role in adrenergic responses. The duos were composed of 2 relatives harboring the same heterozygous KCNQ1 or KCNH2 mutation: 1 with cardiac events and 1 asymptomatic and untreated. The findings were then validated in 2 independent founder populations totaling 174 symptomatic and 162 asymptomatic patients with LQTS, and a meta-analysis was performed. The KCNQ1 rs2074238 T-allele was significantly associated with a decreased risk of symptoms 0.34 (0.19-0.61; P<0.0002) and with shorter QTc (P<0.0001) in the combined discovery and replication cohorts.

Conclusions: We provide evidence that the KCNQ1 rs2074238 polymorphism is an independent risk modifier with the minor T-allele conferring protection against cardiac events in patients with LQTS. This finding is a step toward a novel approach for risk stratification in patients with LQTS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGENETICS.113.000023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3864834PMC
August 2013

[Investigation and treatment of premature beats].

Authors:
Heikki Swan

Duodecim 2013 ;129(6):599-607

HYKS, Meilahden sairaala, sydäntutkimusosasto.

If a patient has premature beats, it is essential to clarify whether they are associated with a heart disorder or some other disease. The basis for an examination for all patients is the rest-ECG. Ultrasound examination is indicated, if the symptoms are severe or findings indicating a heart disorder are present. The occurrence of severe symptoms, such as episodes of tachycardia and attacks of unconsciousness, is mapped in an interview and they are an indication for further investigations within specialized care. Atrial extrasystoles as such do not require any treatment unless they are accompanied by atrial fibrillation.
View Article and Find Full Text PDF

Download full-text PDF

Source
July 2013

Characteristics of atrial fibrillation and comorbidities in familial atrial fibrillation.

J Cardiovasc Electrophysiol 2013 Jul 29;24(7):768-74. Epub 2013 Mar 29.

Department of Cardiology, Helsinki University Central Hospital, Helsinki, Finland.

Introduction: One-third of lone atrial fibrillation (AF) presents as familial disorder. Heterogeneity of both genetic background and clinical manifestations remains largely uncharacterized. We aimed to evaluate the clinical characteristics and especially the triggering factors of familial AF.

Methods And Results: Probands were screened from 84 consecutive lone AF patients seen in our tertiary hospital arrhythmia clinic. Those confirmed to have at least 1 first-degree relative with lone AF were included. 12-lead ECG, Holter recording, and cardiac ultrasound were performed. Data concerning arrhythmias and other medical history were collected. Altogether 17 kindreds with 59 AF patients, 52 of whom had lone AF, were identified. Initiation of AF was atrial extrasystolia (PACs) related in 35%, and vagal or sympathetic in 30% of cases. Within any given family, the characteristics related to AF initiation were the same in two-thirds of kindreds. AV conduction abnormalities were found in 2 families, sinus node dysfunction in 2 families, and both in 3 families. Frequent premature ventricular complexes (>1,000/24 hours) were observed in 9 families. Additional comorbidities included dilative cardiomyopathy and sudden death in 3 families.

Conclusions: In familial AF the proportion of PACs-related AF is lower than expected. The arrhythmia triggers for lone AF in general are heterogeneous but often family specific. Concomitant rhythm disorders, as well as cardiomyopathies, are common in patients with familial AF. A positive family history for AF in an apparently lone AF patient may be a marker for wider spectrum of cardiac pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jce.12127DOI Listing
July 2013

Cell model of catecholaminergic polymorphic ventricular tachycardia reveals early and delayed afterdepolarizations.

PLoS One 2012 4;7(9):e44660. Epub 2012 Sep 4.

Institute of Biomedical Technology, University of Tampere, Tampere, Finland.

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 (Ca(2+)) cycling and electrophysiological properties were studied by Ca(2+) 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 Ca(2+) cycling and electrophysiology in CPVT CMs, reflecting the cardiac phenotype observed in the patients. Catecholaminergic stress led to abnormal Ca(2+) signaling and induced arrhythmias in CPVT CMs. CPVT CMs also displayed reduced sarcoplasmic reticulum (SR) Ca(2+) content, indicating leakage of Ca(2+) 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 Ca(2+) 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0044660PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3433449PMC
January 2013

Stress proneness in molecularly defined long QT syndrome: a study using temperament assessment by behavioural inhibition system scale.

Stress Health 2013 Apr 30;29(2):150-5. Epub 2012 Aug 30.

IBS, Unit of Personality, Work and Health Psychology, University of Helsinki, Helsinki, Finland.

The long QT syndrome (LQTS) is an inherited cardiac disorder that predisposes the mutation carrier to ventricular arrhythmias that can lead to sudden death. The objective of the present study was to replicate the previous finding in terms of stress-related temperament trait, i.e. behavioural inhibition system (BIS). The study subjects included 583 LQTS mutation carriers (256 symptomatic and 327 asymptomatic) from the Finnish LQTS registry and 79 healthy subjects randomly derived from the population-based sample of the Young Finns Study. Symptomatic and asymptomatic LQTS mutation carriers did not differ from each other on BIS (3.27 versus 3.24, p > 0.05), whereas LQTS mutation carriers scored higher on BIS than the comparison group derived from the representative population-based sample (3.25 versus 2.99, p = 0.003, η² = 0.014). BIS was significantly higher in women than in men (3.32 versus 3.06, p < 0.001, η² = 0.017). The results confirm our previous finding of higher stress proneness of LQTS mutation carriers. Their innate stress proneness may have relevance because it increases our understanding on the role of stress in the manifestation of symptoms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/smi.2441DOI Listing
April 2013

[Genetic testing of patients with cardiomyopathies, the resuscitated and victims of sudden death--new international expert recommendations].

Authors:
Heikki Swan

Duodecim 2012 ;128(9):937-44

HYKS, Meilahden Sairaala, Sydäntutkimusossasto.

Recent international expert group recommendations for gene tests of myocardial or conducting system diseases as well as those concerning molecular genetic investigations of persons resuscitated after cardiac arrest or victims of sudden death are summarized. Systematic examination of an index patient forms the basis for correct clinical diagnosis and is a prerequisite for successful genetic testing. The first-degree relatives of victims of unexplained sudden death should be referred to clinical assessment due to the possibility of an inherited heart disease. Genetic testing of sudden death victims should be performed more frequently than previously, but targeting of the tests must be done on the basis of clinical data.
View Article and Find Full Text PDF

Download full-text PDF

Source
August 2012

[Gene tests in cardiac rhythm disturbances--new international expert recommendations].

Authors:
Heikki Swan

Duodecim 2012 ;128(7):697-704

HYKS, Meilahden sairaala, sydäntutkimusosasto.

Gene testing is important in the diagnosis of prolonged QT syndrome and hypertrophic cardiomyopathy, which should be diagnosed already at an asymptomatic stage. An international expert group has recently given recommendations concerning the use of gene tests in the clinical diagnostics of cardiac rhythm disturbances and cardiomyopathies. In these patients diagnostics is demanding and time consuming due to familial aggregation of the diseases. Thus, to facilitate appropriate use of gene testing, the diagnostics should be centralized.
View Article and Find Full Text PDF

Download full-text PDF

Source
August 2012
-->