Sydämen rytmihäiriösairauksille ja sydänperäiselle äkkikuolemalle altistavat geneettiset variantit

Arrhythmogenic right ventricular cardiomyopathy (ARVC) and long QT syndrome (LQTS) are inherited cardiac arrhythmia disorders that predispose to sudden cardiac death (SCD). In ARVC, structural and electrical abnormalities of the heart occur together with progressive replacement of the right ventricular myocardium by adipose and fibrous tissue. Mutations in desmosomal cell adhesion genes may cause ARVC. LQTS manifests with a prolonged electrocardiographic QT interval in a structurally normal heart. LQTS is caused by mutations in cardiac ion channel genes, delaying the repolarization of the ventricular myocardium. The aims of this study were to identify genetic variants predisposing to ARVC, LQTS, and SCD and to assess their prevalence and clinical significance in the Finnish population. Six (18%) of 33 ARVC probands were identified to carry mutations in desmosomal genes. Desmosomal mutations occurred together with disorganization of the intercalated disk structure and demonstrated reduced disease penetrance. The carrier frequency of the desmosomal mutations identified in this study was 1:250 as estimated in a sample of 27 670 Finns. Therefore, an unexpectedly large number of individuals could be at risk of developing ARVC in Finland. However, another trigger is likely to be needed for disease expression. In a clinical sample of 712 LQTS founder mutation carriers, KCNE1 D85N was associated with a 26-ms prolongation of QT interval in males with KCNQ1 G589D, representing thus a potential sex-specific disease-modifying factor. In a population sample of 6808 Finns, KCNE1 D85N together with 13 other genetic variants explained 8.6% of the variation in QT interval, and a 10-ms prolongation of QT interval was associated with a 19% increased risk of SCD. This information could ultimately contribute to assessment of individual susceptibility to LQTS. When studied in a total of 28 323 individuals, two novel common variants, rs41312391 in SCN5A and rs2200733 in 4q25 near PITX2, were associated with risk of SCD. In addition, the associations for rs2383207 in 9p21 and for clinical risk factors for coronary heart disease were replicated. Rare mutations in desmosomal and ion channel genes had a combined carrier frequency of 1:130 in the Finnish population and were detected in individual SCD victims. These results provide novel information for SCD risk prediction and prevention.Oikean kammion arytmogeeninen kardiomyopatia (ARVC) ja pitkä QT -oireyhtymä (LQTS) ovat perinnöllisiä sydämen rytmihäiriösairauksia, jotka altistavat sydänperäiselle äkkikuolemalle. ARVC:lle tyypillisiä piirteitä ovat sydänlihaskudoksen asteittainen korvautuminen rasva- ja sidekudoksella sekä sydämen sähköiset ja rakenteelliset muutokset. Desmosomit ovat soluliitosrakenteita, joiden perinnöllisten muutosten on todettu altistavan ARVC:lle. LQTS ilmenee sydämen sähköisen repolarisaation viivästymisenä, joka voidaan havaita sydänsähkökäyrästä mitattavan QT-ajan pidentymisenä. LQTS aiheutuu usein mutaatioista solukalvon ionikanavarakenteita koodaavissa geeneissä. Tämän tutkimuksen tavoitteena oli tunnistaa ARVC:lle, LQTS:lle ja sydänperäiselle äkkikuolemalle altistavia geenivariantteja sekä arvioida niiden yleisyyttä ja kliinistä merkitystä suomalaisessa väestössä. Kuudella (18 %) 33 ARVC-potilaasta todettiin mutaatioita desmosomin proteiineja koodaavissa geeneissä. Mutaatioita kantavilla potilailla huomattiin muutoksia sydänsolujen liitosrakenteissa. Suomalaisessa väestössä jopa yhden 250 henkilöä kohden havaittiin kantavan jotakin tutkituista rytmihäiriöille altistavista soluliitosmutaatioista. Tutkitut mutaatiot eivät kuitenkaan yksin riitä aiheuttamaan rytmihäiriösairautta. KCNE1 D85N -variantin havaittiin olevan yhteydessä QT-ajan pituuteen LQTS-valtamutaatiota KCNQ1 G589D kantavilla miespotilailla. Suomalaisessa väestöaineistossa KCNE1 D85N yhdessä 13 muun geenivariantin kanssa selittivät 8.6 % variaatiosta QT-ajan pituudessa. QT-ajan pidentyminen 10 millisekunnilla oli yhteydessä 19 % suurentuneeseen sydänperäisen äkkikuoleman riskiin. Näitä tutkimustuloksia voidaan hyödyntää LQTS-potilaiden henkilökohtaisessa riskinarvioinnissa. Yli 28 000 henkilön väestöaineistossa havaittiin kaksi uutta yleistä geneettistä varianttia (toinen SCN5A-geenissä ja toinen PITX2-geenin lähellä), jotka olivat yhteydessä sydänperäisen äkkikuoleman riskiin. Lisäksi yhden aiemmin tunnistetun variantin ja sepelvaltimotaudin riskitekijöiden todettiin lisäävän sydänperäisen äkkikuoleman riskiä. Harvinaisia soluliitos- ja ionikanavamutaatioita esiintyi suomalaisessa väestössä yhteensä yhdellä 130 henkilöä kohden sekä yksittäisillä äkillisesti kuolleilla henkilöillä. Nämä tulokset tuovat uutta tietoa, jota voidaan hyödyntää äkkikuoleman riskinarvioinnissa ja ennaltaehkäisyssä

KCNE1 D85N polymorphism - a sex-specific modifier in type 1 long QT syndrome?

Peer reviewe

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

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 Ca2+ release, has been shown to rescue this abnormal Ca2+ 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 Ca2+ imaging. In iPSC derived CMs with RyR2 mutations in the N-terminal or central region, dantrolene suppressed the Ca2+ 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.Peer reviewe

Genetic Modifiers for the Long-QT Syndrome

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

Search for cardiac calcium cycling gene mutations in familial ventricular arrhythmias resembling catecholaminergic polymorphic ventricular tachycardia

<p>Abstract</p> <p>Background</p> <p>Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe inherited cardiac disorder caused by mutations predominantly in the ryanodine receptor (<it>RyR2</it>) gene. We sought to identify mutations in genes affecting cardiac calcium cycling in patients with CPVT and in less typical familial exercise-related ventricular arrhythmias.</p> <p>Methods and Results</p> <p>We recruited 33 consecutive patients with frequent ventricular premature complexes (VPCs) without structural heart disease and often history of syncope or sudden death in family. Sixteen of the patients featured a phenotype typical of CPVT. In 17 patients, VPCs emerged also at rest. Exercise stress test and echocardiography were performed to each patient and 232 family members. Familial background was evident in 42% of cases (n = 14). We sequenced all the coding exons of the <it>RyR2</it>, <it>FKBP1B</it>, <it>ATP2A2 </it>and <it>SLC8A1 </it>genes from the index patients. Single channel recordings of a mutant RyR2 were performed in planar lipid bilayers. Two novel <it>RyR2 </it>missense mutations (R1051P and S616L) and two <it>RyR2 </it>exon 3 deletions were identified, explaining 25% of the CPVT phenotypes. A rare variant (N3308S) with open probabilities similar to the wild type channels <it>in vitro</it>, was evident in a patient with resting VPCs. No disease-causing variants were detectable in the <it>FKBP1B</it>, <it>ATP2A2 </it>or <it>SLC8A1 </it>genes.</p> <p>Conclusion</p> <p>We report two novel CPVT-causing <it>RyR2 </it>mutations and a novel <it>RyR2 </it>variant of uncertain clinical significance in a patient with abundant resting VPCs. Our data also strengthen the previous assumption that exon 3 deletions of <it>RyR2 </it>should screened for in CPVT and related phenotypes.</p

Common Genetic Variants Associated with Sudden Cardiac Death: The FinSCDgen Study

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

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Lamin A/C mutation affecting primarily the right side of the heart

LMNA mutations are amongst the most important causes of familial dilated cardiomyopathy. The most important cause of arrhythmogenic right ventricular cardiomyopathy (ARVC) is desmosomal pathology. The aim of the study was to elucidate the role of LMNA mutations among Finnish cardiomyopathy patients. We screened 135 unrelated cardiomyopathy patients for LMNA mutations. Because of unusual phenotype, two patients were screened for the known Finnish ARVC-related mutations of desmosomal genes, and their Plakophilin-2b gene was sequenced. Myocardial samples from two patients were examined by immunohistochemical plakoglobin staining and in one case by electron microscopy. We found a new LMNA mutation Phe237Ser in a family of five affected members with a cardiomyopathy affecting primarily the right side of the heart. The phenotype resembles ARVC but does not fulfill the Task Force Criteria. The main clinical manifestations of the mutation were severe tricuspid insufficiency, right ventricular enlargement and failure. Three of the affected patients died of the heart disease, and the two living patients received heart transplants at ages 44 and 47. Electron microscopy showed nuclear blebbing compatible with laminopathy. Immunohisto - chemical analysis did not suggest desmosomal pathology. No desmosomal mutations were found. The Phe237Ser LMNA mutation causes a phenotype different from traditional cardiolaminopathy. Our findings suggest that cardiomyopathy affecting primarily the right side of the heart is not always caused by desmosomal pathology. Our observations highlight the challenges in classifying cardiomyopathies, as there often is significant overlap between the traditional categories.Peer reviewe

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

Potilaslähtöisyys HUS-alueen teho-osastoilla hoitohenkilökunnan arvioimana

Potilaslähtöisyyden tutkiminen on tärkeää, sillä sen on todettu vaikuttavan terveyspalveluiden laatuun, potilaiden hoitoon sitoutumiseen sekä potilastyytyväisyyteen. Tutkimuksissa on havaittu, että potilaslähtöisyys ei kuitenkaan toteudu aina ongelmitta, varsinkaan tehohoidossa. Opinnäytetyömme kuuluu Tarton yliopiston projektiin Patient-/Client-Centredness in Adult Intensive Care. Tämä projekti on osa suurempaa monivuotista hanketta Patient-/client-centredness in adult intensive care, elderly care and health care education. Tämän hankkeen tarkoituksena on kehittää toimintamalleja potilaslähtöisyyden vahvistamiseksi ja tukemiseksi työelämän ja koulutusjärjestelmän yhteistyössä. Opinnäytetyömme tarkoituksena oli tarkastella teho-osastojen hoitohenkilökunnan näkökulmasta potilaslähtöisyyden toteutumista sekä oleellisuutta potilaille ja heidän läheisilleen. Keräsimme kvantitatiivisen tutkimusaineiston yhdeksän HUS-alueen (Helsingin ja Uudenmaan sairaanhoitopiiri) aikuisten teho-osaston hoitohenkilökunnalta ja analysoimme sen. Aineisto kerättiin strukturoidulla kyselylomakkeella, joka pohjautuu tätä projektia varten kehitettyyn mittariin ”Patient-/Client-Centeredness in Adult Intensive Care - Questionnaire for Personnel (P/CCAIC-QPE)”. Kokonaisuudessaan vastaajat arvioivat potilaslähtöisyyden toteutuvan hyvin teho-osastoilla. Vastauksista ilmeni, että hoitajien mielestä potilaat ja heidän läheisensä pitävät potilaslähtöisyyttä kuitenkin vielä oleellisempana asiana tehohoidossa kuin sen käytännössä on katsottu toteutuvan. Tuloksista voidaan siis päätellä, että potilaslähtöisyyden toteuttamisessa tehohoidossa on vielä parannettavaa ja siihen tulisi jatkossa kiinnittää entistä enemmän huomiota.Research of patient-centredness is important because it has been found to affect the quality of health care services, the commitment of the patients to their own treatment and the patient satisfaction. The studies show the patient-centredness not being always fulfilled without problems, especially not in intensive care. Our final project was made as part of the project “Patient-/Client-Centredness in Adult Intensive Care” coordinated by the University of Tartu, Estonia. The purpose of our final project was to study the realisation of patient-centredness and its relevancy to patients and their relatives from the nursing staff´s point of view. We collected and analysed quantitative research material from the nursing staff of nine adult intensive care units of the Hospital District of Helsinki and Uusimaa (HUS), Finland. The material was collected using a structured questionnaire based on an indicator “Patient-/Client-Centredness in Adult Intensive Care – Questionnaire for the Personnel (P/CCAIC-QPE)”, developed for this project. In general, the patient-centredness was evaluated to be well-realised in the Finnish intensive care units. The results showed that, according to the nurses, the patients and their relatives found the patient-centredness to be even a more relevant issue in intensive care than it was realised in practice. This indicates that there is still a need to improve the realisation of the patient-centredness in intensive care in Finland and that, in future, one should pay even more attention to it