BACKGROUND: To assess whether hypoxia, as can be found in obstructive sleep apnea syndrome, is causally associated with the development of heart failure through a direct effect on calcium leakage from the sarcoplasmic reticulum. METHODS: The impact of hypoxia on sarcoplasmic reticulum calcium leakage and expres- sion of RyR2 (ryanodine receptor2) and SERC2a (sarcoplasmic reticulum Ca2+ATPase 2a) was investigated together with the outcomes of JTV-519 and S107 treatment. HL-1 car- diomyocytes were cultured for 7 days on gas-permeable cultureware under control (12% O2) or hypoxic (1% O2) conditions with or without JTV-519 or S107. SRCL was assessed using a Fluo-5N probe. Gene and protein expression was analyzed using qPCR and western blotting. RESULTS: Hypoxic exposure increased sarcoplasmic reticulum calcium leakage by 39% and reduced RyR2 gene expression by 52%. No effect on RyR2 protein expression was observed. Treatment with 1μM JTV-519 reduced sarcoplasmic reticulum calcium leakage by 52% and 35% under control and hypoxic conditions, respectively. Administration of 1 μM JTV-519 increased RyR2 gene expression by 89% in control conditions. No effect on SRCL, RyR2, or SERC2a gene, or protein expression was observed with S107 treatment. CONCLUSION: Hypoxia increased sarcoplasmic reticulum calcium leakage which was ame- liorated by JTV-519 treatment independently of gene or protein expression. JTV-519 rep- resents a possible treatment for obstructive sleep apnea-associated HF.
- MeSH
- lidé MeSH
- maligní hypertermie * terapie MeSH
- mutace MeSH
- ryanodinový receptor vápníkového kanálu genetika MeSH
- vápníkové kanály - typ L MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- dopisy MeSH
- Geografické názvy
- Česká republika MeSH
- Slovenská republika MeSH
Aims: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an ion channelopathy characterized by ventricular arrhythmia during exertion or stress. Mutations in RYR2-coded Ryanodine Receptor-2 (RyR2) and CASQ2-coded Calsequestrin-2 (CASQ2) genes underlie CPVT1 and CPVT2, respectively. However, prognostic markers are scarce. We sought to better characterize the phenotypic and genotypic spectrum of CPVT, and utilize molecular modelling to help account for clinical phenotypes. Methods and results: This is a Pediatric and Congenital Electrophysiology Society multicentre, retrospective cohort study of CPVT patients diagnosed at <19 years of age and their first-degree relatives. Genetic testing was undertaken in 194 of 236 subjects (82%) during 3.5 (1.4-5.3) years of follow-up. The majority (60%) had RyR2-associated CPVT1. Variant locations were predicted based on a 3D structural model of RyR2. Specific residues appear to have key structural importance, supported by an association between cardiac arrest and mutations in the intersubunit interface of the N-terminus, and the S4-S5 linker and helices S5 and S6 of the RyR2 C-terminus. In approximately one quarter of symptomatic patients, cardiac events were precipitated by only normal wakeful activities. Conclusion: This large, multicentre study identifies contemporary challenges related to the diagnosis and prognostication of CPVT patients. Structural modelling of RyR2 can improve our understanding severe CPVT phenotypes. Wakeful rest, rather than exertion, often precipitated life-threatening cardiac events.
- MeSH
- dědičnost MeSH
- dítě MeSH
- fenotyp MeSH
- genetická predispozice k nemoci MeSH
- genetické markery MeSH
- kalsekvestrin genetika MeSH
- komorová tachykardie diagnóza genetika mortalita patofyziologie MeSH
- konformace proteinů MeSH
- lidé MeSH
- mladiství MeSH
- molekulární modely MeSH
- mutace * MeSH
- mutační analýza DNA MeSH
- náhlá srdeční smrt epidemiologie MeSH
- prognóza MeSH
- registrace MeSH
- retrospektivní studie MeSH
- rizikové faktory MeSH
- rodokmen MeSH
- ryanodinový receptor vápníkového kanálu chemie genetika metabolismus MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- pozorovací studie MeSH
Maligní hypertermie (MH) je vzácná, ale velmi obávaná a potencionálně fatální komplikace celkové anestezie. Manifestuje se na základě autozomálně dominantně podmíněné dispozice po kontaktu se spouštěčem. Spouštěči reakce jsou především všechna volatilní anestetika a sukcinylcholin. Její příčinou je porucha regulace kalciového metabolismu ve svalové buňce, způsobené abnormálním ryanodinovým receptorem RYR1. Následkem toho je extrémní svalová kontrakce bez následné relaxace vedoucí k nekontrolovatelné hypermetabolické reakci organismu. Diagnózu MH dispozice je možné potvrdit svalovým in vitro kontrakčním testem, resp. molekulárně genetickým vyšetřením. „Podezřelé“ jedince lze vytipovat pečlivým předoperačním vyšetřením, zejména důkladnou anamnézou. U jedinců s MH dispozicí je nutné vést anestezii odpovídající pravidlům pro anestezii u MH rizikových pacientů. Mortalita této komplikace dnes dosahuje cca 5–10 % (oproti 70–80 % v 70. letech 20. století). Významnému zvýšení přežívání pacientů pomohlo zlepšení perioperačního monitorování, informovanosti zdravotnického personálu a zejména zavedení dantrolenu jako kauzálního léku.
Malignant hyperthermia (MH) is a rare but very dangerous and potentionally fatal complication of general anesthesia. It occurson the basis of an autosomal dominant condition following contact with the trigger. The triggers are volatile anesthetics andsuccinylcholine. The cause of MH is the disorder of calcium metabolism regulation in the muscle cell caused by the abnormalryanodin receptor RYR1. As a result, extreme muscle contraction without relaxation leads to a huge hypermetabolic reaction.Diagnosis of MH disposition can be confirmed by a muscle contraction test in vitro, molecular genetic examination respectively.„Suspicious“ individuals can be identified by careful preoperative examinations and medical history. In patients with MH disposition,if anesthesia is necessary, it is essential to choose special anesthetic procedures without the use of triggers with currentcareful perioperative monitoring with the option of intensive care. Mortality today is about 5–10% (compared to 70–80% in the1970s). Significant increases in patient survival have helped to improve perioperative monitoring, awareness of medical staff and,in particular, the introduction of dantrolene as a causal drug.
- MeSH
- anestetika inhalační * škodlivé účinky MeSH
- celková anestezie * škodlivé účinky MeSH
- dantrolen terapeutické užití MeSH
- dítě MeSH
- kritický stav MeSH
- lidé MeSH
- maligní hypertermie * diagnóza genetika patofyziologie terapie MeSH
- mutace MeSH
- péče o pacienty v kritickém stavu MeSH
- ryanodinový receptor vápníkového kanálu fyziologie genetika MeSH
- sukcinylcholin škodlivé účinky MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
- MeSH
- atorvastatin škodlivé účinky MeSH
- běloši genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- myalgie chemicky indukované genetika MeSH
- pilotní projekty MeSH
- polymorfismus genetický genetika MeSH
- ryanodinový receptor vápníkového kanálu genetika MeSH
- senioři MeSH
- simvastatin škodlivé účinky MeSH
- statiny škodlivé účinky MeSH
- studie případů a kontrol MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- dopisy MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
BACKGROUND: Independent studies have shown that several single nucleotide polymorphisms (SNP) in the human FTO (fat mass and obesity associated) gene are associated with obesity. SNP have also been identified in the pig FTO gene, among which some are associated with selected fat-deposition traits in F2 crosses and commercial populations. In this study, using both commercial pig populations and an experimental Meishan × Pietrain F2 population, we have investigated the association between one FTO SNP and several growth and carcass traits. Association analyses were performed with the FTO polymorphism either alone or in combination with polymorphisms in flanking loci. METHODS: SNP (FM244720:g.400C>G) in exon 3 of porcine FTO was genotyped by PCR-RFLP and tested for associations with some growth, carcass and fat-related traits. Proportions of genetic variance of four pig chromosome 6 genes (FTO, RYR1, LIPE and TGFB1) on selected traits were evaluated using single- and multi-locus models. RESULTS: Linkage analysis placed FTO on the p arm of pig chromosome 6, approximately 22 cM from RYR1. In the commercial populations, allele C of the FTO SNP was significantly associated with back fat depth and allele G with muscling traits. In the Meishan × Pietrain F2 pigs, heterozygotes with allele C from the Pietrain sows and allele G from the Meishan boar were more significantly associated with fat-related traits compared to homozygotes with allele G from the Pietrain and allele G from the Meishan breed. In single- and multi-locus models, genes RYR1, TGFB1 and FTO showed high associations. The contribution in genetic variance from the polymorphism in the FTO gene was highest for back fat depth, meat area on the musculus longissimus lumborum et thoracis tissues and metabolite glucose-6-phosphate dehydrogenase. CONCLUSIONS: Our results show that in pig, FTO influences back fat depth in the commercial populations, while in the Meishan × Pietrain F2 pigs with a CG genotype, heterosis occurs for several fat-related traits.
- MeSH
- dioxygenasy genetika MeSH
- frekvence genu MeSH
- genetické asociační studie MeSH
- genetické lokusy MeSH
- jednonukleotidový polymorfismus MeSH
- mapování chromozomů MeSH
- modely genetické MeSH
- ryanodinový receptor vápníkového kanálu genetika MeSH
- složení těla genetika MeSH
- Sus scrofa anatomie a histologie genetika růst a vývoj MeSH
- transformující růstový faktor beta1 genetika MeSH
- tuková tkáň anatomie a histologie MeSH
- vazebná nerovnováha MeSH
- záda anatomie a histologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Introduction Mutations of RyR2 gene encoding calcium channel of sarcoplazmatic reticulum are the cause of congenital catecholaminergic polymorphic ventricular tachycardia. The aim of this study was to test the hypothesis that RyR2 variants can increase occurrence of malignant arrhythmias in patients with structural heart diseases. Methods The investigated group consisted of 36 patients with structural heart diseases with ICD implanted who suffered arrhythmic storm. In the control group there were 141 patients with coronary artery disease who were hospitalized at our department owing to an acute coronary event and they were alive at least 3 years after the index event. Thus, they could be considered as a group with a low risk of sudden cardiac death. In all of them mutation analysis of RyR2 gene was performed. Results We detected 16 different sequence changes of RyR2 gene in both groups. None of the found nucleotide polymorphisms led to amino acid changes, were located close to splice sites or had any similarity to known splicing enhancer motifs. The occurrence of these variants was not different in both groups. Conclusions The prevalence of RyR2 gene variants was not different in cases versus controls suggesting a limited role of this gene in the arrhythmogenesis in structural heart disease patients.
- MeSH
- defibrilátory implantabilní využití MeSH
- dilatační kardiomyopatie genetika komplikace MeSH
- fibrilace komor etiologie genetika MeSH
- financování organizované MeSH
- flutter komor etiologie genetika MeSH
- funkce levé komory srdeční genetika MeSH
- genetická predispozice k nemoci genetika MeSH
- genetické techniky využití MeSH
- ischemická choroba srdeční genetika komplikace MeSH
- lidé MeSH
- metaanalýza jako téma MeSH
- mutační analýza DNA MeSH
- náhlá srdeční smrt etiologie patologie prevence a kontrola MeSH
- retrospektivní studie MeSH
- rizikové faktory MeSH
- ryanodinový receptor vápníkového kanálu genetika MeSH
- srdeční arytmie etiologie genetika klasifikace MeSH
- statistika jako téma MeSH
- Check Tag
- lidé MeSH
BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare hereditary arrhythmia. The onset of clinical symptoms usually occurs during childhood, and is typically related to exercise. The aim of our study was to describe the clinical characteristics of seven Czech families with CPVT and the results of mutational analysis of the RyR2 gene in these families. METHODS: The subjects and their relatives were investigated at the participating departments. They underwent basic clinical investigation, and history was focused on possible CPVT symptoms, that is, syncopes during exercise. Bicycle ergometry was performed to obtain electrocardiogram recording during adrenergic stimulation. In all the investigated individuals, blood samples were taken for mutation analysis of the RyR2 gene. RESULTS: To date, seven families have been investigated, comprising 11 adults and 13 children. In seven CPVT patients, the indication for examination was syncope during exercise. Diagnosis was confirmed by bicycle ergometry-induced polymorphic ventricular tachycardia. In one relative, polymorphic ventricular tachycardia was also induced. All eight affected individuals were treated with β-blockers and in two, a cardioverter-defibrillator was implanted due to recurrent syncopi. Coding variants of the RyR2 gene were found in four probands. CONCLUSIONS: This is a systematic description of CPVT families in the Czech Republic. Our data support the importance of exercise testing for the diagnosis of CPVT. In addition, RyR2 gene coding variants were found in 50% of affected individuals.
- MeSH
- dítě MeSH
- dospělí MeSH
- genetická predispozice k nemoci genetika MeSH
- heterozygot MeSH
- jednonukleotidový polymorfismus genetika MeSH
- komorová tachykardie diagnóza genetika MeSH
- lidé MeSH
- mladý dospělý MeSH
- mutace genetika MeSH
- rodokmen MeSH
- ryanodinový receptor vápníkového kanálu genetika MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
Abnormal release of Ca(2+) from sarcoplasmic reticulum (SR) via the cardiac ryanodine receptor (RyR2) may contribute to contractile dysfunction in heart failure (HF). We previously demonstrated that RyR2 macromolecular complexes from HF rat were significantly more depleted of FK506 binding protein (FKBP12.6). Here we assessed expression of key Ca(2+) handling proteins and measured SR Ca(2+) content in control and HF rat myocytes. Direct measurements of SR Ca(2+) content in permeabilized cardiac myocytes demonstrated that SR luminal [Ca(2+)] is markedly lowered in HF (HF: DeltaF/F(0) = 26.4+/-1.8, n=12; control: DeltaF/F(0) = 49.2+/-2.9, n=10; P<0.01). Furthermore, we demonstrated that the expression of RyR2 associated proteins (including calmodulin, sorcin, calsequestrin, protein phosphatase 1, protein phosphatase 2A), Ca(2+) ATPase (SERCA2a), PLB phosphorylation at Ser16 (PLB-S16), PLB phosphorylation at Thr17 (PLB-T17), L-type Ca(2+) channel (Cav1.2) and Na(+)- Ca(2+) exchanger (NCX) were significantly reduced in rat HF. Our results suggest that systolic SR reduced Ca(2+) release and diastolic SR Ca(2+) leak (due to defective protein-protein interaction between RyR2 and its associated proteins) along with reduced SR Ca(2+) uptake (due to down-regulation of SERCA2a, PLB-S16 and PLB-T17), abnormal Ca(2+) extrusion (due to down-regulation of NCX) and defective Ca(2+) -induced Ca(2+) release (due to down-regulation of Cav1.2) could contribute to HF.
- MeSH
- financování organizované MeSH
- kalmodulin genetika metabolismus MeSH
- kardiomyocyty metabolismus MeSH
- krysa rodu rattus MeSH
- potkani Sprague-Dawley MeSH
- proteiny vázající takrolimus genetika metabolismus MeSH
- proteiny vázající vápník genetika metabolismus MeSH
- ryanodinový receptor vápníkového kanálu genetika metabolismus MeSH
- sarkoplazmatická Ca2+-ATPáza genetika metabolismus MeSH
- sarkoplazmatické retikulum metabolismus MeSH
- srdeční selhání genetika patofyziologie MeSH
- vápník metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
Cíl: Katecholaminergní polymorfní komorová tachykardie (CPVT) je vzácná dědičná arytmie, která se manifestuje nejčastěji už v dětském věku, typicky při zátěži. Cílem naší práce je klinický popis tří českých rodin s výskytem CPVT a pilotní výsledky mutační analýzy genu RyR2. Metodika: Na zúčastněných pracovištích jsou vyšetřováni probandi a jejich nejbližší příbuzní. Absolvují základní klinické vyšetření, anamnéza je cílena na možné projevy CPVT – synkopy při zátěži. Dále podstupují bicyklovou ergometrii za účelem získání EKG křivek při adrenergní stimulaci. U všech vyšetřených jedinců je proveden odběr krve na izolaci DNA. U probandů byla zahájena analýza genu RyR2. Výsledky: Celkem byly vyšetřeny tři rodiny – jedenáct dospělých, pět dětí, ve kterých se v každé u jednoho z dětí vyskytla synkopa. Indikací k vyšetření byla ve všech třech případech synkopa při zátěži. Diagnóza byla stanovena pomocí ergometrie provokací polymorfní komorové tachykardie. U dalších příbuzných arytmie nebyla vyvolána. Všichni tři postižení byli léčeni beta-blokátorem, u jednoho z nich musel být pro recidivy synkop implantován kardioverter-defi brilátor. U jednoho z probandů byla detekována sekvenční změna c.14101-6A>G a 14101-21A>G blízko 3´-konce intronu 94-95 a 14231+12A>C blízko 5´-konce intronu 95-96. Detekované sekvenční změny nejsou zařazeny do databáze mutací CPVT a dosud nebyly publikovány. Závěry: CPVT je vzácné onemocnění s velmi vysokým rizikem náhlé smrti. Na tuto diagnózu je třeba vždy myslet v případě synkop při zátěži. Klidový elektrokardiogram je zcela normální, k potvrzení diagnózy je nutný zátěžový test. Mutační analýza souvisejících genů umožní identifi kovat asymptomatické jedince, u nichž je pak indikována léčba beta-blokátorem.
Aim: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare hereditary arrhythmia. The onset of clinical symptoms usually occurs during childhood, and is typically related to stress. The aim of our study is to provide clinical characteristics of three Czech families with CPVT and pilot results of mutation analysis of the RyR2 gene. Methods: The subjects and their relatives are investigated at the participating departments. They undergo basic clinical investigation, with their history-taking focused on possible CPVT symptoms, i.e. syncopes during stress. Bicycle ergometry is performed to obtain ECG recordings during adrenergic stimulation. In all the investigated individuals, blood samples are taken for DNA isolation, with mutation analysis of the RyR2 gene started in subjects. Results: To date, three families (11 adults and fi ve children) have been investigated. In three CPVT patients, the indication for examination was syncope during stress. The diagnosis was confi rmed with bicycle ergometry-induced polymorphic ventricular tachycardia. The arrhythmia was not induced in any other relatives. All three aff ected individuals were treated with a beta-blocker, with one having a cardioverter-defi brillator implanted because of recurrent syncopes. Sequence changes c.14101-6A>G and 14101-21A>G close to 3´-end of intron 94-95, and in 14231+12A>C close to 5´-end of intron 95-96 were detected in one subject. The detected sequence changes have not been included in the CPVT mutation database and published yet. Conclusions: CPVT is a rare disease with a high risk of sudden death. This diagnosis must be considered in all cases of exercise-related syncope. A resting electrocardiogram is completely unremarkable. For the confi rmation of the diagnosis an exercise test is necessary. Mutation analysis of related genes may reveal asymptomatic individuals in whom beta-blocker therapy is recommended.
- MeSH
- blokátory kalciových kanálů terapeutické užití MeSH
- defibrilátory implantabilní využití MeSH
- dítě MeSH
- dospělí MeSH
- elektrokardiografie využití MeSH
- financování organizované MeSH
- komorová tachykardie diagnóza genetika MeSH
- lidé MeSH
- mutace genetika MeSH
- ryanodinový receptor vápníkového kanálu genetika MeSH
- synkopa diagnóza etiologie MeSH
- zátěžový test přístrojové vybavení využití MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
