Effects of Epinephrine and Phenylephrine on QT Interval Dispersion in Congenital Long QT Syndrome 11This study was supported by a grant from the Finnish Cardiac Research Foundation, Helsinki.

AbstractObjectives. Measurement of QT interval dispersion during pharmacologic adrenergic stimulation was used to assess the effect of alpha- and beta-adrenergic stimulation on arrhythmic vulnerability in familial long QT syndrome (LQTS).Background. Nonhomogeneity in the ventricular action potential duration causes electrical instability leading to life-threatening ventricular arrhythmias and is markedly increased in LQTS. QT interval dispersion measured from the electrocardiogram (ECG) can be used as an index of nonhomogeneous ventricular repolarization.Methods. Sixteen symptomatic patients with LQTS and nine healthy control subjects were examined at baseline and during epinephrine (mainly beta-adrenergic agonist, 0.05 μg/kg body weight per min) and phenylephrine infusions (alpha-adrenergic agonist, mean 1.4 μg/kg per min). QT interval dispersion was determined from a 12-lead ECG as interlead range and coefficient of variation measured to the end (QTend) and apex (QTapex) of the T wave.Results. At baseline QTenddispersion was greater in patients with LQTS compared with control subjects (mean [±SD] 68 ± 34 vs. 36 ± 7 ms, p = 0.001). QTenddispersion was markedly increased in patients with LQTS by use of epinephrine (from 68 ± 34 to 90 ± 36 ms, p = 0.002), but remained unchanged in control subjects. Phenylephrine did not affect QT dispersion in either group (all p = NS). Atrial pacing to achieve comparable heart rates during baseline and epinephrine and phenylephrine infusions did not influence the magnitude of QT dispersion in either group. QTapexdispersion analysis gave congruent results.Conclusions. Epinephrine but not phenylephrine increased QT dispersion, suggesting that beta-adrenergic stimulation provokes arrhythmias in patients with LQTS by aggravating nonhomogeneity of ventricular repolarization, whereas alpha-adrenergic stimulation is less important for arrhythmic vulnerability. The results also suggest that rapid pacing may not reduce vulnerability to arrhythmias in congenital LQTS

Effects of beta-blockers on ventricular repolarization documented by 24-hour electrocardiography in long QT syndrome type 2

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

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Katekoliamiiniherkkä monimuotoinen kammiotakykardia (CPVT) - harvinainen mutta vaarallinen sydänsairaus

Vertaisarvioitu.Katekoliamiiniherkkä monimuotoinen kammiotakykardia (CPVT) on harvinainen mutta vakava perinnöllinen rytmihäiriösairaus, johon liittyy hoitamattomana merkittävä äkkikuoleman riski. Sairauden tunnusomainen piirre on rasituksen aikana ilmaantuva monimuotoinen kammiolisälyöntisyys, vaikka potilaiden lepo-EKG on normaali eikä sydämessä todeta rakenteellisia poikkeavuuksia. Kliininen rasituskoe on keskeinen tutkimus CPVT:n diagnosoinnissa. Syy rytmihäiriöalttiudelle johtuu sydänlihassolujen kalsiumviestintään vaikuttavista mutaatioista, ja geenivirhe pystytään toteamaan noin kahdessa tapauksessa kolmesta. Lähisukulaisten tutkiminen on tärkeää, jotta kaikki sydäntapahtumille alttiit henkilöt saadaan ehkäisevien toimien sekä hoidon piiriin. CPVT-potilaiden tulee välttää raskasta urheilua ja tilanteita, joissa he voivat altistua voimakkaille yllättäville stressitekijöille. Potilaille aloitetaan beetasalpaajahoito, ja valikoiduissa tapauksissa käytetään flekainidia. Pienelle osalle potilaista on aiheen asentaa defibrilloiva rytmihäiriötahdistin.Peer reviewe

The role of KCNQ1 mutations and maternal beta blocker use during pregnancy in the growth of children with long QT syndrome

Synnynnäinen ionikanavasairaus pitkä QT -oireyhtymä (long QT syndrome, LQTS) on perinnöllinen hengen-vaarallisia rytmihäiriöitä aiheuttava sairaus. LQTS johtuu sydänlihassolujen ionikanavien rakenteita koodaa-vien geenien mutaatioista. Yleisimmät mutaatiot ovat KCNQ1-geenissä, ja ne aiheuttavat sairauden alamuo-don LQT1. KCNQ1 sijaitsee kromosomin 11p15.5 leimautuneella alueella, ja se koodittaa jänniteriippuvaista kaliumkanavaa, Kv7.1:a. Kaksi KCNQ1:n aktivoivaa mutaatiota aiheuttavat autosomaalisesti dominantisti periytyvän kasvuhormonin vajauksen ja äidiltä perittynä ienfibromatoosin. Tutkimuksen tarkoituksena oli analysoida LQTS -potilaiden, joilla on toiminnan hävittävä mutaatio (loss-of-function mutaatio) KCNQ1-geenissä, kasvua ja endokriinisia ominaisuuksia. Keskityimme erityisesti varhaisen kasvun ja parent-of-origin -mutaation suhteeseen. Tutkimuksessa analysoitiin LQT1-potilaiden (n=104) syntymäpituutta ja -painoa, syntymän jälkeistä kasvua ensimmäisen vuoden osalta sekä potilaiden endokriinisia ominaisuuksia. Tutkimuksessa havaittiin, että poti-laat, jotka olivat perineet KCNQ1-mutaation äidiltään, olivat syntymässä lyhyempiä kuin potilaat, jotka olivat perineet mutaation isältään. Jatkoanalyysit osoittivat, että vain potilaat, joiden äidit olivat saaneet beetasal-paajaa raskaana ollessaan, olivat lyhyempiä ja kevyempiä kuin ne potilaat, jotka olivat perineet mutaation isältään. Äidin beetasalpaajan käyttö raskauden aikana oli myös yhteydessä matalampiin napa-TSH-pitoisuuksiin sekä merkittävään saavutuskasvuun ensimmäisen elinvuoden aikana. Myöhemmin eroa ei ha-vaittu. Tutkimuksemme mukaan KCNQ1:n loss-of-function -mutaatiot eivät ole yhteydessä epänormaaliin kasvuun. Sen sijaan analyysiemme mukaan äidin raskauden aikainen beetasalpaajan käyttö näyttää rajoittavan ras-kaudenaikaista LQT1-potilaiden kasvua, mitä seuraa nopea saavutuskasvu ensimmäisen elinvuoden aikaan

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

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

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.Peer reviewe

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

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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