Long QT syndrome (LQTS) is an inherited arrhythmic disorder associated with sudden cardiac death (SCD). This study aimed to identify the clinical and molecular genetic risk factors that contribute to major arrhythmic events (MAEs) in patients with genetically confirmed childhood onset LQTS 1–3. This study was a retrospective double-center study. An MAE was defined as the occurrence of SCD, aborted SCD, appropriate implantable cardioverter defibrillator discharge, or sustained ventricular tachycardia. During a median follow-up of 4.6 years (range 0.1–24.3 years), MAEs occurred in 18 (17.8%) of 101 patients diagnosed with LQTS at a median of 7.7 years (range 0.0–18.0 years) despite the use of beta-blockers in 91.6% of patients at the last follow-up. A multivariate analysis identified a genetic diagnosis of LQTS2 and LQTS3 and variants within the KCNH2 S5-loop-S6 pore region as independent risk factors for MAEs, independent of the QTc value or a history of syncope detected from a univariate analysis. MAEs occur frequently in childhood onset LQTS despite beta-blocker treatment. A detailed molecular genetic diagnosis can contribute to the arrhythmia risk stratification and optimize the use of preventive measures in this vulnerable patient population

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Gain of function of cardiac voltage-gated sodium channel (Nav1.5) leads to Long QT Syndrome Type 3 (LQT3). LQT3 phenotype can be exacerbated by expanding the perinexus, which is an intercellular nanodomain with high density of Nav1.5 in the intercalated disc. Following this finding, we found that elevating extracellular sodium and widening the perinexus synergistically exacerbated LQT3 phenotype, Importantly, we also found that perinexal expansion increases the susceptibility to cardiac arrest in aged LQT3, which demonstrated that perinexal expansion is an arrhythmogenic risk especially in aged LQT3 patients. Furthermore, we observed that the perinexus narrows with aging and conceals LQT3 phenotype, which suggests that perinexal narrowing may have a cardio-protective role during aging in LQT3. Surprisingly, following the finding of the synergistic effect of extracellular sodium elevation and perinexal widening on LQT3 phenotype in drug-induced LQT3 guinea pig hearts, we found that this synergistic effect was not observed in genetically-modified LQT3 mouse hearts, which is due to high sodium also increasing transient outward potassium current (Ito). In summary, the whole project investigated the role of the perinexus in LQT3 from different conditions including sodium, aging and species. The findings in this project discovered the importance of perinexal expansion in LQT3 and also the involvement of Ito in sodium regulating LQT3 phenotype in hearts which functionally express Ito channels. Therefore, a LQT3 animal model which has similar electrophysiology close to human may be a great option for translational purpose. / Doctor of Philosophy / Long QT Syndrome Type 3 (LQT3) is an inherited heart disease with the phenotype of long QT interval in ECG. It has been found that LQT3 phenotype gets worse when a very tiny space in the heart, termed as the perinexus, is wide due to cardiac edema. Following this finding, we also found that increasing sodium concentration together with wide perinexus can further exacerbate LQT3 phenotype in guinea pig hearts. Furthermore, we found that widening the perinexus in aged LQT3 hearts causes cardiac death but not in adult, which suggests that perinexal widening worsens LQT3 phenotype and even leads to cardiac death in aged hearts. Besides, we found that the perinexus narrows with aging and there is no difference in LQT3 phenotype between adult and aged hearts, which suggests that the narrow perinexus during aging may protect the hearts from cardiac death in LQT3. Surprisingly, we discovered that increasing sodium and widening the perinexus together fails to exacerbate LQT3 phenotype when compared with widening the perinexus alone in LQT3 mouse hearts, which is due to high sodium increasing transient outward potassium current (Ito). Notably, Ito channels are not functionally expressed in guinea pig hearts. In summary, the whole project investigated the role of the perinexus in LQT3 from different conditions including sodium, aging and species. The findings in this project discovered the importance of perinexal expansion in LQT3 and also the involvement of Ito in sodium regulating LQT3 phenotype in hearts. Therefore, a LQT3 animal model which has similar electrophysiology close to human may be a great option for translational purpose.

Thesis (PhD)-- Stellenbosch University, 2014. / ENGLISH ABSTRACT: Ventricular arrhythmias are the most important cause of sudden cardiac death (SCD) among adults living in industrialised nations. Genetic factors have substantial effects in determining population-based risk for SCD and may also account for inter-individual variability in susceptibility. Great progress has been made in identifying genes underlying various Mendelian disorders associated with inherited arrhythmia susceptibility. The most well studied familial arrhythmia syndrome is the congenital long QT syndrome (LQTS) caused by mutations in genes encoding subunits of myocardial ion channels. Not all mutation carriers have equal risk for experiencing the clinical manifestations of disease (i.e. syncope, sudden death). This observation has raised the possibility that additional genetic factors may modify the risk of LQTS manifestations. This study establishes the genetic aetiology of LQTS in South Africa and Denmark through the identification and characterisation of LQTS-causative mutations in five previously identified genes, as well as examining possible novel genetic causes of LQTS in a cohort comprising Danish and British probands. We have functionally characterised several of the mutations identified in this study and examined other cardiac phenotypes that may be explained by variants causing repolarisation disorders. / AFRIKAANSE OPSOMMING: Ventrikulêre aritmie bly die enkele belangrikste oorsaak van skielike hart dood (SCD) onder volwassenes wat in geïndustrialiseerde lande woon. Genetiese faktore het aansienlike gevolge in die bepaling van bevolking-gebaseerde risiko vir SCD en kan ook verantwoordelik wees vir die inter-individuele variasie in vatbaarheid. Groot vordering is gemaak in die identifisering van gene onderliggende verskeie Mendeliese siektes wat verband hou met geërf aritmie vatbaarheid. Die mees goed bestudeerde familie aritmie sindroom is die aangebore lang QT-sindroom (LQTS) wat veroorsaak word deur mutasies in gene kode subeenhede van miokardiale ioonkanale. Nie alle mutasie draers het 'n gelyke risiko vir die ervaring van die kliniese manifestasies van die siekte (dws sinkopee, skielike dood). Hierdie waarneming het die moontlikheid genoem dat genetiese faktore anders as die primêre siekte-verwante mutasie kan die risiko van LQTS manifestasies verander. Hierdie studie stel die genetiese oorsake van LQTS in Suid-Afrika en Denemarke deur die identifisering en karakterisering van LQTS-veroorsakende mutasies in vyf voorheen geïdentifiseer gene, asook die behandeling van moontlike nuwe genetiese oorsake van LQTS in 'n groep wat bestaan uit van die Deense en die Britse probands. Ons het funksioneel gekenmerk verskeie van die mutasies wat in hierdie studie ondersoek en ander kardiovaskulêre fenotipes wat deur variante veroorsaak repolarisasie versteurings verduidelik word. / South African National Research Foundation / Harry and Doris Crossley Foundation / Danish Strategic Research Foundation.

Thesis (MScMedSc (Biomedical Sciences. Molecular Biology and Human Genetics))--University of Stellenbosch, 2009. / The human ether-à-go-go-related gene (HERG) encodes the protein underlying the cardiac potassium current IKr. Mutations in HERG may produce defective channels and cause Long QT Syndrome (LQTS), a cardiac disease affecting 1 in 2500 people. The disease is characterised by a prolonged QT interval on a surface electrocardiogram and has a symptomatic variability of sudden cardiac death in childhood to asymptomatic longevity. We hypothesised that genetic variation in the proteins that interact with HERG might modify the clinical expression of LQTS. Yeast two-hybrid methodology was used to screen a human cardiac cDNA library in order to identify putative HERG N-terminus ligands. Successive selection stages reduced the number of putative HERG ligandcontaining colonies (preys) from 268 to 8. Putative prey ligands were sequenced and identified by BLAST-search. False positive ligands were excluded based on their function and subcellular location. Three strong candidate ligands were identified: Rhoassociated coiled-coil containing kinase 1 (ROCK1), γ-sarcoglycan (SGCG) and microtubule-associated protein 1A (MAP1A). In vitro co-immunoprecipitation (Co-IP) and mammalian two-hybrid (M2H) analyses were used to validate these proposed interactions, but failed to do so. This should be further investigated. Analysis of confirmed interactions will shed light on their functional role and might contribute to understanding the symptomatic variability seen in LQTS.

Le syndrome du QT long congénital (LQTS) est une canalopathie génétique, à l’origine de syncopes et mort subite. Le dépistage génétique identifie des variantes génétiques dans 50-70% des cas, suggérant l’implication d’autres gènes. Nous avons recueilli les caractéristiques des patients avec un LQTS à l’ICM, et recruté 12 patients avec un génotype négatif pour le LQTS pour un séquençage à haut débit des exons afin d’identifier de nouvelles variantes causales. Nous avons développé une approche analytique par étapes : (1) les gènes connus du, (2) les gènes dans des loci identifiés par des études d’association sur le QT, et (3) les gènes montrant la même variante chez plusieurs patients. L’analyse génétique a identifié de nouvelles variantes dans: (1) KCNJ2, ANK2 et AKAP9, et (2) dans NOS1AP. (3) Deux patientes avec des phénotypes semblables présentent la même variante homozygote dans TECRL, un nouveau gène candidat dont le rôle est inconnu. / Long QT syndrome (LQTS) is a channelopathy, causing syncope and sudden death. Genetic testing of individuals identifies genetic variants in up to 50-70% of cases, suggesting that additional genes may be involved. We have identified 50 patients with a diagnosis of LQTS at MHI, and recruited 12 patients reported negative for clinical testing of mutations in LQTS for a whole-exome next generation DNA sequencing approach in order to identify new variants and candidate genes. We have developed a stepwise analytic approach that focuses on (1) the known LQTS genes, (2) the genes in loci identified in genome-wide association studies of QT-interval, and (3) the loci showing variants across multiple patients. Our approach identified new variants in (1) KCNJ2, ANK2 and AKAP9, and (2) in NOS1AP. We identify 2 patients with a very similar phenotype with a homozygous variant in TECRL, an novel candidate gene with an unknown role in LQTS.

At present, doctors are not consistent in the way they set the QTc interval in the recovery phase. The main goal of this study was to screen healthy subjects in the two different exercise stress tests and to compare the obtained data from both tests. We wanted to explore whether the heart rate and the QTc interval differs from each other when performed in two different body positions during the recovery phase. The main purpose was to present evidence that would prove or disprove a hypothesis that the figures differ in the different body positions. In the theoretical part we submitted the main information about the heart rate, the QT interval and the relationship between them. We compared the behaviour of the obtained data during the exercise and during the recovery phase. We described the causes of the QTc prolongation and how it is related to the cardiac arrhythmias. In the practical part we examined 20 healthy subjects. Each of them underwent two exercise stress tests on the bicycle ergometer, up to the subjective maximum level of the exercise intensity. The subjects then recovered in two different positions. The first one was a supine position. The second rest position was on the bicycle ergometer set to very low intensity. We found out that the 4-minute recovery phase, the most important for...

Background: Long QT syndrome (LQTS) is a cardiac condition which predisposes individuals to syncope, seizures, and sudden cardiac death. There is a high prevalence of congenital LQTS in a First Nations community in Northern British Columbia due to the founder variant p.V205M in the KCNQ1 gene. Additionally, two other variants of interest are present in this population: the KCNQ1 p.L353L variant, previously noted to modify the phenotype of LQTS in adults, and the CPT1A p.P479L variant, a metabolic variant common in Northern Indigenous populations associated with hypoglycemia and sudden unexpected infant death. Methods: We performed a mixed methods study to better understand the impact of LQTS in children and youth in this First Nations community. To learn about the clinical impact of LQTS, and better understand the effects of the KCNQ1 and CPT1A variants in children, we used statistical analysis to compare the cardiac phenotypes of 211 First Nations children with and without the p.V205M, p.L353L and p.P479L variants, alone and in combination. Ordinary Least Squares linear regression was used to compare the highest peak corrected QT interval (QTc). The peak QTc is an electrocardiogram measurement used in risk stratification of LQTS patients. Logistic regression was used to compare the rates of syncope and seizures experienced in childhood. Additionally, to learn about the lived-experience of LQTS, we interviewed one young First Nations adult about her experiences growing up with LQTS as a teenager. From this interview, we conducted a qualitative case study analysis using Interpretative Phenomenological Analysis. All research was done in partnership with the First Nations community using community-based participatory methods. Results: We found that the p.V205M variant conferred a 22.4ms increase in peak QTc (p<0.001). No other variants or variant interaction effects were observed to have a significant impact on peak QTc. No association between the p.V205M variant and loss of consciousness (LOC) events (syncope and seizures) was observed (OR(95%CI)=1.3(0.6-2.8); p=0.531). However, children homozygous for p.P479L were found to experience 3.3 times more LOC events compared to non-carriers (OR=3.3(1.3-8.3); p=0.011). With regard to the qualitative portion of the thesis, four superordinate (main) themes emerged from the case study: Daily life with Long QT Syndrome, Interactions with Medical Professionals, Finding Reassurance, and The In-Between Age. We found that even though our participant was asymptomatic and felt that she was not impacted by LQTS in her daily life, she considered certain elements of the condition to be stressful, such as taking a daily beta-blocker. Conclusion: These results suggest that while the KCNQ1 p.V205M variant is observed to significantly prolong the peak QTc, the CPT1A p.P479L variant is more strongly associated with LOC events in children from this community. More research is needed to further determine the effect of these variants; however, our preliminary findings suggest management strategies, such as whether beta-blockers are indicated for p.V205M carriers, may need to be reassessed. The importance of developing a holistic, well-balanced approach to medical care, taking into consideration the personal perspectives and unique medical circumstances of each child is exemplified in this study. / Graduate