Primary Arrhythmia Syndromes Research Articles

Characteristics and outcomes of patients with cardiac conditions requiring emergency medical retrieval from the Great Barrier Reef, Australia.

There is limited published data on the burden of cardiac disease among patients requiring emergency medical evacuation from the Great Barrier Reef, a popular tourist destination in Far North Queensland, Australia. The aim of this study was to examine the characteristics and outcomes of patients with cardiac conditions who were retrieved from the northern Great Barrier Reef to Cairns Hospital. This observational study was a planned substudy of a broader analysis of medical retrievals from the Cairns/Cooktown section of the Great Barrier Reef. It included all patients retrieved to Cairns Hospital between July 2016 and January 2020 who were assigned a cardiac diagnosis during their hospital stay. Data were collected about electrocardiograph, cardiac troponin blood test and invasive coronary angiography results as well as final hospital diagnosis. During the study period, 120 patients were retrieved from the Great Barrier Reef to Cairns Hospital, of which 46 (38%) were subsequently diagnosed with a primary cardiac condition(s) or other disease process with clinically significant cardiac involvement. The most common diagnoses were type 2 myocardial infarction (20; 16.7% of all retrievals), primary cardiac arrhythmia (14; 12.5%) and acute coronary syndrome (5; 4.2%). An elevated troponin was recorded in 30% of all retrievals and in 78% of those with a cardiac diagnosis. A total of 14 (30.4%) of patients with a cardiac diagnosis died during their hospital admission. Invasive coronary angiography was performed in 18 cases, of which six patients had obstructive coronary artery disease. Four patients required percutaneous coronary intervention. A high proportion of patients retrieved to Cairns Hospital from the Great Barrier Reef were diagnosed with a primary cardiac condition. This data may assist tourism operators, retrieval organisations and health services to plan for, and respond to, cardiac events among visitors to the reef.

Brugada syndrome, early repolarization syndrome/j-wave syndromes, and a subtype of idiopathic ventricular fibrillation: microstructural cardiomyopathies

Brugada Syndrome is an inherited cardiac channelopathy with a high incidence of ventricular fibrillation and sudden cardiac death in patients with structurally normal hearts. Diagnosis is based on a characteristic electrocardiographic pattern (coved type ST-segment elevation ≥2 mm followed by a negative T-wave in ≥1 in the right precordial leads V1-V2) combined with an absence of gross structural abnormalities and several other criteria. The cornerstone of BrS diagnosis and definition, is its characteristic ECG pattern that can be present spontaneously or unmasked by drugs. This entity was described by the Brugada brothers in 1992 and belongs to a group of diseases known as inherited primary arrhythmia syndromes. The prevalence varies among regions and ethnicities, affecting mostly males. Despite several genes identified, SCN5A seems to be the most affected gene related BrS (≈ 30% of patients). The current main therapy is an implantable cardioverter-defibrillator, but radiofrequency catheter ablation has been recently reported as an effective new treatment.

The Australian Genetic Heart Disease Registry: Insights into healthcare utilisation and outcomes for genetic heart disease

Abstract Background Genetic heart diseases, such as inherited cardiomyopathies and primary arrhythmia syndromes, cause significant morbidity and mortality, including sudden cardiac death at a young age. However, it is not well understood how these patients use health care services. Linking disease registry data to routinely collected health data can provide a more complete and unbiased clinical dataset. Purpose To investigate the health service use of individuals with genetic heart disease by linking a well-characterised cohort of patients from the Australian Genetic Heart Disease Registry (AGHDR) with routinely collected statewide health datasets. Descriptive analysis was used to compare participants by their genetic heart disease diagnosis. Methods Demographic, clinical, and genetic data for AGHDR participants recruited in New South Wales, between 2007-2019 were linked to statewide hospitalisations (available 2001-2019), emergency department (ED) presentations (2005-2019) and mortality registry (2007-2019) by the Centre for Health Record Linkage (CHeReL). Descriptive statistics were used to compare participants by their genetic heart disease diagnosis. Results A total of 1311 AGHDR participants were included, with the following diagnoses: hypertrophic cardiomyopathy (n=898), dilated cardiomyopathy (n=89), arrhythmogenic cardiomyopathy (n=46), left ventricular non-compaction (n=62), long QT syndrome (n=110), Brugada syndrome (n=65), and catecholaminergic polymorphic ventricular tachycardia (n=41). Mean age at diagnosis was 42 years (±18), and 585 (58%) were male. Participants had 8483 hospital admissions, with a median of 16 admissions per participant accounting for intra-hospital transfers (range 1-98). Mean age at first admission was 42 years (±17) (See Table 1 for breakdown by clinical diagnosis). Approximately one-third of hospital admissions were for circulatory system issues, with the remaining for other systems such as the digestive system (12%), musculoskeletal system and connective tissues (8%) and respiratory (5%). There was a total of 5213 ED presentations, with 32% of the cohort presenting >7 times (See Table 2 for breakdown by clinical diagnosis). Episodes were generally of suspected cardiac origin, with top diagnoses including chest pain (n=341, 43%), atrial fibrillation (n=190, 24%), palpitations (n=96, 12%), abdominal pain (n=74, 9%) and syncope (n=64, 8%). There were 49 deaths identified from the mortality registry, of which three occurred <50 years of age, 16 at 50-69 years and 30 at >70 years. Participants with a diagnosis of hypertrophic cardiomyopathy accounted for the majority of deaths (n=45 (92%)). Conclusion We provide important insights into real-world health service utilisation for individuals with genetic heart disease in Australia. Understanding the reasons for hospital admissions or ED presentations may help to identify potential disparities and opportunities for greater surveillance.

Future direction of substrate-based catheter ablation in Brugada syndrome and other inherited primary arrhythmia syndromes: Systematic review and meta-analysis.

Inherited Primary Arrhythmias Syndromes (IPAS), especially Brugada syndrome (BrS), have been associated with arrhythmogenic substrates that can be targeted through ablation. This meta-analysis evaluated the outcomes of catheter ablation (CA) in different types of IPAS based on procedural guidance and location. A systematic search was conducted across multiple databases to identify studies reporting on ventricular arrhythmia (VA) events before and after CA in IPAS, including BrS, Long-QT syndrome (LQTS), Early repolarization syndrome (ERS), and Idiopathic ventricular fibrillation (IVF). The primary outcomes were VA recurrence and VA burden, evaluated through conditional subgroup analysis. Procedural data were collected as secondary outcomes. A total of 21 studies involving 584 IPAS patients who underwent CA were included. Following a mean follow-up duration of 33.5 months, substrate-based ablation demonstrated efficacy in reducing VA recurrence across all types of IPAS [RR 0.23; 95% CI (0.13-0.39); p < .001; I 2 = 74%]. However, activation guidance ablation was found to be effective only in IVF cases. Although recurrences still occurred, CA was successful in reducing VA burden [MD -4.70; 95% CI (-6.11-(-3.29); p < .001; I 2 = 74%]. The mean size of arrhythmogenic substrate was 15.70 cm2 [95% CI (12.34-19.99 cm2)], predominantly distributed in the epicardial right ventricular outflow tract (RVOT) in BrS cases and LQTS [Proportion 0.99; 95% CI (0.96-1.00) and Proportion 0.82; 95% CI ( 0.59-1.00), respectively]. Substrate-based CA has demonstrated effective prevention of VA and reduction in VA burden in IPAS cases.

Sudden cardiac death in the young: A qualitative study of experiences of family members with cardiogenetic evaluation.

Sudden cardiac death (SCD) is a devastating event for the family and the community, especially when it occurs in a young person (<45 years). Genetic heart diseases, including cardiomyopathies and primary arrhythmia syndromes, are an important cause of SCD in the young. Although cardiogenetic evaluation, that is, clinical evaluation, genetic testing, and psychological support, is increasingly performed after SCD, it is unknown how suddenly bereaved family members experience the process. We aimed to explore the experiences of family members with cardiogenetic evaluation after SCD, and their perception of the process and care received. In-depth interviews were conducted with 18 family members of young people (<45 years old) who died suddenly, including parents, siblings, and partners. The interviews were thematically analyzed by two researchers independently. In total, 18 interviews were conducted from 17 families. The following themes were identified: (1) Experiences with postmortem genetic testing including managing expectations and psychological impact, (2) appreciation of care such as access to genetic counseling and relief following cardiac evaluation of relatives, and (3) need for support including unmet psychological support needs and better coordination of care immediately after the death. Although participants appreciated the opportunity for cardiogenetic evaluation, they also experienced a lack of coordination of cardiogenetic and psychological care. Our findings stress the importance of access to expert multidisciplinary teams, including psychological care, to adequately support these families after a SCD in a young family member.

Clinical and genetic characteristics and course of congenital long QT syndrome: A ten-year single center experience

Abstract Funding Acknowledgements Type of funding sources: None. Background Long QT syndrome (LQTS) is an inherited primary arrhythmia syndrome associated with life-threatening ventricular arrhythmia. Objective To report the clinical and genetic characteristics and outcome of LQTS patients in single center inherited arrhythmia clinic. Methods Retrospective review of patients diagnosed LQTS and evaluated by ECG, 12 lead holter, exercise test and genetic testing in inherited arrhythmia clinic from January 212 to January 2022. Results 101 patients (32 families) were included, mean age 24.3± 17 years. Thirteen patients (12.8%) were diagnosed after previous cardiac arrest and six patients (6%) had syncope. Seventy (69.3%) were identified as having LQTS during family screening. 97 patients (97%) were confirmed to have a pathogenic mutation for LQTS genes. Beta blockers were recommended to 74 patients (73%), flecainide to 20 (19.8%). Nine patients (8.9%) received an ICD for secondary prevention and one patient (1%) for primary prevention. During 5.8 ± 2.7 years, dose of beta-blockers increased from propranolol 70 ±42 mg to 105 ±60.3 mg (p= 0.0004), QTC shortening (479 ± 36.9 to 466 ±30.1 msec, p=0.01) in ECG and maximal QTC measured in 12 lead holter (521± 43.9 to 505± 37.8 msec, p=0.01). Maximal heart rates measured in 12 lead holter and exercise test were reduced ( 130± 24.5 to 116 ± 20.2 beats/min p=0.0001 and 152.6±22 to 145± 20.58 beats/min, p=0.043). Seven patients (6.9%) experienced ventricular arrhythmia, five received appropriate ICD shock and two patients that declined beta blockers experienced syncope due to polymorphic ventricular tachycardia and cardiac arrest. The one patient that had the ICD for primary prevention, experienced polymorphic ventricular tachycardia that was successfully treated by the ICD. Conclusions Intensive clinical follow up and an optimal medical therapy in a specialized arrhythmia clinic is associated with a relatively low incidence of sudden cardiac death and a low rate of ICD utilization in LQTS patients.

PO-04-166 DISTURBED PH CONTROL BY A NOVEL SLC4A3 VARIANT IDENTIFIED IN A SHORT QT SYNDROME FAMILY WITH A KCNH2 VARIANT

Short QT syndrome (SQTS) is one of the inherited primary arrhythmia syndromes and characterized by shortened QT intervals leading to ventricular fibrillation (VF) and sudden cardiac death, especially in young people. The major cause of SQTS is pathogenic variants in KCNH2 encoding Kv11.1 which produce IKr. Recently, a novel variant in SLC4A3 encoding the anion exchanger (AE3) has been identified in two SQTS families. However, the pathogenesis of SQTS caused by SLC4A3 variants in the presence of a KCNH2 variant have not been elucidated yet. We aimed to elucidate the functional change of a novel SLC4A3 variant in the interaction with a KCNH2 variant. We performed targeted gene sequencing (TGS) and whole exome sequencing (WES) in SQTS patients. Electrophysiological characteristics of the KCNH2 variant were analyzed using HEK293 cells by patch-clamp methods. We constructed stable HEK293 cell lines expressing SLC4A3 with or without the variant and measured intracellular pH (pHi) by ratiometric pH indicator, BCECF-AM. Using the stable cell lines, we transfected KCNH2 (WT or the variant), KCNQ1 and KCNJ2 and measured IKr, IKs and IK1. We identified a KCNH2 variant, c.280 c>t, p.H70Y by TGS in a 25-year-old man who suffered VF at night and was diagnosed with SQTS after resuscitation. We first performed electrophysiological analysis of KCNH2-H70Y alone, however, the variant affected a little of Ikr properties. Therefore, we performed WES in the proband and his family, and a novel SLC4A3 variant, c.1059 c>a, p.N353K was identified. Both variants were co-segregated in his family with short QT intervals. In the live cell imaging analysis, cells expressing SLC4A3-N353K showed significantly slower pHi alternations than those with WT (figure A), reflecting the loss-of-function effect of exchange kinetics in mutant AE3. In the electrophysiological analysis using stable cell lines expressing SLC4A3, IKs and IK1 did not show any changes in channel properties regardless the presence of SLC4A3-N353K. However, IKr with H70Y showed significantly slow deactivation time constant in the cells expressing SLC4A3-N353K (Figure B and C), which means the gain-of-function effect on Kv11.1. SLC4A3-N353K showed slower alteration of pHi, a loss-of-function effect on AE3. With the expression of SLC4A3-N353K,KCNH2-H70Y decelerated the deactivation kinetics of Ikr, which may lead to shortening of QT intervals in our patient.

Whole exome sequencing in Brugada and long QT syndromes revealed novel rare and potential pathogenic mutations related to the dysfunction of the cardiac sodium channel

BackgroundBrugada syndrome (Brs) and long QT syndrome (LQTs) are the most observed “inherited primary arrhythmia syndromes” and “channelopathies”, which lead to sudden cardiac death.MethodsDetailed clinical information of Brs and LQTs patients was collected. Genomic DNA samples of peripheral blood were conducted for whole-exome sequencing on the Illumina HiSeq 2000 platform. Then, we performed bioinformatics analysis for 200 genes susceptible to arrhythmias and cardiomyopathies. Protein interaction and transcriptomic co-expression were analyzed using the online website and GTEx database.ResultsAll sixteen cases of Brs and six cases of LQTs were enrolled in the current study. Four Brs carried known pathogenic or likely pathogenic of single-point mutations, including SCN5A p.R661W, SCN5A p.R965C, and KCNH2 p.R692Q. One Brs carried the heterozygous compound mutations of DSG2 p.F531C and SCN5A p.A1374S. Two Brs carried the novel heterozygous truncated mutations (MAF < 0.001) of NEBL (p.R882X) and NPPA (p.R107X), respectively. Except for the indirect interaction between NEBL and SCN5A, NPPA directly interacts with SCN5A. These gene expressions had a specific and significant positive correlation in myocardial tissue, with high degrees of co-expression and synergy. Two Brs carried MYH7 p.E1902Q and MYH6 p.R1820Q, which were predicted as "damaging/possibly damaging" and "damaging/damaging" by Polyphen and SIFT algorithm. Two LQTs elicited the pathogenic single splicing mutation of KCNQ1 (c.922-1G > C). Three LQTs carried a single pathogenic mutation of SCN5A p.R1880H, KCNH2 p.D161N, and KCNQ1 p.R243S, respectively. One patient of LQTs carried a frameshift mutation of KCNH2 p. A188Gfs*143.ConclusionsThe truncated mutations of NEBL (p.R882X) and NPPA (p.R107X) may induce Brugada syndrome by abnormally affecting cardiac sodium channel. SCN5A (p.R661W, p.R965C and p.A1374S) and KCNH2 (p.R692Q) may cause Brugada syndrome, while SCN5A (p.R1880H), KCNQ1 (c.922-1G > C and p.R243S) and KCNH2 (p.D161N and p.A188Gfs*143) may lead to long QT syndrome.

Clinical phenotyping of implantable cardioverter defibrillator patients to identify the association of remote device monitoring on survival benefit: a cluster analysis

Abstract Background/Introduction Over the past decade, various studies have demonstrated an association between remote device monitoring (RM) in implantable cardioverter-defibrillator (ICD) patients and all-cause mortality. However, it is unclear which clinical phenotypes account for this survival benefit. Purpose We aimed to identify clinical phenotypes within an ICD population on RM and conventional follow-up (NRM), and evaluate differences in long-term survival per clinical phenotype. Methods This is a single-center, retrospective, observational study of de novo ICD implantations (single- and dual chamber, biventricular and subcutaneous) between 2010 and 2021 in patients ≥18 years old. Data was extracted from electronic health records. Unsupervised two-step cluster analysis (TSC) was performed to identify distinct clinical phenotypes in the RM and NRM cohorts. Multinomial logistic regression analysis was performed to identify cluster characteristics, differences among the different clusters were analysed by Chi-squared test. Variable importance was evaluated for each of the 18 included clinical variables. Survival analysis was performed using the Kaplan-Meier method, log-rank was used to compare survival between groups. Results A total of 1872 ICD patients were analysed using TCS, comprising 1265 RM and 607 NRM patients, respectively. TCS for a mean follow-up duration of 5.4±3.1 years partitioned the RM and NRM groups into six clusters (Table 1). Clusters RM1 (n=444) and NRM3 (n=220) represented a predominantly primary prevention and DCM phenotype. Clusters RM2 (n=300) and NRM2 (n=173) indicated young and secondary prevention phenotypes. Clusters RM3 (n=220) and NRM1 (n=214) comprised an older, male and ischaemic cardiomyopathy (ICM) phenotype. In survival analysis 5-year cumulative incidence of mortality for the subsequent clusters was 7.4%, 4.5%, 11.6%, 41.4%, 29.8%, and 25.1%, respectively (log rank p-value &amp;lt;0.001, Figure 1). Thus, younger and DCM phenotypes (often with genetic aetiologies) experienced superior survival and high rates on RM, whereas older, male and ICM phenotypes with low rates on RM were associated with worse survival. In addition, between-group cluster-comparison of patients on RM only demonstrated important differences in long-term survival, where RM3 (comprising older, male with predominantly ICM) had poorer survival compared to young patients with a high prevalence of DCM, primary arrhythmia syndrome and low proportions of comorbidities (i.e. atrial arrhythmias, cerebral vascular accidents, diabetes mellitus). Conclusion We identify novel clinical phenotypes (clusters) of ICD patients on RM and having conventional follow-up with large differences in long-term survival. Future studies should further explore if these differences reflect benefit from RM, or the underlying natural history of each phenotype. These results may accordingly guide monitoring strategies tailored to specific ICD patient profiles. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Public funding

Calmodulinopathy is a common cause of critical cardiac phenotypes in fetus and infancy

Abstract Background Cardiac calmodulinopathy is a life-threatening arrhythmia syndrome which presents several phenotypes of inherited primary arrhythmia syndrome (IPAS), and caused by mutations in calmodulin-encoded genes (CALM1–3). We aimed clarify the frequency and their clinical characteristics of calmodulinopathy in our IPAS cohort. Methods By using next generation sequencing, we screened arrhythmia related genes including calmodulin-encoding genes in 322 unrelated symptomatic children (0–12 years) who were suspected as IPAS; they included 40 cases with lethal arrhythmic attacks (LAE) under 6-year-old. After gene screening, we investigated their physiological and clinical characteristics about mutation carriers. Results Among 322 children, we identified 6 mutations of calmodulin-encoded genes in 9 probands (2.8%); one CALM1 in 2 probands (N98S), and 5 CALM2 in 7 probands (E46K, D96V, D96G, N98S, E141K). Their clinical diagnoses were long QT syndrome (LQTS, n=4), catecholaminergic polymorphic ventricular tachycardia (CPVT, n=3) and both (n=2). Their age of diagnosis ranges at 0–9 with the median of 5 years. There were three major clinical phenotypes; 1) CALM2-D96V, and E141K: two infants with advanced atrio-ventricular block, significant QTc prolongation, severe heart failure from their fetal period – both of them deceased within 1.5-year-old. Their clinical phenotypes resembled classical Timothy syndrome caused by CACNA1C mutations. 2) CALM1-N98S (n=2), CALM2-N98S (n=2), and CALM2-D96G: four preschoolers with LAEs and one syncope: all of them were 3–5 years old. In addition, a T wave morphology of CALM2-D96G carrier was very similar to LQT1. 3) CALM2-E46K (n=2): two were first diagnosed with neurological and developmental disorders, and showed phenotype of CPVT: their cardiac phenotypes were milder compared with that of 1) or 2). Overall, these phenotypes seemed to be mutation specific (indicated in figure). Their cardiac features were severer, and the onset of LAEs was earlier compared with other genotypes of LQTS/CPVT. As the treatment, β-blocker was effective for control of LAEs. Conclusion Cardiac calmodulinopathy presented serious and potentially lethal phenotypes in fetus or infancy. To prevent cardiac death in them, we must correctly diagnose and start the treatment as earlier as possible. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): MEXT KAKENHI from the Ministry of Education, Culture, Sports, Science, and Technology of Japan

Prevalence and Phenotypic Burden of Monogenic Arrhythmias Using Integration of Electronic Health Records With Genetics.

Inherited primary arrhythmia syndromes and arrhythmogenic cardiomyopathies can lead to sudden cardiac arrest in otherwise healthy individuals. The burden and expression of these diseases in a real-world, well-phenotyped cardiovascular population is not well understood. Whole exome sequencing was performed on 8574 individuals from the CATHGEN cohort (Catheterization Genetics). Variants in 55 arrhythmia-related genes (associated with 8 disorders) were identified and assessed for pathogenicity based on American College of Genetics and Genomics/Association for Molecular Pathology criteria. Individuals carrying pathogenic/likely pathogenic (P/LP) variants were grouped by arrhythmogenic disorder and matched 1:5 to noncarrier controls based on age, sex, and genetic ancestry. Long-term phenotypic data were annotated through deep electronic health record review. Fifty-eight P/LP variants were found in 79 individuals in 12 genes associated with 5 arrhythmogenic disorders (arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome, hypertrophic cardiomyopathy, LMNA-related cardiomyopathy, and long QT syndrome). The penetrance of these P/LP variants in this cardiovascular cohort was 33%, 0%, 28%, 83%, and 4%, respectively. Carriers of P/LP variants associated with arrhythmogenic disorders showed significant differences in ECG, imaging, and clinical phenotypes compared with noncarriers, but displayed no difference in survival. Carriers of novel truncating variants in FLNC, MYBPC3, and MYH7 also developed relevant arrhythmogenic cardiomyopathy phenotypes. In a real-world cardiovascular cohort, P/LP variants in arrhythmia-related genes were relatively common (1:108 prevalence) and most penetrant in LMNA. While hypertrophic cardiomyopathy P/LP variant carriers showed significant differences in clinical outcomes compared with noncarriers, carriers of P/LP variants associated with other arrhythmogenic disorders displayed only ECG differences.

Genetics of idiopathic ventricular fibrillation

Abstract Funding Acknowledgements Type of funding sources: None. Background Idiopathic ventricular fibrillation (IVF) accounts for up to 44% of sudden cardiac deaths (SCD); the diagnostic yield of genetic testing in probands is reported as low as 3%. Purpose The aim of this study is to describe the results of genetic testing in IVF from a high-volume center. Methods All consecutive patients with IVF and genetic testing were retrospectively analyzed. IVF was diagnosed, following HRS/EHRA guidelines, by means of excluding other causes through clinical, imaging and genetic data. Genetic analysis was performed in all patients with SeqCap v3 for Brugada syndrome and with next generation sequencing HiSeq1500 for other inherited primary arrhythmia syndromes. Genetic variants were classified following ACMG as pathogenic (P)/likely pathogenic (LP) or variants of unknown significance (VUS). Results Fourteen patients with IVF were included (Table); an ICD was implanted in all patients. A genetic variant was found in 9 patients (64.3%), 5 patients with a P/LP variant (35.7%) and 4 patients (28.6%) with a VUS variant. Genes mutated with a P/LP variant included: RYR2 in 3 patients and TTN in 2 patients. Genes mutated with a VUS included: MYPN in one patient, SCN4A in one patient, DES in one patient and CACNA1C in one patient. At a mean follow-up of 76 months 5 patients (35.7%) experienced an ICD shock [2 patients (40%) with P/LP variant vs 3 patients (33%) of VUS/no variants, p=NS). Conclusion Genetic testing can be useful in IVF; prognosis is modest with a high rate of ICD shock at long-term follow up.

Abstract 6948: Barriers to Obtaining a Home Aed for Pediatric Patients With Primary Arrhythmia Syndromes

Introduction: Guidelines for primary arrhythmia syndromes (PAS) recommend the presence of automatic external defibrillator (AED) at least during athletic participation. Studies have shown a cost-effective and life-saving benefit to these patients having a home ED. Objective: To evaluate the challenges in obtaining a home AED. Methods: A single center retrospective chart review identified pediatric patients with a PAS in which the obtention of an AED was discussed during a clinical evaluation. These families were then surveyed by telephone regarding the method, ease, and challenges of securing a home AED. Results: Home AED discussion was documented for 28 patients of which 27 (96%) participated in the survey. Nearly all (25 of 27) attempted to obtain an AED; though only 15 (55%) were ultimately successful. Most, 17/25 (68%) initially attempted via insurance; while 4 purchased independently, 2 received a donated AED, and 2 abandoned due to cost. For patients utilizing insurance, only 7 (41%) were successful, with 5/7 utilizing a 3 rd party facilitator of insurance approval (LifeSure). LifeSure successfully gained coverage in 5 of 6 (83%) attempted cases. Of the 10 failing to obtain insurance coverage, 6 do not have an AED, 3 self-purchased one, and 1 received a donated AED. On a difficulty scale of 1-5 (1=easy; 5=very challenging), families perceived the mean difficulty score to obtaining an AED through insurance at 3.5 vs. 1.16 for those not attempting insurance. Insurance was viewed as a major barrier (scale score &gt;3) for 9 of the 17 (53%) families attempting to use it. Mean difficulty score when using LifeSure vs. not, was 1.8 vs 4.5. Families able to afford a self-purchased AED perceived minimal challenges, mean scale score 1.5. Conclusions: When clinically appropriate, families of pediatric patients with a primary arrhythmia syndrome successfully obtained an AED in about half of cases. Insurance was perceived as a major barrier. Use of a 3 rd party service to facilitate insurance coverage was highly successful and relatively simple. Though shown to be life-saving and cost-effective, access to home AED is inequitable and disadvantaged by financial and insurance barriers.

Loss-of-function mutations in cardiac ryanodine receptor channel cause various types of arrhythmias including long QT syndrome.

Gain-of-function mutations in RYR2, encoding the cardiac ryanodine receptor channel (RyR2), cause catecholaminergic polymorphic ventricular tachycardia (CPVT). Whereas, genotype-phenotype correlations of loss-of-function mutations remains unknown, due to a small number of analysed mutations. In this study, we aimed to investigate their genotype-phenotype correlations in patients with loss-of-function RYR2 mutations. We performed targeted gene sequencing for 710 probands younger than 16-year-old with inherited primary arrhythmia syndromes (IPAS). RYR2 mutations were identified in 63 probands, and 3 probands displayed clinical features different from CPVT. A proband with p.E4146D developed ventricular fibrillation (VF) and QT prolongation whereas that with p.S4168P showed QT prolongation and bradycardia. Another proband with p.S4938F showed short-coupled variant of torsade de pointes (scTdP). To evaluate the functional alterations in these three mutant RyR2s and p.K4594Q previously reported in a long QT syndrome (LQTS), we measured Ca2+ signals in HEK293 cells and HL-1 cardiomyocytes as well as Ca2+-dependent [3H]ryanodine binding. All mutant RyR2s demonstrated a reduced Ca2+ release, an increased endoplasmic reticulum Ca2+, and a reduced [3H]ryanodine binding, indicating loss-of-functions. In HL-1 cells, the exogenous expression of S4168P and K4594Q reduced amplitude of Ca2+ transients without inducing Ca2+ waves, whereas that of E4146D and S4938F evoked frequent localized Ca2+ waves. Loss-of-function RYR2 mutations may be implicated in various types of arrhythmias including LQTS, VF, and scTdP, depending on alteration of the channel activity. Search of RYR2 mutations in IPAS patients clinically different from CPVT will be a useful strategy to effectively discover loss-of-function RYR2 mutations.

Cardioverter-related complications: observations from an institutional implantable cardioverter defibrillator registry

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Implantable cardioverter defibrillator (ICD) is gold standard therapy for primary and secondary prevention of sudden cardiac death (SCD) and ventricular tachyarrhythmias. While reducing arrhythmic mortality in patients with left ventricular dysfunction of various causes, inherited primary arrhythmia syndromes and after aborted SCD, these devices can have serious adverse effects including inappropriate shocks and device-related infection. Purpose The aim of this study was to create an institutional ICD registry and to examine the major complications after ICD implantation. Methods We analysed the data concerning all newly implanted ICDs in our institution from 2011 to 2017. All patients received periprocedural antibiotic prophylaxis according to relevant guidelines. Follow-up data was collected from hospital electronic medical records. Results Total number of implanted ICDs was 507 (85.4% male, 57.6 ± 14.0 years-old) and mean follow-up was 34.3 ± 23.8 months. Major complications (infection, large haematoma/hemorrhage, lead displacement/dysfunction) occurred in 18 (3.6%) patients. In 9 (1.8%) cases patients were diagnosed with ICD infection (8 surgical wound/pocket infections and 1 confirmed endocarditis of the lead). Device was explanted in 5 cases (1.0%) while the rest were treated only with antibiotic therapy (empirically or according to swab/blood culture results). All of the infections were successfully resolved and no relapses were noted. Eventually, 3 of 5 devices were reimplanted. One death was recorded 5 month after the explanation. Second most common complication was lead displacement/dysfunction which occurred in 5 (1.0%) patients and was successfully repaired in all cases. Large haematoma and/or hemorrhage at the implantation site were present in 5 (0.8%) patients (2 required surgical revision and transfusion while 2 were managed by needle aspiration). Pneumothorax (2 cases, 0.4%) had to be drained in one patient. There was one case of subclavian vein thrombosis which was treated by anticoagulation. Conclusion Despite appropriate antibiotic prophylaxis, the rate of ICD infections in our institution was relatively higher than the one reported in similar registries. The prevalence of other major complications, including lead dysfunction was quite low. Institutional registries could help monitor and plan actions to resolve ICD-related complications to improve patient outcomes.

Short-coupled ventricular fibrillation represents a distinct phenotype among latent causes of unexplained cardiac arrest: a report from the CASPER registry.

The term idiopathic ventricular fibrillation (IVF) describes survivors of unexplained cardiac arrest (UCA) without a specific diagnosis after clinical and genetic testing. Previous reports have described a subset of IVF individuals with ventricular arrhythmia initiated by short-coupled trigger premature ventricular contractions (PVCs) for which the term short-coupled ventricular fibrillation (SCVF) has been proposed. The aim of this article is to establish the phenotype and frequency of SCVF in a large cohort of UCA survivors. We performed a multicentre study including consecutive UCA survivors from the CASPER registry. Short-coupled ventricular fibrillation was defined as otherwise unexplained ventricular fibrillation initiated by a trigger PVC with a coupling interval of <350 ms. Among 364 UCA survivors, 24/364 (6.6%) met diagnostic criteria for SCVF. The diagnosis of SCVF was obtained in 19/24 (79%) individuals by documented ventricular fibrillation during follow-up. Ventricular arrhythmia was initiated by a mean PVC coupling interval of 274 ± 32 ms. Electrical storm occurred in 21% of SCVF probands but not in any UCA proband (P < 0.001). The median time to recurrent ventricular arrhythmia in SCVF was 31 months. Recurrent ventricular fibrillation resulted in quinidine administration in 12/24 SCVF (50%) with excellent arrhythmia control. Short-coupled ventricular fibrillation is a distinct primary arrhythmia syndrome accounting for at least 6.6% of UCA. As documentation of ventricular fibrillation onset is necessary for the diagnosis, most cases are diagnosed at the time of recurrent arrhythmia, thus the true prevalence of SCVF remains still unknown. Quinidine is effective in SCVF and should be considered as first-line treatment for patients with recurrent episodes.

Investigation of current models of care for genetic heart disease in Australia: A national clinical audit

BackgroundThis sub-study of the Australian Genomics Cardiovascular Genetic Disorders Flagship sought to conduct the first nation-wide audit in Australia to establish the current practices across cardiac genetics clinics. MethodAn audit of records of patients with a suspected genetic heart disease (cardiomyopathy, primary arrhythmia, autosomal dominant congenital heart disease) who had a cardiac genetics consultation between 1st January 2016 and 31 July 2018 and were offered a diagnostic genetic test. ResultsThis audit included 536 records at multidisciplinary cardiac genetics clinics from 11 public tertiary hospitals across five Australian states. Most genetic consultations occurred in a clinic setting (90%), followed by inpatient (6%) and Telehealth (4%). Queensland had the highest proportion of Telehealth consultations (9% of state total). Sixty-six percent of patients had a clinical diagnosis of a cardiomyopathy, 28% a primary arrhythmia, and 0.7% congenital heart disease. The reason for diagnosis was most commonly as a result of investigations of symptoms (73%). Most patients were referred by a cardiologist (85%), followed by a general practitioner (9%) and most genetic tests were funded by the state Genetic Health Service (73%). Nationally, 29% of genetic tests identified a pathogenic or likely pathogenic gene variant; 32% of cardiomyopathies, 26% of primary arrhythmia syndromes, and 25% of congenital heart disease. ConclusionWe provide important information describing the current models of care for genetic heart diseases throughout Australia. These baseline data will inform the implementation and impact of whole genome sequencing in the Australian healthcare landscape.

Frequency of syncope as a presenting symptom in channelopathies diagnosed in childhood. Can the multivariable EGSYS score unmask these children?

Pediatric syncope raises cardiac etiology concern as it might be the first sign of life-threatening arrhythmia syndromes. Our aim was to study the incidence of syncope as the presenting symptom in children with arrhythmia syndromes, and if known, warning signs are helpful to reveal the arrhythmic origin. All data on children with channelopathy was followed by a tertiary pediatric cardiac center between 2000 and 2018 and data were reviewed retrospectively. Forty-eight patients were enrolled, representing long QT syndrome (n = 39), catecholaminergic polymorphic ventricular tachycardia (n = 5), and Brugada syndrome (n = 4). Presenting symptoms were syncope in 13 cases [27%] (including 7 initially mislabeled as epilepsy) and sudden cardiac arrest (SCA) in 9 cases [19%]. In the rest of the group, the concern for arrhythmic etiology was raised by either an abnormal ECG during sports medicine screening (n = 13) [27%] or a positive family history of channelopathy (n = 13) [27%]. None of the patients presenting with SCA had a prior syncopal history. Six patients presenting with syncope and afterward treated with ICD had an appropriate shock. Description of witnessed syncope was available in eight out of thirteen children presenting with syncope. Multivariable EGSYS score suggested cardiac origin (≥ 3 points) in 7 out of 8 (88%) patients.Conclusions: Syncope was a relatively uncommon presenting symptom of channelopathies in this sample and did not always precede sudden cardiac arrests. However, we found that multivariable EGSYS score can identify syncope of arrhythmic origin, raising suspicion for pediatric channelopathies even in patients previously misdiagnosed with epilepsy. What is known: • Cardiac syncope is rare in children but can be the first sign of a potentially fatal primary arrhythmia syndrome and is frequently misdiagnosed as atypical/therapy-resistant epilepsy. • Multivariate EGSYS score is effective to diagnose cardiac syncope in adults. What is new: • Cardiac syncope as a presenting symptom is not common in children with cardiac channelopathies and is not often present before sudden cardiac arrest. • Multivariable EGSYS score might identify cardiac syncope in children with a hereditary and secondary channelopathy.

“Concealed cardiomyopathy” as a cause of previously unexplained sudden cardiac arrest

BackgroundGenetic heart disease is a common cause of sudden cardiac arrest (SCA) in the young and those without an ischaemic precipitant. Identifying a cause of SCA in these patients allows for targeted care and family screening. Current guidelines recommend limited, phenotype-guided genetic testing in SCA survivors where a specific genetic condition is suspected and genetic testing is not recommended in clinically-idiopathic SCA survivors. ObjectiveTo investigate the diagnostic utility of broad, multi-phenotype genetic testing in clinically-idiopathic SCA survivors. MethodsClinically-idiopathic SCA survivors underwent analysis of genes known to be associated with either cardiomyopathy or primary arrhythmia syndromes, following referral to a specialised genetic heart disease clinic in Sydney, Australia between 1997 and 2019. Comprehensive review of clinical records, investigations and re-appraisal of genetic data according to current variant classification criteria was performed. ResultsIn total, 22% (n = 8/36) of clinically-idiopathic SCA survivors (mean age 36.9 ± 16.9 years, 61% male) had a disease-causing variant identified on broad genetic testing. Of these, 7 (88%) variants resided in cardiomyopathy-associated genes (ACTN2, DES, DSP, MYBPC3, MYH7, PKP2) despite structurally normal hearts or sub-diagnostic structural changes at the time of arrest, so-called “concealed cardiomyopathy”. Only one SCA survivor had a variant identified in a channelopathy associated gene (SCN5A). ConclusionExtended molecular analysis with multi-phenotype genetic testing can identify a “concealed cardiomyopathy”, and increase the diagnosis rate for clinically-idiopathic SCA survivors.

Long-Term Follow-Up Study on the Uptake of Genetic Counseling and Predictive DNA Testing in Inherited Cardiac Conditions.

Inherited cardiac conditions present with a wide range of symptoms and may even result in sudden cardiac death. Relatives of probands with a confirmed pathogenic genetic variant are advised predictive DNA testing to enable prevention and treatment. In 2 previous cohort studies of 115 probands with a pathogenic variant, family uptake of genetic counseling was assessed in the first year(s) after test result disclosure to the proband. This study assesses uptake in these cohorts in the 14 to 23 years following disclosure. Uptake was determined retrospectively using patient records. First-degree relatives, and second-degree relatives of a deceased first-degree relative suspected of having an inherited cardiac condition, were considered eligible. Of 717 eligible relatives (598 first-degree and 119 second-degree relatives), 60% attended genetic counseling. Most of them (68.6%) attended genetic counseling in the first year. A total of 98.4% of counseled relatives pursued predictive DNA testing. A total of 49.2% was identified as carrier. Median time between disclosure to the proband and counseling of relatives was 6 months (range: 0-187 months). Attending genetic counseling was observed more frequently in first-degree relatives, female relatives, primary arrhythmia syndromes, relatives with manifest inherited cardiac condition, relatives without children and families with sudden cardiac death in first-degree relatives <40 years. During median follow-up of 16 years, 60.0% of relatives attended genetic counseling, with 41.0% in the first year. Our results may suggest that some relatives are not or inadequately informed or that barriers against genetic counseling are present. Further research is needed into interventions facilitating family communication, increasing awareness among families and healthcare professionals, and lowering thresholds for genetic counseling.