31 results on '"Ingles J"'
Search Results
2. Reimbursed Genes: Early Uptake of Medicare Benefits Schedule Cardiac Testing Items in Australia
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Battese Ellis, K., Longoni, M., Spencer, S., Eades, T., and Ingles, J.
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- 2024
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3. East Jordan & Southern.
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Ingles, J. David
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The East Jordan & Southern was a common carrier in Michigan that originated from 19th-century logging lines. It operated for several decades, growing to 30 miles in the 1920s before declining by a third. Despite having approval to abandon in 1932, it remained in business due to the support of a foundry and cannery in East Jordan. The line discontinued passenger service in 1945 and ultimately shut down at the end of August 1961. Today, one of its trains, No. 6, is still displayed on its old right of way on the shore of Lake Charlevoix. Another train, Combine No. 2, was acquired by the Mid-Continent Railway Museum in Wisconsin. [Extracted from the article]
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- 2024
4. The Experiences, Values and Goals of Patients in Australia Living with Obstructive Hypertrophic Cardiomyopathy: In-Depth Patient Interviews.
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Fifer, S., Pendleton, A., Ingles, J., Godsell, J., Zhong, Y., and Krause, T.
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HYPERTROPHIC cardiomyopathy , *MEDICAL history taking - Published
- 2024
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5. Adjunctive Intravenous Argatroban or Eptifibatide for Ischemic Stroke.
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Adeoye, O., Broderick, J., Derdeyn, C. P., Grotta, J. C., Barsan, W., Bentho, O., Berry, S., Concha, M., Davis, I., Demel, S., Elm, J., Gentile, N., Graves, T., Hoffman, M., Huang, J., Ingles, J., Janis, S., Jasne, A. S., Khatri, P., and Levine, S. R.
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ISCHEMIC stroke , *STROKE patients , *INTRACRANIAL hemorrhage , *ENDOVASCULAR surgery - Abstract
BACKGROUND: Intravenous thrombolysis is a standard treatment of acute ischemic stroke. The efficacy and safety of combining intravenous thrombolysis with argatroban (an anticoagulant agent) or eptifibatide (an antiplatelet agent) are unclear. METHODS: We conducted a phase 3, three-group, adaptive, single-blind, randomized, controlled clinical trial at 57 sites in the United States. Patients with acute ischemic stroke who had received intravenous thrombolysis within 3 hours after symptom onset were assigned to receive intravenous argatroban, eptifibatide, or placebo within 75 minutes after the initiation of thrombolysis. The primary efficacy outcome, the utility-weighted 90-day modified Rankin scale score (range, 0 to 10, with higher scores reflecting better outcomes), was assessed by means of centralized adjudication. The primary safety outcome was symptomatic intracranial hemorrhage within 36 hours after randomization. RESULTS: A total of 514 patients were assigned to receive argatroban (59 patients), eptifibatide (227 patients), or placebo (228 patients). All the patients received intravenous thrombolysis (70% received alteplase, and 30% received tenecteplase), and 225 patients (44%) underwent endovascular thrombectomy. At 90 days, the mean (±SD) utility-weighted modified Rankin scale scores were 5.2±3.7 with argatroban, 6.3±3.2 with eptifibatide, and 6.8±3.0 with placebo. The posterior probability that argatroban was better than placebo was 0.002 (posterior mean difference in utility-weighted modified Rankin scale score, -1.51±0.51) and that eptifibatide was better than placebo was 0.041 (posterior mean difference, -0.50±0.29). The incidence of symptomatic intracranial hemorrhage was similar in the three groups (4% with argatroban, 3% with eptifibatide, and 2% with placebo). Mortality at 90 days was higher in the argatroban group (24%) and the eptifibatide group (12%) than in the placebo group (8°/o). CONCLUSIONS: In patients with acute ischemic stroke treated with intravenous thrombolysis within 3 hours after symptom onset, adjunctive treatment with intravenous argatroban or eptifibatide did not reduce poststroke disability and was associated with increased mortality. [ABSTRACT FROM AUTHOR]
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- 2024
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6. Functional Analysis of an FHOD3 Founder Variant Causing Hypertrophic Cardiomyopathy in the Balkans Population.
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Bagnall, R., Li, S., Ranpura, G., Holliday, M., Hanna, B., Ingles, J., Kumar, S., Semsarian, C., and Lim, S.
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HYPERTROPHIC cardiomyopathy , *FUNCTIONAL analysis - Published
- 2024
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7. Development and Evaluation of a Support Intervention for Families after Sudden Cardiac Death.
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Yeates, L., Baker, A., Gardner, K., Do, J., Stewart, N., Catto, L., Leslie, F., Semsarian, C., Gray, B., McEwen, A., Adlard, L., and Ingles, J.
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CARDIAC arrest - Published
- 2024
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8. Yield of Diagnostic Genetic Testing in a Multidisciplinary Genetic Heart Disease Clinic with Access to Medicare Rebatable Cardiac Testing.
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Nowak, N., Tan, L., Yeates, L., Ingles, J., Gray, B., Medi, C., Raju, H., Sy, R., Ryan, M., Kirk, E., Semsarian, C., and Burns, C.
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GENETIC testing , *GENETIC disorders , *HEART diseases , *DIAGNOSIS methods , *MEDICARE - Published
- 2024
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9. Young Sudden Cardiac Arrest in New South Wales: A Data Linkage Study.
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Leslie, F., Sweeting, J., Faddy, S., Bendall, J., Nedkoff, L., Avis, S., Butters, A., Yeates, L., Dennis, M., Lawley, C., Paratz, E., Investigators, NSW SCA Registry, and Ingles, J.
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CARDIAC arrest - Published
- 2024
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10. Study Protocol for Follow Up of Survivors of Young Sudden Cardiac Arrest in Victoria With Regard to All-Cause Mortality, Implantable Cardioverter Defibrillator Insertion and Detection of Ventricular Arrhythmia.
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Fahy, L., Rowe, S., Nehme, Z., Stub, D., Pflaumer, A., Connell, V., Semsarian, C., Ingles, J., La Gerche, A., and Paratz, E.
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VENTRICULAR arrhythmia , *IMPLANTABLE cardioverter-defibrillators , *CARDIAC arrest , *FOLLOW-up studies (Medicine) , *MORTALITY - Published
- 2024
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11. NSW HEARTS: The NSW Inherited Cardiomyopathy Cohort Study—Clinical and Demographic Characteristics of Participant to Date.
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Catto, L., Baker, A., Stewart, N., Hespe, S., Do, J., Yeates, L., Stafford, F., Krishnan, N., Brown, J., Sweeting, J., Investigators, NSW HEARTS, Butters, A., and Ingles, J.
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DEMOGRAPHIC characteristics , *COHORT analysis , *CARDIOMYOPATHIES , *HEART - Published
- 2024
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12. The Use of Social and Media Advertisement in Direct-to-Participant Recruitment: NSW HEARTS Inherited Cardiomyopathy Cohort Study.
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Baker, A., Catto, L., Stewart, N., Hespe, S., Do, J., Yeates, L., Stafford, F., Krishnan, N., Brown, J., Sweeting, J., Butters, A., and Ingles, J.
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COHORT analysis , *CARDIOMYOPATHIES , *HEART - Published
- 2024
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13. A Validated SCN5A Functional Assay to Adjudicate Variants of Uncertain Significance from the International Brugada Syndrome Genetics Consortia.
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Ma, J., O'Neill, M., Richardson, E., Ingles, J., Thomson, K., Solus, J., Harvey, G., Robertson, P., Bezzina, C., Roden, D., Walsh, R., Vandenberg, J., Glazer, A., and Ng, C.
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BRUGADA syndrome , *CONSORTIA , *GENETICS - Published
- 2024
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14. Tiered Analysis of Australian Genomics Cardiovascular Genetic Disorders Flagship Genomes Increases the Diagnostic Yield of Genetic Testing.
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Chang, Y., Rath, E., Singer, E., Trivedi, G., Soka, M., Macciocca, I., Ingles, J., Semsarian, C., McGaughran, J., Fatkin, D., Giannoulatou, E., and Bagnall, R.
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GENETIC testing , *CARDIOVASCULAR diseases , *GENETIC disorders , *GENOMICS , *GENOMES - Published
- 2024
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15. Long-Term Outcomes After Septal Reduction Therapies in Obstructive Hypertrophic Cardiomyopathy: Insights From the SHARE Registry.
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Maurizi N, Anthiochos P, Owens A, Lakdwala N, Saberi S, Russell MW, Fumagalli C, Skalidis I, Lin KY, Nathan AS, De Feria Alsina A, Reza N, Stendahl JC, Abrams D, Scemsarian C, Clagget B, Lampert R, Wheeler M, Parikh VN, Ashley E, Michels M, Rossano J, Ryan TD, Ingles J, Ware J, Ho CY, Helms AS, Day SM, and Olivotto I
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Background: Septal reduction therapy (SRT) provides substantial symptomatic improvement in patients with obstructive hypertrophic cardiomyopathy (HCM). However, long-term disease course after SRT and predictors of adverse outcomes have not been systematically examined., Methods: Data from 13 high clinical volume HCM centers from the international SHARE (Sarcomeric Human Cardiomyopathy Registry) were analyzed. Patients were followed from the time of SRT until last follow-up or occurrence of heart failure (HF) composite outcome (cardiac transplantation, implantation of a left ventricular assist device, left ventricular ejection fraction <35%, development of New York Heart Association class III or IV symptoms), ventricular arrhythmias composite outcome (sudden cardiac death, resuscitated cardiac arrest, or appropriate implantable cardioverter defibrillator therapy), or HCM-related death. Cox proportional hazards models were used to identify predictors of outcome., Results: Of the 10 225 patients in SHARE, 1832 (18%; 968 [53%] male) underwent SRT, including 455 (25%) with alcohol septal ablation and 1377 (75%) with septal myectomy. The periprocedural 30-day mortality rate was 0.4% (8 of 1832) and 1499 of 1565 (92%) had a maximal left ventricular outflow tract gradient <50 mm Hg at 1 year. After 6.8 years (range, 3.4-9.8 years; 12 565 person-years) from SRT, 77 (4%) experienced HCM-related death (0.6% per year), 236 (13%) a composite HF outcome (1.9% per year), and 87 (5%) a composite ventricular arrhythmia outcome (0.7% per year). Among adults, older age at SRT was associated with a higher incidence of HCM death (hazard ratio, 1.22 [95 CI, 1.1-1.3]; P <0.01) and the HF composite (hazard ratio, 1.14 [95 CI, 1.1-1.2] per 5-year increase; P <0.01) in a multivariable model. Female patients also had a higher risk of the HF composite after SRT (hazard ratio, 1.4 [95 CI, 1.1-1.8]; P <0.01). De novo atrial fibrillation occurred after SRT in 387 patients (21%). Among pediatric patients followed for a median of 13 years after SRT, 26 of 343 (16%) developed the HF composite outcome, despite 96% being free of recurrent left ventricular outflow tract obstruction., Conclusions: Successful short- and long-term relief of outflow tract obstruction was observed in experienced multidisciplinary HCM centers. A subset of patients progressed to develop HF, but event-free survival at 10 years was 83% and ventricular arrhythmias were rare. Older age, female sex, and SRT during childhood were associated with a greater risk of developing HF.
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- 2024
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16. A Call to Action to Improve Cardiac Arrest Outcomes: A Report From the National Summit for Cardiac Arrest.
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La Gerche A, Paratz ED, Bray JE, Jennings G, Page G, Timbs S, Vandenberg JI, Abhayaratna W, Chow CK, Dennis M, Figtree GA, Kovacic JC, Maris J, Nehme Z, Parsons S, Pflaumer A, Puranik R, Stub D, Freitas E, Zecchin R, Cartledge S, Haskins B, and Ingles J
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Sudden cardiac arrest (SCA) represents a major cause of premature mortality globally, with enormous impact and financial cost to victims, families, and communities. SCA prevention should be considered a health priority in Australia. National Cardiac Arrest Summits were held in June 2022 and March 2023, with inclusion from multi-faceted endeavours related to SCA prevention. It was agreed to establish a multidisciplinary Australian Sudden Cardiac Arrest Alliance (AuSCAA) working group charged with developing a national unified strategy, with clear and measurable quality indicators and standardised outcome measures, to amplify the goal of SCA prevention throughout Australia. A multi-faceted prevention strategy will include i) endeavours to progress community awareness, ii) improved fundamental mechanistic understanding, iii) implementation of best-practice resuscitation strategies for all demographics and locations, iv) secondary risk assessment directed to family members, and v) development of (near) real-time registry of cardiac arrest cases to inform areas of need and effectiveness of interventions. Together, we can and should reduce the impact of SCA in Australia., Competing Interests: Declaration of Competing Interest E.D.P. has received speaker fees from Bristol Myers Squibb. All other authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2024
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17. Reproductive options and genetic testing for patients with an inherited cardiac disease.
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Verdonschot JAJ, Paulussen ADC, Lakdawala NK, de Die-Smulders CEM, Ware JS, and Ingles J
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In the past decade, genetic testing for cardiac disease has become part of routine clinical care. A genetic diagnosis provides the possibility to clarify risk for relatives. For family planning, a genetic diagnosis provides reproductive options, including prenatal diagnosis and preimplantation genetic testing, that can prevent an affected parent from having a child with the genetic predisposition. Owing to the complex genetic architecture of cardiac diseases, characterized by incomplete disease penetrance and the interplay between monogenic and polygenic variants, the risk reduction that can be achieved using reproductive genetic testing varies among individuals. Globally, disparities, including regulatory and financial barriers, in access to reproductive genetic tests exist. Although reproductive options are gaining a prominent position in the management of patients with inherited cardiac diseases, specific policies and guidance are lacking. Guidelines recommend that prenatal diagnosis and preimplantation genetic testing are options that should be discussed with families. Health-care professionals should, therefore, be aware of the possibilities and feel confident to discuss the benefits and challenges. In this Review, we provide an overview of the reproductive options in the context of inherited cardiac diseases, covering the genetic, technical, psychosocial and equity considerations, to prepare health-care professionals for discussions with their patients., (© 2024. Springer Nature Limited.)
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- 2024
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18. Clinical features and outcomes in carriers of pathogenic desmoplakin variants.
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Gasperetti A, Carrick RT, Protonotarios A, Murray B, Laredo M, van der Schaaf I, Lekanne RH, Syrris P, Cannie D, Tichnell C, Cappelletto C, Gigli M, Medo K, Saguner AM, Duru F, Gilotra NA, Zimmerman S, Hylind R, Abrams DJ, Lakdawala NK, Cadrin-Tourigny J, Targetti M, Olivotto I, Graziosi M, Cox M, Biagini E, Charron P, Casella M, Tondo C, Yazdani M, Ware JS, Prasad SK, Calò L, Smith ED, Helms AS, Hespe S, Ingles J, Tandri H, Ader F, Peretto G, Peters S, Horton A, Yao J, Dittmann S, Schulze-Bahr E, Qureshi M, Young K, Carruth ED, Haggerty C, Parikh VN, Taylor M, Mestroni L, Wilde A, Sinagra G, Merlo M, Gandjbakhch E, van Tintelen JP, Te Riele ASJM, Elliott PM, Calkins H, and James CA
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Background and Aims: Pathogenic variants in the desmoplakin (DSP) gene are associated with the development of a distinct arrhythmogenic cardiomyopathy phenotype not fully captured by either dilated cardiomyopathy (DCM), non-dilated left ventricular cardiomyopathy (NDLVC), or arrhythmogenic right ventricular cardiomyopathy (ARVC). Prior studies have described baseline DSP cardiomyopathy genetic, inflammatory, and structural characteristics. However, cohort sizes have limited full clinical characterization and identification of clinical and demographic predictors of sustained ventricular arrhythmias (VAs), heart failure (HF) hospitalizations, and transplant/death. In particular, the relevance of acute myocarditis-like episodes for subsequent disease course is largely unknown., Methods: All patients with pathogenic/likely pathogenic (P/LP) DSP variants in the worldwide DSP-ERADOS Network (26 academic institutions across nine countries) were included. The primary outcomes were the development of sustained VA and HF hospitalizations during follow-up. Fine-Gray regressions were used to test association between clinical and instrumental parameters and the development of outcomes., Results: Eight hundred patients [40.3 ± 17.5 years, 47.5% probands, left ventricular ejection fraction (LVEF) 49.5 ± 13.9%] were included. Over 3.7 [1.4-7.1] years, 139 (17.4%, 3.9%/year) and 72 (9.0%, 1.8%/year) patients experienced sustained VA and HF episodes, respectively. A total of 32.5% of individuals did not fulfil diagnostic criteria for ARVC, DCM, or NDLVC; their VA incidence was 0.5%/year. In multivariable regression, risk features associated with the development of VA were female sex [adjusted hazard ratio (aHR) 1.547; P = .025], prior non-sustained ventricular tachycardia (aHR 1.721; P = .009), prior sustained VA (aHR 1.923; P = .006), and LVEF ≤ 50% (aHR: 1.645; P = .032), while for HF, they were the presence of T-wave inversion in 3+ electrocardiogram leads (aHR 2.036, P = .007) and LVEF ≤ 50% (aHR 3.879; P < .001). Additionally, 70 (8.8%) patients experienced a myocardial injury episode at presentation or during follow-up. These episodes were associated with an increased risk of VA and HF thereafter (HR 2.394; P < .001, and HR 5.064, P < .001, respectively)., Conclusions: Patients with P/LP DSP variants experience high rates of sustained VA and HF hospitalizations. These patients demonstrate a distinct clinical phenotype (DSP cardiomyopathy), whose most prominent risk features associated with adverse clinical outcomes are the presence of prior non-sustained ventricular tachycardia or sustained VA, T-wave inversion in 3+ leads on electrocardiogram, LVEF ≤ 50%, and myocardial injury events., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)
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- 2024
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19. A novel tool for arrhythmic risk stratification in desmoplakin gene variant carriers.
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Carrick RT, Gasperetti A, Protonotarios A, Murray B, Laredo M, van der Schaaf I, Dooijes D, Syrris P, Cannie D, Tichnell C, Gilotra NA, Cappelletto C, Medo K, Saguner AM, Duru F, Hylind RJ, Abrams DJ, Lakdawala NK, Cadrin-Tourigny J, Targetti M, Olivotto I, Graziosi M, Cox M, Biagini E, Charron P, Compagnucci P, Casella M, Conte G, Tondo C, Yazdani M, Ware JS, Prasad SK, Calò L, Smith ED, Helms AS, Hespe S, Ingles J, Tandri H, Ader F, Peretto G, Peters S, Horton A, Yao J, Schulze-Bahr E, Dittman S, Carruth ED, Young K, Qureshi M, Haggerty C, Parikh VN, Taylor M, Mestroni L, Wilde A, Sinagra G, Merlo M, Gandjbakhch E, van Tintelen JP, Te Riele ASJM, Elliott P, Calkins H, Wu KC, and James CA
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- Humans, Female, Male, Risk Assessment methods, Adult, Middle Aged, Arrhythmias, Cardiac genetics, Heterozygote, Tachycardia, Ventricular genetics, Desmoplakins genetics
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Background and Aims: Pathogenic desmoplakin (DSP) gene variants are associated with the development of a distinct form of arrhythmogenic cardiomyopathy known as DSP cardiomyopathy. Patients harbouring these variants are at high risk for sustained ventricular arrhythmia (VA), but existing tools for individualized arrhythmic risk assessment have proven unreliable in this population., Methods: Patients from the multi-national DSP-ERADOS (Desmoplakin SPecific Effort for a RAre Disease Outcome Study) Network patient registry who had pathogenic or likely pathogenic DSP variants and no sustained VA prior to enrolment were followed longitudinally for the development of first sustained VA event. Clinically guided, step-wise Cox regression analysis was used to develop a novel clinical tool predicting the development of incident VA. Model performance was assessed by c-statistic in both the model development cohort (n = 385) and in an external validation cohort (n = 86)., Results: In total, 471 DSP patients [mean age 37.8 years, 65.6% women, 38.6% probands, 26% with left ventricular ejection fraction (LVEF) < 50%] were followed for a median of 4.0 (interquartile range: 1.6-7.3) years; 71 experienced first sustained VA events {2.6% [95% confidence interval (CI): 2.0, 3.5] events/year}. Within the development cohort, five readily available clinical parameters were identified as independent predictors of VA and included in a novel DSP risk score: female sex [hazard ratio (HR) 1.9 (95% CI: 1.1-3.4)], history of non-sustained ventricular tachycardia [HR 1.7 (95% CI: 1.1-2.8)], natural logarithm of 24-h premature ventricular contraction burden [HR 1.3 (95% CI: 1.1-1.4)], LVEF < 50% [HR 1.5 (95% CI: .95-2.5)], and presence of moderate to severe right ventricular systolic dysfunction [HR 6.0 (95% CI: 2.9-12.5)]. The model demonstrated good risk discrimination within both the development [c-statistic .782 (95% CI: .77-.80)] and external validation [c-statistic .791 (95% CI: .75-.83)] cohorts. The negative predictive value for DSP patients in the external validation cohort deemed to be at low risk for VA (<5% at 5 years; n = 26) was 100%., Conclusions: The DSP risk score is a novel model that leverages readily available clinical parameters to provide individualized VA risk assessment for DSP patients. This tool may help guide decision-making for primary prevention implantable cardioverter-defibrillator placement in this high-risk population and supports a gene-first risk stratification approach., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)
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- 2024
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20. Multisite Validation of a Functional Assay to Adjudicate SCN5A Brugada Syndrome-Associated Variants.
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Ma JG, O'Neill MJ, Richardson E, Thomson KL, Ingles J, Muhammad A, Solus JF, Davogustto G, Anderson KC, Shoemaker MB, Stergachis AB, Floyd BJ, Dunn K, Parikh VN, Chubb H, Perrin MJ, Roden DM, Vandenberg JI, Ng CA, and Glazer AM
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- Humans, Male, Female, Mutation, Missense, Patch-Clamp Techniques, Adult, Middle Aged, Brugada Syndrome genetics, NAV1.5 Voltage-Gated Sodium Channel genetics
- Abstract
Background: Brugada syndrome is an inheritable arrhythmia condition that is associated with rare, loss-of-function variants in SCN5A . Interpreting the pathogenicity of SCN5A missense variants is challenging, and ≈79% of SCN5A missense variants in ClinVar are currently classified as variants of uncertain significance. Automated patch clamp technology enables high-throughput functional studies of ion channel variants and can provide evidence for variant reclassification., Methods: An in vitro SCN5A -Brugada syndrome automated patch clamp assay was independently performed at Vanderbilt University Medical Center and Victor Chang Cardiac Research Institute. The assay was calibrated according to ClinGen Sequence Variant Interpretation recommendations using high-confidence variant controls (n=49). Normal and abnormal ranges of function were established based on the distribution of benign variant assay results. Odds of pathogenicity values were derived from the experimental results according to ClinGen Sequence Variant Interpretation recommendations. The calibrated assay was then used to study SCN5A variants of uncertain significance observed in 4 families with Brugada syndrome and other arrhythmia phenotypes associated with SCN5A loss-of-function., Results: Variant channel parameters generated independently at the 2 research sites showed strong correlations, including peak I
Na density ( R2 =0.86). The assay accurately distinguished benign controls (24/25 concordant variants) from pathogenic controls (23/24 concordant variants). Odds of pathogenicity values were 0.042 for normal function and 24.0 for abnormal function, corresponding to strong evidence for both American College of Medical Genetics and Genomics/Association for Molecular Pathology benign and pathogenic functional criteria (BS3 and PS3, respectively). Application of the assay to 4 clinical SCN5A variants of uncertain significance revealed loss-of-function for 3/4 variants, enabling reclassification to likely pathogenic., Conclusions: This validated high-throughput assay provides clinical-grade functional evidence to aid the classification of current and future SCN5A -Brugada syndrome variants of uncertain significance., Competing Interests: Dr Glazer is a consultant for BioMarin Inc Victoria Parikh is a scientific advisory board member (Lexeo Therapeutics), clinical advisor (Constantiam Biosciences), and consultant (BioMarin Inc, viz.ai). Dr Parikh also receives research support from BioMarin, Inc. The other authors report no conflicts.- Published
- 2024
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21. ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel: Reappraisal of Genes associated with Hypertrophic Cardiomyopathy.
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Hespe S, Waddell A, Asatryan B, Owens E, Thaxton C, Adduru ML, Anderson K, Brown EE, Hoffman-Andrews L, Jordan E, Josephs K, Mayers M, Peters S, Stafford F, Bagnall RD, Bronicki L, Callewaert B, Chahal CAA, James CA, Jarinova O, Landstrom AP, McNally EM, Murray B, Muiño-Mosquera L, Parikh V, Reuter C, Walsh R, Wayburn B, Ware JS, and Ingles J
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Background: Hypertrophic cardiomyopathy (HCM) is an inherited cardiac condition affecting ~1 in 500 and exhibits marked genetic heterogeneity. Previously published in 2019, 57 HCM-associated genes were curated providing the first systematic evaluation of gene-disease validity. Here we report work by the ClinGen Hereditary Cardiovascular Disorders Gene Curation Expert Panel (HCVD-GCEP) to reappraise the clinical validity of previously curated and new putative HCM genes., Methods: The ClinGen systematic gene curation framework was used to re-classify the gene-disease relationships for HCM and related syndromic entities involving left ventricular hypertrophy. Genes previously curated were included if their classification was not definitive, and if the time since curation was >2-3 years. New genes with literature assertions for HCM were included for initial evaluation. Existing genes were curated for new inheritance patterns where evidence existed. Curations were presented on twice monthly calls, with the HCVD-GCEP composed of 29 individuals from 21 institutions across 6 countries., Results: Thirty-one genes were re-curated and an additional 5 new potential HCM-associated genes were curated. Among the re-curated genes, 17 (55%) genes changed classification: 1 limited and 4 disputed (from no known disease relationship), 9 disputed (from limited), and 3 definitive (from moderate). Among these, 3 (10%) genes had a clinically relevant upgrade, including TNNC1, a 9th sarcomere gene with definitive HCM association. With new evidence, two genes were curated for multiple inheritance patterns ( TRIM63, disputed for autosomal dominant but moderate for autosomal recessive; ALPK3, strong for autosomal dominant and definitive for recessive). CSRP3 was curated for a semi-dominant mode of inheritance (definitive). Nine (29%) genes were downgraded to disputed, further discouraging clinical reporting of variants in these genes. Five genes recently reported to cause HCM were curated: RPS6KB1 and RBM20 (limited), KLHL24 and MT-TI (moderate), and FHOD3 (definitive)., Conclusions: We report 29 genes with definitive, strong or moderate evidence of causation for HCM or isolated LVH, including sarcomere, sarcomere-associated and syndromic conditions., Competing Interests: COMPETING INTERESTS EMM is an advisor to Amgen, Cytokinetics, PepGen, and Tenaya, and is a founder of Ikaika Therapeutics. JW has consulted for MyoKardia, Inc., Pfizer, Foresite Labs, Health Lumen, and Tenaya Therapeutics, and receives research support from Bristol Myers-Squibb. JI receives research grant support from Bristol Myers Squibb unrelated to this work. All other authors declare no competing interests.
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- 2024
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22. The role of genetic testing in management and prognosis of individuals with inherited cardiomyopathies.
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Hespe S, Gray B, Puranik R, Peters S, Sweeting J, and Ingles J
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Inherited cardiomyopathies are a heterogeneous group of heart muscle conditions where disease classification has traditionally been based on clinical characteristics. However, this does not always align with genotype. While there are well described challenges of genetic testing, understanding the role of genotype in patient management is increasingly required. We take a gene-by-gene approach, reviewing current evidence for the role of genetic testing in guiding prognosis and management of individuals with inherited cardiomyopathies. In particular, focusing on causal variants in genes definitively associated with arrhythmogenic cardiomyopathy, dilated cardiomyopathy, and hypertrophic cardiomyopathy. This review identifies genotype-specific disease sub-groups with strong evidence supporting the use of genetics in clinical management and highlights that at present, the spectrum of clinical utility is not reflected in current guidelines. Of 13 guideline or expert consensus statements for management of cardiomyopathies, there are seven gene-specific therapeutic recommendations that have been published from four documents. Understanding how genotype influences phenotype provides evidence for the role of genetic testing for prognostic and therapeutic purposes, moving us closer to precision-medicine based care., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JI receives research grant support from Bristol Myers Squibb. All other authors report no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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23. Expanding the Phenotypic Spectrum of Desminopathy.
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Hespe S and Ingles J
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- Humans, Male, Muscular Dystrophies genetics, Muscular Dystrophies physiopathology, Female, Desmin genetics, Desmin metabolism, Adult, Middle Aged, Electrocardiography, Cardiomyopathies genetics, Cardiomyopathies physiopathology, Phenotype
- Abstract
Competing Interests: Funding Support and Author Disclosures Dr Ingles is the recipient of a National Heart Foundation of Australia Future Leader Fellowship (no. 106732). Dr Hespe has reported that she has no relationships relevant to the contents of this paper to disclose.
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- 2024
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24. Voltage tunes mGlu 5 receptor function, impacting synaptic transmission.
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Boutonnet M, Carpena C, Bouquier N, Chastagnier Y, Font-Ingles J, Moutin E, Tricoire L, Chemin J, and Perroy J
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- Animals, Humans, HEK293 Cells, Membrane Potentials, Neurons metabolism, Neurons physiology, Receptors, N-Methyl-D-Aspartate metabolism, Mice, Receptor, Metabotropic Glutamate 5 metabolism, Synaptic Transmission physiology
- Abstract
Background and Purpose: Voltage sensitivity is a common feature of many membrane proteins, including some G-protein coupled receptors (GPCRs). However, the functional consequences of voltage sensitivity in GPCRs are not well understood., Experimental Approach: In this study, we investigated the voltage sensitivity of the post-synaptic metabotropic glutamate receptor mGlu
5 and its impact on synaptic transmission. Using biosensors and electrophysiological recordings in non-excitable HEK293T cells or neurons., Key Results: We found that mGlu5 receptor function is optimal at resting membrane potentials. We observed that membrane depolarization significantly reduced mGlu5 receptor activation, Gq-PLC/PKC stimulation, Ca2+ release and mGlu5 receptor-gated currents through transient receptor potential canonical, TRPC6, channels or glutamate ionotropic NMDA receptors. Notably, we report a previously unknown activity of the NMDA receptor at the resting potential of neurons, enabled by mGlu5 ., Conclusions and Implications: Our findings suggest that mGlu5 receptor activity is directly regulated by membrane voltage which may have a significant impact on synaptic processes and pathophysiological functions., (© 2024 British Pharmacological Society.)- Published
- 2024
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25. Prevalence of atrial septal defects and patent foramen ovale in a cohort of sudden cardiac death patients undergoing autopsy.
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Fahy L, Rowe S, Nehme Z, Stub D, Zentner D, James P, Pflaumer A, Connell V, Semsarian C, Ingles J, La Gerche A, and Paratz ED
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- Humans, Prospective Studies, Prevalence, Cardiac Catheterization, Autopsy, Treatment Outcome, Foramen Ovale, Patent complications, Foramen Ovale, Patent epidemiology, Heart Septal Defects, Atrial complications, Heart Septal Defects, Atrial epidemiology, Stroke epidemiology, Stroke etiology
- Abstract
Background: Patent foramen ovale (PFO) and atrial septal defects (ASD) have been described in up to 30 % of subjects in autopsy series but contemporary data are scarce. It is important to confirm the prevalence of ASD/PFO in the general population given the potential associated stroke risk and the increasing availability of intervention via PFO closure., Methods: A state-wide prospective out-of-hospital cardiac arrest registry (OHCA) identified all patients aged 1 to 50 years who experienced OHCA in Victoria, Australia from April 2019 to April 2022 and subsequently underwent autopsy with a cardiac cause of death identified. Autopsy was performed including visual description of any ASD and identification of probe patency of foramen ovale., Results: A total of 517 patients underwent autopsy in the setting of sudden cardiac death; 36 patients (6.9 %) had a probe-patent foramen ovale, 2 patients (0.4 %) had secundum ASD, and 2 patients (0.4 %) had both a PFO and ASD (1 of whom had undergone percutaneous repair of both lesions). Twelve patients (2.3 %) had a prior history of cerebrovascular accident either recorded on medical history or detected on neuropathological examination; however none of these patients had a PFO or ASD., Conclusions: The combined rate of PFO and ASD in a cohort of 517 patients undergoing autopsy was 7.9 %. None of these patients had experienced a cerebrovascular accident. This rate of PFOs appears lower than earlier reports and raises the possibility that the relative risk of an associated stroke could be higher than previously estimated., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
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- 2024
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26. Genetic testing in cardiovascular disease.
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Gray MP, Fatkin D, Ingles J, Robertson EN, and Figtree GA
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- Humans, Risk Assessment methods, Cardiovascular Diseases diagnosis, Cardiovascular Diseases genetics, Genetic Predisposition to Disease, Genetic Testing methods
- Abstract
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality globally and is responsible for an estimated one-third of deaths as well as significant morbidity and health care utilisation. Technological and bioinformatic advances have facilitated the discovery of pathogenic germline variants for some specific CVDs, including familial hypercholesterolaemia, cardiomyopathies and arrhythmic syndromes. Use of these genetic tests for earlier disease identification is increasing due, in part, to decreasing costs, Medicare rebates, and consumer comfort with genetic testing. However, CVDs that occur more commonly, including coronary artery disease and atrial fibrillation, do not display monogenic inheritance patterns. Genetically, these diseases have generally been associated with many genetic variants each with a small effect size. This complexity can be expressed mathematically as a polygenic risk score. Genetic testing kits that provide polygenic risk scoring are becoming increasingly available directly to private-paying consumers outside the traditional clinical setting. An improved understanding of the evidence of genetics in CVD will offer clinicians new opportunities for individualised risk prediction and preventive therapy., (© 2024 The Authors. Medical Journal of Australia published by John Wiley & Sons Australia, Ltd on behalf of AMPCo Pty Ltd.)
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- 2024
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27. Clinical interpretation of KCNH2 variants using a robust PS3/BS3 functional patch-clamp assay.
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Thomson KL, Jiang C, Richardson E, Westphal DS, Burkard T, Wolf CM, Vatta M, Harrison SM, Ingles J, Bezzina CR, Kroncke BM, Vandenberg JI, and Ng CA
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- Child, Humans, Death, Sudden, ERG1 Potassium Channel genetics, Heart, Long QT Syndrome diagnosis, Mutation, Missense
- Abstract
Long QT syndrome (LQTS), caused by the dysfunction of cardiac ion channels, increases the risk of sudden death in otherwise healthy young people. For many variants in LQTS genes, there is insufficient evidence to make a definitive genetic diagnosis. We have established a robust functional patch-clamp assay to facilitate classification of missense variants in KCNH2, one of the key LQTS genes. A curated set of 30 benign and 30 pathogenic missense variants were used to establish the range of normal and abnormal function. The extent to which variants reduced protein function was quantified using Z scores, the number of standard deviations from the mean of the normalized current density of the set of benign variant controls. A Z score of -2 defined the threshold for abnormal loss of function, which corresponds to 55% wild-type function. More extreme Z scores were observed for variants with a greater loss-of-function effect. We propose that the Z score for each variant can be used to inform the application and weighting of abnormal and normal functional evidence criteria (PS3 and BS3) within the American College of Medical Genetics and Genomics variant classification framework. The validity of this approach was demonstrated using a series of 18 KCNH2 missense variants detected in a childhood onset LQTS cohort, where the level of function assessed using our assay correlated to the Schwartz score (a scoring system used to quantify the probability of a clinical diagnosis of LQTS) and the length of the corrected QT (QTc) interval., Competing Interests: Declaration of interests M.V. is an employee and stockholder of Invitae Corporation., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2024
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28. Implementation of reimbursement for genomic testing in Australia: early successes and the pathway ahead.
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Mallett AJ, Ingles J, Goranitis I, and Stark Z
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- Humans, Australia, Genetic Testing
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- 2024
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29. Sudden cardiac death in the young: A qualitative study of experiences of family members with cardiogenetic evaluation.
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van den Heuvel L, Do J, Yeates L, Burns C, Semsarian C, and Ingles J
- Subjects
- Humans, Adult, Female, Male, Qualitative Research, Middle Aged, Genetic Counseling, Adolescent, Death, Sudden, Cardiac, Genetic Testing, Family psychology
- Abstract
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., (© 2023 The Authors. Journal of Genetic Counseling published by Wiley Periodicals LLC on behalf of National Society of Genetic Counselors.)
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- 2024
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30. Long-Term Arrhythmic Follow-Up and Risk Stratification of Patients With Desmoplakin-Associated Arrhythmogenic Right Ventricular Cardiomyopathy.
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Gasperetti A, Carrick R, Protonotarios A, Laredo M, van der Schaaf I, Syrris P, Murray B, Tichnell C, Cappelletto C, Gigli M, Medo K, Crabtree P, Saguner AM, Duru F, Hylind R, Abrams D, Lakdawala NK, Massie C, Cadrin-Tourigny J, Targetti M, Olivotto I, Graziosi M, Cox M, Biagini E, Charron P, Casella M, Tondo C, Yazdani M, Ware JS, Prasad S, Calò L, Smith E, Helms A, Hespe S, Ingles J, Tandri H, Ader F, Mestroni L, Wilde A, Merlo M, Gandjbakhch E, Calkins H, Te Riele ASJM, Peter van Tintelen J, Elliot P, and James CA
- Abstract
Background: Patients with likely pathogenic/pathogenic desmoplakin ( DSP ) variants are poorly characterized. Some of them meet diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC), but it is unclear how risk stratification strategies for ARVC perform in this setting., Objectives: The purpose of this study was to characterize arrhythmic outcomes and to test the performance of the recently validated ARVC risk calculator in patients with DSP likely pathogenic/pathogenic variants fulfilling definite 2010 ARVC Task Force Criteria ( DSP -TFC+)., Methods: DSP -TFC+ patients were enrolled from 20 institutions across 3 continents. Ventricular arrhythmias (VA), defined as a composite of sustained ventricular tachycardia (VT), appropriate implantable cardioverter defibrillator therapies, and ventricular fibrillation/sudden cardiac death events in follow-up, were reported as the primary outcome. We tested the performance of the ARVC risk calculator for VA prediction, reporting c-statistics., Results: Among 252 DSP -TFC+ patients (age 39.6 ± 16.9 years, 35.3% male), 94 (37.3%) experienced VA over 44.5 [IQR: 19.6-78.3] months. Patients with left ventricle involvement (n = 194) were at higher VA risk (log-rank P = 0.0239). History of nonsustained VT (aHR 2.097; P = 0.004) showed the strongest association with VA occurrence during the first 5-year follow-up. Neither age ( P = 0.723) nor male sex ( P = 0.200) was associated with VAs at follow-up. In 204 patients without VA at diagnosis, incident VA rate was high (32.8%; 7.37%/y). The ARVC risk calculator performed poorly overall (c-statistic 0.604 [0.594-0.614]) and very poorly in patients with left ventricular disease (c-statistic 0.558 [0.556-0.560])., Conclusions: DSP -TFC+ patients are at substantial risk for VAs. The ARVC risk calculator performs poorly in DSP -TFC+ patients suggesting need for a gene-specific risk algorithm. Meanwhile, DSP -TFC+ patients with nonsustained VT should be considered as high-risk., Competing Interests: The Johns Hopkins ARVC program (Dr James, Gasperetti, Calkins, Carrick, Murray, and Tondo) is supported by the Leonie-Wild Foundation, the Leyla Erkan Family Fund for ARVD Research, the Hugh Calkins, Marvin H. Weiner, and Jacqueline J. Bernstein Cardiac Arrhythmia Center, the Dr Francis P. Chiramonte Private Foundation, the Dr Satish, Rupal, and Robin Shah ARVD Fund at 10.13039/100007880Johns Hopkins, the Bogle Foundation, the Campanella family, the Patrick J. Harrison family, the 10.13039/501100019817Peter French Memorial Foundation, and the Wilmerding Endowments and 10.13039/100000002NIH/10.13039/100006108NCATS UL1 TR003098. ASJMtR and PVT acknowledge support from the Netherlands Cardiovascular Research Initiative, an initiative with support of the Netherlands Heart Foundation, grant nos. CVON2018-30 PREDICT2, CVON2015-12 eDETECT, 2020B005 Double Dose. ASJMtR is supported by the 10.13039/501100001826ZonMW Off-Road Grant 2021. The Zurich ARVC Program is supported by the 10.13039/501100011561Georg und Bertha Schwyzer-Winiker Foundation, 10.13039/501100007252Baugarten Foundation, Wild Foundation, 10.13039/501100001711Swiss National Science Foundation (SNF), and the 10.13039/501100004362Swiss Heart Foundation. The Bologna Cardiomyopathy Registry has received funding support from the 10.13039/501100003196Italian Ministry of Health, RC-2022-2773270 project AAMW received funding from CVON Predict-2. Dr Mestroni is supported by 10.13039/100000002NIH R01HL69071, R01HL116906, R01HL147064, 10.13039/100000002NIH/10.13039/100006108NCATS UL1 TR002535 and UL1 TR001082. Dr Yazdani is supported by 10.13039/501100000274British Heart Foundation FS/CRTF/23/24448 and Alexander Jansons Myocarditis UK. Dr Prasad has received funding from Alexander Jansons Myocarditis UK, 10.13039/501100000833Rosetrees Trust, and 10.13039/501100000274British Heart Foundation. Dr Medo is supported by the 10.13039/100001825Rose Foundation. This work was supported by the 10.13039/501100000265Medical Research Council (UK), 10.13039/501100000274British Heart Foundation [RE/18/4/34215], the 10.13039/501100013342NIHR Imperial College Biomedical Research Centre, the 10.13039/501100000272NIHR Royal Brompton Biomedical Research Centre, and the 10.13039/501100000282Sir Jules Thorn Charitable Trust [21JTA]. Dr Saguner has received educational grants through his institution from Abbott, Bayer Healthcare, Biosense Webster, Biotronik, Boston Scientific, BMS/Pfizer, and Medtronic; and speaker/advisory board/consulting fees from Abbott, Bayer Healthcare, Daiichi-Sankyo, Medtronic, Novartis, and Pfizer. Dr Lakdawala has received unrestricted research support from Pfizer and the O’Hare and Steggall Family Foundations and consulting fees from BMS, Pfizer, Cytokinetics, Sarepta, and Tenaya. Dr Mestroni received educational grant from Greenstone; and advisory board/consulting fees from Tenaya, StrideBio, and Unicure. Dr Gasperetti received advisory board/consulting fees from Lexeo, and has served as an unpaid consultant for StrideBio. Dr James has received research grants from StrideBio Inc and Lexeo Inc; has received advisory board/consulting fees from Pfizer and Lexeo; and has served as an unpaid consultant for StrideBio and Tenaya. Dr Ware has received research support from Bristol-Myers Squibb; and advisory board/consultancy fees from Bristol-Myers Squibb, Foresite Labs, and Pfizer. Dr Calkins is a consultant for Medtronic Inc, Biosense Webster, Pfizer, StrideBio, Rocket, and Abbott. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)
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- 2024
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31. TBX20 loss-of-function variants in families with left ventricular non-compaction cardiomyopathy.
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Chang Y, Wacker J, Ingles J, Macciocca I, King I, Semsarian C, McGaughran J, Weintraub RG, and Bagnall RD
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- Adult, Child, Humans, Mutation, Heart, T-Box Domain Proteins genetics, Cardiomyopathies genetics, Heart Defects, Congenital genetics, Heart Failure genetics
- Abstract
TBX20 encodes a cardiac transcription factor that is associated with atrial septal defects. Recent studies implicate loss-of-function TBX20 variants with left ventricular non-compaction cardiomyopathy (LVNC), although clinical and genetic data in families are limited. We report four families with TBX20 loss-of-function variants that segregate with LVNC. Genetic testing using genome or exome sequencing was performed in index cases, variants were validated with Sanger sequencing, and cascade genetic testing was performed in family members. A multi-exon deletion, small deletion, essential splice site variant and nonsense variant in TBX20 were found in four families. The index cases in two families were symptomatic children with identical congenital heart diseases and LVNC who developed different cardiomyopathy phenotypes with one developing heart failure requiring transplantation. In another family, the child index case had LVNC and congestive heart failure requiring heart transplantation. In the fourth family, the index case was a symptomatic adult with LVNC. In all families, the variants segregated in relatives with isolated LVNC, or with congenital heart disease or cardiomyopathy. Family members displayed a clinical spectrum from asymptomatic to severe presentations including heart failure. Our data strengthen TBX20 loss-of-function variants as a rare cause of LVNC and support TBX20 inclusion in genetic testing of LVNC., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2024
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