ORCID Profile
0000-0002-4846-7676
Current Organisation
Garvan Institute of Medical Research
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Publisher: Elsevier BV
Date: 11-2011
DOI: 10.1016/J.HLC.2011.07.013
Abstract: Inherited gene variants have been implicated increasingly in cardiac disorders but the clinical impact of these discoveries has been variable. For some disorders, such as familial hypertrophic cardiomyopathy, long QT syndrome, and familial hypercholesterolaemia, genetic testing has a high yield and has become an integral part of family management. For other disorders, including dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and atrial fibrillation, relatively less is known about the genes involved and genetic testing has a lower yield. Recent advances in sequencing and array-based technologies promise to change the landscape of our understanding of the genetic basis of human disease and will dramatically increase the rate of detection of genomic variants. Since every in idual is expected to harbour thousands of variants, many of which may be novel, interpretation of the functional significance of any single variant is critical, and should be undertaken by experienced personnel. Genotype results can have a wide range of medical and psychosocial implications for affected and unaffected in iduals and hence, genetic testing should be performed in a specialised cardiac genetic clinic or clinical genetics service where appropriate family management and genetic counselling can be offered.
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1038/GIM.2017.218
Publisher: Elsevier BV
Date: 10-2015
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.HRTHM.2019.05.007
Abstract: Arrhythmogenic cardiomyopathy (ACM) is an arrhythmogenic disorder of the myocardium not secondary to ischemic, hypertensive, or valvular heart disease. ACM incorporates a broad spectrum of genetic, systemic, infectious, and inflammatory disorders. This designation includes, but is not limited to, arrhythmogenic right/left ventricular cardiomyopathy, cardiac amyloidosis, sarcoidosis, Chagas disease, and left ventricular noncompaction. The ACM phenotype overlaps with other cardiomyopathies, particularly dilated cardiomyopathy with arrhythmia presentation that may be associated with ventricular dilatation and/or impaired systolic function. This expert consensus statement provides the clinician with guidance on evaluation and management of ACM and includes clinically relevant information on genetics and disease mechanisms. PICO questions were utilized to evaluate contemporary evidence and provide clinical guidance related to exercise in arrhythmogenic right ventricular cardiomyopathy. Recommendations were developed and approved by an expert writing group, after a systematic literature search with evidence tables, and discussion of their own clinical experience, to present the current knowledge in the field. Each recommendation is presented using the Class of Recommendation and Level of Evidence system formulated by the American College of Cardiology and the American Heart Association and is accompanied by references and explanatory text to provide essential context. The ongoing recognition of the genetic basis of ACM provides the opportunity to examine the erse triggers and potential common pathway for the development of disease and arrhythmia.
Publisher: Elsevier BV
Date: 2020
Publisher: Elsevier BV
Date: 04-2018
DOI: 10.1016/J.HFC.2017.12.001
Abstract: Cardiac genetic testing for inherited cardiomyopathies has become a routine aspect of care. Advances in genetic testing technologies have made testing more comprehensive and affordable. With this increase come greater understanding of the genetic basis of these diseases, but also shines a light on the challenges. Ability to ascertain whether a rare variant is causative of disease is problematic. A genetic diagnosis in a family can offer an invaluable tool for cascade genetic testing of at-risk relatives and avenues for reproductive testing options. A careful approach to cardiac genetic testing that recognizes where there is potential for harm ensures the best possible outcomes for families.
Publisher: Elsevier BV
Date: 04-2020
DOI: 10.1016/J.HLC.2019.11.003
Abstract: At least one-third of adults living with an inherited cardiac condition report clinically-significant levels of psychological distress. Poorer health-related quality of life compared with population norms is also consistently reported. These outcomes are associated with younger patient age, having an implantable cardioverter defibrillator, and receipt of uncertain clinical test results, and can influence self-management behaviours, such as adherence to potentially critical life-preserving medications. According to the Common Sense Model of Illness, people use information from multiple sources to 'make sense' of their health condition, and how they conceptualise the condition can strongly influence adaptation and coping responses. Previous studies with people with inherited cardiac conditions show that illness perceptions, such as greater perceived consequences and a poorer understanding of the condition, are associated with greater psychological distress and poorer adherence to medication. The Common Sense Model provides one potential framework for identifying patients who may be more vulnerable to adverse health outcomes, and for developing early interventions to reduce the physical and psychosocial burden of these conditions. Interventions based on the Common Sense Model have successfully improved physical and psychosocial outcomes associated with other cardiac conditions, and could be tailored for use with patients with an inherited cardiac condition (ICC).
Publisher: Elsevier BV
Date: 10-2013
DOI: 10.1016/J.IJCARD.2013.06.006
Abstract: Sudden cardiac death is a tragic complication of a number of genetic heart diseases. Implantable cardioverter defibrillator (ICD) therapy plays an important role in prevention of sudden death. The psychological consequences of ICD therapy in young people with genetic heart disease are poorly understood. This study sought to better understand psychological wellbeing and identify symptoms of posttraumatic stress in young people who had experienced an ICD shock. Eligible patients (ICD implanted over 12 months prior) with an inherited cardiomyopathy or primary arrhythmogenic disorder, enrolled in the Australian Genetic Heart Disease Registry were included. Ninety patients completed the Hospital Anxiety and Depression Scale (HADS). Those patients who had an ICD shock (n=31) also completed the Impact of Events Scale-Revised (IES-R). While the mean HADS-Anxiety and IES-R scores were within the normal range in the total group (n=90), a significant subgroup reported symptoms of anxiety (38%), depression (17%) and posttraumatic stress (31%) indicative of the potential need for referral to clinical care. Overall, greater psychological distress in ICD patients was associated with female gender, a history of syncope, other comorbid medical conditions, and reporting of other distressing events (i.e., ICD complications). In those with an ICD shock, higher posttraumatic stress scores were associated with female gender and longer time to first shock. Patients with genetic heart diseases can experience psychological difficulties, including anxiety, depression and posttraumatic stress, related to ICD implantation and subsequent shocks. This signals the importance of offering patients access to targeted interventions, including psychological care and support.
Publisher: Elsevier BV
Date: 08-2016
Publisher: Wiley
Date: 19-11-2015
Publisher: Elsevier BV
Date: 04-2005
DOI: 10.1016/J.AMJCARD.2004.12.045
Abstract: In this study, patients with obstructive hypertrophic cardiomyopathy (HC) were treated with dual-chamber pacemaker therapy. Long-term follow-up analysis showed that dual-chamber pacemaker therapy in selected patients resulted in a significant reduction in symptoms and in the left ventricular outflow tract gradient, which was maintained up to 10 years after implantation. Dual-chamber pacing is of potential long-term benefit in selected groups of patients with obstructive HC.
Publisher: Wiley
Date: 30-09-2016
DOI: 10.1007/S10897-016-0017-Z
Abstract: Genetic assessment for inherited cardiovascular disease (CVD) is increasingly available, due in part to rapid innovations in genetic sequencing technologies. While genetic testing is aimed at reducing uncertainty, it also produces awareness of potential medical conditions and can leave patients feeling uncertain about their risk, especially if there are ambiguous results. This uncertainty can produce psychological distress for patients and their families undergoing the assessment process. Additionally, patients may experience psychological distress related to living with inherited CVD. In order to more effectively manage the psychosocial challenges related to genetic assessment for CVD, a multidisciplinary model expanded to include psychologists and other allied health professionals is outlined. A case study is provided to illustrate how psychological distress can manifest in a patient living with inherited CVD, as well as proposed psychological management of this patient. Finally, a guide for genetic counselors is provided to aid in identifying and managing common psychological reactions to genetic assessment for CVD.
Publisher: Elsevier BV
Date: 10-2021
Publisher: Oxford University Press (OUP)
Date: 28-06-2023
Publisher: BMJ
Date: 10-2017
Publisher: Cold Spring Harbor Laboratory
Date: 29-09-2022
DOI: 10.1101/2022.09.28.22280480
Abstract: Sudden cardiac death (SCD) is a devastating event for the family and the community, especially when it occurs in a young person ( years). Genetic heart diseases, including cardiomyopathies and primary arrhythmia syndromes, are an important cause of SCD in the young. Although cardiogenetic evaluation, i.e., 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 eighteen family members of young people ( years old) who died suddenly, including parents, siblings and partners. The interviews were thematically analysed 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 counselling 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.
Publisher: BMJ
Date: 20-04-2016
DOI: 10.1136/BMJ.I1270
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2015
Publisher: Elsevier BV
Date: 08-2014
DOI: 10.1016/J.TCM.2014.05.009
Abstract: Genetic testing is an important and necessary aspect of the management of families with cardiac genetic conditions. Commercial genetic tests are available for most cardiac genetic diseases, and increasing uptake amongst patients has contributed to a vastly improved knowledge of the genetic basis of these diseases. The incredible advances in genetic technologies have translated to faster, more comprehensive, and inexpensive commercial genetic tests and has completely changed the landscape of commercial genetic testing in recent years. While there are enormous challenges, mostly relating to interpretation of variants, the value of a genetic diagnosis should not be underestimated. In almost all cases, the single greatest utility is for the predictive genetic testing of family members. This review will describe the value of cardiac genetic testing in the current climate of rapid genetic advancements.
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.HRTHM.2019.09.019
Abstract: Arrhythmogenic cardiomyopathy (ACM) is an arrhythmogenic disorder of the myocardium not secondary to ischemic, hypertensive, or valvular heart disease. ACM incorporates a broad spectrum of genetic, systemic, infectious, and inflammatory disorders. This designation includes, but is not limited to, arrhythmogenic right/left ventricular cardiomyopathy, cardiac amyloidosis, sarcoidosis, Chagas disease, and left ventricular noncompaction. The ACM phenotype overlaps with other cardiomyopathies, particularly dilated cardiomyopathy with arrhythmia presentation that may be associated with ventricular dilatation and/or impaired systolic function. This expert consensus statement provides the clinician with guidance on evaluation and management of ACM and includes clinically relevant information on genetics and disease mechanisms. PICO questions were utilized to evaluate contemporary evidence and provide clinical guidance related to exercise in arrhythmogenic right ventricular cardiomyopathy. Recommendations were developed and approved by an expert writing group, after a systematic literature search with evidence tables, and discussion of their own clinical experience, to present the current knowledge in the field. Each recommendation is presented using the Class of Recommendation and Level of Evidence system formulated by the American College of Cardiology and the American Heart Association and is accompanied by references and explanatory text to provide essential context. The ongoing recognition of the genetic basis of ACM provides the opportunity to examine the erse triggers and potential common pathway for the development of disease and arrhythmia.
Publisher: Massachusetts Medical Society
Date: 23-06-2016
Publisher: Cold Spring Harbor Laboratory
Date: 21-12-2021
DOI: 10.1101/2021.12.19.21268076
Abstract: Genetic testing for hypertrophic cardiomyopathy (HCM) is considered a key aspect of management. Communication of genetic test results to the proband and their family members, can be a barrier to effective uptake. We hypothesized that a communication aid would facilitate effective communication, and sought to evaluate knowledge and communication of HCM risk to at-risk relatives. This was a prospective randomized controlled trial. Consecutive HCM patients attending a specialized clinic, who agreed to participate, were randomized to the intervention or current clinical practice. The intervention consisted of a genetic counselorled appointment, separate to their clinical cardiology review, and guided by a communication booklet which could be written in and taken home. Current clinical practice was defined as the return of the genetic result by a genetic counselor and cardiologist, often as part of a clinical cardiology review. The primary outcome was the ability and confidence of the in idual to communicate genetic results to at-risk relatives. The a priori outcome of improved communication amongst HCM families did not show statistically significant differences between the control and intervention group, though the majority of probands in the intervention group achieved fair communication (n=13/22) and had higher genetic knowledge scores than those in the control group (7 ± 3 versus 6 ± 3). A total of 29% of at-risk relatives were not informed of a genetic result in their family. Communication amongst HCM families remains challenging, with nearly a third of at-risk relatives not informed of a genetic result. We show a significant gap in the current approach to supporting family communication about genetics. Australian New Zealand Clinical Trials Registry: ACTRN12617000706370 Communication between family members regarding genetic testing can be a barrier to effective uptake. Communication is a challenge in HCM families, with nearly a third of at-risk relatives not informed of a genetic result. There is a significant gap in the current approaches to supporting family communication about genetics.
Publisher: Elsevier BV
Date: 05-2021
Publisher: Springer Science and Business Media LLC
Date: 21-03-2019
Publisher: Elsevier BV
Date: 12-2011
Publisher: Elsevier BV
Date: 05-2013
DOI: 10.1016/J.IJCARD.2011.08.083
Abstract: Health status is an important outcome measure that incorporates multiple dimensions of health, including symptoms, functional status, and psychosocial factors. While health status has been shown to be a predictor for hospital readmission, morbidity and mortality in the heart failure setting, there are limited data in cardiac genetic disease. We examined health status in a number of cardiac genetic disease groups compared to the general Australian population. A total of 409 in iduals were assessed. In iduals with inherited cardiomyopathies [hypertrophic cardiomyopathy (HCM), familial dilated cardiomyopathy (FDC), arrhythmogenic right ventricular cardiomyopathy (ARVC)] and primary arrhythmogenic disorders [long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT)], as well as their first-degree relatives, completed the Medical Outcomes Survey Short Form-36 (SF-36). The physical and mental component scores (PCS and MCS) and SF-6D utility score were assessed. Patients with HCM (p<0.001), FDC (p<0.05), and CPVT (p<0.05) were found to have a significantly lower PCS, while patients with LQTS (p<0.01) had a lower MCS. In iduals at risk of HCM (p<0.0001) and genotype positive-phenotype negative HCM patients (p<0.01) both had a higher PCS and utility scores compared to the clinically affected HCM population. In iduals at risk of LQTS had significantly higher PCS than those with a clinical diagnosis of LQTS (p<0.05) and similarly in iduals at risk of FDC had significantly higher PCS than FDC patients (p<0.05). In HCM, female gender (p=0.002), presence of co-morbidities (p<0.0001) and higher NYHA functional class (p<0.0001) were predictors of a lower PCS. Patients with a clinical diagnosis of a genetic heart disease have an impaired health status, related to both physical and mental function. Clinical management strategies in such patient groups need to consider health status as an important outcome measure.
Publisher: Elsevier BV
Date: 10-2014
Publisher: Oxford University Press (OUP)
Date: 25-08-2023
Publisher: Elsevier BV
Date: 05-2018
Publisher: Wiley
Date: 13-10-2015
DOI: 10.1111/JCE.12827
Abstract: The accurate prediction of the risk of sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM) remains elusive. Corrected QT interval (QTc) duration is a known risk factor in various cardiac conditions. Single nucleotide polymorphisms (SNPs) have been linked to QTc length, and to SCD. Here we investigated the role of 21 candidate SNPs in QTc duration and SCD events in patients with HCM. This HCM registry-based study included patients with an ECG, medical history, first SCD event data, and DNA available. Each in idual SNP was assessed using logistic regression for associations with 2 outcomes: a prolonged QTc ( ≥440 milliseconds), and first SCD event (SCD, resuscitated cardiac arrest, and appropriate implantable cardioverter defibrillator (ICD) shock for ventricular fibrillation/ventricular tachycardia (VF/VT). In 272 HCM patients, there were 31 SCD events (8 SCD, 9 resuscitated cardiac arrest, 14 ICD shocks for VF/VT 11%). A QTc ≥ 500 milliseconds was associated with SCD events on multivariate analysis (odds ratio [OR] = 4.0, 95% confidence interval [CI], 1.19-12.02, P = 0.016). In 228 Caucasian patients, 2 SNPs in the NOS1AP gene (rs10494366 and rs12143842) were associated with a prolonged QTc after correction for multiple testing. This remained significant after adjustment for current age, sex, and ≥1 SCD risk factor (OR 1.59 per copy of the minor allele, 95% CI 1.08-2.39, P = 0.022, and OR 1.63, 95% CI 1.09-2.49, P = 0.020, respectively). No SNPs were directly associated with SCD events. SNPs in the NOS1AP gene influence QTc interval duration but we have not demonstrated a direct association with the risk of SCD.
Publisher: Springer London
Date: 10-2014
Publisher: Elsevier BV
Date: 12-2013
DOI: 10.1038/GIM.2013.44
Abstract: Genetic testing for hypertrophic cardiomyopathy has been commercially available for almost a decade however, low mutation detection rate and cost have hindered uptake. This study sought to identify clinical variables that can predict probands with hypertrophic cardiomyopathy in whom a pathogenic mutation will be identified. Probands attending specialized cardiac genetic clinics across Australia over a 10-year period (2002-2011), who met clinical diagnostic criteria for hypertrophic cardiomyopathy and who underwent genetic testing for hypertrophic cardiomyopathy were included. Clinical, family history, and genotype information were collected. A total of 265 unrelated in iduals with hypertrophic cardiomyopathy were included, with 138 (52%) having at least one mutation identified. The mutation detection rate was significantly higher in the probands with hypertrophic cardiomyopathy with an established family history of disease (72 vs. 29%, P < 0.0001), and a positive family history of sudden cardiac death further increased the detection rate (89 vs. 59%, P < 0.0001). Multivariate analysis identified female gender, increased left-ventricular wall thickness, family history of hypertrophic cardiomyopathy, and family history of sudden cardiac death as being associated with greatest chance of identifying a gene mutation. Multiple mutation carriers (n = 16, 6%) were more likely to have suffered an out-of-hospital cardiac arrest or sudden cardiac death (31 vs. 7%, P = 0.012). Family history is a key clinical predictor of a positive genetic diagnosis and has direct clinical relevance, particularly in the pretest genetic counseling setting.
Publisher: Wiley
Date: 23-09-2017
DOI: 10.1007/S10897-017-0152-1
Abstract: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited arrhythmogenic disease with a high risk of sudden cardiac death. The impact on health-related quality of life (HR-QoL) and psychosocial outcomes is not known. We sought to provide the first description of HR-QoL and psychosocial wellbeing of adults with CPVT, parents of affected children and at-risk relatives. Participants were recruited through the Australian Genetic Heart Disease Registry and invited to complete a cross-sectional survey comprising a number of validated scales and open-ended questions. Thirty-five participants completed surveys (response rate 65%), including 19 with CPVT, 10 unaffected parents of a child with CPVT, and 7 at-risk relatives (one participant considered patient and parent). Young patients <40 years were significantly more likely to report anxiety (p = 0.04), depression (p = 0.03) and posttraumatic stress symptoms (p = 0.02) compared to older CPVT patients. Further, young patients with an implantable cardioverter defibrillator (ICD) reported significantly worse device-related distress (p = 0.04) and shock anxiety (p = 0.003). Patients with a genetic diagnosis had worse psychological adaptation than those patients without a gene result. Parents perceived their affected children to have poor quality of life across all subdomains compared to healthy age-matched children, however quality of life of parents and at-risk relatives was comparable to population norms. Ongoing psychosocial care is required for young people with CPVT. Those with an ICD and/or undergoing genetic testing may require additional support. The challenges of CPVT management should extend beyond the clinical and genetic aspects of care to incorporate greater psychosocial support, and further reinforces the need for a multidisciplinary approach to care.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2015
Publisher: Elsevier BV
Date: 06-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2023
DOI: 10.1161/CIRCULATIONAHA.122.062517
Abstract: The development of left ventricular systolic dysfunction (LVSD) in hypertrophic cardiomyopathy (HCM) is rare but serious and associated with poor outcomes in adults. Little is known about the prevalence, predictors, and prognosis of LVSD in patients diagnosed with HCM as children. Data from patients with HCM in the international, multicenter SHaRe (Sarcomeric Human Cardiomyopathy Registry) were analyzed. LVSD was defined as left ventricular ejection fraction % on echocardiographic reports. Prognosis was assessed by a composite of death, cardiac transplantation, and left ventricular assist device implantation. Predictors of developing incident LVSD and subsequent prognosis with LVSD were assessed using Cox proportional hazards models. We studied 1010 patients diagnosed with HCM during childhood ( years of age) and compared them with 6741 patients with HCM diagnosed as adults. In the pediatric HCM cohort, median age at HCM diagnosis was 12.7 years (interquartile range, 8.0–15.3), and 393 (36%) patients were female. At initial SHaRe site evaluation, 56 (5.5%) patients with childhood-diagnosed HCM had prevalent LVSD, and 92 (9.1%) developed incident LVSD during a median follow-up of 5.5 years. Overall LVSD prevalence was 14.7% compared with 8.7% in patients with adult-diagnosed HCM. Median age at incident LVSD was 32.6 years (interquartile range, 21.3–41.6) for the pediatric cohort and 57.2 years (interquartile range, 47.3–66.5) for the adult cohort. Predictors of developing incident LVSD in childhood-diagnosed HCM included age years at HCM diagnosis (hazard ratio [HR], 1.72 [CI, 1.13–2.62), male sex (HR, 3.1 [CI, 1.88–5.2), carrying a pathogenic sarcomere variant (HR, 2.19 [CI, 1.08–4.4]), previous septal reduction therapy (HR, 2.34 [CI, 1.42–3.9]), and lower initial left ventricular ejection fraction (HR, 1.53 [CI, 1.38–1.69] per 5% decrease). Forty percent of patients with LVSD and HCM diagnosed during childhood met the composite outcome, with higher rates in female participants (HR, 2.60 [CI, 1.41–4.78]) and patients with a left ventricular ejection fraction % (HR, 3.76 [2.16–6.52]). Patients with childhood-diagnosed HCM have a significantly higher lifetime risk of developing LVSD, and LVSD emerges earlier than for patients with adult-diagnosed HCM. Regardless of age at diagnosis with HCM or LVSD, the prognosis with LVSD is poor, warranting careful surveillance for LVSD, especially as children with HCM transition to adult care.
Publisher: Wiley
Date: 17-11-2022
DOI: 10.1002/JGC4.1651
Abstract: Genetic testing for hypertrophic cardiomyopathy (HCM) is considered a key aspect of management. Communication of genetic test results to the proband and their family members, can be a barrier to effective uptake. We hypothesized that a communication aid would facilitate effective communication, and sought to evaluate knowledge and communication of HCM risk to at‐risk relatives. This was a prospective randomized controlled trial. Consecutive HCM patients attending a specialized clinic, who agreed to participate, were randomized to the intervention or current clinical practice. The intervention consisted of a genetic counselor‐led appointment, separate to their clinical cardiology review, and guided by a communication booklet which could be written in and taken home. Current clinical practice was defined as the return of the genetic result by a genetic counselor and cardiologist, often as part of a clinical cardiology review. The primary outcome was the ability and confidence of the in idual to communicate genetic results to at‐risk relatives. The a priori outcome of improved communication among HCM families did not show statistically significant differences between the control and intervention group, though the majority of probands in the intervention group achieved fair communication ( n = 13/22) and had higher genetic knowledge scores than those in the control group (7 ± 3 versus 6 ± 3). A total of 29% of at‐risk relatives were not informed of a genetic result in their family. Communication among HCM families remains challenging, with nearly a third of at‐risk relatives not informed of a genetic result. We show a significant gap in the current approach to supporting family communication about genetics. Australian New Zealand Clinical Trials Registry: ACTRN12617000706370.
Publisher: Elsevier BV
Date: 04-2020
DOI: 10.1016/J.IJCARD.2019.12.059
Abstract: Fabry disease is a rare X-linked genetic disorder in which cardiac manifestations include LVH, contractile dysfunction, and fibrosis, visible on cardiac MRI (cMRI) as late gadolinium enhancement (LGE) of the myocardium. Fabry's disease is an important diagnosis to make as treatment is available as lifelong replacement of the deficient enzyme. To define the prevalence of Fabry disease in a cohort of patients with unexplained LGE on cMRI. The study population was recruited from patients aged >16 years who had cMRI performed between 2010 and 2018 to investigate LVH, idiopathic LV dysfunction and/or idiopathic ventricular arrhythmia. Patients with 'unexplained' LGE i.e. without a genetic diagnosis of an alternate cardiomyopathy such as HCM or biopsy-proven infiltrative cardiomyopathy such as sarcoid or amyloid, were tested for Fabry disease by either genetic testing or the Dried Blood Spot test (Sanofi-Genzyme). Of the 79 patients with unexplained LGE on cMRI, 2 patients tested positive for Fabry disease, both using genetic sequencing techniques. The prevalence of Fabry disease in this selected cohort was 2.5%. Specifically, 1 patient was a 65 year old male and the other patient a 75 year old female. In both cases, the pattern and distribution of LGE on cMRI was of patchy mid-wall enhancement in the inferoseptum. Unexplained LGE on cMRI may be an isolated manifestation of late-onset Fabry disease. This finding should prompt testing for Fabry disease given this is a potentially treatable condition.
Publisher: Elsevier BV
Date: 02-2005
DOI: 10.1016/J.YJMCC.2004.12.006
Abstract: Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disorder caused by mutations in sarcomeric proteins. Cardiac troponin I (cTnI) is a key switch molecule in the sarcomere. Mutations in cTnI have been identified in <1% of genotyped HCM families. To study the prevalence, clinical significance and functional consequences of cTnI mutations, genetic testing was performed in 120 consecutive Australian families with HCM referred to a tertiary referral centre, and results correlated with clinical phenotype. Each cTnI mutation identified was tested in a mammalian two-hybrid system to evaluate the functional effects of these mutations on troponin complex interactions. Disease-causing missense mutations were identified in four families (3.3%). Two mutations were located at the same codon in exon 7 (R162G, R162P), and two in exon 8 (L198P, R204H). All four mutations change amino acid residues which are highly conserved and were not found in normal populations. Follow-up family screening has identified a total of seven clinically affected members in these four families, with a further four members who carry the gene mutation but have no clinical evidence of disease. Age at clinical presentation was variable (range 15-68 years) and the mean septal wall thickness was 19.3 +/- 4.6 mm (range 7-33 mm) in clinically affected in iduals, including children. In all four families, at least one member had a sudden cardiac death event, including previous cardiac arrest, indicating a more malignant form of HCM. All four mutations disrupted functional interactions with troponin C and T and this may account for the increased severity of disease in these families. Gene mutations in cTnI occur in Australian families with HCM with a prevalence higher than previously reported and may be associated with a clinically more malignant course, reflecting significant disruptions to troponin complex interactions.
Publisher: Elsevier BV
Date: 02-2008
Publisher: Elsevier BV
Date: 06-2014
DOI: 10.1016/J.HRTHM.2014.03.017
Abstract: The evolution of genetic testing in the past few years has been astounding. In a matter of only a few years, we now have comprehensive gene tests comprising vast panels of "cardiac" genes, whole exome sequencing (the entire coding region) and even whole genome sequencing (the entire genome). Making the call as to whether a DNA variant is causative or benign is difficult and the focus of intense research efforts. In most cases, the final answer will not be a simple yes/no outcome but rather a graded continuum of pathogenicity. This allows classification of variants in a more probabilistic way. How we convey this to a patient is the challenge, and certainly shines a spotlight on the important skills of the cardiac genetic counselor. This is an exciting step forward, but the overwhelming complexity of the information generated from these tests means our current practices of conveying genetic information to the family must be carefully considered. Despite the challenges, a genetic diagnosis in a family has great benefit both in reassuring unaffected family members and removing the need for lifetime clinical surveillance. The multidisciplinary specialized clinic model, incorporating genetic counselors, cardiologists and geneticists, provides the ideal framework for ensuring the best possible care for genetic heart disease families.
Publisher: Elsevier BV
Date: 12-2008
DOI: 10.1016/J.HLC.2008.05.603
Abstract: A National Genetic Heart Disease Registry has recently been established, with the aim to enroll every family in Australia with a genetically determined cardiomyopathy or primary arrhythmic disorder. The Registry seeks to further our understanding of the impact and burden of disease in this population increase awareness and provide education to health professionals and families and establish a large cardiac genetic cohort as a resource for approved research studies. The Registry is currently recruiting families with inherited cardiomyopathies (e.g. hypertrophic cardiomyopathy) and primary arrhythmogenic disorders (e.g. long QT syndrome), with scope to expand this in the future. Affected in iduals, as well as their first-degree (at-risk) family members are eligible to enroll. Participants are currently being recruited from cardiac genetics clinics in approved recruitment sites and hope to expand to other Australian centres including general cardiology practice in the future. A significant focus of the Registry is to improve understanding and create awareness of inherited heart diseases, which includes ensuring families are aware of genetic testing options and current clinical screening recommendations for at-risk family members. A Registry Advisory Committee has been established under the NHMRC Guidelines, and includes a representative from each major recruitment centre. This committee approves all decisions relating to the Registry including approval of research studies. A National Genetic Heart Disease Registry will provide a valuable resource to further our knowledge of the clinical and genetic aspects of these diseases. Since most of the current data about the prevalence, natural history and outcomes of genetic heart diseases has emanated from the United States and Europe, characterising these Australian populations will be of significant benefit, allowing for more informed and specific health care planning and resource provision.
Publisher: Elsevier BV
Date: 04-2014
DOI: 10.1038/GIM.2013.138
Abstract: Major advances have been made in our understanding and clinical application of genetic testing in hypertrophic cardiomyopathy. Determining pathogenicity of a single-nucleotide variant remains a major clinical challenge. This study sought to reassess single-nucleotide variant classification in hypertrophic cardiomyopathy probands. Consecutive probands with hypertrophic cardiomyopathy with a reported pathogenic mutation or variation of uncertain significance were included. Family and medical history were obtained. Each single-nucleotide variant was reassessed by a panel of four reviewers for pathogenicity based on established criteria together with updated cosegregation data and current population-based allele frequencies. From 2000 to 2012, a total of 136 unrelated hypertrophic cardiomyopathy probands had genetic testing, of which 63 (46%) carried at least one pathogenic mutation. MYBPC3 (n = 34 47%) and MYH7 (n = 23 32%) gene variants together accounted for 79%. Five variants in six probands (10%) were reclassified: two variation of uncertain significance were upgraded to pathogenic, one variation of uncertain significance and one pathogenic variant were downgraded to benign, and one pathogenic variant (found in two families) was downgraded to variation of uncertain significance. None of the reclassifications had any adverse clinical consequences. Given the rapid growth of genetic information available in both disease and normal populations, periodic reassessment of single-nucleotide variant data is essential in hypertrophic cardiomyopathy.
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.IJCARD.2016.12.019
Abstract: Caffeinated energy drinks may trigger serious cardiac effects. The aim of this study was to determine the cardiovascular effects of caffeinated energy drink consumption in patients with familial long QT syndrome (LQTS). From 2014-2016, 24 LQTS patients aged 16-50 years were recruited to a randomized, double-blind, cross-over study of energy drink (ED) versus control (CD) with participants acting as their own controls (one week washout). The primary study outcome was an increase in corrected QT interval (QTc) by >20ms. Secondary outcomes were changes in systolic and diastolic blood pressure. In 24 patients with LQTS (no dropout), mean age was 29±9 years, 13/24 (54%) were female, and 8/24 (33%) were probands. Intention to treat analysis revealed no significant change in QTc with ED compared with CD (12±28ms vs 16±27ms, 3% vs 4%, p=0.71). The systolic and diastolic blood pressure significantly increased with ED compared to CD (peak change 7±16mmHg vs 1±16mmHg, 6% vs 0.8%, p=0.046 and 8±10 vs 2±9mmHg, 11% vs 3% p=0.01 respectively). These changes correlated with significant increases in serum caffeine (14.6±11.3 vs 0.5±0.1μmol/L, p<0.001) and serum taurine (737±199 vs -59±22μmol/L, p<0.001). There were three patients with dangerous QTc prolongation of ≥50ms following energy drink consumption. Caffeinated energy drinks have significant haemodynamic effects in patients with LQTS, especifically an acute increase in blood pressure. Since dangerous QTc prolongation was seen in some LQTS patients, we recommend caution in young patients with LQTS consuming energy drinks.
Publisher: Elsevier BV
Date: 03-2019
Publisher: BMJ
Date: 10-2005
Publisher: Elsevier BV
Date: 07-2018
DOI: 10.1016/J.HRTHM.2018.03.015
Abstract: There is limited evidence that Brugada Syndrome (BrS) is due to SCN1B variants (BrS5). This gene may be inappropriately included in routine genetic testing panels for BrS or Sudden Arrhythmic Death Syndrome (SADS). We sought to characterize the genotype-phenotype correlation in families who had BrS and SADS with reportedly pathogenic SCN1B variants and to review their pathogenicity. Families with BrS and SADS were assessed from 6 inherited arrhythmia centers worldwide, and a comprehensive literature review was performed. Clinical characteristics including relevant history, electrocardiographic parameters and drug provocation testing results were studied. SCN1B genetic testing results were reclassified using American College of Medical Genetics criteria. A total of 23 SCN1B genotype-positive in iduals were identified from 8 families. Four probands (17%) experienced ventricular fibrillation or sudden cardiac death at the time of presentation. All family members were free from syncope or ventricular arrhythmias. Only 2 of 23 genotype-positive in iduals (9%) demonstrated a spontaneous BrS electrocardiographic pattern. Drug challenge testing for BrS in 87% (13 of 15) was negative. There was no difference in PR interval (161 ± 7 ms vs 165 ± 9 ms P = .83), QRS duration (101 ± 6 ms vs 89 ± 5 ms P = .35), or corrected QT interval (414 ± 35 ms vs 405 ± 8 ms P = .7) between genotype-positive and genotype-negative family members. The overall frequency of previously implicated SCN1B variants in the Genome Aggregation Database browser is 0.004%, exceeding the estimated prevalence of BrS owing to SCN1B (0.0005%), including 15 of 23 in iduals (65%) who had the p.Trp179X variant. The lack of genotype-phenotype concordance among families, combined with the high frequency of previously reported mutations in the Genome Aggregation Database browser, suggests that SCN1B is not a monogenic cause of BrS or SADS.
Publisher: Elsevier BV
Date: 04-2013
Publisher: Elsevier BV
Date: 10-2013
Publisher: Elsevier BV
Date: 2012
Publisher: Cold Spring Harbor Laboratory
Date: 15-12-2021
DOI: 10.1101/2021.12.13.472492
Abstract: Modern sequencing technologies have revolutionised our detection of gene variants. In most genes, including KCNH2 , the majority of missense variants are currently classified as variants of uncertain significance (VUS). The aim of this study is to investigate the utility of an automated patch-cl assay for aiding clinical variant classification in the KCNH2 gene. The assay was designed according to recommendations of the ClinGen sequence variant interpretation framework. Thirty-one control variants of known clinical significance (17 pathogenic/likely pathogenic, 14 benign/likely benign) were heterozygously expressed in Flp-In HEK293 cells. Variants were analysed for effects on current density and channel gating. A panel of 44 VUS was then assessed for reclassification. All 17 pathogenic variant controls had reduced current density and 13/14 benign variant controls had normal current density, which enabled determination of normal and abnormal ranges for applying moderate or supporting evidence strength for variant classification. Inclusion of KCNH2 functional assay evidence enabled us to reclassify 6 out of 44 VUS as likely pathogenic. The high-throughput patch cl assay can provide moderate strength evidence for clinical interpretation of clinical KCNH2 variants and demonstrates the value proposition for developing automated patch cl assays for other ion channel genes.
Publisher: JMIR Publications Inc.
Date: 05-2023
Abstract: enetic heart diseases such as hypertrophic cardiomyopathy can cause significant morbidity and mortality, ranging from syncope, chest pain and palpitations to heart failure and sudden cardiac death. These diseases are inherited in an autosomal dominant fashion, meaning family members of affected in iduals have a one in two chance of also inheriting the disease (‘at-risk relatives’). The healthcare utilisation patterns of in iduals with a genetic heart disease including emergency department presentations and hospital admissions, are poorly understood. By linking genetic heart disease registry data to routinely collected health data we aim to provide a more comprehensive clinical dataset to examine the burden of disease on in iduals, families and healthcare systems. he objective of this study is to link the Australian Genetic Heart Disease (AGHD) Registry with routinely collected whole-population health datasets to investigate the healthcare utilisation of in iduals with a genetic heart disease and their at-risk relatives. This linked dataset will allow for investigation of differences in outcomes and healthcare utilisation due to disease, sex, socioeconomic status and other factors. he AGHD Registry is a nationwide dataset which began in 2007 and aims to recruit in iduals with a genetic heart disease and their family members. In this study, demographic, clinical, and genetic data (available 2007-2019) for AGHD Registry participants and at-risk relatives residing in New South Wales (NSW) Australia, were linked to routinely collected health data. These data included NSW based datasets covering hospitalisations (2001-2019) and emergency department presentations (2005-2019), and both state-wide and national mortality registries (2007-2019). The linkage was performed by the Centre for Health Record Linkage (CHeReL). Investigations stratifying by diagnosis, age, sex, socioeconomic status and gene status will be undertaken and reported using descriptive statistics. SW AGHD Registry participants were linked to routinely collected health datasets using probabilistic matching (November 2019). Of 1720 AGHD Registry participants, 1384 had linkages with 11,610 hospital records, 7032 emergency department records and 60 death records. Data assessment and harmonisation were performed, and descriptive data analysis is underway. e intend to provide insights into the healthcare utilisation patterns of in iduals with a genetic heart disease and their at-risk relatives, including frequency of hospital admissions and differences due to factors such as disease, sex and socioeconomic status. Identifying disparities and potential barriers to care may highlight specific healthcare needs (e.g. between sexes) and factors impacting healthcare access and utilisation. > ERR1-10.2196/48636
Publisher: Elsevier BV
Date: 10-2017
DOI: 10.1038/GIM.2017.15
Abstract: Sudden death in the young is a devastating complication of inherited heart disorders. Finding the precise cause of death is important, but it is often unresolved after postmortem investigation. The addition of postmortem genetic testing, i.e., the molecular autopsy, can identify additional causes of death. We evaluated DNA extracted from formalin-fixed paraffin-embedded postmortem tissue for exome sequencing-based molecular autopsy after sudden death in the young. We collected clinical and postmortem information from patients with sudden death. Exome sequencing was performed on DNA extracted from fixed postmortem tissue. Variants relevant to the cause of death were sought. Five patients with genetically unresolved sudden death were recruited. DNA extracted from fixed postmortem tissue was degraded. Exome sequencing achieved 20-fold coverage of at least 82% of coding regions. A threefold excess of singleton variants was found in the exome sequencing data of one patient. We found a de novo SCN1A frameshift variant in a patient with sudden unexpected death in epilepsy and a LMNA nonsense variant in a patient with dilated cardiomyopathy. DNA extracted from fixed postmortem tissue is applicable to exome sequencing-based molecular autopsy. Fixed postmortem tissues are an untapped resource for exome-based studies of rare causes of sudden death.Genet Med advance online publication 23 March 2017.
Publisher: Elsevier BV
Date: 06-2008
DOI: 10.1016/J.IJCARD.2007.05.001
Abstract: The cause of sudden death in young people remains unknown in up to 50% of postmortem cases. Mutations in the ion channel genes are known to cause primary arrhythmogenic disorders such as long QT and Brugada syndromes, which can present with sudden cardiac death and a negative autopsy. In this study, 59 sudden unexplained deaths occurring in Australians aged </=35 years with a negative autopsy, from 1994-2002, were studied. Genomic DNA was extracted from paraffin-embedded tissues. Genetic analysis of the KCNQ1 and SCN5A genes was performed using denaturing high-performance liquid chromatography and direct DNA sequencing. Nine DNA sequence variants were identified in the KCNQ1 gene and 9 sequence variants were identified in the SCN5A gene. In total, 23 out of 59 cases were found to have at least one DNA variant in KCNQ1 or SCN5A, of which one, H558R in the SCN5A gene, caused an amino acid substitution. None of the DNA variants were determined to be disease causing as they were also identified in control populations. In conclusion, no disease-causing mutations were found in the KCNQ1 or SCN5A genes in this cohort. A more selective screening approach, including only in iduals with a clinical or family history of arrhythmogenic disorders, may yield greater success in identifying disease-causing mutations in cohorts of young in iduals who have died suddenly.
Publisher: Elsevier BV
Date: 05-2004
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2019
DOI: 10.1161/CIRCGEN.118.002368
Abstract: MYBPC3 splicing errors are a common cause of hypertrophic cardiomyopathy (HCM). Variants affecting essential splice-site dinucleotides inhibit splicing, whereas the impact of variants at conserved flanking nucleotides is less clear. We evaluated the contribution of MYBPC3 splice-site variants in a large cohort of patients with HCM and assessed the impact on splicing with RNA analysis. Patients attending a specialized multidisciplinary clinic, with a clinical diagnosis of HCM and genetic testing of at least 46 cardiomyopathy-associated genes, were included. Patients with variants in MYBPC3 splice sites with in silico-predicted effects on splicing were selected. RNA was extracted from fresh venous blood or paraffin-embedded myocardial tissue of the patients, lified, and sequenced. Variants were classified for pathogenicity using the American College of Medical Genetics and Genomics guidelines. We found 29 rare MYBPC3 splice-site variants in 56 of 557 (10%) unrelated HCM probands. Three variants were not predicted to alter RNA splicing, and 13 essential splice dinucleotide, nonsense, and short insertion or deletion variants were not further assessed. RNA analysis was performed on 9 variants (c.654+5G C, c.772G A, c.821+3G T, c.927-9G A, c.1090G A, c.1624G A, c.1624+4A T, c.3190+5G A, and c.3491-3C G), and RNA splicing errors were confirmed for 7. Four variants in 4 families resulted in clinically meaningful reclassifications. After RNA analysis, 4 of 56 (7%) families with MYBPC3 splice-site variants were reclassified from uncertain clinical significance to likely pathogenic. RNA analysis of splice-site variants can assist in understanding pathogenicity and increase the diagnostic yield of genetic testing in HCM.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2017
DOI: 10.1161/CIRCGENETICS.116.001666
Abstract: Multiple likely pathogenic athogenic (LP/P ≥2) variants in patients with hypertrophic cardiomyopathy were described 10 years ago with a prevalence of 5%. We sought to re-examine the significance of multiple rare variants in patients with hypertrophic cardiomyopathy in the setting of comprehensive and targeted panels. Of 758 hypertrophic cardiomyopathy probands, we included 382 with ≥45 cardiomyopathy genes screened. There were 224 (59%) with ≥1 rare variant (allele frequency ≤0.02%). Variants were analyzed using varying sized gene panels to represent comprehensive or targeted testing. Based on a 45-gene panel, 127 (33%) had a LP/P variant, 139 (36%) had variants of uncertain significance, and 66 (17%) had multiple rare variants. A targeted 8-gene panel yielded 125 (32%) LP/P variants, 52 (14%) variants of uncertain significance, and 14 (4%) had multiple rare variants. No proband had 2 LP/P variants. Including affected family members (total n=412), cluster-adjusted analyses identified a phenotype effect, with younger age (odds ratio, 0.95 95% confidence interval, 0.92–0.98 P =0.004) and family history of sudden cardiac death (odds ratio, 3.5 95% confidence interval, 1.3–9.9 P =0.02) significantly more likely in multiple versus single variant patients when considering an 8-gene panel but not larger panels. Those with multiple variants had worse event-free survival from all-cause death, cardiac transplantation, and cardiac arrest (log-rank P =0.008). No proband had multiple LP/P variants in contrast to previous reports. However, multiple rare variants regardless of classification were seen in 4% and contributed to earlier disease onset and cardiac events. Our findings support a cumulative variant hypothesis in hypertrophic cardiomyopathy.
Publisher: Elsevier BV
Date: 06-2019
Publisher: Oxford University Press (OUP)
Date: 26-03-2021
DOI: 10.1093/EURHEARTJ/EHAB148
Abstract: Childhood-onset hypertrophic cardiomyopathy (HCM) is far less common than adult-onset disease, thus natural history is not well characterized. We aim to describe the characteristics and outcomes of childhood-onset HCM. We performed an observational cohort study of 7677 HCM patients from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). Hypertrophic cardiomyopathy patients were stratified by age at diagnosis [& year (infancy), 1–18 years (childhood), & years (adulthood)] and assessed for composite endpoints reflecting heart failure (HF), life-threatening ventricular arrhythmias, atrial fibrillation (AF), and an overall composite that also included stroke and death. Stratifying by age of diagnosis, 184 (2.4%) patients were diagnosed in infancy 1128 (14.7%) in childhood and 6365 (82.9%) in adulthood. Childhood-onset HCM patients had an ∼2%/year event rate for the overall composite endpoint, with ventricular arrhythmias representing the most common event in the 1st decade following baseline visit, but HF and AF becoming more common by the end of the 2nd decade. Sarcomeric variants were more common in childhood-onset HCM (63%) and carried a worse prognosis than non-sarcomeric disease, including a greater than two-fold increased risk of HF [HRadj 2.39 (1.36–4.20), P = 0.003] and 67% increased risk of the overall composite outcome [HRadj 1.67 (1.16–2.41), P = 0.006]. When compared with adult-onset HCM, childhood-onset was 36% more likely to develop life-threatening ventricular arrhythmias [HRadj 1.36 (1.03–1.80)] and twice as likely to require transplant or ventricular assist device [HRadj 1.99 (1.23–3.23)]. Patients with childhood-onset HCM are more likely to have sarcomeric disease, carry a higher risk of life-threatening ventricular arrythmias, and have greater need for advanced HF therapies. These findings provide insight into the natural history of disease and can help inform clinical risk stratification.
Publisher: Springer Science and Business Media LLC
Date: 03-09-2021
DOI: 10.1007/S11897-021-00526-X
Abstract: We explore the sex-specific interaction of genetics and the environment on the clinical course and outcomes of hypertrophic cardiomyopathy (HCM). Women account for approximately one-third of patients in specialist HCM centres and reported in observational studies. As a result, evidence informing clinical guideline recommendations is based predominantly on risk factors and outcomes seen in men. However, disease progression appears to be different between the sexes. Women present at a more advanced stage of disease, are older at diagnosis, have higher symptom burden, carry greater risk for heart failure and are at greater risk of mortality compared to men. Women are more likely to be gene-positive, while men are more likely to be gene-negative. The risk of sudden cardiac death and access to specialised care do not differ between the sexes. Reporting sex-disaggregated results is essential to identify the mechanisms leading to sex differences in HCM.
Publisher: Oxford University Press (OUP)
Date: 29-08-2022
Abstract: The causes, circumstances, and preventability of young sudden cardiac arrest remain uncertain. A prospective state-wide multi-source registry identified all out-of-hospital cardiac arrests (OHCAs) in 1–50 year olds in Victoria, Australia, from 2019 to 2021. Cases were adjudicated using hospital and forensic records, clinic assessments and interviews of survivors and family members. For confirmed cardiac causes of OHCA, circumstances and cardiac history were collected. National time-use data was used to contextualize circumstances. 1319 OHCAs were included. 725 (55.0%) cases had a cardiac aetiology of OHCA, with coronary disease (n = 314, 23.8%) the most common pathology. Drug toxicity (n = 226, 17.1%) was the most common non-cardiac cause of OHCA and the second-most common cause overall. OHCAs were most likely to occur in sleep (n = 233, 41.2%). However, when compared to the typical Australian day, OHCAs occurred disproportionately more commonly during exercise (9% of patients vs. 1.3% of typical day, P = 0.018) and less commonly while sedentary (39.6 vs. 54.6%, P = 0.047). 38.2% of patients had known standard modifiable cardiovascular risk factors. 77% of patients with a cardiac cause of OHCA had not reported cardiac symptoms nor been evaluated by a cardiologist prior to their OHCA. Approximately half of OHCAs in the young have a cardiac cause, with coronary disease and drug toxicity dominant aetiologies. OHCAs disproportionately occur during exercise. Of patients with cardiac cause of OHCA, almost two-thirds have no standard modifiable cardiovascular risk factors, and more than three-quarters had no prior warning symptoms or interaction with a cardiologist.
Publisher: BMJ
Date: 2019
DOI: 10.1136/BMJOPEN-2018-026627
Abstract: Genetic testing for hypertrophic cardiomyopathy (HCM) in the era of genomics brings unique challenges for genetic counselling. The number of genes routinely included in an HCM gene panel has increased markedly, many with minimal if any robust evidence of gene–disease association. Subsequently, there is a greater chance of uncertain genetic findings. The responsibility of communicating this information with at-risk relatives lies with the index case (proband). We have developed a communication aid to assist with the delivery of genetic results to the proband. We have previously shown the aid is feasible and acceptable and have now developed a study protocol for a randomised controlled trial of a genetic counsellor-led intervention incorporating the communication aid. This is a prospective randomised controlled trial. We will investigate the impact of a genetic counsellor-led intervention to return proband genetic results using a custom-designed communication aid. We aim to improve knowledge and empowerment. The primary outcome of this trial is the ability and confidence of the proband to communicate genetic results to at-risk relatives. Secondary outcomes will assess genetic knowledge, satisfaction with services, outcomes from genetic counselling and psychological adaptation to genetic information. This study has been approved by and is in strict accordance with the Sydney Local Health District Ethics Review Committee (X16-0030 22/01/2016 version 1). Results from this trial will be prepared as a manuscript and submitted to peer-reviewed journals for publication as well as submission for presentation at national and international meetings. ACTRN12617000706370.
Publisher: American Medical Association (AMA)
Date: 03-2016
Publisher: Elsevier BV
Date: 11-2022
DOI: 10.1016/J.JACC.2022.09.029
Abstract: Genetic testing following sudden cardiac death (SCD) is currently guided by autopsy findings, despite the inherent challenges of autopsy examination and mounting evidence that malignant arrhythmia may occur before structural changes in inherited cardiomyopathy, so-called "concealed cardiomyopathy" (CCM). The authors sought to identify the spectrum of genes implicated in autopsy-inconclusive SCD and describe the impact of identifying CCM on the ongoing care of SCD families. Using a standardized framework for adjudication, autopsy-inconclusive SCD cases were identified as having a structurally normal heart or subdiagnostic findings of uncertain significance on autopsy. Genetic variants were classified for pathogenicity using the American College of Medical Genetics and Genomics guidelines. Family follow-up was performed where possible. Twenty disease-causing variants were identified among 91 autopsy-inconclusive SCD cases (mean age 25.4 ± 10.7 years) with a similar rate regardless of the presence or absence of subdiagnostic findings (25.5% vs 18.2% P = 0.398). Cardiomyopathy-associated genes harbored 70% of clinically actionable variants and were overrepresented in cases with subdiagnostic structural changes at autopsy (79% vs 21% P = 0.038). Six of the 20 disease-causing variants identified were in genes implicated in arrhythmogenic cardiomyopathy. Nearly two-thirds of genotype-positive relatives had an observable phenotype either at initial assessment or subsequent follow-up, and 27 genotype-negative first-degree relatives were released from ongoing screening. Phenotype-directed genetic testing following SCD risks under recognition of CCM. Comprehensive evaluation of the decedent should include assessment of genes implicated in cardiomyopathy in addition to primary arrhythmias to improve diagnosis of CCM and optimize care for families.
Publisher: BMJ
Date: 08-2022
DOI: 10.1136/BMJOPEN-2021-053785
Abstract: To codesign an online support intervention for families after sudden cardiac death (SCD) in the young ( years). Codesign of an SCD family intervention by stakeholder focus groups. Families and healthcare professionals with experience in SCD in the young. Semistructured online focus groups were held with key stakeholders, that is, family members who had experienced young SCD, healthcare professionals and researchers based in New South Wales, Australia. Guided discussions were used to develop an online support intervention. Thematic analysis of discussions and iterative feedback on draft materials guided content development. Four focus groups were held (4–6 participants per group, 12 unique participants). Stakeholder involvement facilitated development of high-level ideas and priority issues. Creative content and materials were developed based on user preference for stories, narratives and information reflecting everyday experience of families navigating the legal and medical processes surrounding SCD, normalising and supporting grief responses in the context of family relationships and fostering hope. Emphasis on accessibility led to the overarching need for digital information and online engagement. These insights allowed development of an online intervention—COPE-SCD: A COmmunity suPporting familiEs after Sudden Cardiac Death—which includes a website and online support programme. Using codesign with stakeholders we have developed a support intervention that addresses the needs of SCD families and aims to fill a large gap in existing healthcare. We will evaluate COPE-SCD to determine whether this is an effective intervention for support of families following a young SCD.
Publisher: Wiley
Date: 22-02-2018
DOI: 10.1007/S10897-018-0218-8
Abstract: Families with a history of hypertrophic cardiomyopathy (HCM) may be offered genetic testing in addition to clinical surveillance. Asymptomatic family members who are gene positive (silent gene carriers) represent a new group of "patients" who may not develop HCM, with little evidence available to assist clinical management. This study explored experiences of HCM genetic testing to identify potential benefits and harms. Thirty-two in iduals previously offered genetic testing for HCM were recruited. Semi-structured interviews were conducted face-to-face or by phone, and transcribed audio-recordings were coded using framework analysis. Key themes were as follows: (1) helping the next generation, (2) misunderstanding risk, (3) discrepancy between actual erceived impact. Participants described multiple psychological (shock, worry, uncertainty) and behavioural (career, sport, insurance, family planning) consequences, depending on perceived risk. Most considered only the benefits of genetic testing for children or grandchildren, but there were some cases of significant adverse impact. The interpretation of the HCM genetic test result is variable for silent gene carriers and can lead to psychological and behavioural changes. The impact of a positive gene result may be mitigated by increased clarity of the clinical consequences and efforts to ensure informed decision-making, highlighting even further the important role of cardiac genetic counselling.
Publisher: Cold Spring Harbor Laboratory
Date: 29-04-2021
DOI: 10.1101/2021.04.26.21256086
Abstract: Genetic heart diseases often affect young people, can be clinically heterogeneous and pose an increased risk of sudden cardiac death (SCD). The implantable cardioverter defibrillator (ICD) is a lifesaving therapy. Impacts on prospective and long-term psychological and health-related quality of life (HR-QoL) after ICD implant in patients with genetic heart diseases are unknown. We investigate the psychological functioning and HR-QoL over time in patients with genetic heart diseases who receive an ICD, and identify risk factors for poor psychological functioning and HR-QoL. A longitudinal, prospective study design was used. Patients attending a specialised clinic and diagnosed with a genetic heart disease, for which they received an ICD between May 2012 and January 2015, were eligible. Baseline surveys were completed prior to ICD implantation with five-year follow-up after ICD implant. We measured psychological functioning (Hospital Anxiety Depression Scale, Florida Shock Anxiety Scale), HR-QoL (Short-Form 36v2) and device acceptance (Florida Patient Acceptance Scale). There were 40 patients with an inherited cardiomyopathy or arrhythmia syndrome included (mean age 46.3 ± 14.2 years 65.0% males). Mean psychological and HR-QoL measures were within normative ranges during follow-up. After 12 months, 33.3% and 19.4% of participants showed clinically elevated levels of anxiety and depression, respectively. Longitudinal mixed effect analysis showed significant improvements from baseline to first follow-up for the overall cohort, with variability increasing after 36 months. Low education and female gender predicted worse mental HR-QoL and anxiety over time, while comorbidities predicted depression and worse physical HR-QoL. While the majority of patients with a genetic heart disease adjust well to their ICD implant, a subset of patients’ experience poor psychological and HR-QoL outcomes.
Publisher: AMPCo
Date: 30-07-2018
DOI: 10.5694/MJA17.01183
Abstract: To quantify the number of implantable cardioverter-defibrillator (ICD) procedures in Australia by year, patient age and sex, and to estimate age group-specific population rates and the associated costs. Design, setting: Retrospective observational study analysis of Australian National Hospital Morbidity Database hospital procedures data. Patients with an ICD insertion, replacement, adjustment, or removal procedure code, July 2002 - June 2015. Number of ICD procedures by procedure year, patient age (0-34, 35-69, 70 years or more) and sex age group-specific population procedure rates number of procedures associated with complications. The number of ICD procedures increased from 1844 in 2002-03 to 6504 in 2014-15 more than 75% of procedures were in men. In 2014-15, the ICD insertion rate for people aged 70 years or more was 78.1 per 100 000 population, 22 per 100 000 for those aged 35-69 years, and 1.40 per 100 000 people under 35. The reported complication rate decreased from 45% in 2002-03 to 19% in 2014-15, partly because of a change in the coding of complications. The number of removals corresponded to at least 4% of the number of insertions each year. The aggregate cost of hospitalisations with an ICD procedure during 2011-14 was $445 644 566. ICD procedures are becoming more frequent in Australia, particularly in people aged 70 or more. Patterns of care associated with ICD therapy, particularly patient- and hospital-related factors associated with adverse events, should be investigated to better understand and improve patient outcomes.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 28-04-2020
DOI: 10.1161/CIRCULATIONAHA.119.044366
Abstract: The term “end stage” has been used to describe hypertrophic cardiomyopathy (HCM) with left ventricular systolic dysfunction (LVSD), defined as occurring when left ventricular ejection fraction is %. The prognosis of HCM-LVSD has reportedly been poor, but because of its relative rarity, the natural history remains incompletely characterized. Data from 11 high-volume HCM specialty centers making up the international SHaRe Registry (Sarcomeric Human Cardiomyopathy Registry) were used to describe the natural history of patients with HCM-LVSD. Cox proportional hazards models were used to identify predictors of prognosis and incident development. From a cohort of 6793 patients with HCM, 553 (8%) met the criteria for HCM-LVSD. Overall, 75% of patients with HCM-LVSD experienced clinically relevant events, and 35% met the composite outcome (all-cause death [n=128], cardiac transplantation [n=55], or left ventricular assist device implantation [n=9]). After recognition of HCM-LVSD, the median time to composite outcome was 8.4 years. However, there was substantial in idual variation in natural history. Significant predictors of the composite outcome included the presence of multiple pathogenic/likely pathogenic sarcomeric variants (hazard ratio [HR], 5.6 [95% CI, 2.3–13.5]), atrial fibrillation (HR, 2.6 [95% CI, 1.7–3.5]), and left ventricular ejection fraction % (HR, 2.0 [95% CI, 1.3–2.8]). The incidence of new HCM-LVSD was ≈7.5% over 15 years. Significant predictors of developing incident HCM-LVSD included greater left ventricular cavity size (HR, 1.1 [95% CI, 1.0–1.3] and wall thickness (HR, 1.3 [95% CI, 1.1–1.4]), left ventricular ejection fraction of 50% to 60% (HR, 1.8 [95% CI, 1.2, 2.8]–2.8 [95% CI, 1.8–4.2]) at baseline evaluation, the presence of late gadolinium enhancement on cardiac magnetic resonance imaging (HR, 2.3 [95% CI, 1.0–4.9]), and the presence of a pathogenic/likely pathogenic sarcomeric variant, particularly in thin filament genes (HR, 1.5 [95% CI, 1.0–2.1] and 2.5 [95% CI, 1.2–5.1], respectively). HCM-LVSD affects ≈8% of patients with HCM. Although the natural history of HCM-LVSD was variable, 75% of patients experienced adverse events, including 35% experiencing a death equivalent an estimated median time of 8.4 years after developing systolic dysfunction. In addition to clinical features, genetic substrate appears to play a role in both prognosis (multiple sarcomeric variants) and the risk for incident development of HCM-LVSD (thin filament variants).
Publisher: Oxford University Press (OUP)
Date: 16-06-2022
Abstract: Sports Cardiology practice commonly involves the evaluation of athletes for genetically determined cardiac conditions that may predispose to malignant arrhythmias, heart failure, and sudden cardiac death. High-level exercise can lead to electrical and structural cardiac remodelling which mimics inherited cardiac conditions (ICCs). Differentiation between 'athlete's heart' and pathology can be challenging and often requires the whole armamentarium of available investigations. Genetic studies over the last 30 years have identified many of the genetic variants that underpin ICCs and technological advances have transformed genetic testing to a more readily available and affordable clinical tool which may aid diagnosis, management, and prognosis. The role of genetic testing in the evaluation and management of athletes with suspected cardiac conditions is often unclear beyond the context of specialist cardio-genetics centres. This document is aimed at physicians, nurses, and allied health professionals involved in the athlete's care. With the expanding role and availability of genetic testing in mind, this document was created to address the needs of the broader sports cardiology community, most of whom work outside specialized cardio-genetics centres, when faced with the evaluation and management of athletes with suspected ICC. The first part of the document provides an overview of basic terminology and principles and offers guidance on the appropriate use of genetic testing in the assessment of such athletes. It outlines key considerations when contemplating genetic testing, highlighting the potential benefits and pitfalls, and offers a roadmap to genetic testing. The second part of the document presents common clinical scenarios in Sports Cardiology practice, outlining the diagnostic, prognostic, and therapeutic implications of genetic testing, including impact on exercise recommendations. The scope of this document does not extend to a comprehensive description of the genetic basis, investigation, or management of ICCs.
Publisher: Wiley
Date: 06-11-2016
DOI: 10.1002/AJMG.A.37455
Abstract: Ongoing challenges of clinical assessment of long QT syndrome (LQTS) highlight the importance of genetic testing in the diagnosis of asymptomatic at-risk family members. Effective access, uptake, and communication of genetic testing are critical for comprehensive cascade family screening and prevention of disease complications such as sudden cardiac death. The aim of this study was to describe factors influencing uptake of LQTS genetic testing, including those relating to access and family communication. We show those who access genetic testing are overrepresented by the socioeconomically advantaged, and that although overall family communication is good, there are some important barriers to be addressed. There were 75 participants (aged 18 years or more, with a clinical and/or genetic diagnosis of LQTS response rate 71%) who completed a survey including a number of validated scales demographics and questions about access, uptake, and communication. Mean age of participants was 46 ± 16 years, 20 (27%) were males and 60 (80%) had genetic testing with a causative gene mutation in 42 (70%). Overall uptake of cascade testing within families was 60% after 4 years from proband genetic diagnosis. All participants reported at least one first-degree relative had been informed of their risk, whereas six (10%) reported at least one first-degree relative had not been informed. Those who were anxious or depressed were more likely to perceive barriers to communicating. Genetic testing is a key aspect of care in LQTS families and intervention strategies that aim to improve equity in access and facilitate effective family communication are needed.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-02-2020
Publisher: Wiley
Date: 15-03-2016
Publisher: Cold Spring Harbor Laboratory
Date: 26-10-2021
DOI: 10.1101/2021.10.16.21264154
Abstract: Truncating variants in desmoplakin ( DSP tv) are an important cause of arrhythmogenic cardiomyopathy (ACM), however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics of DSP tv cardiomyopathy. In iduals with DSP tv and any cardiac phenotype, and their gene-positive family members were included from multiple international centers. Clinical data and family history information were collected. Event-free survival from ventricular arrhythmia was assessed. Variant location was compared between cases and controls, and literature review of reported DSP tv performed. There were 98 probands and 72 family members (mean age at diagnosis 43 ± 18 years, 59% female) with a DSP tv, of which 146 were considered clinically affected. Ventricular arrhythmia (sudden cardiac arrest, sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator therapy) occurred in 56 (33%) in iduals. DSP tv location and proband status were independent risk factors for ventricular arrhythmia, while prior risk factors showed no association. Further, gene region was important with variants in cases (cohort n=98, Clinvar n=168) more likely to occur in the regions resulting in nonsense mediated decay of both major DSP isoforms, compared to n=124 gnomAD control variants (148 [83.6%] versus 29 [16.4%], p .0001). In the largest series of in iduals with DSP tv, we demonstrate variant location is a novel risk factor for ventricular arrhythmia, can inform variant interpretation, and provide critical insights to allow precision-based clinical management.
Publisher: Informa UK Limited
Date: 2006
DOI: 10.1080/10425170600724998
Abstract: Hypertrophic cardiomyopathy (HCM) is a genetically heterogenous disease caused by mutations in genes that primarily encode sarcomeric proteins. No mutation is identified in up to 40% of HCM patients, suggesting other causative genes exist. Natriuretic peptide precursor B (NPPB also known as "BNP") is a cardiac hormone involved in body fluid homeostasis and cardiac myocyte growth. NPPB concentrations are markedly increased in patients with ventricular hypertrophy, and it is therefore possible mutations in the NPPB gene could cause HCM. Genomic DNA was extracted from peripheral blood in 238 consecutive probands with HCM. The coding regions and intron/exon boundaries in the NPPB gene were lified by PCR, and products were screened for sequence variants using high-performance liquid chromatography, followed by direct DNA sequencing. Four sequence variants in the NPPB gene were identified in 9 of the 238 probands screened. Two of the variants were intronic, one was a synonymous variant at codon 79, and the final variant resulted in an amino acid substitution from arginine to histidine at codon 47 (Arg47His). The Arg47His variant was identified in a control population consisting of 204 chromosomes at an allelic frequency of 0.5%, and is therefore unlikely to cause disease. No disease causing mutations were identified in the NPPB gene in this cohort, indicating that mutations in this gene are unlikely to be responsible for HCM.
Publisher: Elsevier BV
Date: 07-2018
DOI: 10.1016/J.JACC.2018.04.078
Abstract: Whole genome sequencing (WGS) is a comprehensive genetic testing approach that reports most types of nucleotide variants. This study sought to assess WGS for hypertrophic cardiomyopathy (HCM) in which prior genetic testing did not establish a molecular diagnosis, and as a first-line genetic test. WGS was performed on 58 unrelated patients with HCM, 14 affected family members, and 2 unaffected parents of a severely affected proband. The authors searched for nucleotide variants in coding regions of 184 candidate cardiac hypertrophy genes. They also searched for nucleotide variants in deep intronic regions that alter RNA splicing, large genomic rearrangements, and mitochondrial genome variants. RNA analysis was performed to validate splice-altering variants. The authors found a pathogenic or likely pathogenic variant in 9 of 46 families (20%) for which prior genetic testing was inconclusive. Three families had variants in genes not included in prior genetic testing. One family had a pathogenic variant that was filtered out with prior exome sequencing. Five families had pathogenic variants in noncoding regions, including 4 with deep intronic variants that activate novel splicing, and 1 mitochondrial genome variant. As a first-line genetic test, WGS identified a pathogenic variant in 5 of 12 families (42%) that had never received prior genetic testing. WGS identified additional genetic causes of HCM over targeted gene sequencing approaches. Extending genetic screening to deep intronic regions identified pathogenic variants in 9% of gene-elusive HCM. These findings translate to more accurate diagnosis and management in HCM families.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2021
DOI: 10.1161/CIRCHEARTFAILURE.120.007537
Abstract: Clinical studies of hypertrophic cardiomyopathy are over-represented by in iduals of European ethnicity, with less known about other ethnic groups. We investigated differences between patients in a multiethnic Australian hypertrophic cardiomyopathy population. We performed a retrospective cohort study of 836 unrelated hypertrophic cardiomyopathy probands attending a specialized clinic between 2002 and 2020. Major ethnic groups were European (n=611), East Asian (n=75), South Asian (n=58), and Middle Eastern and North African (n=68). The minor ethnicity groups were Oceanian (n=9), People of the Americas (n=7), and African (n=8). One-way ANOVA with Dunnett post hoc test and Bonferroni adjustment were performed. Mean age of the major ethnic groups was 54.9±16.9 years, and 527 (65%) were male. Using the European group as the control, East Asian patients had a lower body mass index (29 versus 25 kg/m 2 , P .0001). South Asians had a lower prevalence of atrial fibrillation (10% versus 31%, P =0.024). East Asians were more likely to have apical hypertrophy (23% versus 6%, P .0001) and Middle Eastern and North African patients more likely to present with left ventricular outflow tract obstruction (46% versus 34%, P =0.0003). East Asians were less likely to undergo genetic testing (55% versus 85%, P .0001) or have an implantable cardioverter-defibrillator implanted (19% versus 36%, P =0.037). East Asians were more likely to have a causative variant in a gene other than MYBPC3 or MYH7 , whereas Middle Eastern and North African and South Asians had the highest rates of variants of uncertain significance (27% and 21%, P .0001). There are few clinical differences based on ethnicity, but importantly, we identify health disparities relating to access to genetic testing and implantable cardioverter-defibrillator use. Unless addressed, these gaps will likely widen as we move towards precision-medicine–based care of in iduals with hypertrophic cardiomyopathy.
Publisher: Wiley
Date: 16-01-2020
DOI: 10.1111/JCE.14346
Abstract: The prevalence and clinical course of atrial fibrillation (AF) in hypertrophic cardiomyopathy (HCM) is well described, though less so for other inherited cardiomyopathies (familial dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, left ventricular noncompaction) and inherited arrhythmia syndromes (long QT syndrome, Brugada syndrome or catecholaminergic polymorphic ventricular tachycardia [CPVT]). We examined the frequency, clinical characteristics and AF-related management and outcomes amongst this patient population. We retrospectively studied consecutive probands with inherited cardiomyopathy (n = 962) and inherited arrhythmia syndromes (n = 195) evaluated between 2002 and 2018. AF was observed in 5% to 31% of patients, with the highest frequency in HCM. Age of AF onset was 45.8 ± 21.9 years in the inherited arrhythmia syndromes compared with 53.3 ± 15.3 years in the inherited cardiomyopathies, with four CPVT patients developing AF at a median age of 20 years. Overall, 11% of patients with AF had a transient ischemic attack or stroke of which a total of 80% were anticoagulated with 48% of events occurring at a CHA Up to one-third of inherited heart disease patients will develop AF. While common general population risk factors are key in patients with HCM, the genotype is independently associated with AF. Amongst inherited arrhythmia syndromes, AF is less common, though often occurs below the age of 50 years.
Publisher: Elsevier BV
Date: 09-2018
DOI: 10.1016/J.AMJCARD.2018.05.023
Abstract: Hypertrophic cardiomyopathy (HC) is the most common genetic heart disease. Consensus guidelines recommend restriction from competitive and/or high-intensity physical activities however, sufficient light-moderate intensity physical activity remains important for health and wellbeing. This study aimed to evaluate the effectiveness and appeal of a control theory-based intervention to increase physical activity levels in in iduals with HC. A pre to post trial of HC participants (n = 25) recruited from May 2016 to April 2017 from a specialized, multidisciplinary clinic was conducted. A 12-week intervention based on principles of control theory was developed. The primary outcome measures were self-reported leisure and transport-related physical activity. The mean age of participants was 42 ± 13years and the majority were men (n = 15, 60%). Although both the primary (self-report) and secondary (objective) outcome measures of physical activity increased, such as leisure-time physical activity: 98 ± 132 minutes per week to 151 ± 218 minutes per week, these were not statistically significant. Secondary outcome measures improved, including physical health-related quality of life (HR-QoL 43 ± 6 to 50 ± 8, p = 0.004), self-efficacy (14 ± 3 to 16 ± 4, p <0.001), and the number of barriers identified (4 ± 3 to 3 ± 2 barriers, p = 0.02). This simple, easy-to-administer intervention to promote physical activity in HC improved willingness to undertake physical activity, increased self-efficacy, and improved physical quality of life. This may help patients overcome perceived barriers and a lack of confidence regarding physical activity, with the ultimate goal to improve overall health outcomes in HC patients.
Publisher: Elsevier BV
Date: 09-2013
Publisher: Springer Science and Business Media LLC
Date: 12-01-2021
Publisher: Cold Spring Harbor Laboratory
Date: 26-12-2020
DOI: 10.1101/2020.12.23.20248816
Abstract: Thorough investigation of sudden cardiac death (SCD) in those aged 1-40 years commonly reveals a heritable cause, yet access to postmortem genetic testing is variable. We explore practices of postmortem genetic testing and attitudes of healthcare professionals worldwide. A survey was administered among healthcare professionals recruited through professional associations, social media and networks of researchers. Topics included practices around postmortem genetic testing, level of confidence in healthcare professionals’ ability, and attitudes towards postmortem genetic testing practices. There were 112 respondents, with 93% from North America, Europe and Australia and 7% from South America, Asia and Africa. Only 30% reported autopsy as mandatory, and overall practices were largely case-by-case and not standardised. North American respondents (87%) more often perceived practices as ineffective compared to those from Europe (58%) and Australia/New Zealand (48%, p= 0.002). Where a heritable cause is suspected, 69% considered postmortem genetic testing and 61% offered genetic counseling to surviving family members financial resources varied widely. Half believed practices in their countries perpetuated health inequalities. Postmortem genetic testing is not consistently available in the investigation of young SCD despite being a recommendation in international guidelines. Access to postmortem genetic testing, guided by well-resourced multidisciplinary teams, is critical in ascertaining a cause of death in many cases.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-07-2021
DOI: 10.1161/CIRCULATIONAHA.120.053033
Abstract: Each of the cardiomyopathies, classically categorized as hypertrophic cardiomyopathy, dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy, has a signature genetic theme. Hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy are largely understood as genetic diseases of sarcomere or desmosome proteins, respectively. In contrast, genes spanning gene ontologies have been implicated in DCM, representing a complex and erse genetic architecture. To clarify this, a systematic curation of evidence to establish the relationship of genes with DCM was conducted. An international panel with clinical and scientific expertise in DCM genetics evaluated evidence supporting monogenic relationships of genes with idiopathic DCM. The panel used the Clinical Genome Resource semiquantitative gene-disease clinical validity classification framework with modifications for DCM genetics to classify genes into categories on the basis of the strength of currently available evidence. Representation of DCM genes on clinically available genetic testing panels was evaluated. Fifty-one genes with human genetic evidence were curated. Twelve genes (23%) from 8 gene ontologies were classified as having definitive ( BAG3 , DES , FLNC , LMNA , MYH7 , PLN , RBM20 , SCN5A , TNNC1 , TNNT2 , TTN ) or strong ( DSP ) evidence. Seven genes (14% ACTC1 , ACTN2 , JPH2 , NEXN , TNNI3 , TPM1 , VCL ) including 2 additional ontologies were classified as moderate evidence these genes are likely to emerge as strong or definitive with additional evidence. Of these 19 genes, 6 were similarly classified for hypertrophic cardiomyopathy and 3 for arrhythmogenic right ventricular cardiomyopathy. Of the remaining 32 genes (63%), 25 (49%) had limited evidence, 4 (8%) were disputed, 2 (4%) had no disease relationship, and 1 (2%) was supported by animal model data only. Of the 16 evaluated clinical genetic testing panels, most definitive genes were included, but panels also included numerous genes with minimal human evidence. In the curation of 51 genes, 19 had high evidence (12 definitive/strong, 7 moderate). It is notable that these 19 genes explain only a minority of cases, leaving the remainder of DCM genetic architecture incompletely addressed. Clinical genetic testing panels include most high-evidence genes however, genes lacking robust evidence are also commonly included. We recommend that high-evidence DCM genes be used for clinical practice and that caution be exercised in the interpretation of variants in variable-evidence DCM genes.
Publisher: Public Library of Science (PLoS)
Date: 13-04-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2019
DOI: 10.1161/CIRCHEARTFAILURE.118.005371
Abstract: Variants in the cardiomyocyte-specific RNA splicing factor RBM20 have been linked to familial cardiomyopathy, but the causative genetic architecture and clinical consequences of this disease are incompletely defined. To define the genetic architecture of RBM20 cardiomyopathy, we first established a database of RBM20 variants associated with cardiomyopathy and compared these to variants observed in the general population with respect to their location in the RBM20 coding transcript. We identified 2 regions significantly enriched for cardiomyopathy-associated variants in exons 9 and 11. We then assembled a registry of 74 patients with RBM20 variants from 8 institutions across the world (44 index cases and 30 from cascade testing). This RBM20 patient registry revealed highly prevalent family history of sudden cardiac death (51%) and cardiomyopathy (72%) among index cases and a high prevalence of composite arrhythmias (including atrial fibrillation, nonsustained ventricular tachycardia, implantable cardiac defibrillator discharge, and sudden cardiac arrest, 43%). Patients harboring variants in cardiomyopathy-enriched regions identified by our variant database analysis were enriched for these findings. Further, these characteristics were more prevalent in the RBM20 registry than in large cohorts of patients with dilated cardiomyopathy and TTNtv cardiomyopathy and not significantly different from a cohort of patients with LMNA -associated cardiomyopathy. Our data establish RBM20 cardiomyopathy as a highly penetrant and arrhythmogenic cardiomyopathy. These findings underline the importance of arrhythmia surveillance and family screening in this disease and represent the first step in defining the genetic architecture of RBM20 disease causality on a population level.
Publisher: Oxford University Press (OUP)
Date: 08-04-2013
Abstract: Sudden cardiac death (SCD) in the young is a devastating event and often due to an underlying genetic heart disease. Managing these families is complicated by uncertainty regarding clinical management and profound grief. This study sought to evaluate psychological wellbeing and experiences of at-risk relatives following SCD in the young. Relatives who attended a specialized clinic following the SCD of a relative were invited to complete the Hospital Anxiety and Depression Scale (HADS) and a series of open-ended questions. Primary outcome measures were the HADS anxiety and depression subscales and a thematic qualitative analysis of the open-ended responses was performed. Clinical and genetic data were collected from the medical record. Fifty relatives from 29 families returned surveys. The mean time since death was 4±2 years (mean age at death 23±10 years, 79% males). There was significant impairment in mean anxiety (8.7±4.3, p<0.0001) and depression (5.8±3.6, p<0.0001) scores compared to the general population. Mothers showed significantly impaired anxiety (10.9±4.0, p=0.001) and depression (7.3±3.3, p=0.001) scores, with 53% having an anxiety score above 11 suggesting probable anxiety disorder. Participants revealed a number of factors that have helped and hindered their ability to cope with the death, and their decisions relating to clinical screening. The SCD of a young relative has significant and long-term emotional implications for the family, particularly for the mother.
Publisher: Springer Science and Business Media LLC
Date: 15-10-2020
DOI: 10.1038/S41439-020-00120-Y
Abstract: The genetic etiology and heritability of left ventricular noncompaction (LVNC) in adults is unclear. This study sought to assess the value of genetic testing in adults with LVNC. Adults diagnosed with LVNC while undergoing screening in the context of a family history of cardiomyopathy were excluded. Clinical data for 35 unrelated patients diagnosed with LVNC at ≥18 years of age were retrospectively analyzed. Left ventricular (LV) dysfunction, electrocardiogram (ECG) abnormalities, cardiac malformations or syndromic features were identified in 25 patients 10 patients had isolated LVNC in the absence of cardiac dysfunction or syndromic features. Exome sequencing was performed, and analysis using commercial panels targeted 193 nuclear and mitochondrial genes. Nucleotide variants in coding regions or in intron-exon boundaries with predicted impacts on splicing were assessed. Fifty-four rare variants were identified in 35 nuclear genes. Across all 35 LVNC patients, the clinically meaningful genetic diagnostic yield was 9% (3/35), with heterozygous likely pathogenic or pathogenic variants identified in the NKX2-5 and TBX5 genes encoding cardiac transcription factors. No pathogenic variants were identified in patients with isolated LVNC in the absence of cardiac dysfunction or syndromic features. In conclusion, the diagnostic yield of genetic testing in adult index patients with LVNC is low. Genetic testing is most beneficial in LVNC associated with other cardiac and syndromic features, in which it can facilitate correct diagnoses, and least useful in adults with only isolated LVNC without a family history. Cardiac transcription factors are important in the development of LVNC and should be included in genetic testing panels.
Publisher: Wiley
Date: 08-04-2021
DOI: 10.1002/JOA3.12449
Abstract: This international multidisciplinary document intends to provide clinicians with evidence‐based practical patient‐centered recommendations for evaluating patients and decedents with (aborted) sudden cardiac arrest and their families. The document includes a framework for the investigation of the family allowing steps to be taken, should an inherited condition be found, to minimize further events in affected relatives. Integral to the process is counseling of the patients and families, not only because of the emotionally charged subject, but because finding (or not finding) the cause of the arrest may influence management of family members. The formation of multidisciplinary teams is essential to provide a complete service to the patients and their families, and the varied expertise of the writing committee was formulated to reflect this need. The document sections were ided up and drafted by the writing committee members according to their expertise. The recommendations represent the consensus opinion of the entire writing committee, graded by Class of Recommendation and Level of Evidence. The recommendations were opened for public comment and reviewed by the relevant scientific and clinical document committees of the Asia Pacific Heart Rhythm Society (APHRS) and the Heart Rhythm Society (HRS) the document underwent external review and endorsement by the partner and collaborating societies. While the recommendations are for optimal care, it is recognized that not all resources will be available to all clinicians. Nevertheless, this document articulates the evaluation that the clinician should aspire to provide for patients with sudden cardiac arrest, decedents with sudden unexplained death, and their families.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2021
DOI: 10.1161/CIRCGEN.120.003202
Abstract: Transcriptome sequencing can improve genetic diagnosis of Mendelian diseases but requires access to tissue expressing disease-relevant transcripts. We explored genetic testing of hypertrophic cardiomyopathy using transcriptome sequencing of patient-specific human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs). We also explored whether antisense oligonucleotides (AOs) could inhibit aberrant mRNA splicing in hiPSC-CMs. We derived hiPSC-CMs from patients with hypertrophic cardiomyopathy due to MYBPC3 splice-gain variants, or an unresolved genetic cause. We used transcriptome sequencing of hiPSC-CM RNA to identify pathogenic splicing and used AOs to inhibit this splicing. Transcriptome sequencing of hiPSC-CMs confirmed aberrant splicing in 2 people with previously identified MYBPC3 splice-gain variants (c.1090+453C T and c.1224-52G A). In a patient with an unresolved genetic cause of hypertrophic cardiomyopathy following genome sequencing, transcriptome sequencing of hiPSC-CMs revealed erse cryptic exon splicing due to an MYBPC3 c.1928-569G T variant, and this was confirmed in cardiac tissue from an affected sibling. Antisense oligonucleotide treatment demonstrated almost complete inhibition of cryptic exon splicing in one patient-specific hiPSC-CM line. Transcriptome sequencing of patient specific hiPSC-CMs solved a previously undiagnosed genetic cause of hypertrophic cardiomyopathy and may be a useful adjunct approach to genetic testing. Antisense oligonucleotide inhibition of cryptic exon splicing is a potential future personalized therapeutic option.
Publisher: Elsevier BV
Date: 04-2020
DOI: 10.1016/J.HLC.2019.10.014
Abstract: Inherited heart diseases include numerous conditions, from the more prevalent hypertrophic cardiomyopathy (HCM) and familial hypercholesterolaemia (FH), to the comparatively less common inherited arrhythmia syndromes, such as long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT) and Brugada syndrome (BrS). Genetic testing has evolved rapidly over the last decade and is now considered a mainstream component of clinical management of inherited heart diseases. Cardiac manifestations can also be part of wider syndromes, and genetic testing can play a critical role in clarifying the underlying aetiological basis of disease in some cases. The greatest utility of a genetic diagnosis, however, comes from the ability to elucidate disease risk amongst asymptomatic at-risk family members. Given the nuances and challenges, cardiac genetic testing is best performed in a multidisciplinary specialised clinic with access to cardiac genetic counselling.
Publisher: Oxford University Press (OUP)
Date: 18-11-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2019
DOI: 10.1161/CIRCGEN.119.002460
Abstract: Genetic testing for families with hypertrophic cardiomyopathy (HCM) provides a significant opportunity to improve care. Recent trends to increase gene panel sizes often mean variants in genes with questionable association are reported to patients. Classification of HCM genes and variants is critical, as misclassification can lead to genetic misdiagnosis. We show the validity of previously reported HCM genes using an established method for evaluating gene-disease associations. A systematic approach was used to assess the validity of reported gene-disease associations, including associations with isolated HCM and syndromes including left ventricular hypertrophy. Genes were categorized as having definitive, strong, moderate, limited, or no evidence of disease causation. We also reviewed current variant classifications for HCM in ClinVar, a publicly available variant resource. Fifty-seven genes were selected for curation based on their frequent inclusion in HCM testing and prior association reports. Of 33 HCM genes, only 8 (24%) were categorized as definitive ( MYBPC3 , MYH7 , TNNT2 , TNNI3 , TPM1 , ACTC1 , MYL2 , and MYL3 ) 3 had moderate evidence ( CSRP3, TNNC1 , and JPH2 33%) and 22 (66%) had limited (n=16) or no evidence (n=6). There were 12 of 24 syndromic genes definitively associated with isolated left ventricular hypertrophy. Of 4191 HCM variants in ClinVar, 31% were in genes with limited or no evidence of disease association. The majority of genes previously reported as causative of HCM and commonly included in diagnostic tests have limited or no evidence of disease association. Systematically curated HCM genes are essential to guide appropriate reporting of variants and ensure the best possible outcomes for HCM families.
Publisher: Elsevier BV
Date: 05-2015
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2011
Publisher: Wiley
Date: 12-12-2006
DOI: 10.1111/J.1445-5994.2006.01241.X
Abstract: The sudden death of a young person is a devastating event for both the family and community. Over the last decade, significant advances have been made in understanding both the clinical and genetic basis of sudden cardiac death in the young. Many of the causes of sudden death in the young are due to genetic heart disorders, which can lead to both structural (e.g. hypertrophic cardiomyopathy) and arrhythmogenic (e.g. familial long QT syndrome) abnormalities. Most commonly, sudden cardiac death in the young can be the first presentation of an underlying heart problem, leaving the family at a loss as to why an otherwise healthy young person has died. Not only is this a tragic event for those involved, but it also presents a medical challenge to the clinician involved in the management of the surviving family members. Evaluation of families requires a multidisciplinary approach, which should include cardiologists, a clinical geneticist, a genetic counsellor and the forensic pathologist directly involved in the sudden death case. This multifaceted cardiac genetic service is crucial in the evaluation and management of the clinical, genetic, psychological and social complexities observed in families in which there has been a young sudden cardiac death.
Publisher: Elsevier BV
Date: 06-2020
Publisher: Elsevier BV
Date: 03-2010
DOI: 10.1016/J.JACC.2009.11.016
Abstract: This study describes a genome-wide linkage analysis of a large family with clinically heterogeneous hypertrophic cardiomyopathy (HCM). Familial HCM is a disorder characterized by genetic heterogeneity. In as many as 50% of HCM cases, the genetic cause remains unknown, suggesting that other genes may be involved. Clinical evaluation, including clinical history, physical examination, electrocardiography, and 2-dimensional echocardiography, was performed, and blood was collected from family members (n = 23) for deoxyribonucleic acid analysis. The family was genotyped with markers from the 10-cM AB PRISM Human Linkage mapping set (Applied Biosystems, Foster City, California), and 2-point linkage analysis was performed. Affected family members showed marked clinical ersity, ranging from asymptomatic in iduals to those with syncope, heart failure, and premature sudden death. The disease locus for this family was mapped to chromosome 1q42.2-q43, near the marker D1S2850 (logarithm of odds ratio = 2.82, theta = 0). A missense mutation, Ala119Thr, in the alpha-actinin-2 (ACTN2) gene was identified that segregated with disease in the family. An additional 297 HCM probands were screened for mutations in the ACTN2 gene using high-resolution melt analysis. Three causative ACTN2 mutations, Thr495Met, Glu583Ala, and Glu628Gly, were identified in an additional 4 families (total 1.7%) with HCM. This is the first genome-wide linkage analysis that shows mutations in ACTN2 cause HCM. Mutations in genes encoding Z-disk proteins account for a small but significant proportion of genotyped HCM families.
Publisher: Elsevier BV
Date: 04-2015
DOI: 10.1016/J.IJCARD.2015.03.070
Abstract: Social determinants of health play an important role in explaining poor health outcomes across many chronic disease states. The impact of the social gradient in the setting of an inherited heart disease, hypertrophic cardiomyopathy (HCM), has not been investigated. This study sought to profile the socioeconomic status of patients attending a specialized multidisciplinary clinic and to determine the impact on clinical factors, psychosocial wellbeing and adherence to medical advice. Patients with HCM and at-risk relatives attending a specialized multidisciplinary clinic in Sydney Australia between 2011 and 2013 were included. Clinical, socioeconomic, geographic remoteness and adherence data were available. A broader clinic and registry-based group completed a survey including psychological wellbeing, health-related quality of life, Morisky Medication Adherence Scale and in idual-level socioeconomic information. Over a 3-year period, 486 patients were seen in the specialized clinic. There was an over-representation of patients from socioeconomically advantaged and the least geographically remote areas. Socioeconomic disadvantage was associated with comorbidities, poor psychological wellbeing and health-related quality of life, lower understanding of HCM and more complex clinical management issues such as NYHA class, atrial fibrillation and left ventricular outflow tract obstruction. Approximately 10% of patients were non-adherent to medical advice, and poor medication adherence was seen in 30% of HCM patients with associated factors being younger age, minority ethnicity, anxiety and poor mental quality of life. Of all the patients attending a specialized cardiac genetic clinic, there is an overrepresentation of patients from very advantaged and major metropolitan areas and suggests that those most in need of a multidisciplinary approach to care are not accessing it.
Publisher: Elsevier BV
Date: 05-2021
Publisher: American Medical Association (AMA)
Date: 2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2021
DOI: 10.1161/CIRCEP.121.009834
Abstract: The overall incidence of sudden cardiac death is considerably lower among women than men, reflecting significant and often under-recognized sex differences. Women are older at time of sudden cardiac death, less likely to have a prior cardiac diagnosis, and less likely to have coronary artery disease identified on postmortem examination. They are more likely to experience their death at home, during sleep, and less likely witnessed. Women are also more likely to present in pulseless electrical activity or systole rather than ventricular fibrillation or ventricular tachycardia. Conversely, women are less likely to receive bystander cardiopulmonary resuscitation or receive cardiac intervention post-arrest. Underpinning sex disparities in sudden cardiac death is a paucity of women recruited to clinical trials, coupled with an overall lack of prespecified sex-disaggregated evidence. Thus, predominantly male-derived data form the basis of clinical guidelines. This review outlines the critical sex differences concerning epidemiology, cause, risk factors, prevention, and outcomes. We propose 4 broad areas of importance to consider: physiological, personal, community, and professional factors.
Publisher: CSIRO Publishing
Date: 2015
DOI: 10.1071/AH14226
Abstract: Objective The aim of the present study was to develop criteria to identify sudden cardiac death (SCD) and estimate population rates of SCD using administrative mortality and hospital morbidity records in Western Australia. Methods Four criteria were developed using place, death within 24 h, principal and secondary diagnoses, underlying and associated cause of death, and/or occurrence of a post mortem to identify SCD. Average crude, age-standardised and age-specific rates of SCD were estimated using population person-linked administrative data. Results In all, 9567 probable SCDs were identified between 1997 and 2010, with one-third aged ≥35 years having no prior admission for cardiovascular disease. SCD was more frequent in men (62.1%). The estimated average annual crude SCD rate for the period was 34.6 per 100 000 person-years with an average annual age-standardised rate of 37.8 per 100 000 person-years. Age-specific standardised rates were 1.1 per 100 000 person-years and 70.7 per 100 000 person-years in people aged 1–34 and ≥35 years, respectively. Ischaemic heart disease (IHD) was recorded as the underlying cause of death in approximately 80% of patients aged ≥35 years, followed by valvular heart disease and heart failure. IHD was the most common cause of death in those aged 1–34 years, followed by unspecified cardiomyopathy and dysrhythmias. Conclusions Administrative morbidity and mortality data can be used to estimate rates of SCD and therefore provide a suitable methodology for monitoring SCD over time. The findings highlight the magnitude of SCD and its potential for public health prevention. What is known about the topic? There is considerable variability in rates of SCD worldwide. Different data sources and varied methods of case ascertainment likely contribute to this variation. What does this paper add? The rate of SCD in Australia is low compared with international estimates from USA, Ireland, Netherlands and China. Two in every three cases of SCD aged ≥35 years had a hospitalisation history of cardiovascular disease, highlighting the opportunity for prevention. What are the implications for practitioners? High-quality person-linked administrative hospital morbidity and registered mortality data can be used to estimate rates of SCD in the population. Understanding the magnitude and distribution of SCD is imperative for developing effective public health policy and prevention measures.
Publisher: Oxford University Press (OUP)
Date: 30-11-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2022
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1016/J.HRTHM.2018.08.027
Abstract: Brugada syndrome (BrS) is a primary arrhythmia syndrome affecting 1 in 2000 of the general population. Genetic testing identifies pathogenic variants in the sodium voltage-gated channel α-subunit 5 gene (SCN5A) in up to 25% of familial BrS. Balanced translocations, which involve the exchange of the ends of 2 different chromosomes, are found in approximately 1 in 500 people. They usually are benign and only rarely are reported to cause arrhythmogenic disorders. The purpose of this study was to identify the genetic mechanism underlying a family with BrS, sick sinus syndrome, cardiac hypertrophy, sudden cardiac death, and multiple miscarriages. We clinically evaluated family members with an electrocardiogram, 2-dimensional echocardiogram, and provocation testing with ajmaline challenge. Cytogenetic testing included karyotype and fluorescent in situ hybridization (FISH) analysis. We performed gene panel, exome, and genome sequencing analysis. Sequencing of 128 cardiac genes and exome sequencing of a family with BrS, sick sinus syndrome, cardiac hypertrophy, sudden cardiac death, and multiple miscarriages did not reveal a pathogenic variant. Karyotype and FISH analysis identified a balanced translocation breaking the SCN5A gene on chromosome 3 and the multiple chromosome maintenance 10 gene (MCM10) on chromosome 10 t(3 )(p22.2 13). We characterized both translocation breakpoint junctions using genome sequencing and found no regions of sequence homology. A balanced translocation breaking SCN5A is a novel mechanism underlying disease in a family with BrS, sick sinus syndrome, cardiac hypertrophy, and sudden cardiac death. Genome sequencing can identify rare chromosomal aberrations causing inherited diseases that may otherwise be missed using gene panel and exome sequencing-based approaches.
Publisher: BMJ
Date: 07-2016
Publisher: Elsevier BV
Date: 03-2015
DOI: 10.1016/J.JACC.2015.01.019
Abstract: Hypertrophic cardiomyopathy (HCM) is an important genetic heart muscle disease for which prevalence in the general population has not been completely resolved. For the past 20 years, most data have supported the occurrence of HCM at about 1 in 500. However, the authors have interrogated a number of relevant advances in cardiovascular medicine, including widespread fee-for-service genetic testing, population genetic studies, and contemporary diagnostic imaging, as well as a greater index of suspicion and recognition for both the clinically expressed disease and the gene-positive-phenotype-negative subset (at risk for developing the disease). Accounting for the potential impact of these initiatives on disease occurrence, the authors have revisited the prevalence of HCM in the general population. They suggest that HCM is more common than previously estimated, which may enhance its recognition in the practicing cardiovascular community, allowing more timely diagnosis and the implementation of appropriate treatment options for many patients.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2017
DOI: 10.1161/CIRCGENETICS.116.001671
Abstract: Hypertrophic cardiomyopathy is a genetically heterogeneous myocardial disease with causal variants identified. Nonunique variants account for disease in many families. We sought to characterize nonunique variants in Australian families and determine whether they arise from common ancestral mutations or recurrent mutation events. Genetic test results of 467 index patients from apparently unrelated families with hypertrophic cardiomyopathy were evaluated. Causal variants were found in 185 of 467 (40%) families. Nonunique variants accounted for 122 of 185 (66%) families. The most common single genetic cause of hypertrophic cardiomyopathy is the recurrent MYBPC3 (myosin-binding protein-C) variant c.1504C T, p.Arg502Trp, which was found in 13 of 185 (7%) families with a causal variant identified. Thirteen variants in MYBPC3 and MYH7 (myosin heavy chain 7) were each identified times and accounted for 78 of 185 (42%) hypertrophic cardiomyopathy families with a causal variant. Haplotype analysis of these 13 variants was performed on 126 in iduals from 70 Australian families, and 11 variants arose through recurrent mutation events. Two variants, MYBPC3 c.1928-2A G and MYH7 c.2681A G, p.Glu894Gly, were found on 1 haplotype in 6 families each, supportive of a single mutation event inherited from a common ancestor. The majority of families with a causal variant identified have a nonunique variant. Discovery of the genetic origins of human disease forms a fundamental basis for improved understanding of disease pathogenesis and phenotype development.
Publisher: BMJ
Date: 09-2023
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.AHJ.2019.04.001
Abstract: Thrill-seeking activities are a favorite pastime for people of all ages. Patients with hypertrophic cardiomyopathy (HCM) are often barred from participation on the basis of danger for arrhythmias. Our aim was to collect information regarding the safety of thrill-seeking activities for HCM patients. An anonymous online survey invited adult HCM patients to report participation in 11 activities (rollercoaster riding, jet skiing, rafting, bungee jumping, rappelling, paragliding, kayaking/canoeing, motor racing, snowboarding, BASE jumping and sky ing) before and after HCM diagnosis, along with major (ICD shock, syncope) or minor (nausea, dizziness, palpitations, chest pain) adverse events related to participation, and relevant physician advice. Six hundred forty-seven HCM patients completed the survey, with 571 (88.2%) reporting participation in ≥1 TSAs (participant age 50.85 ± 14.21, 56.6% female, 8143 post-diagnosis participations). At time of survey, 457 participants (70.6%) were ICD-carriers or had ≥1 risk factor for sudden cardiac death. Nine (1.5%) participants reported a major event during or immediately after (60 minutes) of surveyed activity. Minor adverse events were reported by 181 participants (31.6%). In addition, 8 participants reported a major adverse event >60 minutes later but within the same day. Regarding physician advice, of the 213 responders (32.9%) receiving specific advice, 56 (26.2%) were told safety data is absent with no definitive recommendation, while 24 (11.2%) and 93 (43.6%) were told TSAs were respectively safe or dangerous. In this cohort, participation in thrill-seeking activities rarely caused major adverse events. This information can be used for shared-decision making between providers and patients.
Publisher: Elsevier BV
Date: 09-2007
DOI: 10.1016/J.YJMCC.2007.06.009
Abstract: Genes encoding Ca(2+) regulatory proteins responsible for Ca(2+) homeostasis have been suggested as possible candidates for FHC. Mutations in sarcomere genes account for approximately 50% of all FHC cases indicating other genes, including those involved in Ca(2+) handling, may account for the remainder. The aim of this study was to identify causative mutations in genes involved in Ca(2+) regulation in patients with familial hypertrophic cardiomyopathy (FHC). An Australian cohort of 252 unrelated familial hypertrophic cardiomyopathy patients were screened for mutations in the Ca(2+) regulatory genes, sorcin (SRI), calstabin (FKBP1B), calsequestrin (CASQ2), phospholamban (PLN), sarcolipin (SLN), calreticulin (CALR3) and calmodulin (CALM). A total of 17 exonic DNA variants were identified in the 7 Ca(2+) regulatory genes studied, of which 4 were considered of pathogenic significance. Two novel mutations in the CALR3 gene were identified (Lys82Arg, Arg73Gln) and one truncation mutation in the PLN gene (Leu39Ter). A variant was also identified in the CASQ2 gene (Asp63Glu). These four variants were all novel, resulted in changes in conserved amino acids and were not identified in a normal population. In conclusion, mutations in Ca(2+) handling genes are an infrequent but important cause of FHC. DNA variants in Ca(2+) genes may also be involved as modifying factors in phenotype development. Further evaluation of the role of defects in Ca(2+) regulation will shed light on the molecular pathogenesis of FHC.
Publisher: Oxford University Press (OUP)
Date: 14-06-2017
Abstract: Physical activity is associated with improved quality of life. Patients with an implantable cardioverter defibrillator (ICD) face unique clinical and psychological challenges. Factors such as fear of ICD shock may negatively impact on physical activity, while a sense of protection gained from the ICD may instil confidence to be active. We aimed to examine the impact of an ICD on physical activity levels and factors associated with amount of activity. Two cross-sectional studies were conducted. Accelerometer data (seven-day) was collected in March–November 2015 for 63 consecutively recruited hypertrophic cardiomyopathy patients, with or without an ICD, aged ⩾18 years. A survey study was conducted in July–August 2016 of 155 in iduals aged ⩾18 years with an inherited heart disease and an ICD in situ. Based on the International Physical Activity Questionnaire, mean leisure time physical activity was 239 ± 300 min/week with 51% meeting physical activity guidelines. Accelerometry showed that mean moderate–vigorous physical activity was the same for patients with and without an ICD (254 ± 139 min/week versus 300 ± 150 min/week, p=0.23). Nearly half of survey participants ( n=73) said their device made them more confident to exercise. Being anxious about ICD shocks was the only factor associated with not meeting physical activity guidelines. Patients with inherited heart disease adjust differently to their ICD device, and for many it has no impact on physical activity. Discussion regarding the appropriate level of physical activity and potential barriers will ensure best possible outcomes in this unique patient group.
Publisher: Elsevier BV
Date: 10-2011
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2020
DOI: 10.1161/CIRCGEN.120.002929
Abstract: Pathogenic variants in MYBPC3 , encoding cardiac MyBP-C (myosin binding protein C), are the most common cause of familial hypertrophic cardiomyopathy. A large number of unique MYBPC3 variants and relatively small genotyped hypertrophic cardiomyopathy cohorts have precluded detailed genotype-phenotype correlations. Patients with hypertrophic cardiomyopathy and MYBPC3 variants were identified from the Sarcomeric Human Cardiomyopathy Registry. Variant types and locations were analyzed, morphological severity was assessed, and time-event analysis was performed (composite clinical outcome of sudden death, class III/IV heart failure, left ventricular assist device/transplant, atrial fibrillation). For selected missense variants falling in enriched domains, myofilament localization and degradation rates were measured in vitro. Among 4756 genotyped patients with hypertrophic cardiomyopathy in Sarcomeric Human Cardiomyopathy Registry, 1316 patients were identified with adjudicated pathogenic truncating (N=234 unique variants, 1047 patients) or nontruncating (N=22 unique variants, 191 patients) variants in MYBPC3 . Truncating variants were evenly dispersed throughout the gene, and hypertrophy severity and outcomes were not associated with variant location (grouped by 5′–3′ quartiles or by founder variant subgroup). Nontruncating pathogenic variants clustered in the C3, C6, and C10 domains (18 of 22, 82%, P .001 versus Genome Aggregation Database common variants) and were associated with similar hypertrophy severity and adverse event rates as observed with truncating variants. MyBP-C with variants in the C3, C6, and C10 domains was expressed in rat ventricular myocytes. C10 mutant MyBP-C failed to incorporate into myofilaments and degradation rates were accelerated by ≈90%, while C3 and C6 mutant MyBP-C incorporated normally with degradation rate similar to wild-type. Truncating variants account for 91% of MYBPC3 pathogenic variants and cause similar clinical severity and outcomes regardless of location, consistent with locus-independent loss-of-function. Nontruncating MYBPC3 pathogenic variants are regionally clustered, and a subset also cause loss of function through failure of myofilament incorporation and rapid degradation. Cardiac morphology and clinical outcomes are similar in patients with truncating versus nontruncating variants.
Publisher: Springer Science and Business Media LLC
Date: 28-12-2022
DOI: 10.1186/S13073-022-01149-0
Abstract: The diagnostic yield of genetic testing for inherited cardiac diseases is up to 40% and is primarily indicated for screening of at-risk relatives. Here, we evaluate the role of genomics in diagnosis and management among consecutive in iduals attending a specialised clinic and identify those with the highest likelihood of having a monogenic disease. A retrospective audit of 1697 consecutive, unrelated probands referred to a specialised, multidisciplinary clinic between 2002 and 2020 was performed. A concordant clinical and genetic diagnosis was considered solved. Cases were classified as likely monogenic based on a score comprising a positive family history, young age at onset, and severe phenotype, whereas low-scoring cases were considered to have a likely complex aetiology. The impact of a genetic diagnosis was evaluated. A total of 888 probands fulfilled the inclusion criteria, and genetic testing identified likely pathogenic or pathogenic (LP/P) variants in 330 in iduals (37%) and suspicious variants of uncertain significance (VUS) in 73 (8%). Research-focused efforts identified 46 (5%) variants, missed by conventional genetic testing. Where a variant was identified, this changed or clarified the final diagnosis in a clinically useful way for 51 (13%). The yield of suspicious VUS across ancestry groups ranged from 15 to 20%, compared to only 10% among Europeans. Even when the clinical diagnosis was uncertain, those with the most monogenic disease features had the greatest diagnostic yield from genetic testing. Research-focused efforts can increase the diagnostic yield by up to 5%. Where a variant is identified, this will have clinical utility beyond family screening in 13%. We demonstrate the value of genomics in reaching an overall diagnosis and highlight inequities based on ancestry. Acknowledging our incomplete understanding of disease phenotypes, we propose a framework for prioritising likely monogenic cases to solve their underlying cause of disease.
Publisher: Springer Science and Business Media LLC
Date: 21-09-2022
Publisher: Cold Spring Harbor Laboratory
Date: 21-05-2021
DOI: 10.1101/2021.05.20.21257559
Abstract: To co-design an online support intervention for families after sudden cardiac death (SCD) in the young ( years). Co-design of a SCD family intervention by stakeholder focus groups. Families and healthcare professionals with experience in SCD in the young. Semi-structured online focus groups were held with key stakeholders, i.e. family members who had experienced young SCD, healthcare professionals and researchers. Guided discussions were used to develop an online support intervention. Thematic analysis of discussions and iterative feedback on draft materials guided content development. Four focus groups were held (10-12 participants per group). Stakeholder involvement facilitated development of high-level ideas and priority issues. Creative content and materials were developed based on user preference for stories, narratives and information reflecting everyday experience of families navigating the legal and medical processes surrounding SCD, normalising and supporting grief responses in the context of family relationships, and fostering hope. Emphasis on accessibility led to the overarching need for digital information and online engagement. These insights allowed development of an online intervention - COPE-SCD: A COmmunity suPporting familiEs after Sudden Cardiac Death - which includes a website and online support program. Using co-design with stakeholders we have developed a support intervention that directly addresses the needs of SCD families and fills a large gap in existing health care. We will evaluate COPE-SCD to determine whether this is an effective intervention for support of families following a young SCD. Healthcare providers and consumer representatives participated as stakeholders in support intervention design. Co-design allowed development of a support intervention incorporating innovative ideas to meet user needs. Focus groups were limited in size and may not fully represent the needs of the wider community affected by sudden cardiac death in the young.
Publisher: Elsevier BV
Date: 07-2021
Publisher: Cold Spring Harbor Laboratory
Date: 08-02-2022
DOI: 10.1101/2022.02.04.22270485
Abstract: The diagnostic yield of genetic testing for inherited cardiac diseases is up to 40% and primarily indicated for screening of at-risk relatives. Here we evaluate the role of genomics in diagnosis and management among consecutive in iduals attending a specialised clinic and identify those with highest likelihood of having a monogenic disease. Retrospective audit of 1697 consecutive, unrelated probands referred to a specialised, multidisciplinary clinic between 2002 and 2020. A concordant clinical and genetic diagnosis was considered solved. Cases were classified as likely monogenic based on a score comprising a positive family history, young age at onset and severe phenotype, whereas low scoring cases were considered to have a likely complex aetiology. The impact of a genetic diagnosis was evaluated. A total of 888 probands fulfilled inclusion criteria, and genetic testing identified likely pathogenic or pathogenic (LP/P) variants in 330 in iduals (37%), and suspicious variants of uncertain significance (VUS) in 73 (8%). Research-focused efforts identified 46 (5%) variants, missed by conventional genetic testing. Where a variant was identified, this changed or clarified the final diagnosis in a clinically useful way for 51 (13%). The yield of suspicious VUS across ancestry groups ranged from 15-20%, compared to only 10% among Europeans. Even when the clinical diagnosis was uncertain, those with the most monogenic disease features had the greatest diagnostic yield from genetic testing. Research-focused efforts can increase the diagnostic yield by up to 5%. Where a variant is identified, this will have clinical utility beyond family screening in 13%. We demonstrate the value of genomics in reaching an overall diagnosis, and highlight inequities based on ancestry. Acknowledging our incomplete understanding of disease phenotypes, we propose a framework for prioritising likely monogenic cases to solve their underlying cause of disease.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 31-03-2015
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2018
Publisher: Elsevier BV
Date: 05-2018
DOI: 10.1016/J.HRTHM.2017.11.024
Abstract: Given the dynamic nature of the electrical activity of the heart and ongoing challenges in the diagnostics of inherited heart rhythm disorders, genetic information can be a vital aspect of family management. Communication of genetic information is complex, and the responsibility to convey this information to the family lies with the proband. Current practice falls short, requiring additional support from the clinician and multidisciplinary team. Communication is a 2-part iterative process, reliant on both the understanding of the probands and their ability to effectively communicate with relatives. With the surge of high-throughput genetic testing, results generated are increasingly complex, making the task of communication more challenging. Here we discuss 3 key issues. First, the probabilistic nature of genetic test results means uncertainty is inherent to the practice. Second, secondary findings may arise. Third, personal preferences, values, and family dynamics also come into play and must be acknowledged when considering how best to support effective communication. Here we provide insight into the challenges and provide practical advice for clinicians to support effective family communication. These strategies include acknowledging and managing genetic uncertainty, genetic counseling and informed consent, and consideration of personal and familial barriers to effective communication. We will explore the potential for developing resources to assist clinicians in providing patients with sufficient knowledge and support to communicate complex information to their at-risk relatives. Specialized multidisciplinary clinics remain the best equipped to manage patients and families with inherited heart rhythm disorders given the need for a high level of information and support.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2020
Publisher: BMJ
Date: 07-2020
DOI: 10.1136/OPENHRT-2019-001120
Abstract: The sudden cardiac death (SCD) of a young person is a devastating event for any parent. Inherited heart disease is often either identified or assumed to be the cause. Few studies have explored the psychosocial impact to the surviving at-risk family members. We sought to investigate the needs of parents who have experienced the SCD of their child (≤45 years). A quantitative needs analysis questionnaire was developed based on semistructured interviews, including one focus group and a review of relevant literature. Eligible participants were invited to participate in this cross-sectional survey study. There were 38 parents who completed a quantitative survey. Parents’ perceived needs for information and support spanned medical, psychosocial, spiritual and financial domains. Of the support and information needs assessed, medical needs were identified as the most important domain, followed by psychosocial, spiritual and financial. Importantly, psychosocial information and support needs were reported as the most unmet need, endorsed by 54% of parents. Medical information and support needs were reported as unmet by almost one third of parents. The two most endorsed needs were ‘To have the option of whether or not you would pursue genetic testing for yourself or family members’ and ‘To understand what happened’. This work demonstrates for the first time, the multifactorial needs of parents after SCD in the young. With the greatest unmet need reported as psychosocial needs, there is clear necessity to find ways of integrating psychological support in to the care of families after SCD in the young.
Publisher: Springer Science and Business Media LLC
Date: 16-06-2021
DOI: 10.1038/S41525-021-00211-X
Abstract: Genetic testing is used to optimise the management of inherited cardiovascular disorders that can cause sudden cardiac death. Yet more genotype–phenotype correlation studies from populations not ascertained on clinical symptoms or family history of disease are required to improve understanding of gene penetrance. We performed targeted sequencing of 25 genes used routinely in clinical genetic testing for inherited cardiovascular disorders in a population of 13,131 asymptomatic older in iduals (mean age 75 years) enrolled in the ASPREE trial. Participants had no prior history of cardiovascular disease events, dementia or physical disability at enrolment. Variants were classified following ACMG/AMP standards. Sudden and rapid cardiac deaths were clinically adjudicated as ASPREE trial endpoints, and assessed during mean 4.7 years of follow-up. In total, 119 participants had pathogenic/deleterious variants in one of the 25 genes analysed (carrier rate of 1 in 110 or 0.9%). Participants carried variants associated with hypertrophic cardiomyopathy ( N = 24), dilated cardiomyopathy (N = 29), arrhythmogenic right-ventricular cardiomyopathy ( N = 22), catecholaminergic polymorphic ventricular tachycardia ( N = 4), aortopathies ( N = 1), and long-QT syndrome ( N = 39). Among 119 carriers, two died from presumed sudden/rapid cardiac deaths during follow-up (1.7%) both with pathogenic variants in long-QT syndrome genes ( KCNQ1 , SCN5A ). Among non-carriers, the rate of sudden/rapid cardiac deaths was significantly lower (0.08%, 11/12936, p 0.001). Variants associated with inherited cardiovascular disorders are found in asymptomatic in iduals aged 70 years and older without a history of cardiovascular disease.
Publisher: BMJ
Date: 29-11-2012
DOI: 10.1136/HEARTJNL-2011-300368
Abstract: Traditional management of families with hypertrophic cardiomyopathy (HCM) involves periodic lifetime clinical screening of family members, an approach that does not identify all gene carriers owing to incomplete penetrance and significant clinical heterogeneity. Limitations in availability and cost have meant genetic testing is not part of routine clinical management for many HCM families. To determine the cost-effectiveness of the addition of genetic testing to HCM family management, compared with clinical screening alone. A probabilistic Markov decision model was used to determine cost per quality-adjusted life-year and cost for each life-year gained when genetic testing is included in the management of Australian families with HCM, compared with the conventional approach of periodic clinical screening alone. The incremental cost-effectiveness ratio (ICER) was $A785 (£510 or €587) per quality-adjusted life-year gained, and $A12 720 (£8261 or €9509) per additional life-year gained making genetic testing a very cost-effective strategy. Sensitivity analyses showed that the cost of proband genetic testing was an important variable. As the cost of proband genetic testing decreased, the ICER decreased and was cost saving when the cost fell below $A248 (£161 or €185). In addition, the mutation identification rate was also important in reducing the overall ICER, although even at the upper limits, the ICER still fell well within accepted willingness to pay bounds. The addition of genetic testing to the management of HCM families is cost-effective in comparison with the conventional approach of regular clinical screening. This has important implications for the evaluation of families with HCM, and suggests that all should have access to specialised cardiac genetic clinics that can offer genetic testing.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2022
DOI: 10.1161/CIRCGEN.121.003686
Abstract: The causes of cardiomyopathy in children are less well described than in adults. We evaluated the clinical diagnoses and genetic causes of childhood cardiomyopathy and outcomes of cascade genetic testing in family members. We recruited children from a pediatric cardiology service or genetic heart diseases clinic. We performed Sanger, gene panel, exome or genome sequencing and classified variants for pathogenicity using American College of Molecular Genetics and Genomics guidelines. Cardiomyopathy was diagnosed in 221 unrelated children aged ≤18 years. Children mostly had hypertrophic cardiomyopathy (n=98, 44%) or dilated cardiomyopathy (n=89, 40%). The highest genetic testing diagnostic yields were in restrictive cardiomyopathy (n=16, 80%) and hypertrophic cardiomyopathy (n=65, 66%), and lowest in dilated cardiomyopathy (n=26, 29%) and left ventricular noncompaction (n=3, 25%). Pathogenic variants were primarily found in genes encoding sarcomere proteins, with TNNT2 and TNNI3 variants associated with more severe clinical outcomes. Ten children (4.5%) had multiple pathogenic variants. Genetic test results prompted review of clinical diagnosis in 14 families with syndromic, mitochondrial or metabolic gene variants. Cascade genetic testing in 127 families confirmed 24 de novo variants, recessive inheritance in 8 families, and supported reclassification of 12 variants. Genetic testing of children with cardiomyopathy supports a precise clinical diagnosis, which may inform prognosis.
Publisher: Elsevier BV
Date: 08-2023
Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.TCM.2016.04.010
Abstract: Inherited cardiovascular diseases pose unique and complex psychosocial challenges for families, including coming to terms with life-long cardiac disease, risk of sudden death, grief related to the sudden death of a loved one, activity restrictions, and inheritance risk to other family members. Psychosocial factors impact not only mental health but also physical health and cooperation with clinical recommendations. We describe an interdisciplinary approach to the care of families with inherited cardiovascular disease, in which psychological care provided by specialized cardiac genetic counselors, nurses, and psychologists is embedded within the cardiovascular care team. We report illustrative cases and the supporting literature to demonstrate common scenarios, as well as practical guidance for clinicians working in the inherited cardiovascular disease setting.
Publisher: Elsevier BV
Date: 10-2021
DOI: 10.1016/J.HRTHM.2021.03.037
Abstract: Thorough investigation of sudden cardiac death (SCD) in those aged 1-40 years commonly reveals a heritable cause, yet access to postmortem genetic testing is variable. The purpose of this study was to explore practices of postmortem genetic testing and attitudes of health care professionals worldwide. A survey was administered among health care professionals recruited through professional associations, social media, and networks of researchers. Topics included practices around postmortem genetic testing, level of confidence in health care professionals' ability, and attitudes toward postmortem genetic testing practices. There were 112 respondents, with 93% from North America, Europe, and Australia/New Zealand, and 7% from South America, Asia and Africa. Only 30% reported autopsy as mandatory, and overall practices were largely case by case and not standardized. North American respondents (87%) more often perceived practices as ineffective compared to those from Europe (58%) and Australia/New Zealand (48% P = .002). Where a heritable cause is suspected, 69% considered postmortem genetic testing and 61% offered genetic counseling to surviving family members. Financial resources varied widely. Half of participants believed practices in their countries perpetuated health inequalities. Postmortem genetic testing is not consistently available in the investigation of young SCD despite being a recommendation in international guidelines. Access to postmortem genetic testing, which is critical in ascertaining a cause of death in many cases, must be guided by well-resourced, multidisciplinary teams.
Publisher: Elsevier BV
Date: 08-2012
DOI: 10.1038/GIM.2012.47
Abstract: Purpose:A genetic diagnosis is an extremely useful tool in the management and care of families with inherited heart diseases, particularly in allowing clarification of risk status of asymptomatic family members. The psychosocial consequences of genetic testing in this group are poorly understood. This longitudinal pilot study sought to determine changes in health-related quality of life in patients and asymptomatic family members undergoing genetic testing for inherited heart diseases.Methods:In iduals attending two specialized multidisciplinary cardiac genetic clinics in Australia were invited to participate. Patients undergoing proband or predictive genetic testing for an inherited cardiomyopathy or primary arrhythmogenic disorder were eligible. The Medical Outcomes Short Form-36 (version 2) was administered before the genetic result was given, and follow-up surveys were completed 1-3, 6, and 12 months after the result was given.Results:A total of 54 in iduals with hypertrophic cardiomyopathy, familial dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, and long QT syndrome completed baseline and at least one follow-up survey, including 33 probands and 21 asymptomatic relatives. Physical and mental component scores analyzed at baseline and 1-3 months were found to be unchanged in all groups. Furthermore, no significant differences were observed up to 12 months after result.Conclusion:In this longitudinal pilot study, no change in health-related quality of life was observed up to 12 months after the result was given in patients and their asymptomatic family members undergoing genetic testing for an inherited heart disease.Genet Med 2012 advance online publication 3 May 2012.
Publisher: Elsevier BV
Date: 05-2021
Publisher: Cold Spring Harbor Laboratory
Date: 16-10-2023
Publisher: Elsevier BV
Date: 09-2023
Publisher: Elsevier BV
Date: 03-2019
Publisher: Cold Spring Harbor Laboratory
Date: 29-12-2021
DOI: 10.1101/2021.12.28.21267792
Abstract: The majority of clinical genetic testing focuses almost exclusively on regions of the genome that directly encode proteins. The important role of variants in non-coding regions in penetrant disease is, however, increasingly being demonstrated, and the use of whole genome sequencing in clinical diagnostic settings is rising across a large range of genetic disorders. Despite this, there is no existing guidance on how current guidelines designed primarily for variants in protein-coding regions should be adapted for variants identified in other genomic contexts. We convened a panel of clinical and research scientists with wide-ranging expertise in clinical variant interpretation, with specific experience in variants within non-coding regions. This panel discussed and refined an initial draft of the guidelines which were then extensively tested and reviewed by external groups. We discuss considerations specifically for variants in non-coding regions of the genome. We outline how to define candidate regulatory elements, highlight ex les of mechanisms through which non-coding region variants can lead to penetrant monogenic disease, and outline how existing guidelines can be adapted for these variants. These recommendations aim to increase the number and range of non-coding region variants that can be clinically interpreted, which, together with a compatible phenotype, can lead to new diagnoses and catalyse the discovery of novel disease mechanisms.
Publisher: Oxford University Press (OUP)
Date: 31-10-2021
Abstract: Sudden cardiac death (SCD) is the most common mode of death in childhood hypertrophic cardiomyopathy (HCM). The newly developed HCM Risk-Kids model provides clinicians with in idualized estimates of risk. The aim of this study was to externally validate the model in a large independent, multi-centre patient cohort. A retrospective, longitudinal cohort of 421 patients diagnosed with HCM aged 1–16 years independent of the HCM Risk-Kids development and internal validation cohort was studied. Data on HCM Risk-Kids predictor variables (unexplained syncope, non-sustained ventricular tachycardia, maximal left ventricular wall thickness, left atrial diameter, and left ventricular outflow tract gradient) were collected from the time of baseline clinical evaluation. The performance of the HCM Risk-Kids model in predicting risk at 5 years was assessed. Twenty-three patients (5.4%) met the SCD end-point within 5 years, with an overall incidence rate of 2.03 per 100 patient-years [95% confidence interval (CI) 1.48–2.78]. Model validation showed a Harrell’s C-index of 0.745 (95% CI 0.52–0.97) and Uno’s C-index 0.714 (95% 0.58–0.85) with a calibration slope of 1.15 (95% 0.51–1.80). A 5-year predicted risk threshold of ≥6% identified 17 (73.9%) SCD events with a corresponding C-statistic of 0.702 (95% CI 0.60–0.81). This study reports the first external validation of the HCM Risk-Kids model in a large and geographically erse patient population. A 5-year predicted risk of ≥6% identified over 70% of events, confirming that HCM Risk-Kids provides a method for in idualized risk predictions and shared decision-making in children with HCM.
Publisher: Elsevier BV
Date: 07-2020
Publisher: Oxford University Press (OUP)
Date: 11-03-2015
Abstract: The sudden death of a young, apparently fit and healthy person is amongst the most challenging scenarios in clinical medicine. Sudden cardiac death (SCD) is a devastating and tragic outcome of a number of underlying cardiovascular diseases. While coronary artery disease and acute myocardial infarction are the most common causes of SCD in older populations, genetic (inherited) cardiac disorders comprise a substantial proportion of SCD cases aged 40 years and less. This includes the primary arrhythmogenic disorders such as long QT syndromes and inherited cardiomyopathies, namely hypertrophic cardiomyopathy. In up to 30% of young SCD, no cause of death is identified at postmortem, so-called autopsy-negative or sudden arrhythmic death syndrome (SADS). Management of families following SCD begins with a concerted effort to identify the cause of death in the decedent, based on either premorbid clinical details or the pathological findings at postmortem. Where no cause of death is identified, genetic testing of deoxyribonucleic acid extracted from postmortem blood (the molecular autopsy) may identify a cause of death in up to 30% of SADS cases. Irrespective of the genetic testing considerations, all families in which a sudden unexplained death has occurred require targeted and standardized clinical testing in an attempt to identify relatives who may be at-risk of having the same inherited heart disease and therefore also predisposed to an increased risk of SCD. Optimal care of SCD families therefore requires dedicated and appropriately trained staff in the setting of a specialized multidisciplinary cardiac genetic clinic.
Publisher: Elsevier BV
Date: 05-2019
DOI: 10.1038/GIM.2018.21
Publisher: Cold Spring Harbor Laboratory
Date: 03-07-2019
DOI: 10.1101/19000877
Abstract: The sudden cardiac death (SCD) of a young person is a devastating event for any parent. Inherited heart disease is often either identified or assumed to be the cause. Few studies have explored the psychosocial impact to the surviving at-risk family members. We sought to investigate the needs of parents who have experienced the SCD of their child (≤45 years). A quantitative needs analysis questionnaire was developed based on semi-structured interviews, including one focus group, and a review of relevant literature. There were 38 parents who completed a cross-sectional quantitative survey. Parents’ perceived needs for information and support spanned medical, psychosocial, spiritual and financial domains. Medical information and support needs were identified as the most important domains, followed by psychosocial, spiritual and financial information and support needs. Importantly, psychosocial information and support needs were reported as the most unmet need, endorsed by 54% of parents. Medical information and support needs were reported as unmet by almost one third of parents. The two most endorsed needs were “To have the option of whether or not you would pursue genetic testing for yourself or family members” and “To understand what happened”. This work demonstrates for the first time, the multifactorial needs of parents after SCD in the young. With the greatest unmet need reported as psychosocial needs, there is clear necessity to find ways of integrating psychological support in to the care of families after SCD in the young. There is currently very little known about the needs of families following a sudden cardiac death due to inherited heart diseases. We know there is significant risk of poor psychological outcomes including posttraumatic stress and prolonged grief, even years after the death, however this is one of the first studies to formally evaluate the needs of parents during this time. We show that medical information and support needs are ranked very highly, but psychosocial support needs are the most unmet. Our findings provide a platform for developing an approach to delivering psychosocial support interventions in this population. Currently clinical and research efforts in this setting focus on clinical and genetic aspects of care. Here we show the critical need to also focus on the psychological care needs in this population. These data will help to guide services in integrating psychological support in to their multidisciplinary clinic models.
Publisher: Elsevier BV
Date: 03-2021
Publisher: Elsevier BV
Date: 04-2013
DOI: 10.1016/J.JCHF.2013.01.004
Abstract: This study sought to determine factors predicting appropriate implantable cardioverter defibrillator (ICD) therapy in a large cohort of patients with hypertrophic cardiomyopathy (HCM). HCM is the leading cause of sudden cardiac death in those age ≤35 years. ICD therapy is offered to select patients at increased risk for sudden cardiac death. Currently, there are no clinical predictors of appropriate ICD therapy in HCM. Patients attending the HCM clinic in Sydney, Australia, and who had undergone ICD insertion were included. Baseline data on clinical and ICD characteristics were collected. The primary endpoint was the proportion of patients who experienced at least 1 appropriate therapy from the ICD. Of 164 HCM patients included (62% male mean follow-up, 6 ± 4 years [range, 0 to 19 years]), 21 patients (13%) had at least 1 appropriate therapy. Corrected QT (QTc) interval was the strongest clinical predictor of appropriate ICD therapy (458 ± 30 ms vs. 430 ± 35 ms p = 0.001). Multivariate logistic regression analysis demonstrated a 1.2-fold increased likelihood of appropriate therapy per 10-ms increase in QTc, independent of left ventricular wall thickness (LVWT) (odds ratio: 1.2 95% confidence interval [CI]: 1.03 to 1.39 p = 0.02) and sex (odds ratio: 1.2 95% CI: 1.07 to 1.42 p = 0.003). On analysis of cumulative event-free survival from appropriate ICD therapy, the risk for an appropriate ICD therapy in the subgroup with prolonged QT was >3-fold that in the subgroup without prolonged QT, after adjustment for LVWT (hazard ratio: 3.2 95% CI: 1.02 to 9.88 p = 0.047) and sex (hazard ratio, 3.7 95% CI, 1.22 to 11.41 p = 0.02). The findings from this study suggest that QTc interval prolongation is a novel clinical predictor of appropriate ICD therapy in HCM.
Publisher: Public Library of Science (PLoS)
Date: 05-08-2020
Publisher: Oxford University Press (OUP)
Date: 30-05-2019
Abstract: In patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), implantable cardioverter-defibrillator (ICD) shocks are sometimes ineffective and may even trigger fatal electrical storms. We assessed the efficacy and complications of ICDs placed in patients with CPVT who presented with a sentinel event of sudden cardiac arrest (SCA) while undiagnosed and therefore untreated. We analysed 136 patients who presented with SCA and in whom CPVT was diagnosed subsequently, leading to the initiation of guideline-directed therapy, including β-blockers, flecainide, and/or left cardiac sympathetic denervation. An ICD was implanted in 79 patients (58.1%). The primary outcome of the study was sudden cardiac death (SCD). The secondary outcomes were composite outcomes of SCD, SCA, appropriate ICD shocks, and syncope. After a median follow-up of 4.8 years, SCD had occurred in three patients (3.8%) with an ICD and none of the patients without an ICD (P = 0.1). SCD, SCA, or appropriate ICD shocks occurred in 37 patients (46.8%) with an ICD and 9 patients (15.8%) without an ICD (P & 0.0001). Inappropriate ICD shocks occurred in 19 patients (24.7%) and other device-related complications in 22 patients (28.9%). In previously undiagnosed patients with CPVT who presented with SCA, an ICD was not associated with improved survival. Instead, the ICD was associated with both a high rate of appropriate ICD shocks and inappropriate ICD shocks along with other device-related complications. Strict adherence to guideline-directed therapy without an ICD may provide adequate protection in these patients without all the potential disadvantages of an ICD.
Publisher: Springer Science and Business Media LLC
Date: 11-10-2023
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1016/J.HLC.2016.11.021
Abstract: Community-wide trends data for sudden cardiac death (SCD) are scarce, unlike widely reported declines in cardiovascular disease (CVD) mortality. Using administrative data, we aimed to examine population-level trends in SCD, stratified by sex, age and prior CVD hospitalisation. Person-linked mortality and hospital morbidity data were used to identify SCD and determine hospitalisation and comorbidity using a 10-year hospitalisation lookback period. Log-linear Poisson regression was used to calculate annual rate changes and rate ratios. In Western Australia, 7160 SCD cases were identified from 1997 to 2010 with males comprising 69%. Overall age-standardised SCD rates decreased by 17% in men and 31% in women from 1997-2001 to 2007-2010. The annual rate reduction was higher in women than men (-4.0%/year versus -2.3%/year p=0.0039). Significant reductions were observed for 55-69 year-old and 70-84 year-old men and women but not for the 35-54 year-olds. The overall relative risk comparing men to women increased slightly from 2.4 in 1997 to 3.0 in 2010 (trend p=0.0039) but differed across age groups. The relative risk declined in 35-54 year-olds from 5.1 to 3.2 whereas it increased from 2.9 to 3.9 in 55-69 year-olds and 1.9 to 2.3 in 70-84 year-olds. Declining trends in SCD rates were observed in those with and without prior CVD and were similar to CVD mortality trends (-4.9%/year in men and -5.5%/year in women). Trends in rates of SCD fell in middle to older aged men and women, with and without CVD, and mirrored the fall in fatal CVD. Limited improvement in 35-54 year-olds requires further investigation.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2023
DOI: 10.1161/CIRCGEN.121.003672
Abstract: Truncating variants in desmoplakin ( DSP tv) are an important cause of arrhythmogenic cardiomyopathy however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics of DSP tv cardiomyopathy. In iduals with DSP tv and any cardiac phenotype, and their gene-positive family members were included from multiple international centers. Clinical data and family history information were collected. Event-free survival from ventricular arrhythmia was assessed. Variant location was compared between cases and controls, and literature review of reported DSP tv performed. There were 98 probands and 72 family members (mean age at diagnosis 43±8 years, 59% women) with a DSP tv, of which 146 were considered clinically affected. Ventricular arrhythmia (sudden cardiac arrest, sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator therapy) occurred in 56 (33%) in iduals. DSP tv location and proband status were independent risk factors for ventricular arrhythmia. Further, gene region was important with variants in cases (cohort n=98 Clinvar n=167) more likely to occur in the regions resulting in nonsense mediated decay of both major DSP isoforms, compared with n=124 genome aggregation database control variants (148 [83.6%] versus 29 [16.4%] P .0001). In the largest series of in iduals with DSP tv, we demonstrate that variant location is a novel risk factor for ventricular arrhythmia, can inform variant interpretation, and provide critical insights to allow for precision-based clinical management.
Publisher: Springer Science and Business Media LLC
Date: 03-05-2017
DOI: 10.1038/EJHG.2017.66
Publisher: Springer International Publishing
Date: 2016
Publisher: BMJ
Date: 28-09-2017
DOI: 10.1136/BMJ.J4101
Publisher: Cold Spring Harbor Laboratory
Date: 09-10-2023
Publisher: JMIR Publications Inc.
Date: 20-09-2023
DOI: 10.2196/48636
Publisher: Proceedings of the National Academy of Sciences
Date: 03-03-2021
Abstract: Genetics, notably pathogenic genetic variants in sarcomere protein genes, play a major role in development of hypertrophic cardiomyopathy (HCM). However, degree of contribution from epigenetic and environmental factors in clinical presentation of HCM is currently unclear. We investigated phenotypic differences between identical twins with pathogenic sarcomere protein gene variants and demonstrated their discordant HCM presentation despite having virtually identical genomes. Our study underscores the important contribution of epigenetics and environment in disease progression in genetically diagnosed HCM patients.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2017
DOI: 10.1161/CIRCGENETICS.116.001620
Abstract: Yield of causative variants in hypertrophic cardiomyopathy (HCM) is increased in some probands, suggesting different clinical subgroups of disease occur. We hypothesized that a negative family history and no sarcomere mutations represent a nonfamilial subgroup of HCM. We sought to determine the prevalence, natural history, and potential clinical implications of this nonfamilial subgroup of HCM. Four hundred and thirteen unrelated probands with HCM seen in a specialized HCM center between 2002 and 2015 and genetic testing performed were included in this retrospective cohort study. There were 251 (61%) probands with no reported family history of HCM, including 166 (40% of total) probands with no sarcomere mutation, that is, nonfamilial HCM. Quantified family pedigree data revealed no difference in mean number of first-degree relatives screened between nonfamilial and sarcomere-positive groups. Adjusted predictors of nonfamilial status were older age (odds ratio, 1.04 95% confidence interval, 1.02–1.06 P =0.0001), male sex (odds ratio, 1.96 95% confidence interval, 1.11–3.45 P =0.02), hypertension (odds ratio, 2.80 95% confidence interval, 1.57–5.00 P =0.0005), and nonasymmetric septal morphology (odds ratio, 3.41 95% confidence interval, 1.64–7.08 P =0.001). They had a less severe clinical course with greater event-free survival from major cardiac events ( P =0.04) compared with sarcomere-positive HCM probands. Genotype prediction scores showed good performance in identifying genotype-positive patients (area under the curve, 0.71–0.75) and, in combination with pedigree characteristics, were further improved. Approximately 40% of HCM probands have a nonfamilial subtype, with later onset and less severe clinical course. We propose a revised clinical pathway for management, highlighting the role of genetic testing, a detailed pedigree, and refined clinical surveillance recommendations for family members.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-09-2020
DOI: 10.1161/CIRCULATIONAHA.120.045723
Abstract: Genetic variants in calsequestrin-2 ( CASQ2 ) cause an autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT), although isolated reports have identified arrhythmic phenotypes among heterozygotes. Improved insight into the inheritance patterns, arrhythmic risks, and molecular mechanisms of CASQ2 -CPVT was sought through an international multicenter collaboration. Genotype-phenotype segregation in CASQ2 -CPVT families was assessed, and the impact of genotype on arrhythmic risk was evaluated using Cox regression models. Putative dominant CASQ2 missense variants and the established recessive CASQ2-p.R33Q variant were evaluated using oligomerization assays and their locations mapped to a recent CASQ2 filament structure. A total of 112 in iduals, including 36 CPVT probands (24 homozygotes/compound heterozygotes and 12 heterozygotes) and 76 family members possessing at least 1 presumed pathogenic CASQ2 variant, were identified. Among CASQ2 homozygotes and compound heterozygotes, clinical penetrance was 97.1% and 26 of 34 (76.5%) in iduals had experienced a potentially fatal arrhythmic event with a median age of onset of 7 years (95% CI, 6–11). Fifty-one of 66 CASQ2 heterozygous family members had undergone clinical evaluation, and 17 of 51 (33.3%) met diagnostic criteria for CPVT. Relative to CASQ2 heterozygotes, CASQ2 homozygote/compound heterozygote genotype status in probands was associated with a 3.2-fold (95% CI, 1.3–8.0 P =0.013) increased hazard of a composite of cardiac syncope, aborted cardiac arrest, and sudden cardiac death, but a 38.8-fold (95% CI, 5.6–269.1 P .001) increased hazard in genotype-positive family members. In vitro turbidity assays revealed that p.R33Q and all 6 candidate dominant CASQ2 missense variants evaluated exhibited filamentation defects, but only p.R33Q convincingly failed to dimerize. Structural analysis revealed that 3 of these 6 putative dominant negative missense variants localized to an electronegative pocket considered critical for back-to-back binding of dimers. This international multicenter study of CASQ2 -CPVT redefines its heritability and confirms that pathogenic heterozygous CASQ2 variants may manifest with a CPVT phenotype, indicating a need to clinically screen these in iduals. A dominant mode of inheritance appears intrinsic to certain missense variants because of their location and function within the CASQ2 filament structure.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2013
Publisher: Cold Spring Harbor Laboratory
Date: 20-06-2023
DOI: 10.1101/2023.06.17.23291422
Abstract: Women with HCM present at a more advanced stage of the disease and have a higher risk of heart failure and death. The factors contributing to these differences are unclear. We aimed to investigate sex differences in clinical and genetic factors associated with adverse outcomes in the Sarcomeric Human Cardiomyopathy Registry (SHaRe). Cox proportional hazard models were fit with a sex interaction term to determine if significant sex differences existed in the association between risk factors and outcomes. Models were fit separately for women and men to find the sex-specific hazard ratio. After a mean follow-up of 6.4 years, women had a higher risk of heart failure (HR 1.51 95% CI 1.21-1.88, p=0.0003) but a lower risk of atrial fibrillation (0.74 0.59-0.93 p .0001) and ventricular arrhythmia (0.60 0.38-0.94 p=0.027) than men. No sex difference was observed for death (p=0.84). Sarcomere-positive men had a higher risk of heart failure and death, not seen in women (p-heterogeneity=0.006 & p-heterogeneity=0.035, respectively). MYBPC3 variants were associated with lower heart failure risk in women than other HCM subgroups, with no significant change for men (p-heterogeneity .0001). Women with moderate risk of ventricular arrhythmia (4% to % ESC risk score) were at a higher risk of ventricular arrhythmia than those scoring %, not observed in men (p-heterogeneity= 0.019). Clinical and genetic factors contributing to adverse outcomes in HCM affect women and men differently. Research to inform sex-specific management of HCM could improve outcomes for both sexes.
Publisher: Elsevier BV
Date: 08-2017
Publisher: Elsevier BV
Date: 06-2018
DOI: 10.1016/J.HLC.2017.12.012
Abstract: In iduals with hypertrophic cardiomyopathy (HCM) may be asymptomatic or display activity-limiting symptoms. A common cause of symptoms is left ventricular outflow tract obstruction (LVOTO), which may impact the in iduals' ability to undertake physical activity. This study sought to examine daily step count as a potential marker of exercise capacity, which may represent a proxy marker of disease severity in HCM. A cross-sectional study of 63 HCM patients was conducted from March to November 2015. Participants wore an ActiGraph GT3X+ (Pensacola, Florida, USA) accelerometer for 7 days. Minutes per day of light, moderate and vigorous physical activity and step count were calculated, and those with LVOTO were compared to those without. Similarly, those with good functional capacity (New York Heart Association NYHA class I) were compared to those with NYHA class II-IV. The majority of HCM patients were male (n=45, 71%) with mean age of 48.8±14.9years. Hypertrophic cardiomyopathy patients with history of LVOTO and those NYHA class II-IV took significantly fewer steps per day (LV obstruction: 5527±2370 versus 7027±2095, p=0.01 and NYHA: 5346±1898 versus 6801±2339, p=0.03). No differences were observed across the different intensities of physical activity. Measurement of daily step count may be a useful and simple tool to determine exercise capacity and provide an indicator of disease severity in in iduals with HCM.
Publisher: Springer Science and Business Media LLC
Date: 09-11-2017
Publisher: Springer Science and Business Media LLC
Date: 27-04-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2020
Publisher: American Medical Association (AMA)
Date: 10-2017
DOI: 10.1001/JAMACARDIO.2017.2352
Abstract: Genetic testing is a valuable tool for managing inherited cardiovascular disease in patients and families, including hypertrophic, dilated, and arrhythmogenic cardiomyopathies and inherited arrhythmias. By identifying the molecular etiology of disease, genetic testing can improve diagnostic accuracy and refine family management. However, unique features associated with genetic testing affect the interpretation and application of results and differentiate it from traditional laboratory-based diagnostics. Clinicians and patients must have accurate and realistic expectations about the yield of genetic testing and its role in management. Familiarity with the rationale, implications, benefits, and limitations of genetic testing is essential to achieve the best possible outcomes. Successfully incorporating genetic testing into clinical practice requires (1) recognizing when inherited cardiovascular disease may be present, (2) identifying appropriate in iduals in the family for testing, (3) selecting the appropriate genetic test, (4) understanding the complexities of result interpretation, and (5) effectively communicating the results and implications to the patient and family. Obtaining a detailed family history is critical to identify families who will benefit from genetic testing, determine the best strategy, and interpret results. Instead of focusing on an in idual patient, genetic testing requires consideration of the family as a unit. Consolidation of care in centers with a high level of expertise is recommended. Clinicians without expertise in genetic testing will benefit from establishing referral or consultative networks with experienced clinicans in specialized multidisciplinary clinics. Genetic testing provides a foundation for transitioning to more precise and in idualized management. By distinguishing phenotypic subgroups, identifying disease mechanisms, and focusing family care, gene-based diagnosis can improve management. Successful integration of genetic testing into clinical practice requires understanding of the complexities of testing and effective communication of the implications to patients and families.
Publisher: Elsevier BV
Date: 08-2004
DOI: 10.1016/J.IJCARD.2004.05.003
Abstract: Hypertrophic cardiomyopathy is an inherited primary disorder of the myocardium characterised by clinical heterogeneity. The severity and rate of progression of hypertrophy is an important factor in prognosis, and is likely to be dependent on factors including age, the disease-causing gene mutation, environmental influences and genetic modifiers. To study the influence of age on progression of hypertrophy, 62 patients with hypertrophic cardiomyopathy followed up for a minimum of 2 years were studied to determine the changes in left ventricular hypertrophy based on transthoracic M-mode and 2D echocardiography. DNA studies were performed to determine the role of the angiotensin-converting enzyme (ACE) gene deletion polymorphism in modulating progression of left ventricular hypertrophy. Sixty-two patients were followed-up over a period of 6.0 +/- 3.2 years (range 2-16 years). Patient data were analysed in two age groups: group 1 (patients aged < or = 30 years at first echocardiogram) had an increase in left ventricular septal wall thickness from 23.8 +/- 8.9 to 28.8 +/- 8.7 mm (p 30 years) had a smaller but significant increase from 17.8 +/- 4.2 to 19.5 +/- 6.2 mm (p < 0.05). DNA analysis of the ACE gene deletion polymorphism showed those with the deletion/deletion (D/D) genotype had a greater progression of left ventricular hypertrophy compared to those carrying the other ACE genotypes (increase in hypertrophy: 6.2 +/- 3.3 vs. 1.7 +/- 4.2 mm p < 0.01, D/D vs. I/D genotype 2.8 +/- 5.8 mm p = ns, D/D vs. I/I genotype). This association was independent of age, body mass and resting blood pressure. Progression of left ventricular hypertrophy is most evident in the first 3 decades of life, but is also observed in older age groups. Presence of the ACE gene D/D polymorphism may be an important marker to identify those in iduals with hypertrophic cardiomyopathy who are likely to have more progressive disease, and therefore at higher risk of adverse clinical outcomes.
Publisher: Elsevier BV
Date: 07-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2017
Publisher: Elsevier BV
Date: 10-2014
Publisher: Elsevier BV
Date: 05-2019
Publisher: Elsevier BV
Date: 02-2017
Publisher: Elsevier BV
Date: 2016
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 21-07-2020
DOI: 10.1161/CIRCULATIONAHA.120.047235
Abstract: Hypertrophic cardiomyopathy is the leading cause of sudden cardiac death (SCD) in children and young adults. Our objective was to develop and validate a SCD risk prediction model in pediatric hypertrophic cardiomyopathy to guide SCD prevention strategies. In an international multicenter observational cohort study, phenotype-positive patients with isolated hypertrophic cardiomyopathy years of age at diagnosis were eligible. The primary outcome variable was the time from diagnosis to a composite of SCD events at 5-year follow-up: SCD, resuscitated sudden cardiac arrest, and aborted SCD, that is, appropriate shock following primary prevention implantable cardioverter defibrillators. Competing risk models with cause-specific hazard regression were used to identify and quantify clinical and genetic factors associated with SCD. The cause-specific regression model was implemented using boosting, and tuned with 10 repeated 4-fold cross-validations. The final model was fitted using all data with the tuned hyperparameter value that maximizes the c-statistic, and its performance was characterized by using the c-statistic for competing risk models. The final model was validated in an independent external cohort (SHaRe [Sarcomeric Human Cardiomyopathy Registry], n=285). Overall, 572 patients met eligibility criteria with 2855 patient-years of follow-up. The 5-year cumulative proportion of SCD events was 9.1% (14 SCD, 25 resuscitated sudden cardiac arrests, and 14 aborted SCD). Risk predictors included age at diagnosis, documented nonsustained ventricular tachycardia, unexplained syncope, septal diameter z -score, left ventricular posterior wall diameter z score, left atrial diameter z score, peak left ventricular outflow tract gradient, and presence of a pathogenic variant. Unlike in adults, left ventricular outflow tract gradient had an inverse association, and family history of SCD had no association with SCD. Clinical and clinical/genetic models were developed to predict 5-year freedom from SCD. Both models adequately discriminated between patients with and without SCD events with a c-statistic of 0.75 and 0.76, respectively, and demonstrated good agreement between predicted and observed events in the primary and validation cohorts (validation c-statistic 0.71 and 0.72, respectively). Our study provides a validated SCD risk prediction model with % prediction accuracy and incorporates risk factors that are unique to pediatric hypertrophic cardiomyopathy. An in idualized risk prediction model has the potential to improve the application of clinical practice guidelines and shared decision making for implantable cardioverter defibrillator insertion. URL: www.clinicaltrials.gov Unique identifier: NCT0403679.
Publisher: Elsevier BV
Date: 12-2015
Publisher: Elsevier BV
Date: 08-2008
DOI: 10.1016/J.YJMCC.2008.05.016
Abstract: Hypertrophic cardiomyopathy (HCM) is a clinically heterogeneous disease, which suggests that a number of factors exist which modify disease outcome. Gender may be one such factor as more males present with the disease compared with females. The aim of the present study was to determine if an association exists between genetic variation in sex hormone receptors and the development of left ventricular hypertrophy in HCM. The study population included 200 unrelated in iduals from an Australian HCM cohort. Clinical evaluation was performed. Genetic analysis of the androgen receptor (AR), estrogen receptor 1 (ESR1), estrogen receptor 2 (ESR2), and aromatase (CYP19A1) genes, was carried out in all patients. Fewer (CAG)n repeats within the AR gene were significantly associated with higher maximal left ventricular wall thickness (LVWT) in males (P=0.008), adjusting for age. Male carriers of the A allele at SNP rs6915267, located in the promoter region of ESR1, had an 11% decrease in mean LVWT compared to male GG homozygotes (P=0.047). We report for the first time that variation at the AR gene is associated with left ventricular hypertrophy in males with HCM. Understanding the impact of sex hormones on phenotype will be helpful in the risk stratification and clinical management of HCM patients.
Publisher: Oxford University Press (OUP)
Date: 07-09-2021
DOI: 10.1093/EURHEARTJ/EHAB598
Abstract: Risk stratification algorithms for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM) and regional differences in clinical practice have evolved over time. We sought to compare primary prevention implantable cardioverter defibrillator (ICD) implantation rates and associated clinical outcomes in US vs. non-US tertiary HCM centres within the international Sarcomeric Human Cardiomyopathy Registry. We included patients with HCM enrolled from eight US sites (n = 2650) and five non-US (n = 2660) sites and used multivariable Cox-proportional hazards models to compare outcomes between sites. Primary prevention ICD implantation rates in US sites were two-fold higher than non-US sites (hazard ratio (HR) 2.27 [1.89–2.74]), including in in iduals deemed at high 5-year SCD risk (≥6%) based on the HCM risk-SCD score (HR 3.27 [1.76–6.05]). US ICD recipients also had fewer traditional SCD risk factors. Among ICD recipients, rates of appropriate ICD therapy were significantly lower in US vs. non-US sites (HR 0.52 [0.28–0.97]). No significant difference was identified in the incidence of SCD/resuscitated cardiac arrest among non-recipients of ICDs in US vs. non-US sites (HR 1.21 [0.74–1.97]). Primary prevention ICDs are implanted more frequently in patients with HCM in US vs. non-US sites across the spectrum of SCD risk. There was a lower rate of appropriate ICD therapy in US sites, consistent with a lower-risk population, and no significant difference in SCD in US vs. non-US patients who did not receive an ICD. Further studies are needed to understand what drives malignant arrhythmias, optimize ICD allocation, and examine the impact of different ICD utilization strategies on long-term outcomes in HCM.
No related grants have been discovered for Jodie Ingles.