Publications by authors named "Christopher Semsarian"

314 Publications

Latent Causes of Sudden Cardiac Arrest.

JACC Clin Electrophysiol 2022 06;8(6):806-821

Center for Cardiovascular Innovation, Heart Rhythm Services, Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada; Victorian Heart Institute, Monash University, Clayton, Victoria, Australia.

Inherited arrhythmia syndromes are a common cause of apparently unexplained cardiac arrest or sudden cardiac death. These include long QT syndrome and Brugada syndrome, with a well-recognized phenotype in most patients with sufficiently severe disease to lead to cardiac arrest. Less common and typically less apparent conditions that may not be readily evident include catecholaminergic polymorphic ventricular tachycardia, short QT syndrome and early repolarization syndrome. In cardiac arrest patients whose extensive testing does not reveal an underlying etiology, a diagnosis of idiopathic ventricular fibrillation or short-coupled ventricular fibrillation is assigned. This review summarizes our current understanding of the less common inherited arrhythmia syndromes and provides clinicians with a practical approach to diagnosis and management.
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http://dx.doi.org/10.1016/j.jacep.2021.12.014DOI Listing
June 2022

The Impact of Ethnicity on Athlete ECG Interpretation: A Systematic Review.

J Cardiovasc Dev Dis 2022 Jun 8;9(6). Epub 2022 Jun 8.

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney 2050, Australia.

Athlete ECG interpretation criteria have been developed and refined from research in athlete populations; however, current guidelines are based on available data primarily from Caucasian and Black athletes. This study aimed to assess the impact of ethnicity on ECG interpretation in athletes. A systematic review was conducted of the MEDLINE, EMBASE, Scopus, SPORTDiscus, and Web of Science databases, for papers that assessed athlete screening ECGs and compared findings on the basis of ethnicity. Fifty-one papers which compared ECGs from various ethnicities were included. Most studies assessed Black athletes against Caucasian athletes and found a greater prevalence of T-wave inversion (TWI) (2.6-22.8% vs. 0-5.0%) and anterior TWI (3.7-14.3% vs. 0.6-2.0%). Black athlete subgroups in Africa had TWI (20-40%) and anterior TWI (4.3-18.7%) at a higher prevalence than other Black athletes. Athletes who were defined as mixed-race, Asian, and Pacific Islander are potentially more like Black athletes than Caucasian athletes. Black ethnicity is known to have an impact on the accurate interpretation of athlete ECGs; however, there is nuance related to origin of both parents. Asian and Pacific Islander origin also may impact athlete ECG interpretation. Further research is required to assist in distinguishing abnormal and normal athlete ECGs in different ethnic populations.
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http://dx.doi.org/10.3390/jcdd9060183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9225578PMC
June 2022

Frequency, Penetrance, and Variable Expressivity of Dilated Cardiomyopathy-Associated Putative Pathogenic Gene Variants in UK Biobank Participants.

Circulation 2022 Jul 16;146(2):110-124. Epub 2022 Jun 16.

Center for Inherited Cardiovascular Diseases, WellSpan Health, Lancaster, PA (G.S.D., C.A.A.C.).

Background: There is a paucity of data regarding the phenotype of dilated cardiomyopathy (DCM) gene variants in the general population. We aimed to determine the frequency and penetrance of DCM-associated putative pathogenic gene variants in a general adult population, with a focus on the expression of clinical and subclinical phenotype, including structural, functional, and arrhythmic disease features.

Methods: UK Biobank participants who had undergone whole exome sequencing, ECG, and cardiovascular magnetic resonance imaging were selected for study. Three variant-calling strategies (1 primary and 2 secondary) were used to identify participants with putative pathogenic variants in 44 DCM genes. The observed phenotype was graded DCM (clinical or cardiovascular magnetic resonance diagnosis); early DCM features, including arrhythmia or conduction disease, isolated ventricular dilation, and hypokinetic nondilated cardiomyopathy; or phenotype-negative.

Results: Among 18 665 individuals included in the study, 1463 (7.8%) possessed ≥1 putative pathogenic variant in 44 DCM genes by the main variant calling strategy. A clinical diagnosis of DCM was present in 0.34% and early DCM features in 5.7% of individuals with putative pathogenic variants. ECG and cardiovascular magnetic resonance analysis revealed evidence of subclinical DCM in an additional 1.6% and early DCM features in an additional 15.9% of individuals with putative pathogenic variants. Arrhythmias or conduction disease (15.2%) were the most common early DCM features, followed by hypokinetic nondilated cardiomyopathy (4%). The combined clinical/subclinical penetrance was ≤30% with all 3 variant filtering strategies. Clinical DCM was slightly more prevalent among participants with putative pathogenic variants in definitive/strong evidence genes as compared with those with variants in moderate/limited evidence genes.

Conclusions: In the UK Biobank, ≈1 of 6 of adults with putative pathogenic variants in DCM genes exhibited early DCM features potentially associated with DCM genotype, most commonly manifesting with arrhythmias in the absence of substantial ventricular dilation or dysfunction.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.058143DOI Listing
July 2022

Higher rates but similar causes of young out-of-hospital cardiac arrest in rural Australian patients.

Aust J Rural Health 2022 Jun 15. Epub 2022 Jun 15.

Baker Heart and Diabetes Institute, Prahran, Vic., Australia.

Objective: To determine whether young rural Australians have higher rates or different underlying causes of out-of-hospital cardiac arrest (OHCA).

Design: A case-control design identified patients experiencing an OHCA, then compared annual OHCA rates and underlying causes in rural versus metropolitan Victoria. OHCA causes were defined as either cardiac or non-cardiac, with specific aetiologies including coronary disease, cardiomyopathy, unascertained cause of arrest, drug toxicity, respiratory event, neurological event and other cardiac and non-cardiac. For OHCAs with confirmed cardiac aetiology, cardiovascular risk profiles were compared.

Setting: A state-wide prospective OHCA registry (combining ambulance, hospital and forensic data) in the state of Victoria, Australia (population 6.5 million).

Participants: Victorians aged 1-50 years old experienced an OHCA between April 2019 and April 2020.

Main Outcome Measures: Rates and underlying causes of OHCA in young rural and metropolitan Victorians.

Results: Rates of young OHCA were higher in rural areas (OHCA 22.5 per 100 000 rural residents vs. 13.4 per 100 000 metropolitan residents, standardised incidence ratio 168 (95% CI 101-235); confirmed cardiac cause of arrest 12.1 per 100 000 rural residents versus 7.5 per 100 000 metropolitan residents, standardised incidence ratio 161 (95% CI 71-251). The underlying causation of the OHCA and cardiovascular risk factor burden did not differ between rural and metropolitan areas.

Conclusion: Higher rates of OHCA occur in young rural patients, with standardised incidence ratio of 168 compared to young metropolitan residents. Rural status did not influence causes of cardiac arrest or known cardiovascular risk factor burden in young patients experiencing OHCA.
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http://dx.doi.org/10.1111/ajr.12890DOI Listing
June 2022

Improving community-based first response to out of hospital cardiac arrest (FirstCPR): protocol for a cluster randomised controlled trial.

BMJ Open 2022 06 9;12(6):e057175. Epub 2022 Jun 9.

Westmead Applied Research Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia

Introduction: Out-of-hospital cardiac arrest (OHCA) is associated with poor survival outcomes, but prompt bystander action can more than double survival rates. Being trained, confident and willing-to-perform cardiopulmonary resuscitation (CPR) are known predictors of bystander action. This study aims to assess the effectiveness of a community organisation targeted multicomponent education and training initiative on being willing to respond to OHCAs. The study employs a novel approach to reaching community members via social and cultural groups, and the intervention aims to address commonly cited barriers to training including lack of availability, time and costs.

Methods And Analysis: FirstCPR is a cluster randomised trial that will be conducted across 200 community groups in urban and regional Australia. It will target community groups where CPR training is not usual. Community groups (clusters) will be stratified by region, size and organisation type, and then randomly assigned to either immediately receive the intervention programme, comprising digital and in-person education and training opportunities about CPR and OHCA over 12 months, or a delayed programme implementation. The primary outcome is self-reported 'training and willingness-to-perform CPR' at 12 months. It will be assessed through surveys of group members that consent in intervention versus control groups and administered prior to control groups receiving the intervention. The primary analysis will follow intention-to-treat principles, use log binomial regression accounting for baseline covariates and be conducted at the individual level, while accounting for clustering within communities. Focus groups and interviews will be conducted to examine barriers and enablers to implementation and costs will also be examined.

Ethics And Dissemination: Ethical approval was obtained from The University of Sydney. Findings from this study will be disseminated via presentations at scientific conferences, publications in peer-reviewed journals, scientific and lay reports.

Trial Registration Number: ACTRN12621000367842.
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http://dx.doi.org/10.1136/bmjopen-2021-057175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9185498PMC
June 2022

Prevalence of Coronary Artery Anomalies in Young and Middle-Aged Sudden Cardiac Death Victims (from a Prospective State-Wide Registry).

Am J Cardiol 2022 07 31;175:127-130. Epub 2022 May 31.

Sports Cardiology, Baker Heart and Diabetes Institute, Melbourne, Australia; Cardiology Department, Alfred Hospital, Melbourne, Australia; Cardiology Department, St. Vincent's Hospital, Melbourne, Australia.

Coronary artery anomalies (CAAs) have been previously implicated as a major cause of young sudden cardiac death (SCD), particularly in exercise-related SCD, with a prevalence of up to 33%. A state-wide prospective out-of-hospital cardiac arrest registry identified all patients aged 1 to 50 years who experienced an SCD and underwent autopsy from April 2019 to April 2021. Rates of normal anatomy, normal variants, and CAAs were identified, and circumstances and causes of death for patients with CAAs examined. Of 1,477 patients who experienced cardiac arrest during the study period, 490 underwent autopsy and were confirmed to have experienced SCD. Of these 490 patients, 5 (1%) had a CAA identified, with 3 having anomalies of coronary origin and 2 having anomalies of coronary course. In no cases were the CAA deemed responsible for the SCD. In 2 cases, severe coronary disease and intra-coronary thrombus with histological evidence of acute myocardial infarction were identified. In the third, critical coronary disease was found, the fourth had an unrelated thoracic aortic dissection, and the fifth had cardiomegaly in the setting of illicit drug use. Of 27 patients who experienced their SCD during exercise, only 1 had a CAA identified (the patient with thoracic aortic dissection). In conclusion, in this prospective cohort of consecutive young patients with SCD who underwent autopsy, CAAs occurred in 1% of patients and did not cause any deaths. The role of CAAs in causing young and middle-aged SCD appears to be less significant than previously hypothesized.
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http://dx.doi.org/10.1016/j.amjcard.2022.03.055DOI Listing
July 2022

Diverse stakeholder engagement at the heart of co-designing cardiac arrest care.

Heart Rhythm O2 2022 Apr 20;3(2):213-217. Epub 2022 Jan 20.

Clinical Research Domain, Baker Heart & Diabetes Institute, Melbourne, Australia.

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http://dx.doi.org/10.1016/j.hroo.2021.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9043393PMC
April 2022

A prospective longitudinal study of health-related quality of life and psychological wellbeing after an implantable cardioverter-defibrillator in patients with genetic heart diseases.

Heart Rhythm O2 2022 Apr 8;3(2):143-151. Epub 2022 Feb 8.

Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, Australia.

Background: Genetic heart diseases (GHDs) 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 GHDs are unknown.

Objectives: Investigate the psychological functioning and HR-QoL over time in patients with GHDs who receive an ICD, and identify risk factors for poor psychological functioning and HR-QoL.

Methods: A longitudinal, prospective study design was used. Patients attending a specialized clinic, diagnosed with a GHD for which they received an ICD between May 2012 and January 2015, were eligible. Baseline surveys were completed prior to ICD implantation with 5-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).

Results: Forty patients were included (mean age 46.3 ± 14.2 years; 65.0% male). 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. Nontertiary education and female sex predicted worse mental HR-QoL and anxiety over time, while comorbidities predicted depression and worse physical HR-QoL.

Conclusion: While the majority of patients with a GHD adjust well to their ICD implant, a subset of patients experience poor psychological and HR-QoL outcomes.
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http://dx.doi.org/10.1016/j.hroo.2022.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9043389PMC
April 2022

Rare sudden unexpected death in epilepsy SCN5A variants cause changes in channel function implicating cardiac arrhythmia as a cause of death.

Epilepsia 2022 06 22;63(6):e57-e62. Epub 2022 Apr 22.

Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia.

Sudden unexpected death in epilepsy (SUDEP) is a leading cause of premature death in epilepsy. The underlying pathological mechanisms are likely to be multifactorial. Cardiac arrhythmia has been suggested as a cause of death in some patients with SUDEP. SCN5A encodes the cardiac Na 1.5 sodium channel. SCN5A variants that result in either loss or gain of channel function cause cardiac arrhythmias. Rare SCN5A variants have been reported in SUDEP cases, but the impact of these variants on channel function is unknown. Here, we use whole-cell voltage clamp recordings to perform functional analyses of rare SCN5A SUDEP variants, p.V223G, p.I397V, and p.R523C. Expression and biophysical properties, including activation, inactivation, and recovery from inactivation, were probed. Each SCN5A variant significantly impacted human Na 1.5 channel function, indicating that they could cause cardiac arrhythmias. The patient carrying the p.R523C variant was on lamotrigine, an antiseizure medication implicated in SUDEP. Therapeutic concentration of lamotrigine caused a slowing of the rate of recovery from inactivation and a hyperpolarizing shift in the voltage of inactivation of human Na 1.5 wild-type, but not p.R523C channels, implicating a gene-by-drug interaction. These data suggest that SCN5A arrhythmogenic variants may confer increased risk of sudden death in individuals with epilepsy.
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http://dx.doi.org/10.1111/epi.17254DOI Listing
June 2022

Whole genome sequencing delineates regulatory, copy number, and cryptic splice variants in early onset cardiomyopathy.

NPJ Genom Med 2022 Mar 14;7(1):18. Epub 2022 Mar 14.

Cardiology Department, Royal Children's Hospital, Melbourne, Australia.

Cardiomyopathy (CMP) is a heritable disorder. Over 50% of cases are gene-elusive on clinical gene panel testing. The contribution of variants in non-coding DNA elements that result in cryptic splicing and regulate gene expression has not been explored. We analyzed whole-genome sequencing (WGS) data in a discovery cohort of 209 pediatric CMP patients and 1953 independent replication genomes and exomes. We searched for protein-coding variants, and non-coding variants predicted to affect the function or expression of genes. Thirty-nine percent of cases harbored pathogenic coding variants in known CMP genes, and 5% harbored high-risk loss-of-function (LoF) variants in additional candidate CMP genes. Fifteen percent harbored high-risk regulatory variants in promoters and enhancers of CMP genes (odds ratio 2.25, p = 6.70 × 10 versus controls). Genes involved in α-dystroglycan glycosylation (FKTN, DTNA) and desmosomal signaling (DSC2, DSG2) were most highly enriched for regulatory variants (odds ratio 6.7-58.1). Functional effects were confirmed in patient myocardium and reporter assays in human cardiomyocytes, and in zebrafish CRISPR knockouts. We provide strong evidence for the genomic contribution of functionally active variants in new genes and in regulatory elements of known CMP genes to early onset CMP.
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http://dx.doi.org/10.1038/s41525-022-00288-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8921194PMC
March 2022

Predictors and outcomes of in-hospital referrals for forensic investigation after young sudden cardiac death.

Heart Rhythm 2022 06 4;19(6):937-944. Epub 2022 Feb 4.

Baker Heart and Diabetes Institute, Prahran, Victoria, Australia; Alfred Hospital, Prahran, Victoria, Australia; St Vincent's Hospital Melbourne, Fitzroy, Victoria, Australia.

Background: Forensic investigations are recommended following sudden cardiac death (SCD) to determine cause of death and identify living relatives at potential risk. Not all young SCD patients are referred to coronial services.

Objective: The purpose of this study was to identify referral rates, predictors, and outcomes of young SCD patients who die in-hospital following out-of-hospital cardiac arrest (OHCA).

Methods: A prospective 2-year analysis of in-hospital deaths following OHCA in Victoria, Australia, was conducted using a statewide registry combining data from ambulance, hospital, and forensic resources.

Results: OHCA caused 26.3% of all deaths (n = 1301) in Victorians aged 1-50 years. Rates of prehospital and in-hospital referral to coronial services were 95.0% and 59.5%, respectively. Factors independently predicting in-hospital coronial referral were age <40 years, death in the emergency department, and rural status (odds ratios 4.07, 8.91, and 3.43, respectively). Establishing a diagnosis of coronary disease in-hospital substantially reduced odds of coronial referral (odds ratio 0.07). Of 107 SCD patients referred to the coroner from hospitals, 25 (23.3%) had illicit substances identified on toxicologic analysis. Eighty-one patients (75.7%) underwent autopsy, with cause of death determined in 65 cases (80.2%). Sixteen deaths (19.8%) remained unascertained after autopsy and ancillary investigations.

Conclusion: More than one-fourth of young Victorian deaths result from OHCA. Approximately half of patients dying in-hospital following OHCA are referred to the coroner. Patients referred are younger, more likely to die in the emergency department, and reside rurally. Forensic assessment identifies high rates of illicit drug use in young SCD patients and provides a definitive cause of death for most patients.
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http://dx.doi.org/10.1016/j.hrthm.2022.01.035DOI Listing
June 2022

Ventricular fibrillation and sudden cardiac arrest in apical hypertrophic cardiomyopathy: Two case reports.

World J Clin Cases 2021 Dec;9(35):11102-11107

Department ofCardiology, Gachon University Gil Medical Center, Incheon 21556, South Korea.

Background: Apical hypertrophic cardiomyopathy (HCM) is considered to have a benign prognosis in terms of cardiovascular mortality. This serial case report aimed to raise awareness of ventricular fibrillation (VF) and sudden cardiac death (SCD) in apical HCM.

Case Summary: Here we describe two rare cases of apical HCM that presented with documented VF and sudden cardiac collapse. These patients were previously not recommended for primary prevention using implantable cardioverter-defibrillator (ICD) therapy based on current guidelines. However, both received ICD therapy for the secondary prevention of SCD.

Conclusion: These cases illustrate serious complications including VF and aborted sudden cardiac arrest in apical HCM patients who are initially not candidates for primary prevention using ICD implantation based on current guidelines.
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http://dx.doi.org/10.12998/wjcc.v9.i35.11102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8678876PMC
December 2021

Gene variant effects across sodium channelopathies predict function and guide precision therapy.

Brain 2022 Jan 17. Epub 2022 Jan 17.

Department of Neuroscience, Physiology and Pharmacology, UCL, London WC1E 6BT, UK.

Pathogenic variants in the voltage-gated sodium channel gene family (SCNs) lead to early onset epilepsies, neurodevelopmental disorders, skeletal muscle channelopathies, peripheral neuropathies and cardiac arrhythmias. Disease-associated variants have diverse functional effects ranging from complete loss-of-function to marked gain-of-function. Therapeutic strategy is likely to depend on functional effect. Experimental studies offer important insights into channel function, but are resource intensive and only performed in a minority of cases. Given the evolutionarily conserved nature of the sodium channel genes we investigated whether similarities in biophysical properties between different voltage-gated sodium channels can predict function and inform precision treatment across sodium channelopathies. We performed a systematic literature search identifying functionally assessed variants in any of the nine voltage-gated sodium channel genes until 28 April 2021. We included missense variants that had been electrophysiologically characterised in mammalian cells in whole-cell patch-clamp recordings. We performed an alignment of linear protein sequences of all sodium channel genes and correlated variants by their overall functional effect on biophysical properties. Of 951 identified records, 437 sodium channel-variants met our inclusion criteria and were reviewed for functional properties. Of these, 141 variants were epilepsy-associated (SCN1/2/3/8A), 79 had a neuromuscular phenotype (SCN4/9/10/11A), 149 were associated with a cardiac phenotype (SCN5/10A) and 68 (16%) were considered benign. We detected 38 missense variant pairs with an identical disease-associated variant in a different sodium channel gene. 35 out of 38 of those pairs resulted in similar functional consequences indicating up to 92% biophysical agreement between corresponding sodium channel variants (odds ratio = 11.3; 95% CI = 2.8 to 66.9; P < 0.001). Pathogenic missense variants were clustered in specific functional domains, whereas population variants were significantly more frequent across non conserved domains (odds ratio = 18.6; 95% CI = 10.9 to 34.4; P < 0.001). Pore-loop regions were frequently associated with loss-of-function (LoF) variants, whereas inactivation sites were associated with gain-of-function (GoF; odds ratio = 42.1, 95% CI = 14.5 to 122.4; P < 0.001), whilst variants occurring in voltage-sensing regions comprised a range of gain- and loss-of-function effects. Our findings suggest that biophysical characterisation of variants in one SCN-gene can predict channel function across different SCN-genes where experimental data are not available. The collected data represent the first GoF versus LoF topological map of SCN proteins indicating shared patterns of biophysical effects aiding variant analysis and guiding precision therapy. We integrated our findings into a free online webtool to facilitate functional sodium channel gene variant interpretation (http://SCN-viewer.broadinstitute.org).
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http://dx.doi.org/10.1093/brain/awac006DOI Listing
January 2022

Models of cardiovascular surgery biobanking to facilitate translational research and precision medicine.

ESC Heart Fail 2022 02 21;9(1):21-30. Epub 2021 Dec 21.

Cardiovascular Precision Laboratory, The University of Sydney, Sydney, New South Wales, 2006, Australia.

Biobanking in health care has evolved over the last few decades from simple biological sample repositories to complex and dynamic units with multi-organizational infrastructure networks and has become an essential tool for modern medical research. Cardiovascular tissue biobanking provides a unique opportunity to utilize cardiac and vascular samples for translational research into heart failure and other related pathologies. Current techniques for diagnosis, classification, and treatment monitoring of cardiac disease relies primarily on interpretation of clinical signs, imaging, and blood biomarkers. Further research at the disease source (i.e. myocardium and blood vessels) has been limited by a relative lack of access to quality human cardiac tissue and the inherent shortcomings of most animal models of heart disease. In this review, we describe a model for cardiovascular tissue biobanking and databasing, and its potential to facilitate basic and translational research. We share techniques to procure endocardial samples from patients with hypertrophic cardiomyopathy, heart failure with reduced ejection fraction, and heart failure with preserved ejection fraction, in addition to aortic disease samples. We discuss some of the issues with respect to data collection, privacy, biobank consent, and the governance of tissue biobanking. The development of tissue biobanks as described here has significant scope to improve and facilitate translational research in multi-omic fields such as genomics, transcriptomics, proteomics, and metabolomics. This research heralds an era of precision medicine, in which patients with cardiovascular pathology can be provided with optimized and personalized medical care for the treatment of their individual phenotype.
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http://dx.doi.org/10.1002/ehf2.13768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8787984PMC
February 2022

An International Multicenter Cohort Study on β-Blockers for the Treatment of Symptomatic Children With Catecholaminergic Polymorphic Ventricular Tachycardia.

Circulation 2022 02 7;145(5):333-344. Epub 2021 Dec 7.

The Royal Children's Hospital, Melbourne, Australia (A.D.).

Background: Symptomatic children with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for recurrent arrhythmic events. β-Blockers decrease this risk, but studies comparing individual β-blockers in sizeable cohorts are lacking. We aimed to assess the association between risk for arrhythmic events and type of β-blocker in a large cohort of symptomatic children with CPVT.

Methods: From 2 international registries of patients with CPVT, variant-carrying symptomatic children (defined as syncope or sudden cardiac arrest before β-blocker initiation and age at start of β-blocker therapy <18 years), treated with a β-blocker were included. Cox regression analyses with time-dependent covariates for β-blockers and potential confounders were used to assess the hazard ratio (HR). The primary outcome was the first occurrence of sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter-defibrillator shock, or syncope. The secondary outcome was the first occurrence of any of the primary outcomes except syncope.

Results: We included 329 patients (median age at diagnosis, 12 [interquartile range, 7-15] years, 35% females). Ninety-nine (30.1%) patients experienced the primary outcome and 74 (22.5%) experienced the secondary outcome during a median follow-up of 6.7 (interquartile range, 2.8-12.5) years. Two-hundred sixteen patients (66.0%) used a nonselective β-blocker (predominantly nadolol [n=140] or propranolol [n=70]) and 111 (33.7%) used a β1-selective β-blocker (predominantly atenolol [n=51], metoprolol [n=33], or bisoprolol [n=19]) as initial β-blocker. Baseline characteristics did not differ. The HRs for both the primary and secondary outcomes were higher for β1-selective compared with nonselective β-blockers (HR, 2.04 [95% CI, 1.31-3.17]; and HR, 1.99 [95% CI, 1.20-3.30], respectively). When assessed separately, the HR for the primary outcome was higher for atenolol (HR, 2.68 [95% CI, 1.44-4.99]), bisoprolol (HR, 3.24 [95% CI, 1.47-7.18]), and metoprolol (HR, 2.18 [95% CI, 1.08-4.40]) compared with nadolol, but did not differ from propranolol. The HR of the secondary outcome was only higher in atenolol compared with nadolol (HR, 2.68 [95% CI, 1.30-5.55]).

Conclusions: β1-selective β-blockers were associated with a significantly higher risk for arrhythmic events in symptomatic children with CPVT compared with nonselective β-blockers, specifically nadolol. Nadolol, or propranolol if nadolol is unavailable, should be the preferred β-blocker for treating symptomatic children with CPVT.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.056018DOI Listing
February 2022

Time to Reconsider the Diagnosis of "Left Ventricular Noncompaction" in Adults?

Heart Lung Circ 2022 Mar 24;31(3):301-303. Epub 2021 Nov 24.

Agnes Ginges Centre for Molecular Cardiology Centenary Institute, The University of Sydney, Sydney, NSW, Australia; Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; Wiser Healthcare, The University of Sydney, Sydney, NSW, Australia; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.hlc.2021.10.016DOI Listing
March 2022

Inflammation and Immune Response in Arrhythmogenic Cardiomyopathy: State-of-the-Art Review.

Circulation 2021 11 15;144(20):1646-1655. Epub 2021 Nov 15.

Department of Cardiology, Barts Heart Centre, Barts Health NHS Trust, London, United Kingdom (M.Y.K., A.A.C.).

Arrhythmogenic cardiomyopathy (ACM) is a primary disease of the myocardium, predominantly caused by genetic defects in proteins of the cardiac intercalated disc, particularly, desmosomes. Transmission is mostly autosomal dominant with incomplete penetrance. ACM also has wide phenotype variability, ranging from premature ventricular contractions to sudden cardiac death and heart failure. Among other drivers and modulators of phenotype, inflammation in response to viral infection and immune triggers have been postulated to be an aggravator of cardiac myocyte damage and necrosis. This theory is supported by multiple pieces of evidence, including the presence of inflammatory infiltrates in more than two-thirds of ACM hearts, detection of different cardiotropic viruses in sporadic cases of ACM, the fact that patients with ACM often fulfill the histological criteria of active myocarditis, and the abundance of anti-desmoglein-2, antiheart, and anti-intercalated disk autoantibodies in patients with arrhythmogenic right ventricular cardiomyopathy. In keeping with the frequent familial occurrence of ACM, it has been proposed that, in addition to genetic predisposition to progressive myocardial damage, a heritable susceptibility to viral infections and immune reactions may explain familial clustering of ACM. Moreover, considerable in vitro and in vivo evidence implicates activated inflammatory signaling in ACM. Although the role of inflammation/immune response in ACM is not entirely clear, inflammation as a driver of phenotype and a potential target for mechanism-based therapy warrants further research. This review discusses the present evidence supporting the role of inflammatory and immune responses in ACM pathogenesis and proposes opportunities for translational and clinical investigation.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.055890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9034711PMC
November 2021

External validation of the HCM Risk-Kids model for predicting sudden cardiac death in childhood hypertrophic cardiomyopathy.

Eur J Prev Cardiol 2022 03;29(4):678-686

Centre for Inherited Cardiovascular Diseases, Great Ormond Street Hospital, London WC1N 3JH, UK.

Aims: 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 individualized estimates of risk. The aim of this study was to externally validate the model in a large independent, multi-centre patient cohort.

Methods And Results: 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).

Conclusions: This study reports the first external validation of the HCM Risk-Kids model in a large and geographically diverse patient population. A 5-year predicted risk of ≥6% identified over 70% of events, confirming that HCM Risk-Kids provides a method for individualized risk predictions and shared decision-making in children with HCM.
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http://dx.doi.org/10.1093/eurjpc/zwab181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8967478PMC
March 2022

Hypertrophic cardiomyopathy: a practical approach to guideline directed management.

Lancet 2021 12 30;398(10316):2102-2108. Epub 2021 Sep 30.

Agnes Ginges Centre for Molecular Cardiology Centenary Institute, University of Sydney, Sydney, NSW, Australia; Sydney Medical School Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Cardiology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.

Hypertrophic cardiomyopathy, one of the most common genetic cardiovascular conditions, will be encountered by nearly every health-care provider regardless of specialty. In 2020, new hypertrophic cardiomyopathy management guidelines were published, updating and evolving preceding versions. This Seminar provides a concise review and practical guide to the updated recommendations for patients with hypertrophic cardiomyopathy.
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http://dx.doi.org/10.1016/S0140-6736(21)01205-8DOI Listing
December 2021

Decision-making and experiences of preimplantation genetic diagnosis in inherited heart diseases: a qualitative study.

Eur J Hum Genet 2022 02 21;30(2):187-193. Epub 2021 Sep 21.

Cardio Genomics Program at Centenary Institute, The University of Sydney, Sydney, NSW, Australia.

Preimplantation genetic diagnosis (PGD) ensures a disease-causing variant is not passed to the next generation, including for inherited heart diseases. PGD is known to cause significant emotional burden, but little is known about how parents experience PGD to select against inherited heart disease. We aim to understand how people with inherited heart disease, and their partners, experience and make decisions about PGD. Participants were recruited from a specialised inherited heart disease clinic. Qualitative semi-structured interviews were conducted with adult participants who had considered PGD. A semi-structured interview schedule explored overall experiences and reasons for undergoing PGD. Broad topics included experience of disease, reproductive history, psychosocial and financial considerations. Interviews were recorded, transcribed verbatim and thematically analysed using a framework method. Twenty participants were included (15 with inherited cardiomyopathy, 3 with inherited arrhythmia syndrome and 2 partners). In contemplating PGD, participants considered 3 main issues: past experience of disease e.g. sudden cardiac death, sport restrictions and clinical heterogeneity; intergenerational responsibilities; and practical considerations such as finances and maternal age. Among those who chose to undergo PGD (n = 7/18), past experience of a significant cardiac event, such as family history of sudden cardiac death, was important in the decision process. The decision to undergo PGD for inherited heart disease is complex and influenced by individual values and experience of disease. We highlight key areas where further discussion may assist in PGD decision processes.
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http://dx.doi.org/10.1038/s41431-021-00963-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8821668PMC
February 2022

Myosin Modulation in Hypertrophic Cardiomyopathy and Systolic Heart Failure: Getting Inside the Engine.

Circulation 2021 09 7;144(10):759-762. Epub 2021 Sep 7.

Hypertrophic Cardiomyopathy Center, Department of Cardiology, Westchester Medical Center, Valhalla, NY (S.S.N.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.056324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611636PMC
September 2021

Worldwide differences in primary prevention implantable cardioverter defibrillator utilization and outcomes in hypertrophic cardiomyopathy.

Eur Heart J 2021 10;42(38):3932-3944

Department of Medicine, Brigham and Women's Hospital, Cardiovascular Medicine Division, 75 Francis Street, Boston, MA 02115, USA.

Aims: 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.

Methods And Results: 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 individuals 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]).

Conclusion: 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.
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http://dx.doi.org/10.1093/eurheartj/ehab598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8497072PMC
October 2021

Genetic Testing for Heritable Cardiovascular Diseases in Pediatric Patients: A Scientific Statement From the American Heart Association.

Circ Genom Precis Med 2021 10 20;14(5):e000086. Epub 2021 Aug 20.

Genetic diseases that affect the cardiovascular system are relatively common and include cardiac channelopathies, cardiomyopathies, aortopathies, hypercholesterolemias, and structural diseases of the heart and great vessels. The rapidly expanding availability of clinical genetic testing leverages decades of research into the genetic origins of these diseases, helping inform diagnosis, clinical management, and prognosis. Although a number of guidelines and statements detail best practices for cardiovascular genetic testing, there is a paucity of pediatric-focused statements addressing the unique challenges in testing in this vulnerable population. In this scientific statement, we seek to coalesce the existing literature around the use of genetic testing for cardiovascular disease in infants, children, and adolescents.
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http://dx.doi.org/10.1161/HCG.0000000000000086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8546375PMC
October 2021

Sex Disparities in Sudden Cardiac Death.

Circ Arrhythm Electrophysiol 2021 08 16;14(8):e009834. Epub 2021 Aug 16.

Cardio Genomics Program at Centenary Institute (A.B., J.I.), The University of Sydney.

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.
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http://dx.doi.org/10.1161/CIRCEP.121.009834DOI Listing
August 2021

Electrophysiological and Structural Remodeling of the Atria in a Mouse Model of Troponin-I Mutation Linked Hypertrophic Cardiomyopathy: Implications for Atrial Fibrillation.

Int J Mol Sci 2021 Jun 28;22(13). Epub 2021 Jun 28.

Centre for Heart Rhythm Disorders, South Australian Health and Medical Research Institute (SAHMRI), University of Adelaide and the Royal Adelaide Hospital, Adelaide, SA 5000, Australia.

Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disorder affecting one in 500 of the general population. Atrial fibrillation (AF) is the most common arrhythmia in patients with HCM. We sought to characterize the atrial electrophysiological and structural substrate in young and aging Gly203Ser cardiac troponin-I transgenic (HCM) mice. At 30 weeks and 50 weeks of age ( = 6 per strain each group), the left atrium was excised and placed on a multi-electrode array (MEA) for electrophysiological study; subsequent histological analyses and plasma samples were analyzed for biomarkers of extracellular matrix remodeling and cell adhesion and inflammation. Wild-type mice of matched ages were included as controls. Young HCM mice demonstrated significantly shortened atrial action potential duration (APD), increased conduction heterogeneity index (CHI), increased myocyte size, and increased interstitial fibrosis without changes in effective refractory periods (ERP), conduction velocity (CV), inflammatory infiltrates, or circulating markers of extracellular matrix remodeling and inflammation. Aging HCM mice demonstrated aggravated changes in atria electrophysiology and structural remodeling as well as increased circulating matrix metalloproteinases (MMP)-2, MMP-3, and VCAM-1 levels. This model of HCM demonstrates an underlying atrial substrate that progresses with age and may in part be responsible for the greater propensity for AF in HCM.
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http://dx.doi.org/10.3390/ijms22136941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267948PMC
June 2021

Randomized controlled trial of perhexiline on regression of left ventricular hypertrophy in patients with symptomatic hypertrophic cardiomyopathy (RESOLVE-HCM trial).

Am Heart J 2021 10 25;240:101-113. Epub 2021 Jun 25.

College of Medicine and Public Health, Flinders University, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia; Department of Cardiovascular Medicine, Flinders Medical Centre, Adelaide, Australia. Electronic address:

Background: The presence and extent of left ventricular hypertrophy (LVH) is a major determinant of symptoms in patients with hypertrophic cardiomyopathy (HCM). There is increasing evidence to suggest that myocardial energetic impairment represents a central mechanism leading to LVH in HCM. There is currently a significant unmet need for disease-modifying therapy that regresses LVH in HCM patients. Perhexiline, a potent carnitine palmitoyl transferase-1 (CPT-1) inhibitor, improves myocardial energetics in HCM, and has the potential to reduce LVH in HCM.

Objective: The primary objective is to evaluate the effects of perhexiline treatment on the extent of LVH, in symptomatic HCM patients with at least moderate LVH.

Methods/design: RESOLVE-HCM is a prospective, multicenter double-blind placebo-controlled randomized trial enrolling symptomatic HCM patients with at least moderate LVH. Sixty patients will be randomized to receive either perhexiline or matching placebo. The primary endpoint is change in LVH, assessed utilizing cardiovascular magnetic resonance (CMR) imaging, after 12-months treatment with perhexiline.

Summary: RESOLVE-HCM will provide novel information on the utility of perhexiline in regression of LVH in symptomatic HCM patients. A positive result would lead to the design of a Phase 3 clinical trial addressing long-term effects of perhexiline on risk of heart failure and mortality in HCM patients.
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http://dx.doi.org/10.1016/j.ahj.2021.06.010DOI Listing
October 2021
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