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Reducing sudden death in young people in Australia and New Zealand: The TRAGADY initiative
Abstract
Best-practice guidelines mandate a full postmortem examination in these deaths to identify genetic causes and allow potentially life-saving interventions in the victim's relatives.
... 10 Determining the aetiology of a sudden death is largely dependent on autopsy findings and thus causes can be grouped into structural and non-structural pathologies. 13 ...
... This may improve diagnostic yield through the identification of subtle structural cardiac causes or to adjudicate equivocal findings. 13,26 Left ventricular hypertrophy without myocyte disarray on histological examination, mitral valve prolapse and anomalous coronary arteries without evidence of ischaemia are examples of equivocal findings which, although they have an association with SCD are insufficient to deliver a definitive cause of death. Non-invasive imaging or virtual autopsy is not yet routine in the investigation of SCD. ...
Sudden cardiac death (SCD) is a devastating and all too common result of both acquired and genetic heart diseases. The profound sadness endured by families is compounded by the risk many of these deaths confer upon surviving relatives. For those with known cardiac disease, disease‐specific therapy and risk stratification are key to reducing sudden death. For families of a SCD victim, uncovering a definitive cause of death can help relieve the agonising uncertainty and is a vital first step in screening surviving relatives and instituting therapy to reduce SCD risk. Increasing knowledge about the molecular mechanisms and genetic drivers of malignant arrhythmias in the diverse clinical entities that can cause SCD is vital if we are to optimise risk stratification and personalise patient care. Advances in diagnostic tools, disease‐specific therapy and defibrillator technology are improving outcomes for patients and their families but there is still much progress to be made.
... All unexplained SCD and controls underwent post-mortem evaluation as specified by VIFM Standard Operating Procedure Standards for Medicolegal Death Investigation 7,9,10 . The autopsies were therefore performed in a standard manner and included: external examination including height and weight; examination of major organs including weight; distribution and stenoses in major arteries. ...
Aims:
Unexplained sudden cardiac death (SCD) may be attributable to cardiogenetic disease. Presence or absence of autopsy anomalies detected following premature sudden death direct appropriate clinical evaluation of at-risk relatives towards inherited cardiomyopathies or primary arrhythmia syndromes, respectively. We investigated the relevance of non-diagnostic pathological abnormalities of indeterminate causality (uncertain) such as myocardial hypertrophy, fibrosis, or inflammatory infiltrates to SCD.
Methods and results:
At-risk relatives of unexplained SCD cases aged 1-64 years without prior cardiac disease (n = 98) with either normal and negative (40%, true sudden arrhythmic death syndrome; SADS) or isolated non-diagnostic (60%, uncertain sudden unexplained death; SUD) cardiac histological autopsy findings at a central forensic pathology unit were referred to the regional unexplained SCD clinic for clinical cardiac phenotyping. Uncertain SUD were older than true SADS cases (31.8 years vs. 21.1 years, P < 0.001). A cardiogenetic diagnosis was established in 24 families (24.5%) following investigation of 346 referred relatives. The proportions of uncertain SUD and true SADS explained by familial cardiogenetic diagnoses were similar (20% vs. 31%, P = 0.34, respectively), with primary arrhythmia syndromes predominating. Unexplained SCD cases were more likely than matched non-cardiac premature death controls to demonstrate at least one uncertain autopsy finding (P < 0.001).
Conclusion:
Primary arrhythmia syndromes predominate as familial cardiogenetic diagnoses amongst both uncertain SUD and true SADS cases. Non-diagnostic or uncertain histological findings associate with SUD, though cannot be attributed a causative status. At-risk relatives of uncertain SUD cases should be evaluated for phenotypic evidence of both ion channel disorders and cardiomyopathies.
A morte súbita cardíaca (MSC) é uma morte súbita inesperada devido a uma doença cardíaca, que quase sempre é confirmada no exame post-mortem. A morte inesperada ocorre dentro de uma hora após o início dos sintomas e é atribuída a uma causa cardíaca. Apesar de ser responsável por quase metade de todas as mortes relacionadas com doença arterial coronariana (DAC), sua incidência está diminuindo devido ao avanço contínuo na prevenção, tratamento e manejo. O uso cada vez maior de desfibrilador cardíaco implantável (CDI) tem sido um fator importante no declínio desses números. A DAC continua a ser a principal patologia associada à MSC, porém as mortes por DAC diminuíram de forma significativa nas últimas décadas. Os avanços nas estratégias de tratamento agudo e na prevenção contribuíram para esse declínio. Como consequência, a incidência de MSC e DAC tem diminuído paralelamente. O aumento do conhecimento e da pesquisa está melhorando a compreensão dos mecanismos em torno da doença.
Despite major advancements in cardiovascular medicine, sudden cardiac death (SCD) continues to be an enormous medical and societal challenge, claiming millions of lives every year. Efforts to prevent SCD are hampered by imperfect risk prediction and inadequate solutions to specifically address arrhythmogenesis. Although resuscitation strategies have witnessed substantial evolution, there is a need to strengthen the organisation of community interventions and emergency medical systems across varied locations and health-care structures. With all the technological and medical advances of the 21st century, the fact that survival from sudden cardiac arrest (SCA) remains lower than 10% in most parts of the world is unacceptable. Recognising this urgent need, the Lancet Commission on SCD was constituted, bringing together 30 international experts in varied disciplines. Consistent progress in tackling SCD will require a completely revamped approach to SCD prevention, with wide-sweeping policy changes that will empower the development of both governmental and community-based programmes to maximise survival from SCA, and to comprehensively attend to survivors and decedents' families after the event. International collaborative efforts that maximally leverage and connect the expertise of various research organisations will need to be prioritised to properly address identified gaps. The Commission places substantial emphasis on the need to develop a multidisciplinary strategy that encompasses all aspects of SCD prevention and treatment. The Commission provides a critical assessment of the current scientific efforts in the field, and puts forth key recommendations to challenge, activate, and intensify efforts by both the scientific and global community with new directions, research, and innovation to reduce the burden of SCD worldwide.
Background:
Sudden cardiac arrest (SCA) in young people aged 1 to 50 years often occurs with no presenting symptoms or risk factors prompting screening for cardiovascular disease prior to their cardiac arrest. Approximately 3,000 young Australians suffer from sudden cardiac death (SCD) each year, making this a major public health issue. However, there is significant variation in the way incidence is estimated resulting in discrepancy across reporting which impacts our ability to understand and prevent these devastating events. We describe the New South Wales (NSW) Sudden Cardiac Arrest Registry: a retrospective, data linkage study which will identify all SCAs in the young in NSW from 2009 through to June 2022.
Objective:
To determine the incidence, demographic characteristics and causes of SCA in young people. We will develop an NSW-based registry that will contribute to a greater understanding of SCA including risk factors and outcomes.
Methods:
The cohort will include all people who experience a SCA in the NSW community aged between 1 to 50 years. Cases will be identified using the following three datasets: the Out of Hospital Cardiac Arrest Register housed at NSW Ambulance, the NSW Emergency Department Data Collection, and the National Coronial Information System. Data from eight datasets will be collected, anonymised and linked for the entire cohort. Analysis will be undertaken and reported using descriptive statistics.
Conclusions:
The NSW SCA registry will be an important resource for the improved understanding of SCA and inform the widespread impacts it has on individuals, their families and society.
Sudden death is one of the major causes of death in young adults. Sudden death could be a result from both genetic and environmental or acquired factors. Understanding the genetic etiology is crucial to prevent preventable sudden death for those who are not aware of their genetic condition. In fact, the spectrum of causes of sudden death is complex and varied. In this study, we reviewed the genes that are associated with multiple causes of sudden death in terms of both sudden cardiac death and sudden noncardiac death. A summary of genetic risk factors of the major causes of genetic relevant sudden death is also provided. We believe this review could benefit the researchers who are interested in sudden death genetic studies or the young people who are concerning about their own risk on sudden death.
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 divided 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.
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 divided 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.
Sudden cardiac death (SCD) of a young person is a devastating and tragic ultimate outcome of a collection of cardiac disorders. The death often occurs in people who were thought to be well, by definition is sudden, can occur without prior warning symptoms, and is often the first presentation of an underlying genetic heart disease. Many of the genetic heart diseases are caused by single genetic variants that have a one-in-two chance of being inherited by each first-degree relative. Therefore, the surviving family not only have to deal with the sudden loss of a young family member but are also left with the compounding uncertainty as to whether SCD could strike again in another family member. In recent years, our ability to identify the causes of SCD in the young has improved. Finding a precise genetic cause of death allows cascade genetic testing of family members to identify those who are at risk and facilitate early intervention to prevent another sudden death. Thus, investigations to define the precise cause of SCD of a young person not only bring a level of closure for the family but are also of vital clinical relevance.
Forty per cent (40%) of sudden unexpected natural deaths in people under 35 years of age are associated with a negative autopsy, and the cardiac ion channelopathies are the prime suspects in such cases. Long QT syndrome (LQTS), Brugada syndrome (BrS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) are the most commonly identified with genetic testing. The cellular action potential driving the heart cycle is shaped by a specific series of depolarising and repolarising ion currents mediated by ion channels. Alterations in any of these currents, and in the availability of intracellular free calcium, leaves the myocardium vulnerable to polymorphic ventricular tachycardia or ventricular fibrillation. Each channelopathy has its own electrocardiogram (ECG) signature, typical mode of presentation, and most commonly related gene. Long QT type 1 (gene, KCNQ1) and CPVT (gene, RyR2) typically present with cardiac events (ie syncope or cardiac arrest) during or immediately after exercise in young males; long QT type 2 (gene, KCNH2) after startle or during the night in adult females-particularly early post-partum, and long QT type 3 and Brugada syndrome (gene, SCN5A) during the night in young adult males. They are commonly misdiagnosed as seizure disorders. Fever-triggered cardiac events should also raise the suspicion of BrS. This review summarises genetics, cellular mechanisms, risk stratification and treatments. Beta blockers are the mainstay of treatment for long QT syndrome and CPVT, and flecainide is remarkably effective in CPVT. Brugada syndrome is genetically a more complex disease than the others, and risk stratification and management is more difficult.
Recently, the implantable cardioverter-defibrillator (ICD) has been promoted for prevention of sudden death in hypertrophic cardiomyopathy (HCM). However, the effectiveness and appropriate selection of patients for this therapy is incompletely resolved.
To study the relationship between clinical risk profile and incidence and efficacy of ICD intervention in HCM.
Multicenter registry study of ICDs implanted between 1986 and 2003 in 506 unrelated patients with HCM. Patients were judged to be at high risk for sudden death; had received ICDs; underwent evaluation at 42 referral and nonreferral institutions in the United States, Europe, and Australia; and had a mean follow-up of 3.7 (SD, 2.8) years. Measured risk factors for sudden death included family history of sudden death, massive left ventricular hypertrophy, nonsustained ventricular tachycardia on Holter monitoring, and unexplained prior syncope.
Appropriate ICD intervention terminating ventricular tachycardia or fibrillation.
The 506 patients were predominately young (mean age, 42 [SD, 17] years) at implantation, and most (439 [87%]) had no or only mildly limiting symptoms. ICD interventions appropriately terminated ventricular tachycardia/fibrillation in 103 patients (20%). Intervention rates were 10.6% per year for secondary prevention after cardiac arrest (5-year cumulative probability, 39% [SD, 5%]), and 3.6% per year for primary prevention (5-year probability, 17% [SD, 2%]). Time to first appropriate discharge was up to 10 years, with a 27% (SD, 7%) probability 5 years or more after implantation. For primary prevention, 18 of the 51 patients with appropriate ICD interventions (35%) had undergone implantation for only a single risk factor; likelihood of appropriate discharge was similar in patients with 1, 2, or 3 or more risk markers (3.83, 2.65, and 4.82 per 100 person-years, respectively; P = .77). The single sudden death due to an arrhythmia (in the absence of advanced heart failure) resulted from ICD malfunction. ICD complications included inappropriate shocks in 136 patients (27%).
In a high-risk HCM cohort, ICD interventions for life-threatening ventricular tachyarrhythmias were frequent and highly effective in restoring normal rhythm. An important proportion of ICD discharges occurred in primary prevention patients who had undergone implantation for a single risk factor. Therefore, a single marker of high risk for sudden death may be sufficient to justify consideration for prophylactic defibrillator implantation in selected patients with HCM.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disorder characterized by adrenergically mediated polymorphic ventricular tachyarrhythmias. Genetic investigations have identified two variants of the disease: an autosomal dominant form associated with mutations in the gene encoding the cardiac ryanodine receptor (RyR2) and a recessive form associated with homozygous mutations in the gene encoding the cardiac isoform of calsequestrin (CASQ2). Functional characterization of mutations identified in the RyR2 and CASQ2 genes has demonstrated that CPVT are caused by derangements of the control of intracellular calcium. Investigations in a knock-in mouse model have shown that CPVT arrhythmias are initiated by delayed afterdepolarizations and triggered activity. In the present article, we review clinical and molecular understanding of CPVT and discuss the most recent approaches to develop novel therapeutic strategies for the disease.
Hypertrophic cardiomyopathy is a genetic disease associated with a risk of ventricular tachyarrhythmias and sudden death, especially in young patients.
We conducted a retrospective multicenter study of the efficacy of implantable cardioverter-defibrillators in preventing sudden death in 128 patients with hypertrophic cardiomyopathy who were judged to be at high risk for sudden death.
At the time of the implantation of the defibrillator, the patients were 8 to 82 years old (mean [+/-SD], 40+/-16), and 69 patients (54 percent) were less than 41 years old. The average follow-up period was 3.1 years. Defibrillators were activated appropriately in 29 patients (23 percent), by providing defibrillation shocks or antitachycardia pacing, with the restoration of sinus rhythm; the average age at the time of the intervention was 41 years. The rate of appropriate defibrillator discharge was 7 percent per year. A total of 32 patients (25 percent) had episodes of inappropriate discharges. In the group of 43 patients who received defibrillators for secondary prevention (after cardiac arrest or sustained ventricular tachycardia), the devices were activated appropriately in 19 patients (11 percent per year). Of 85 patients who had prophylactic implants because of risk factors (i.e., for primary prevention), 10 had appropriate interventions (5 percent per year). The interval between implantation and the first appropriate discharge was highly variable but was substantially prolonged (four to nine years) in six patients. In all 21 patients with stored electrographic data and appropriate interventions, the interventions were triggered by ventricular tachycardia or fibrillation.
Ventricular tachycardia or fibrillation appears to be the principal mechanism of sudden death in patients with hypertrophic cardiomyopathy. In high-risk patients with hypertrophic cardiomyopathy, implantable defibrillators are highly effective in terminating such arrhythmias, indicating that these devices have a role in the primary and secondary prevention of sudden death.
To determine the causes of sudden cardiac death in people aged 35 years or younger.
A review of all autopsies performed between 1 January 1994 and 31 December 2002 at a major Sydney forensic medicine department serving an area with over 2 million people.
Incidence of various types of cardiac disease causing sudden death in those aged <or= 35 years; proportion of deaths in which no cause was found at autopsy.
There were 10 199 autopsies performed during the study period. Of these, 2986 (29.2%) deaths occurred in people aged <or= 35 years; 193 were classified as sudden cardiac deaths. The cause of sudden death in this group was not established in 60 (31%), and was presumed to be due to primary arrhythmogenic disorders. Coronary artery disease occurred in 46 (24%), hypertrophic cardiomyopathy/unexplained left ventricular hypertrophy in 29 (15%), and myocarditis in 23 (12%).
Unexplained deaths, presumed to result from sudden primary arrhythmogenic causes, occur in young Australians with structurally normal hearts. That underlying disease-causing genetic defects may be involved has clinical implications for family members.
Sudden death mostly follows from cardiac disorders that elicit lethal ventricular arrhythmias. In young individuals, it often remains unexplained because history and/or postmortem analysis are absent or provide no clue. Because such sudden unexplained deaths (SUDs) may have heritable causes, cardiological and genetic assessment of surviving relatives of SUD victims may reveal the underlying disease and unmask presymptomatic carriers. We aimed to establish the diagnostic yield of such assessments.
We investigated 43 consecutive families with > or =1 SUD victim who died at < or =40 years of age. All studied relatives underwent resting/exercise ECG and Doppler echocardiography. Molecular genetic analysis was conducted to confirm the diagnosis. We identified an inherited disease and likely cause of death in 17 of 43 families (40%). Twelve families had primary electrical disease: catecholaminergic polymorphic ventricular tachycardia (5 families), long-QT syndrome (4 families), Brugada syndrome (2 families), and long-QT/Brugada syndrome (1 family). Furthermore, we found arrhythmogenic right ventricular cardiomyopathy (3 families), hypertrophic cardiomyopathy (1 family), and familial hypercholesterolemia (1 family). Molecular genetic analysis provided confirmation in 10 families. Finding the diagnosis was more likely when more relatives were examined and in families with > or =2 SUD victims < or =40 years of age. The resting/exercise ECG had a high diagnostic yield. These efforts unmasked 151 presymptomatic disease carriers (8.9 per family).
Examination of relatives of young SUD victims has a high diagnostic yield, with identification of the disease in 40% of families and 8.9 presymptomatic carriers per family. Simple procedures (examining many relatives) and routine tests (resting/exercise ECG) constitute excellent diagnostic strategies. Molecular genetics provide strong supportive information.
Sudden death is rare in young people, but it has a disproportionate impact on the community.
The purpose of this study was to determine the causes of sudden, natural death in persons aged 5-35 years.
All autopsies conducted at a forensic medicine facility in the years 1995-2004 (inclusive) were reviewed. This facility serves more than 2.5 million people in the eastern part of Sydney, Australia. Data collected included subject age, height, weight, gender, circumstances of death, and pathologic findings at autopsy. Deaths caused by trauma, accidental causes, drowning, and drug toxicity were excluded from analysis.
There were 427 nontraumatic, sudden deaths in the 10-year period (70.7% male). Cardiac causes accounted for 56.4%, noncardiac causes 39.3%, and undetermined cause 4.3%. The most common cardiac cause of sudden death was presumed arrhythmia in those with no or minimal structural heart disease (29.0%). Other cardiac causes were acute myocardial infarction (24.5%), myocarditis (11.6%), hypertrophic cardiomyopathy (5.8%), aortic dissection (5.4%), and dilated cardiomyopathy (5.4%). More than two thirds of deaths caused by acute myocardial infarction occurred in the age group from 30-35 years. Sudden cardiac death occurred during physical activity in 10.8% of cases. Sudden cardiac death was reported in a first-degree relative in 4.5% of decedents. The most common noncardiac causes of sudden death were epilepsy (23.8%), intracerebral hemorrhage (23.8%), asthma (16.1%), and pulmonary embolism (12.5%).
Presumed cardiac arrhythmia is the most common cause of sudden, natural death in the young. There was no reported history of sudden death among the relatives of most decedents.
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.
This study sought to determine the spectrum and prevalence of long QT syndrome (LQTS)-associated mutations in a large cohort of autopsy-negative sudden unexplained death (SUD).
Potentially heritable arrhythmia syndromes may explain a significant proportion of SUD in the young. Here, comprehensive postmortem LQTS genetic testing was performed in a cohort of SUD cases.
From September 1998 to March 2004, 49 cases of SUD (30 male patients, average age at death 14.2 +/- 10.9 years) were referred by medical examiners/coroners to Mayo Clinic's Sudden Death Genomics Laboratory. Using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing, open reading frame/splice site mutational analysis was conducted for all 8 genes implicated in the pathogenesis of either LQTS (LQT1 to LQT6) or multisystem disorders involving either QT or QU prolongation.
Ten LQTS-associated mutations (4 novel) were discovered in 10 SUD cases (20%, 8 female patients, average age at death 18.0 +/- 11.8 years). The LQTS susceptibility mutations LQT1 (5), LQT2 (3), and LQT3 (2) were far more common among women (8 of 18, 44%) than men (2 of 30, 6.7%, p < 0.008). The activities at the time of SUD included sleep (5), exertion (2), auditory arousal (1), and undetermined (2). Sudden death was the sentinel event in two-thirds of the cases.
In this cardiac channel-focused molecular autopsy investigation of SUD, over one-third of decedents harbored a putative cardiac channel mutation: 7 previously reported to host mutations in the RyR2-encoded calcium release channel and now 10 with LQTS susceptibility mutations. Accordingly, postmortem cardiac channel genetic testing should be pursued in the evaluation of autopsy-negative SUD.