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Family History and Warning Symptoms Precede Sudden Cardiac Death in Arrhythmogenic Right Ventricular Cardiomyopathy (from a Nationwide Study in Sweden)

Open AccessPublished:July 11, 2022DOI:https://doi.org/10.1016/j.amjcard.2022.05.015
      Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease explaining about 4% of sudden cardiac death (SCD) cases in the young in Sweden. This study aimed to describe the circumstances preceding SCD in all victims <35 years of age who received an autopsy-confirmed diagnosis of ARVC from January 1, 2000, to December 31, 2010, in Sweden (n = 22). Data on demographics, medical and family history, circumstances of death, and anatomopathological findings were collected from several compulsory national health registries, clinical records, family interviews, and autopsy reports. Registry-based data were compared with age-matched, gender-matched, and geographically-matched population controls. During the 6 months preceding SCD, 15 cases (68%) had experienced symptoms of cardiac origin, mainly syncope or presyncope (54%) and chest discomfort (27%). A total of 8 cases (36%) had sought medical care because of cardiac symptoms. The occurrence of hospital visits was significantly increased in cases compared with controls (odds ratio 4.62 [1.35 to 15.8]). A total of 10 cases (45%) had a family history of SCD. The most common activity at the time of death was exercise (41%). A complete cardiac investigation was seldom performed; only 1 case was diagnosed with ARVC before death. In conclusion, in this nationwide study, we observed a high prevalence of symptoms of cardiac origin, healthcare use, and family history of SCD preceding SCD in the young caused by ARVC. Increased awareness of these warning signals in younger patients is critical to improving risk stratification and early disease detection.

      Introduction

      Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease affecting 1:1000 to 1:5000 patients.
      • Basso C
      • Corrado D
      • Marcus FI
      • Nava A
      • Thiene G.
      Arrhythmogenic right ventricular cardiomyopathy.
      ,
      • James CA
      • Syrris P
      • van Tintelen JP
      • Calkins H.
      The role of genetics in cardiovascular disease: arrhythmogenic cardiomyopathy.
      ARVC is characterized by integrity loss of the intercalated disk, followed by apoptosis and fibrofatty replacement of the myocardium, leading to arrhythmia and impaired systolic function.
      • Basso C
      • Corrado D
      • Marcus FI
      • Nava A
      • Thiene G.
      Arrhythmogenic right ventricular cardiomyopathy.
      ,
      • Saffitz JE.
      The pathobiology of arrhythmogenic cardiomyopathy.
      Early disease recognition is a pervasive challenge; patients can present with a spectrum of ventricular arrhythmias, from benign premature extrasystoles (ventricular extrasystoles) to sustained ventricular tachycardias (VTs) and sudden cardiac death (SCD) before detectable structural changes occur.
      • Basso C
      • Corrado D
      • Marcus FI
      • Nava A
      • Thiene G.
      Arrhythmogenic right ventricular cardiomyopathy.
      ,
      • Saffitz JE.
      The pathobiology of arrhythmogenic cardiomyopathy.
      ARVC is indeed one of the leading causes of SCD in the younger population, explaining 5% to 15% of SCD cases in Europe and up to 32% of SCD in competitive athletes.
      • Corrado D
      • Thiene G
      • Nava A
      • Rossi L
      • Pennelli N.
      Sudden death in young competitive athletes: clinicopathologic correlations in 22 cases.
      • Corrado D
      • Basso C
      • Thiene G.
      Sudden cardiac death in young people with apparently normal heart.
      • Tabib A
      • Loire R
      • Chalabreysse L
      • Meyronnet D
      • Miras A
      • Malicier D
      • Thivolet F
      • Chevalier P
      • Bouvagnet P.
      Circumstances of death and gross and microscopic observations in a series of 200 cases of sudden death associated with arrhythmogenic right ventricular cardiomyopathy and/or dysplasia.
      • Finocchiaro G
      • Papadakis M
      • Robertus JL
      • Dhutia H
      • Steriotis AK
      • Tome M
      • Mellor G
      • Merghani A
      • Malhotra A
      • Behr E
      • Sharma S
      • Sheppard MN.
      Etiology of sudden death in sports: insights from a United Kingdom regional registry.
      • Sadjadieh G
      • Jabbari R
      • Risgaard B
      • Olesen MS
      • Haunso S
      • Tfelt-Hansen J
      • Winkel BG.
      Nationwide (Denmark) study of symptoms preceding sudden death due to arrhythmogenic right ventricular cardiomyopathy.
      In Sweden, the incidence of SCD in patients aged 1 to 35 years between 2000 and 2010 was 1.3 × 100.000 person-year, and ARVC was the cause of death in 22 cases (4%).
      • Wisten A
      • Krantz P
      • Stattin EL.
      Sudden cardiac death among the young in Sweden from 2000 to 2010: an autopsy-based study.
      ,
      • Stattin EL
      • Hagström E
      • Dahl N
      • Strömsöe A
      • Delgado-Vega AM
      • Klar J
      • Bodil S
      • Börjesson M
      • Wisten A.
      The Swedish study of sudden cardiac death in the young (SUDDY) 2000–2010 – a complete nationwide cohort of SCDs.
      In the present study, we describe the family history, symptoms, hospital care use, and circumstances of the death of these 22 patients, based on data from national health registries, medical records (MRs), family interviews, and autopsy reports.

      Methods

      All subjects aged 1 to 35 years who died of SCD with autopsy-confirmed ARVC as the probable cause of death from January 1, 2000, to December 31, 2010, in Sweden were included in the study (n = 22). Cases were identified through nationwide registry data from the Swedish National Board of Forensic Medicine and the Swedish Cause of Death Registry. Autopsy reports and death certificates were manually reviewed by a single forensic pathologist to confirm the postmortem ARVC diagnosis. The nationally standardized autopsy protocols followed during the study period, and the criteria by which SCD subjects were selected have been previously described.
      • Wisten A
      • Krantz P
      • Stattin EL.
      Sudden cardiac death among the young in Sweden from 2000 to 2010: an autopsy-based study.
      For every case, 5 controls matched by gender, birth year, and county were identified from the Swedish Register of the Total Population and Population Changes (n = 110). Parents of the cases were identified from the Swedish Multi-generation Register.
      Data from cases, patients, and controls were extracted from the SUDDY (Swedish SUDden Cardiac Death of the Young study database), which integrates multisource data from several mandatory Swedish National Health Registries (Supplementary Table 1).
      • Stattin EL
      • Hagström E
      • Dahl N
      • Strömsöe A
      • Delgado-Vega AM
      • Klar J
      • Bodil S
      • Börjesson M
      • Wisten A.
      The Swedish study of sudden cardiac death in the young (SUDDY) 2000–2010 – a complete nationwide cohort of SCDs.
      Data from the National Patient Registry (NPR), the Swedish Cause of Death Registry, and the longitudinal integrated database for health insurance and labor market studies LISA were specifically retrieved for this study. The NPR includes all hospital visits (hospitalizations and outpatient visits) from all Swedish private and public caregivers. Primary care visits are not covered. Hospital visits and registered diagnoses related to the cardiovascular system, according to the 10th International Statistical Classification of Diseases and Related Health Problems (ICD-10) (R00-R09, R55, R56, I42-I43, I44-I49, I30-41, I50-52), were compared between cases and controls. The time preceding SCD was defined as the 6 months before death occurred. The date when the control was the same age as the matched case at the date of death was taken as the reference date. MRs from all hospital visits were retrieved. MRs from primary care visits were retrieved only when they were included in the autopsy report. Electrocardiograms (ECGs) were collected from MRs and premilitary conscription examination and revised by a cardiologist with expertise in ARVC and arrhythmias, together with the reports from echocardiography, cardiac magnet resonance imaging, and 24 hours ECG recordings when performed. All MRs were pseudonymized by assigning each subject a case number.
      In 16 cases (73%), a parent or spouse agreed to answer a standardized interview-based questionnaire over the phone, including a three-generation family history.
      In Sweden, autopsies are performed either at the regional centers of the Swedish National Board of Forensic Medicine (forensic autopsy) or the hospital clinical pathology departments (clinical autopsy). Full reports from the forensic and clinical autopsies were available.
      Data from the MRs, family interviews, and autopsy reports were systematically extracted and integrated using a standardized protocol, including (1) medical history, (2) symptoms before death, (3) information on intensity and frequency of physical activity, including previous sports participation; (4) family history of SCD, cardiomyopathy, arrhythmogenic syndrome or implantable cardioverter-defibrillator (Only family history before the index case died was included); (5) time and circumstances of death, prodromal symptoms; and (6) autopsy findings. All cardiac investigations performed were retrospectively assessed according to the ARVC 2010 Task Force Criteria (TFC).
      • Marcus FI
      • McKenna WJ
      • Sherrill D
      • Basso C
      • Bauce B
      • Bluemke DA
      • Calkins H
      • Corrado D
      • Cox MG
      • Daubert JP
      • Fontaine G
      • Gear K
      • Hauer R
      • Nava A
      • Picard MH
      • Protonotarios N
      • Saffitz JE
      • Sanborn DM
      • Steinberg JS
      • Tandri H
      • Thiene G
      • Towbin JA
      • Tsatsopoulou A
      • Wichter T
      • Zareba W.
      Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the task force criteria.
      Exercise-related SCD was defined as an SCD that occurred during or within 1 hour after exercise.
      • Levine BD
      • Baggish AL
      • Kovacs RJ
      • Link MS
      • Maron MS
      • Mitchell JH
      American Heart Association Electrocardiography and Arrhythmias Committee of Council on Clinical Cardiology, Council on Cardiovascular Disease in Young, Council on Cardiovascular and Stroke Nursing, Council on Functional Genomics and Translational Biology, and American College of Cardiology. Eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities: Task Force 1: Classification of sports: dynamic, static, and impact: a scientific statement From the American Heart Association and American College of Cardiology.
      ,
      • Maron BJ
      • Chaitman BR
      • Ackerman MJ
      • Bayés de Luna A
      • Corrado D
      • Crosson JE
      • Deal BJ
      • Driscoll DJ
      • Estes NA
      • Araújo CG
      • Liang DH
      • Mitten MJ
      • Myerburg RJ
      • Pelliccia A
      • Thompson PD
      • Towbin JA
      • Van Camp SP
      Working Groups of the American Heart Association Committee on Exercise, Cardiac Rehabilitation, and Prevention, Councils on Clinical Cardiology and Cardiovascular Disease in the Young. Recommendations for physical activity and recreational sports participation for young patients with genetic cardiovascular diseases.
      Sports-related SCD was defined as exercise-related SCD in competitive athletes. Competitive sports were defined as sports in which the athletes trained on a regular basis and participated in official sports competitions.
      • Levine BD
      • Baggish AL
      • Kovacs RJ
      • Link MS
      • Maron MS
      • Mitchell JH
      American Heart Association Electrocardiography and Arrhythmias Committee of Council on Clinical Cardiology, Council on Cardiovascular Disease in Young, Council on Cardiovascular and Stroke Nursing, Council on Functional Genomics and Translational Biology, and American College of Cardiology. Eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities: Task Force 1: Classification of sports: dynamic, static, and impact: a scientific statement From the American Heart Association and American College of Cardiology.
      ,
      • Maron BJ
      • Chaitman BR
      • Ackerman MJ
      • Bayés de Luna A
      • Corrado D
      • Crosson JE
      • Deal BJ
      • Driscoll DJ
      • Estes NA
      • Araújo CG
      • Liang DH
      • Mitten MJ
      • Myerburg RJ
      • Pelliccia A
      • Thompson PD
      • Towbin JA
      • Van Camp SP
      Working Groups of the American Heart Association Committee on Exercise, Cardiac Rehabilitation, and Prevention, Councils on Clinical Cardiology and Cardiovascular Disease in the Young. Recommendations for physical activity and recreational sports participation for young patients with genetic cardiovascular diseases.
      Recreational sports were defined as sports in which the participants trained either regularly or inconsistently without requiring systematic training or pursuing excellence.
      • Levine BD
      • Baggish AL
      • Kovacs RJ
      • Link MS
      • Maron MS
      • Mitchell JH
      American Heart Association Electrocardiography and Arrhythmias Committee of Council on Clinical Cardiology, Council on Cardiovascular Disease in Young, Council on Cardiovascular and Stroke Nursing, Council on Functional Genomics and Translational Biology, and American College of Cardiology. Eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities: Task Force 1: Classification of sports: dynamic, static, and impact: a scientific statement From the American Heart Association and American College of Cardiology.
      ,
      • Maron BJ
      • Chaitman BR
      • Ackerman MJ
      • Bayés de Luna A
      • Corrado D
      • Crosson JE
      • Deal BJ
      • Driscoll DJ
      • Estes NA
      • Araújo CG
      • Liang DH
      • Mitten MJ
      • Myerburg RJ
      • Pelliccia A
      • Thompson PD
      • Towbin JA
      • Van Camp SP
      Working Groups of the American Heart Association Committee on Exercise, Cardiac Rehabilitation, and Prevention, Councils on Clinical Cardiology and Cardiovascular Disease in the Young. Recommendations for physical activity and recreational sports participation for young patients with genetic cardiovascular diseases.
      The study was approved first by the Regional Ethical Review Boards at Umeå and later at Uppsala University (Dnr: 2017/430 and 2017/431). Participating parents signed informed consent.
      Descriptive statistics were presented as numbers and percentages for categorical variables, and mean and SDs for continuous variables. Odds ratios (ORs) (95% confidence intervals [CI]) comparing cases and controls were assessed using conditional logistic regression accounting for matching. The p <0.05 from 2-sided tests were considered statistically significant. The analyses were performed with SPSS Statistical Software Version 26.0 (IBM SPSS Statistics, Armonk, New York) and R Version 4.0, 2020 (http://www.R-project.org) (The R Foundation for Statistical Computing, Vienna, Austria).

      Results

      The sociodemographic characteristics of the 22 patients aged <35 years who died of SCD caused by autopsy-confirmed ARVC from 2000 to 2010 and 110 matched controls are listed in Table 1. The age of death ranged from 12 to 35 years, and 64% were male. Cases were evenly distributed during time and across the country (Supplementary Table 2).
      Table 1Sociodemographic characteristics of cases and controls
      Cases (n = 22)Controls (n = 110)P-value
      Sex
       - Women8 (36%)40 (36%)-
       - Men14 (64%)70 (64%)-
      Age (years)
       - Mean (±SD, min-max)

      -Min-max
      23.6 (±6.35)

      12-35
      23.6 (±6.23)

      12-35
      -
      Education level
      The socioeconomics information on education level and family type corresponds to the year prior to death (by November 30th) for cases and controls ≥16 years of age. Differences between cases and controls were calculated by conditional logistic regression. SD = standard deviation.
      0.731
       - Compulsory school4 (24%)29 (31%)
       - Secondary upper school10 (59%)48 (51%)
       - University3 (18%)17 (18%)
       - Unknown5 (23%)16 (15%)
      Family type
      The socioeconomics information on education level and family type corresponds to the year prior to death (by November 30th) for cases and controls ≥16 years of age. Differences between cases and controls were calculated by conditional logistic regression. SD = standard deviation.
      0.032
       - Married10 (53%)27 (29%)
       - Cohabitant3 (16%)12 (13%)
       - Single6 (32%)55 (58%)
       - Unknown3 (14%)16 (15%)
      low asterisk The socioeconomics information on education level and family type corresponds to the year prior to death (by November 30th) for cases and controls ≥16 years of age. Differences between cases and controls were calculated by conditional logistic regression.SD = standard deviation.
      During the 6 months preceding death, 15 cases (68%) were reported to have experienced warning symptoms such as palpitations (41%), syncope (27%), presyncope (27%), chest discomfort (27%, defined as either chest pain or dyspnea), and seizures (14%) (Figure 1, Table 2). A total of 8 subjects (36%) sought medical care for cardiac symptoms during this period (Figure 1). They received a diagnosis of myocarditis (n = 1), right ventricular outflow tract (RVOT) tachycardia (n = 1), ARVC (n = 1), dyspepsia (n = 2), or none (n = 3). A total of 2 additional subjects had healthcare visits for other reasons, a postpartum complication and a preauricular cyst excision, respectively.
      Figure 1
      Figure 1Symptoms, family history, and healthcare visits preceding SCD caused by ARVC. The figure summarizes the data on (A) preceding cardiac symptoms, family history, and healthcare use in the 22 victims of SCD caused by ARVC. In panel (B), healthcare visits are specified by type and number of days before SCD occurred. Data has been collected from the NPR, medical records, autopsy reports, and family interviews. In total, 10 subjects sought medical care during the 6 months preceding SCD, including 1 primary care visit and 9 hospital visits. A total of 8 consulted because of cardiac symptoms, whereas 2 (cases nr 8 and nr 17) consulted for other reasons. Cases nr 14 and nr 16 did not seek care before SCD, and no previous symptoms were reported in the autopsy investigation or medical records; however, their relatives did not provide any information and data has been marked as unknown. FH = family history, ICD=implantable cardioverter-defibrillator, SCD=sudden cardiac death
      Table 2Clinical characteristics of cases suffering SCD due to ARVC
      Symptoms six months preceding sudden cardiac deathNumber (%)
      All symptoms15 (68%)
      Syncope6 (27%)
      Presyncope6 (27%)
      Chest discomfort6 (27%)
      Palpitations9 (41%)
      Seizures3 (14%)
      No symptoms6 (27%)
      Medical history
      Cardiomyopathy (ARVC)1 (4.5%)
      Channelopathy1 (4.5%)
      Myocarditis1 (4.5%)
      Aborted SCD1 (4.5%)
      Impaired systolic cardiac function
       - Right ventricle (FAC<40)1 (4.5%)
       - Left ventricle (LV-EF<55%)1 (4.5%)
      Ventricular tachycardia
       - Sustained1 (4.5%)
       - Non-sustained4 (18%)
       - PVC> 500/24 hours2 (9%)
      Seizures3 (14%)
      Cardiac investigation performedMinor - major TFC fulfilled
      Echocardiography4 (18%)1 (4.5) - 0
      ECG11 (50%)
      Repolarization abnormalities2 (9) - 2 (9)
      Depolarization abnormalities1 (4.5) - 1 (4.5)
      24-hours ECG recording3 (14%)0 - 2 (9)
      The table shows the number of cases with arrhythmogenic right ventricle cardiomyopathy (ARVC) that were reported to have symptoms during the six months preceding SCD (sudden cardiac death), as well as information on previous medical history and cardiac investigations from birth according the medical records. Available full reports of echocardiograms and electrocardiograms (ECG) where evaluated according to the ARVC 2010 Task Force Criteria (TFC).
      • Marcus FI
      • McKenna WJ
      • Sherrill D
      • Basso C
      • Bauce B
      • Bluemke DA
      • Calkins H
      • Corrado D
      • Cox MG
      • Daubert JP
      • Fontaine G
      • Gear K
      • Hauer R
      • Nava A
      • Picard MH
      • Protonotarios N
      • Saffitz JE
      • Sanborn DM
      • Steinberg JS
      • Tandri H
      • Thiene G
      • Towbin JA
      • Tsatsopoulou A
      • Wichter T
      • Zareba W.
      Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the task force criteria.
      FAC = fractional area change; LV-EF = left ventricle ejection fraction; PVC = Premature ventricular complex.
      Based on national data from the NPR alone, 41% of the cases (9 of 22) had registered at least 1 hospital visit compared with 17% (19 of 110) of the controls (OR 4.63 [95% CI 1.35 to 15.8] p = 0.010). Furthermore, a cardiac-related ICD-10 diagnosis code was registered in 5 case hospital visits compared with none of the controls (p <0.001) (Table 3).
      Table 3Hospital visits and diagnoses (ICD-10 codes) registered in the National Patient Registry (NPR) six months preceding SCD
      CasesControlsP-value
      Hospital visits(n = 22)(n = 110)
      Any hospitalization or outpatient visit9 (41%)19 (17%)0.010
      Hospitalizations5 (23%)5 (4.5%)0.009
      Outpatient8 (42%)18 (19%)0.032
      Any hospitalization or outpatient visit with a cardiac-related ICD-10 code5 (23%)0 (0%)<0.0001
      Hospital visits with cardiac-related ICD-10 codes
      ICD-10 codes are shown only for cases and controls who had either a hospitalisation and/or an outpatient visit in the NPR. When the individual did not receive any ICD-10 code in any of the visits, the observation was defined as missing.
      (n = 9)(n = 19)
      No statistical test was performed between cases and controls for individual ICD-10 codes since the numbers are small and the matching between cases and controls is broken. ICD-10 = International Statistical Classification of Diseases and Related Health Problems (ICD) version 10; NPR = National Patient Registry.
      Symptoms and signs involving the circulatory and respiratory systems (R00- R09)1 (11%)0 (0%)
      Syncope and collapse (R55)1 (11%)0 (0%)
      Convulsions (R56)1 (11%)0 (0%)
      Cardiomyopathies (I42-I43)0 (0%)0 (0%)
      Arrhythmic heart disease (I44-I49)2 (22%)0 (0%)
      Other heart diseases (I30-41,I50-I52)1 (11%)0 (0%)
      Visits without ICD codes (missing)2 (22%)6 (5.5%)
      Data is presented as the number and percentages (%) of hospitalizations and/or outpatient visits within 180 days prior to death (death date excluded). The date when the controls were the same age as the matched case at the date of death was used as a reference date. The overall number of hospitalizations and/or outpatient visits as well as the number of visits with defined cardiac-related ICD-10 codes in the NPR were compared between cases and controls using conditional logistic regression. Note that primary care visits are not covered by the NPR.
      low asterisk ICD-10 codes are shown only for cases and controls who had either a hospitalisation and/or an outpatient visit in the NPR. When the individual did not receive any ICD-10 code in any of the visits, the observation was defined as missing.
      No statistical test was performed between cases and controls for individual ICD-10 codes since the numbers are small and the matching between cases and controls is broken.ICD-10 = International Statistical Classification of Diseases and Related Health Problems (ICD) version 10; NPR = National Patient Registry.
      A history of VT was present in 4 cases (19%). One of these was (the only case) diagnosed with ARVC before death. Another case had a slightly impaired left ventricular ejection fraction (approximately 50%). After extensive investigation with echocardiography, coronary angiography, and signal average ECG, this case was diagnosed with benign RVOT tachycardia and was scheduled for an ablation, but died the day before the procedure. The third case had survived a cardiac arrest at the age of 10 years and was diagnosed with long QT syndrome (LQTS). Genetic testing could not confirm the diagnosis. The fourth case had documented ventricular extrasystoles and a non-sustained VT during a neck surgery at the age of 11 years, but further investigation was not performed. Two years later, this patient experienced seizures and received a diagnosis of epilepsy, despite an inconclusive electroencephalogram. None of the cases had received an implantable cardioverter-defibrillator.
      A 12-lead ECG was available for 11 cases, of which 3 were performed within 6 months before death (range 14 days to 17 years). Echocardiography was performed on 4 subjects because of syncope/presyncope (n = 2), seizures (n = 1), or within the framework of family screening (n = 1). Further investigation with 24 hours ECG monitoring was performed in 3 of them. Retrospectively, 4 cases fulfilled at least 1 major or minor criteria according to the later implemented 2010 TFC,
      • Marcus FI
      • McKenna WJ
      • Sherrill D
      • Basso C
      • Bauce B
      • Bluemke DA
      • Calkins H
      • Corrado D
      • Cox MG
      • Daubert JP
      • Fontaine G
      • Gear K
      • Hauer R
      • Nava A
      • Picard MH
      • Protonotarios N
      • Saffitz JE
      • Sanborn DM
      • Steinberg JS
      • Tandri H
      • Thiene G
      • Towbin JA
      • Tsatsopoulou A
      • Wichter T
      • Zareba W.
      Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the task force criteria.
      including 2 who fulfilled criteria for definitive ARVC diagnosis and 1 for a borderline diagnosis (Supplementary Table 3). One individual had clinical suspicion of myotonic dystrophy type 1; however, no cardiac examination nor genetic testing was documented in the MRs.
      A total of 8 cases (36%) were female. Of them, 4 had previously been pregnant, and 3 had a history of spontaneous (not recurrent) abortions. One case had an emergency cesarean section because of fetal stress and significant intrapartum hemorrhage 2 months before death, and another was 8 weeks pregnant at the time of death.
      A total of 10 subjects (45%) had a family history of SCD (Figure 1). Of those, only 2 occurred in first-degree relatives and the rest in second-degree relatives. Moreover, 4 cases had lost 2 or more relatives because of SCD, and in 7 relatives, SCD had occurred before the age of 40. In addition, 2 cases had a living relative with an arrhythmogenic syndrome (Table 4). Genetic testing had only been performed in the case diagnosed with LQTS without the identification of any disease-causing variants.
      Table 4Family history before SCD due to ARVC
      Family historyNumber (%)TFC fulfilled
      SCD in relatives10 (45%)
       - Arrhythmogenic right ventricular cardiomyopathy1 (4.5%)FDR1 Major criterion
       - Myotonic dystrophy type 11 (4.5%) FDR
       - Sudden arrhythmic death syndrome1 (4.5%)
       - Hypertrophic Cardiomyopathy1 (4.5%)
       - Myocarditis1 (4.5%)
       - Unknown cause of SCD5 (18%)
      Cardiac diseases in living relatives2 (9%)
       - Arrhythmogenic right ventricular cardiomyopathy1 (4.5%) FDR1 Minor criterion
       - Catecholaminergic polymorphic ventricular tachycardia1 (4.5%) FDR
      ICD in living relatives3 (14%)
      Epilepsy in living relatives1 (4.5%) FDR
      The table shows the number of cases who had a family history of SCD or a living relative with an arrhythmogenic syndrome at the time of death. The causes of SCD in relatives are shown. In five relatives the postmortem diagnosis after SCD was unknown. Family history of ICD and epilepsy were included, as they were considered suggestive of cardiac disease. Family history was investigated among all first- (FDR) and second-degree relatives. ARVC TFC diagnostic criteria were fulfilled only in two cases who had a FDR with ARVC, including one who suffered SCD.
      ARVC = arrhythmogenic right ventricle cardiomyopathy, TFC = Task Force Criteria, ICD = implantable cardioverter defibrillator, SCD = sudden cardiac death.
      Most subjects were physically active, and 23% were involved in competitive sports, whereas 55% practiced recreational sports activities. Most (68%) participated in high dynamic physical activities such as soccer, ice hockey, basketball, running, floorball, and swimming (Table 5). Death was exercise-related in 9 cases (41%), occurring either during exercise (n = 5) or <1 hour after exercise (n = 4). Two of these subjects were competitive athletes and therefore considered to have a sports-related death. The next most common activities were rest (23%), sleep (23%), and daily routine activities (14%) (Figure 2).
      Table 5History of physical activity among subjects who suffered SCD caused by ARVC
      Physical activityNumber (%)
      Type of sports
      Low dynamic4 (18%)
      Moderate dynamic0
      High dynamic15 (68%)
      Unknown1 (4.5%)
      Frequency of training (times/week)
      <22 (9%)
      2-47 (32%)
      >53 (13.5%)
      Unknown8 (36%)
      Intensity of training
      Competitive5 (23%)
      Recreational12 (54.5%)
      None2 (9%)
      Unknown3 (13.5%)
      The table presents the type, frequency and intensity level of physical activity prior to death. The intensity level is classified based on the peak dynamic component during exercise.
      • Levine BD
      • Baggish AL
      • Kovacs RJ
      • Link MS
      • Maron MS
      • Mitchell JH
      American Heart Association Electrocardiography and Arrhythmias Committee of Council on Clinical Cardiology, Council on Cardiovascular Disease in Young, Council on Cardiovascular and Stroke Nursing, Council on Functional Genomics and Translational Biology, and American College of Cardiology. Eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities: Task Force 1: Classification of sports: dynamic, static, and impact: a scientific statement From the American Heart Association and American College of Cardiology.
      • Maron BJ
      • Chaitman BR
      • Ackerman MJ
      • Bayés de Luna A
      • Corrado D
      • Crosson JE
      • Deal BJ
      • Driscoll DJ
      • Estes NA
      • Araújo CG
      • Liang DH
      • Mitten MJ
      • Myerburg RJ
      • Pelliccia A
      • Thompson PD
      • Towbin JA
      • Van Camp SP
      Working Groups of the American Heart Association Committee on Exercise, Cardiac Rehabilitation, and Prevention, Councils on Clinical Cardiology and Cardiovascular Disease in the Young. Recommendations for physical activity and recreational sports participation for young patients with genetic cardiovascular diseases.
      Figure 2
      Figure 2Activity at the time of sudden cardiac death because of ARVC. The figure shows the activity at the time of death in all cases of SCD because of ARVC. The most common activity was exercise in 41% of cases, of which 9% occurred in competitive athletes and was therefore defined as sports-related SCD. The remaining 32% of cases practiced sports as recreational activities. The next most common activities were rest (no physical activity) and sleep. SCD = sudden cardiac death.
      A total of 7 subjects (32%) experienced prodromal symptoms immediately before cardiac arrest, including chest pain, palpitations, seizures, or nausea; 5 (23%) collapsed without any prodromal symptoms, and in 10 cases, death was unwitnessed (45%).
      The autopsy findings are listed in Table 6. All cases received a postmortem diagnosis of ARVC as the probable cause of death after a forensic (12 of 22) or a clinical autopsy (10 of 22) (inclusion criteria). Histopathological examination was performed in all cases. Complementary microbiology and toxicology investigations were performed in 4 and 13 cases, respectively. The myocardial changes (fibrosis, fatty infiltration, or both) were evident only after microscopic histopathological examination in 13 cases (60%), and biventricular involvement was present in 12 (55%). In 2 cases, blood samples were collected at the autopsy and archived in a research biobank for future studies, but no genetic testing was done.
      Table 6Autopsy findings among SCD victims due to ARVC
      Autopsy finding
      Autopsy type (n = 22)Number (%)
       - Forensic autopsy12 (55%)
       - Clinical autopsy10 (45%)
      Heart measurements (n
      Some measurements and complementary microbiology and toxicology investigations were performed only in some individuals (n indicated between brackets), the number of available autopsies with complete data is indicated in the brackets. RV = right ventricle; LV = left ventricle; BV = biventricular.
      )
      Average (min-max)
       - Heart weight gr (n=21)383.9 (230-550)
       - LV wall thickness mm (n=8)14.4 (12-20)
       - RV wall thickness mm (n=7)3.71 (1-6)
      Myocardial changes (n=22)Number (%)
       - RV fibrofatty infiltration9 (41%)
       - BV fibrofatty infiltration5 (23%)
       - RV fatty infiltration5 (23%)
       - BV fatty infiltration2 (9%)
       - RV fibrosis4 (18%)
       - BV fibrosis9 (41%)
       - Inflammatory infiltrates6 (27%)
       - RV wall thinning11 (50%)
       - BV wall thinning2 (9%)
       - RV dilatation6 (27%)
       - BV dilatation7 (32%)
      Summary of findings described in the autopsy reports among victims of SCD due to ARVC. A forensic or a clinical autopsy was performed in all the study subjects.
      low asterisk Some measurements and complementary microbiology and toxicology investigations were performed only in some individuals (n indicated between brackets), the number of available autopsies with complete data is indicated in the brackets.RV = right ventricle; LV = left ventricle; BV = biventricular.

      Discussion

      The most important finding in this nationwide study is that most young patients who died of SCD because of ARVC had experienced cardiac symptoms during the last 6 months preceding death. The most common symptoms were syncope/pre-syncope followed by chest discomfort, consistent with previous reports.
      • Sadjadieh G
      • Jabbari R
      • Risgaard B
      • Olesen MS
      • Haunso S
      • Tfelt-Hansen J
      • Winkel BG.
      Nationwide (Denmark) study of symptoms preceding sudden death due to arrhythmogenic right ventricular cardiomyopathy.
      ,
      • Dalal D
      • Nasir K
      • Bomma C
      • Prakasa K
      • Tandri H
      • Piccini J
      • Roguin A
      • Tichnell C
      • James C
      • Russell SD
      • Judge DP
      • Abraham T
      • Spevak PJ
      • Bluemke DA
      • Calkins H.
      Arrhythmogenic right ventricular dysplasia: a United States experience.
      ,
      • Wisten A
      • Messner T.
      Symptoms preceding sudden cardiac death in the young are common but often misinterpreted.
      Health care use in cases was significantly higher compared with age-matched, gender-matched, and geographically-matched population controls, and a large proportion of the cases had a family history of sudden premature death. Despite this, only a few of the symptomatic cases were further assessed for malignant arrhythmias. Retrospectively, 4 cases fulfilled at least 1 major ECG criterion for ARVC during a health care visit according to the later implemented 2010 TFC. However, the ECG was considered normal at that time in 3 of the cases. Significant dilatation of either the right ventricle (27%) or both ventricles (32%) was evident on autopsy, suggesting that most subjects could probably have been diagnosed if echocardiography had been performed. These findings emphasize why early recognition of the disease in patients seeking medical care with alarming symptoms and family history is critical, as SCD can be the first disease manifestation, often before detectable structural changes occur.
      About half of the cases had a family history of SCD, and some had lost multiple relatives because of early SCD. The affected patients were more often second-degree relatives, probably reflecting the incomplete penetrance of the disease estimated to be up to 50%.
      • Groeneweg JA
      • Bhonsale A
      • James CA
      • te Riele AS
      • Dooijes D
      • Tichnell C
      • Murray B
      • Wiesfeld AC
      • Sawant AC
      • Kassamali B
      • Atsma DE
      • Volders PG
      • de Groot NM
      • de Boer K
      • Zimmerman SL
      • Kamel IR
      • van der Heijden JF
      • Russell SD
      • Jan Cramer M
      • Tedford RJ
      • Doevendans PA
      • van Veen TA
      • Tandri H
      • Wilde AA
      • Judge DP
      • van Tintelen JP
      • Hauer RN
      • Calkins H
      Clinical presentation, long-term follow-up, and outcomes of 1001 arrhythmogenic right ventricular dysplasia/cardiomyopathy patients and family members.
      ,
      • Quarta G
      • Muir A
      • Pantazis A
      • Syrris P
      • Gehmlich K
      • Garcia-Pavia P
      • Ward D
      • Sen-Chowdhry S
      • Elliott PM
      • McKenna WJ.
      Familial evaluation in arrhythmogenic right ventricular cardiomyopathy: impact of genetics and revised task force criteria.
      This also indicates a considerable risk of death in first-degree and second-degree relatives of SCD victims and, therefore, the need for comprehensive clinical evaluation of surviving relatives. The importance of careful family history for patients at risk of SCD is well recognized.
      • Priori SG
      • Blomstrom-Lundqvist C
      • Mazzanti A
      • Blom N
      • Borggrefe M
      • Camm J
      • Elliott PM
      • Fitzsimons D
      • Hatala R
      • Hindricks G
      • Kirchhof P
      • Kjeldsen K
      • Kuck KH
      • Hernandez-Madrid A
      • Nikolaou N
      • Norekval TM
      • Spaulding C
      • Van Veldhuisen DJ.
      2015 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death.
      Despite this, it was poorly documented in the MRs, even for the athletes. The 2010 TFC only considers a positive family history of ARVC or SCD <35 years in first-degree relatives as a major criterion.
      • Marcus FI
      • McKenna WJ
      • Sherrill D
      • Basso C
      • Bauce B
      • Bluemke DA
      • Calkins H
      • Corrado D
      • Cox MG
      • Daubert JP
      • Fontaine G
      • Gear K
      • Hauer R
      • Nava A
      • Picard MH
      • Protonotarios N
      • Saffitz JE
      • Sanborn DM
      • Steinberg JS
      • Tandri H
      • Thiene G
      • Towbin JA
      • Tsatsopoulou A
      • Wichter T
      • Zareba W.
      Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the task force criteria.
      However, given the phenotypic overlap of inherited cardiomyopathies and arrhythmogenic syndromes, all cases of cardiac disease and unexplained deaths in first-degree and second-degree relatives should be taken into consideration during family history assessment.
      Our results agree with previous nationwide studies in Sweden, Denmark, and the United States, also reporting a high prevalence of symptoms, medical contacts, and family history.
      • Sadjadieh G
      • Jabbari R
      • Risgaard B
      • Olesen MS
      • Haunso S
      • Tfelt-Hansen J
      • Winkel BG.
      Nationwide (Denmark) study of symptoms preceding sudden death due to arrhythmogenic right ventricular cardiomyopathy.
      ,
      • Wisten A
      • Messner T.
      Symptoms preceding sudden cardiac death in the young are common but often misinterpreted.
      ,
      • Miles C
      • Finocchiaro G
      • Papadakis M
      • Gray B
      • Westaby J
      • Ensam B
      • Basu J
      • Parry-Williams G
      • Papatheodorou E
      • Paterson C
      • Malhotra A
      • Robertus JL
      • Ware JS
      • Cook SA
      • Asimaki A
      • Witney A
      • Ster IC
      • Tome M
      • Sharma S
      • Behr ER
      • Sheppard MN
      Sudden death and left ventricular involvement in arrhythmogenic cardiomyopathy.
      ,
      • Gupta R
      • Tichnell C
      • Murray B
      • Rizzo S
      • Te Riele A
      • Tandri H
      • Judge DP
      • Thiene G
      • Basso C
      • Calkins H
      • James CA
      Comparison of features of fatal versus nonfatal cardiac arrest in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy.
      In Sweden, the same trend, including a low diagnostic rate, was observed in young victims of SCD because of ARVC in a nationwide study from 1992 to 1999,
      • Wisten A
      • Messner T.
      Symptoms preceding sudden cardiac death in the young are common but often misinterpreted.
      indicating that no significant improvement was made in the risk assessment of young patients who sought medical care because of heart-related symptoms during the following 10 years.
      In line with previous studies, the prevalence of exercise-related SCD observed in ARVC subjects (41%) was higher than in all SCD victims from the SUDDY cohort (12%).
      • Tabib A
      • Loire R
      • Chalabreysse L
      • Meyronnet D
      • Miras A
      • Malicier D
      • Thivolet F
      • Chevalier P
      • Bouvagnet P.
      Circumstances of death and gross and microscopic observations in a series of 200 cases of sudden death associated with arrhythmogenic right ventricular cardiomyopathy and/or dysplasia.
      ,
      • Sadjadieh G
      • Jabbari R
      • Risgaard B
      • Olesen MS
      • Haunso S
      • Tfelt-Hansen J
      • Winkel BG.
      Nationwide (Denmark) study of symptoms preceding sudden death due to arrhythmogenic right ventricular cardiomyopathy.
      ,
      • Dalal D
      • Nasir K
      • Bomma C
      • Prakasa K
      • Tandri H
      • Piccini J
      • Roguin A
      • Tichnell C
      • James C
      • Russell SD
      • Judge DP
      • Abraham T
      • Spevak PJ
      • Bluemke DA
      • Calkins H.
      Arrhythmogenic right ventricular dysplasia: a United States experience.
      ,
      • Miles C
      • Finocchiaro G
      • Papadakis M
      • Gray B
      • Westaby J
      • Ensam B
      • Basu J
      • Parry-Williams G
      • Papatheodorou E
      • Paterson C
      • Malhotra A
      • Robertus JL
      • Ware JS
      • Cook SA
      • Asimaki A
      • Witney A
      • Ster IC
      • Tome M
      • Sharma S
      • Behr ER
      • Sheppard MN
      Sudden death and left ventricular involvement in arrhythmogenic cardiomyopathy.
      ,
      • Wisten A
      • Börjesson M
      • Krantz P
      • Stattin EL.
      Exercise related sudden cardiac death (SCD) in the young - pre-mortal characterization of a Swedish nationwide cohort, showing a decline in SCD among athletes.
      Although only 9% of exercise-related deaths occurred in subjects considered competitive athletes, most subjects practiced sports as recreational activities. Independently of the level of training, most victims (68%) were involved in high dynamic sports.
      In contrast to our results, a recent study in the United Kingdom on SCD victims because of arrhythmogenic cardiomyopathy reported a much lower frequency of symptoms and a higher percentage of sports-related SCD.
      • Miles C
      • Finocchiaro G
      • Papadakis M
      • Gray B
      • Westaby J
      • Ensam B
      • Basu J
      • Parry-Williams G
      • Papatheodorou E
      • Paterson C
      • Malhotra A
      • Robertus JL
      • Ware JS
      • Cook SA
      • Asimaki A
      • Witney A
      • Ster IC
      • Tome M
      • Sharma S
      • Behr ER
      • Sheppard MN
      Sudden death and left ventricular involvement in arrhythmogenic cardiomyopathy.
      However, this cohort consists of an older population with a broader phenotypic spectrum of arrhythmogenic cardiomyopathy.
      A total of 8 cases in our cohort were female (36%). Recent complications during delivery and pregnancy at the time of SCD were observed. Pregnancy has been, however, considered to be well-tolerated in ARVC regarding arrhythmias and heart failure.
      • Hodes AR
      • Tichnell C
      • Te Riele AS
      • Murray B
      • Groeneweg JA
      • Sawant AC
      • Russell SD
      • van Spaendonck-Zwarts KY
      • van den Berg MP
      • Wilde AA
      • Tandri H
      • Judge DP
      • Hauer RN
      • Calkins H
      • van Tintelen JP
      • James CA
      Pregnancy course and outcomes in women with arrhythmogenic right ventricular cardiomyopathy.
      • Gandjbakhch E
      • Varlet E
      • Duthoit G
      • Fressart V
      • Charron P
      • Himbert C
      • Maupain C
      • Bordet C
      • Hidden-Lucet F
      • Nizard J.
      Pregnancy and newborn outcomes in arrhythmogenic right ventricular cardiomyopathy/dysplasia.
      • Platonov PG
      • Castrini AI
      • Svensson A
      • Christiansen MK
      • Gilljam T
      • Bundgaard H
      • Madsen T
      • Heliö T
      • Christensen AH
      • Åström MA
      • Carlson J
      • Edvardsen T
      • Jensen HK
      • Haugaa KH
      • Svendsen JH.
      Pregnancies, ventricular arrhythmias, and substrate progression in women with arrhythmogenic right ventricular cardiomyopathy in the Nordic ARVC Registry.
      More studies investigating the role of pregnancy in ARVC are needed.
      The results of the present study highlight how challenging it is to recognize ARVC early and identify young patients at risk of SCD. Remarkably, most cases who sought medical care before death underwent minimal, if any, investigation, reflecting an unfortunate trend to underestimate symptoms in younger patients. Warning symptoms of possible impaired cardiac function in children and adolescents should not be overlooked, and expedited complete cardiac evaluation should be guaranteed, particularly in the presence of a family history of SCD or other inherited cardiovascular disorders, as the time window to intervene is very narrow.
      • Gupta R
      • Tichnell C
      • Murray B
      • Rizzo S
      • Te Riele A
      • Tandri H
      • Judge DP
      • Thiene G
      • Basso C
      • Calkins H
      • James CA
      Comparison of features of fatal versus nonfatal cardiac arrest in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy.
      The limitations of the study include that it is retrospective and based on autopsies performed at different centers following standardized protocols available at the time of investigation. To overcome this, all autopsy reports in the SUDDY cohort were manually revised to confirm the diagnosis; however, we cannot exclude that some ARVC cases went unrecognized. Cases whose deaths were not sudden and resuscitated victims of SCD are not included; this study is, therefore, a series of cases with the worst outcome. Retrieving retrospective data through phone calls and questionnaires to family members may lead to underreporting or erroneous recall of symptoms, signs, and history of physical activity of the deceased. However, registry-based data regarding medical contacts was consistent with the information provided by the relatives. Finally, postmortem genetic testing was not routinely performed during the study period; therefore, the ARVC diagnosis was not genetically confirmed in any of the cases. Recommendations are in place today to include genetic testing as part of the postmortem investigation of SCD.
      • Fellmann F
      • van El CG
      • Charron P
      • Michaud K
      • Howard HC
      • Boers SN
      • Clarke AJ
      • Duguet AM
      • Forzano F
      • Kauferstein S
      • Kayserili H
      • Lucassen A
      • Mendes Á
      • Patch C
      • Radojkovic D
      • Rial-Sebbag E
      • Sheppard MN
      • Tassé AM
      • Temel SG
      • Sajantila A
      • Basso C
      • Wilde AAM
      • Cornel MC
      on behalf of European Society of Human Genetics
      European Council of Legal Medicine, European Society of Cardiology working group on myocardial and pericardial diseases, European Reference Network for rare, low prevalence and complex diseases of the heart (ERN GUARD-Heart), Association for European Cardiovascular Pathology. European recommendations integrating genetic testing into multidisciplinary management of sudden cardiac death.
      ,
      • Basso C
      • Aguilera B
      • Banner J
      • Cohle S
      • d'Amati G
      • de Gouveia RH
      • di Gioia C
      • Fabre A
      • Gallagher PJ
      • Leone O
      • Lucena J
      • Mitrofanova L
      • Molina P
      • Parsons S
      • Rizzo S
      • Sheppard MN
      • Mier MPS
      • Kim Suvarna S
      • Thiene G
      • van der Wal A
      • Vink A
      • Michaud K
      Association for European Cardiovascular Pathology. Guidelines for autopsy investigation of sudden cardiac death: 2017 update from the Association for European Cardiovascular Pathology.
      In conclusion, in this nationwide, longitudinal study of SCD in the young, we observed that most victims of SCD caused by ARVC had warning symptoms of cardiac origin, with syncope/presyncope being the most prevalent symptom before death. Despite that half of the patients with cardiac symptoms had sought medical care, only 1 was recognized as having a potentially fatal disease. Furthermore, family history of SCD and arrhythmogenic disease was common but in most cases, overlooked and inherited cardiac disease was not suspected.

      Disclosures

      The authors have no conflicts of interest to declare.

      Acknowledgment

      The authors would like to express their gratitude to Peter Krantz, PhD, Department of Forensic Medicine, Lund University, Lund, Sweden, for selecting and evaluating the forensic report of all SCDs included in the study. The authors sincerely thank family members who agreed to participate in the study.

      Data availability

      Because of Swedish legislation, the data is not freely accessible. However, within a collaboration, aggregated data would be available.

      Appendix. Supplementary materials

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