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Symptoms Before Sudden Arrhythmic Death Syndrome: A Nationwide Study Among the Young in Denmark CHARLOTTE GLINGE, B.M.,∗ ,† REZA JABBARI, M.D.,∗ ,† BJARKE RISGAARD, M.D.,∗ ,† THOMAS HADBERG LYNGE, B.M.,∗ ,† THOMAS ENGSTRØM, M.D., Ph.D., D.M.S.C.,‡ CHRISTINE M. ALBERT, M.D., M.P.H.,§ STIG HAUNSØ, M.D., D.M.S.C.,∗ ,†,‡ BO GREGERS WINKEL, M.D., Ph.D.,∗ ,†,‡ and JACOB TFELT-HANSEN, M.D., D.M.S.C.∗ ,†,‡ From the ∗ Danish National Research Foundation Centre for Cardiac Arrhythmia (DARC), University of Copenhagen, Denmark; †Laboratory of Molecular Cardiology, Department of Cardiology, The Heart Centre; ‡Department of Medicine and Surgery, Copenhagen University Hospital, Rigshospitalet, Denmark; and §Center for Arrhythmia Prevention, Division of Preventive Medicine, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
Symptoms Before SADS. Introduction: No studies in an unselected and nationwide setting have characterized the symptoms and medical history of patients with sudden arrhythmic death syndrome (SADS). The aim of this study was to identify and describe the symptoms and medical history of patients before the presentation of SADS. Methods and Results: We have previously identified all of the autopsied sudden cardiac deaths (SCD; n = 314) in Danes aged 1–35 years between 2000 and 2006. After comprehensive pathological and toxicological investigation did not reveal a cause of SCD, 136 of the patients were identified as SADS. The National Patient Registry was utilized to obtain information on all in- and outpatient activity in Danish hospitals. All medical records from hospitals and general practitioners, including death certificates and autopsy reports were reviewed. Before death, 48 (35%) SADS patients had cardiac symptoms; among these, 30 (22%) had contacted the healthcare system. Antecedent symptoms (symptoms >24 hours before death) were present in 34 (25%) patients. Prodromal symptoms (symptoms ࣘ24 hours before death) were present in 23 (17%) patients. Cardiac symptoms included chest pain (n = 16, 12%), dyspnea (n = 18, 13%), palpitations (n = 2, 1%), presyncope/syncope (n = 23, 17%), and aborted SCD (n = 2, 1%). In addition, seizures (n = 25, 18%) were prevalent. In 61 (45%) SADS cases, no previous medical history were recorded. Conclusion: In this unselected, nationwide study of 136 young SADS patients, 35% had experienced cardiac symptoms before death, most commonly presyncope/syncope, but only one out of five had contacted a healthcare provider with cardiac symptoms. (J Cardiovasc Electrophysiol, Vol. 26, pp. 761-767, July 2015) antecedent cardiac symptoms, prodromal cardiac symptoms, sudden arrhythmic death syndrome, sudden cardiac death, sudden unexplained death Introduction Autopsies in cases of young sudden unexpected deaths are essential in establishing a cause of death. However, a significant proportion of sudden cardiac deaths (SCD) remain unexplained after autopsy. Sudden arrhythmic death syndrome (SADS) is defined as a SCD that remains unexplained after comprehensive post-mortem evaluation, including histology Danish National Research Foundation Centre for Cardiac Arrhythmia (DARC), University of Copenhagen, Denmark; Laboratory of Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Denmark; The John and Birthe Meyer Foundation; The Research Fund of Rigshospitalet, Copenhagen University Hospital, Rigshospitalet, Denmark. Disclosures: None. Address for correspondence: Charlotte Glinge, B.M., Laboratory of Molecular Cardiology, Copenhagen University Hospital, Rigshospitalet, 9312, Juliane Maries Vej 20, 2100 Copenhagen. Fax: (+45)35456500; E-mail: [email protected] Manuscript received 14 August 2014; Revised manuscript received 23 February 2015; Accepted for publication 19 March 2015. doi: 10.1111/jce.12674
and toxicology screening.1 The frequency of these autopsynegative SADS cases has been variably reported as ranging from 14% to 43% of all SCDs in young persons aged ࣘ35 years.2-8 Despite extensive research, the prevention of SADS remains challenging. The key to reduce the burden of SADS and prevent further sudden deaths among relatives is to identify the individuals at risk. This, in part, requires an understanding of the symptoms prior to presentation with SADS as well as demographic analyses that may elucidate the underlying cause of death. Premonitory signs and symptoms are often absent in sudden death patients,9 but symptoms can occur during the days or weeks before SCD.10,11 Although symptoms prior to sudden death in SADS patients may have poor predictive values and low sensitivities, it is important to characterize them as they may have value in the overall evaluation of a patient’s risk of SADS. Previous studies have reported symptoms preceding SADS in 4–58% of patients.12-16 However, as these studies were based of on selected cases referred to tertiary cardiac centers, they may not be representative for the general population. To date, no studies have systematically and nonselectively investigated the symptoms that SADS patients experience prior to death. Therefore, the aim of this study was to identify and describe the symptoms and medical
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Journal of Cardiovascular Electrophysiology
Vol. 26, No. 7, July 2015
tives and eyewitnesses, an external examination of the body, previous medical conditions and the preliminary conclusion before autopsy.2 In cases where individuals or patients are found dead and/or the death is sudden and unexpected, external examinations are mandatory by law and informed consent from relatives is not required. These examinations are performed by medical doctors together with the police, and the information from these examinations can be found in the supplemental information field on the death certificate irrespective of whether an autopsy was performed. If the external examination cannot establish the cause of death, a forensic autopsy is conducted. Danish death certificates are informative and highly suitable to identify sudden unexpected deaths and exclude suicide victims due to the large supplemental information field (see supplementary data, Winkel et al.).2 Figure 1. Flowchart of the process used to identify young sudden arrhythmic death syndrome (SADS) in Denmark between 2000–2006. The 136 SADS cases were included in this study.
history preceding SADS presentation in a nationwide cohort of unselected, young SADS patients. Methods Study Population We have previously identified all SCDs among Danes aged 1–35 years between 2000 and 2006.2 All deaths were included (n = 6,396), and 314 were autopsied SCDs. Structural heart disease was the cause of death in 178 of the autopsied cases; the most frequent cause of SCD due to structural heart disease was coronary heart disease (CAD) (13%), followed by myocarditis (7%), hypertrophic heart (6%), and arrhythmogenic right ventricular cardiomyopathy (ARVC) (5%). We identified 136 SADS cases after comprehensive pathological and toxicological investigations, corresponding to 43% of all autopsied SCDs. The 136 SADS patients were included in the current study (Fig. 1). For comparison, the SADS cases were compared with a control group in the same age group and time interval; these were subjects who died in traffic accidents (n = 74).10,11 The study was approved by the Regional Ethics Committee (KF 01272484), the Danish Data Protection Agency (2005-41-5237), and the Danish National Board of Health (7-505-29-58/1-5). Danish Registries and Death Certificates All individuals with permanent residence in Denmark are assigned a unique personal Civil Registration Number (CRN) that enables nationwide registers to link to individual level providers from various sources. We used CRNs to retrieve information on previous medical history from the National Patient Registry (NPR) and obtained death certificates. Since 1978, the NPR has contained information on all in- and outpatient activity in Danish hospitals. Diagnoses are coded according to the International Classification of Diseases (ICD), with ICD-8 codes used from 1977 to 1993, and ICD-10 codes used since 1994.17 The content, validity, and coverage of the NPR has previously been described and its diagnoses have been validated. Danish death certificate, which can only be issued by medical doctors, includes information on the circumstances of the death including interviews with rela-
Data Collection The methods used for this study have previously been described in detail by our group.2,10 In brief, we used the NPR, death certificates and autopsy reports to find all information on previous relevant links to the healthcare system. This included review of records from hospitals as well as GPs. The NPR in Denmark allows easy access to premortem medical records such that we were able to identify all previous hospital admissions for each case. Danish death certificates are resourceful due to the supplemental information field and highly suitable for identifying symptoms. In most SADS cases, cardiac as well as other symptoms are described in detail in the supplementary information. This information was collected at the time of death by the medical doctors, reported from interviews with relatives, or even obtained from GPs.2 Using the CRNs, we were able to identify the GPs by contacting Danish municipalities and counties. We then contacted the GPs to obtain full medical records. All individuals in Denmark have a GP whom they contact for nonemergency medical attention. Definitions We defined SCD in autopsied cases as “sudden, natural unexpected death of unknown, or cardiac etiology; in unwitnessed cases as a person last seen alive and functioning normally
Symptoms Before Sudden Arrhythmic Death Syndrome: A Nationwide Study Among the Young in Denmark CHARLOTTE GLINGE, B.M.,∗ ,† REZA JABBARI, M.D.,∗ ,† BJARKE RISGAARD, M.D.,∗ ,† THOMAS HADBERG LYNGE, B.M.,∗ ,† THOMAS ENGSTRØM, M.D., Ph.D., D.M.S.C.,‡ CHRISTINE M. ALBERT, M.D., M.P.H.,§ STIG HAUNSØ, M.D., D.M.S.C.,∗ ,†,‡ BO GREGERS WINKEL, M.D., Ph.D.,∗ ,†,‡ and JACOB TFELT-HANSEN, M.D., D.M.S.C.∗ ,†,‡ From the ∗ Danish National Research Foundation Centre for Cardiac Arrhythmia (DARC), University of Copenhagen, Denmark; †Laboratory of Molecular Cardiology, Department of Cardiology, The Heart Centre; ‡Department of Medicine and Surgery, Copenhagen University Hospital, Rigshospitalet, Denmark; and §Center for Arrhythmia Prevention, Division of Preventive Medicine, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
Symptoms Before SADS. Introduction: No studies in an unselected and nationwide setting have characterized the symptoms and medical history of patients with sudden arrhythmic death syndrome (SADS). The aim of this study was to identify and describe the symptoms and medical history of patients before the presentation of SADS. Methods and Results: We have previously identified all of the autopsied sudden cardiac deaths (SCD; n = 314) in Danes aged 1–35 years between 2000 and 2006. After comprehensive pathological and toxicological investigation did not reveal a cause of SCD, 136 of the patients were identified as SADS. The National Patient Registry was utilized to obtain information on all in- and outpatient activity in Danish hospitals. All medical records from hospitals and general practitioners, including death certificates and autopsy reports were reviewed. Before death, 48 (35%) SADS patients had cardiac symptoms; among these, 30 (22%) had contacted the healthcare system. Antecedent symptoms (symptoms >24 hours before death) were present in 34 (25%) patients. Prodromal symptoms (symptoms ࣘ24 hours before death) were present in 23 (17%) patients. Cardiac symptoms included chest pain (n = 16, 12%), dyspnea (n = 18, 13%), palpitations (n = 2, 1%), presyncope/syncope (n = 23, 17%), and aborted SCD (n = 2, 1%). In addition, seizures (n = 25, 18%) were prevalent. In 61 (45%) SADS cases, no previous medical history were recorded. Conclusion: In this unselected, nationwide study of 136 young SADS patients, 35% had experienced cardiac symptoms before death, most commonly presyncope/syncope, but only one out of five had contacted a healthcare provider with cardiac symptoms. (J Cardiovasc Electrophysiol, Vol. 26, pp. 761-767, July 2015) antecedent cardiac symptoms, prodromal cardiac symptoms, sudden arrhythmic death syndrome, sudden cardiac death, sudden unexplained death Introduction Autopsies in cases of young sudden unexpected deaths are essential in establishing a cause of death. However, a significant proportion of sudden cardiac deaths (SCD) remain unexplained after autopsy. Sudden arrhythmic death syndrome (SADS) is defined as a SCD that remains unexplained after comprehensive post-mortem evaluation, including histology Danish National Research Foundation Centre for Cardiac Arrhythmia (DARC), University of Copenhagen, Denmark; Laboratory of Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Denmark; The John and Birthe Meyer Foundation; The Research Fund of Rigshospitalet, Copenhagen University Hospital, Rigshospitalet, Denmark. Disclosures: None. Address for correspondence: Charlotte Glinge, B.M., Laboratory of Molecular Cardiology, Copenhagen University Hospital, Rigshospitalet, 9312, Juliane Maries Vej 20, 2100 Copenhagen. Fax: (+45)35456500; E-mail: [email protected] Manuscript received 14 August 2014; Revised manuscript received 23 February 2015; Accepted for publication 19 March 2015. doi: 10.1111/jce.12674
and toxicology screening.1 The frequency of these autopsynegative SADS cases has been variably reported as ranging from 14% to 43% of all SCDs in young persons aged ࣘ35 years.2-8 Despite extensive research, the prevention of SADS remains challenging. The key to reduce the burden of SADS and prevent further sudden deaths among relatives is to identify the individuals at risk. This, in part, requires an understanding of the symptoms prior to presentation with SADS as well as demographic analyses that may elucidate the underlying cause of death. Premonitory signs and symptoms are often absent in sudden death patients,9 but symptoms can occur during the days or weeks before SCD.10,11 Although symptoms prior to sudden death in SADS patients may have poor predictive values and low sensitivities, it is important to characterize them as they may have value in the overall evaluation of a patient’s risk of SADS. Previous studies have reported symptoms preceding SADS in 4–58% of patients.12-16 However, as these studies were based of on selected cases referred to tertiary cardiac centers, they may not be representative for the general population. To date, no studies have systematically and nonselectively investigated the symptoms that SADS patients experience prior to death. Therefore, the aim of this study was to identify and describe the symptoms and medical
762
Journal of Cardiovascular Electrophysiology
Vol. 26, No. 7, July 2015
tives and eyewitnesses, an external examination of the body, previous medical conditions and the preliminary conclusion before autopsy.2 In cases where individuals or patients are found dead and/or the death is sudden and unexpected, external examinations are mandatory by law and informed consent from relatives is not required. These examinations are performed by medical doctors together with the police, and the information from these examinations can be found in the supplemental information field on the death certificate irrespective of whether an autopsy was performed. If the external examination cannot establish the cause of death, a forensic autopsy is conducted. Danish death certificates are informative and highly suitable to identify sudden unexpected deaths and exclude suicide victims due to the large supplemental information field (see supplementary data, Winkel et al.).2 Figure 1. Flowchart of the process used to identify young sudden arrhythmic death syndrome (SADS) in Denmark between 2000–2006. The 136 SADS cases were included in this study.
history preceding SADS presentation in a nationwide cohort of unselected, young SADS patients. Methods Study Population We have previously identified all SCDs among Danes aged 1–35 years between 2000 and 2006.2 All deaths were included (n = 6,396), and 314 were autopsied SCDs. Structural heart disease was the cause of death in 178 of the autopsied cases; the most frequent cause of SCD due to structural heart disease was coronary heart disease (CAD) (13%), followed by myocarditis (7%), hypertrophic heart (6%), and arrhythmogenic right ventricular cardiomyopathy (ARVC) (5%). We identified 136 SADS cases after comprehensive pathological and toxicological investigations, corresponding to 43% of all autopsied SCDs. The 136 SADS patients were included in the current study (Fig. 1). For comparison, the SADS cases were compared with a control group in the same age group and time interval; these were subjects who died in traffic accidents (n = 74).10,11 The study was approved by the Regional Ethics Committee (KF 01272484), the Danish Data Protection Agency (2005-41-5237), and the Danish National Board of Health (7-505-29-58/1-5). Danish Registries and Death Certificates All individuals with permanent residence in Denmark are assigned a unique personal Civil Registration Number (CRN) that enables nationwide registers to link to individual level providers from various sources. We used CRNs to retrieve information on previous medical history from the National Patient Registry (NPR) and obtained death certificates. Since 1978, the NPR has contained information on all in- and outpatient activity in Danish hospitals. Diagnoses are coded according to the International Classification of Diseases (ICD), with ICD-8 codes used from 1977 to 1993, and ICD-10 codes used since 1994.17 The content, validity, and coverage of the NPR has previously been described and its diagnoses have been validated. Danish death certificate, which can only be issued by medical doctors, includes information on the circumstances of the death including interviews with rela-
Data Collection The methods used for this study have previously been described in detail by our group.2,10 In brief, we used the NPR, death certificates and autopsy reports to find all information on previous relevant links to the healthcare system. This included review of records from hospitals as well as GPs. The NPR in Denmark allows easy access to premortem medical records such that we were able to identify all previous hospital admissions for each case. Danish death certificates are resourceful due to the supplemental information field and highly suitable for identifying symptoms. In most SADS cases, cardiac as well as other symptoms are described in detail in the supplementary information. This information was collected at the time of death by the medical doctors, reported from interviews with relatives, or even obtained from GPs.2 Using the CRNs, we were able to identify the GPs by contacting Danish municipalities and counties. We then contacted the GPs to obtain full medical records. All individuals in Denmark have a GP whom they contact for nonemergency medical attention. Definitions We defined SCD in autopsied cases as “sudden, natural unexpected death of unknown, or cardiac etiology; in unwitnessed cases as a person last seen alive and functioning normally
