Juliane Theilade

Nationwide study of sudden cardiac death in persons aged 1–35 years

AIMS The aim of this investigation was to study the incidence of sudden cardiac death (SCD) in persons aged 1-35 years in a nationwide setting (5.38 million people) by systematic evaluation of all deaths. METHODS AND RESULTS All deaths in persons aged 1-35 years in Denmark in 2000-06 were included. Death certificates were read independently by two physicians. The National Patient Registry was used to retrieve information on prior medical history. All autopsy reports were read and the cause of death was revised based on autopsy findings. We identified 625 cases of sudden unexpected death (10% of all deaths), of which 156 (25%) were not autopsied. Of the 469 autopsied cases, 314 (67%) were SCD. The most common cardiac cause of death was ischaemic heart disease (13%); 29% of autopsied sudden unexpected death cases were unexplained. In 45% of SCD cases, the death was witnessed; 34% died during sleep; 89% were out-of-hospital deaths. Highest possible incidence rate of SCD in the young was 2.8 per 100 000 person-years including non-autopsied cases of sudden unexpected death. Excluding those, the incidence rate declined to 1.9 per 100 000 person-years. CONCLUSIONS A total of 7% of all deaths in the young can be attributed to SCD, when including non-autopsied cases (autopsy ratio 75%). The incidence rate of SCD in the young of 2.8 per 100 000 person-years is higher than previously reported.

Incidence and etiology of sports-related sudden cardiac death in Denmark—Implications for preparticipation screening

BACKGROUND Studies on incidences of sports-related sudden cardiac death (SrSCD) are few and data are needed for the discussion of preparticipation screening for cardiac disease. OBJECTIVE We sought to chart the incidence and etiology of SrSCD in the young in Denmark (population 5.4 million) and to compare this to the incidence of sudden cardiac death (SCD) in the background population. METHODS All 5,662 death certificates for decedents in the period 2000 to 2006 in the age group 12 to 35 years in Denmark were read independently by 2 physicians to identify cases of SCD. Information from autopsy reports, selected hospital records, and multiple registries was used to identify cases of SCD and SrSCD. SrSCD was defined as SCD occurring during or within 1 hour after exercise in a competitive athlete. The size of the athlete population was estimated from national survey data. RESULTS Fifteen (range 0 to 5 per year) cases of SrSCD were found, 8 of which had antecedent symptoms. The incidence rate was 1.21 (95% confidence interval [CI]: 0.68 to 2.00) per 100,000 athlete person-years. The most common autopsy findings were arrhythmogenic right ventricular cardiomyopathy (n = 4), sudden unexplained death (n = 4), and coronary artery disease (n = 2). The incidence of SCD in the general population age 12 to 35 was 3.76 (95% CI: 3.42 to 4.14) per 100,000 person-years. CONCLUSION In Denmark, SrSCD is a rare occurrence and the incidence rate is lower than that of SCD in the general population. This may imply a low value of preparticipation screening of athletes in Denmark.

The prevalence and relevance of the Brugada-type electrocardiogram in the Danish general population: data from the Copenhagen City Heart Study.

AIMS The prevalence of the Brugada-type electrocardiogram (ECG) in the Danish population is not known. METHODS AND RESULTS Inhabitants from the city of Copenhagen, Denmark, have participated in a prospective study since 1976. Four cross-sectional surveys have been carried out. Follow-up was performed using public registers. At each examination, the participants had an ECG registered. ECGs, showing right bundle branch block (RBBB) were examined for a possible Brugada-type pattern. A total of 42,560 ECGs had been registered from 18,974 participants. 1,284 had been coded as RBBB. Among these ECGs, we found no ECGs showing type 1 Brugada pattern, and 14 showing type 2 or 3 pattern. The prevalence of the total number of ECGs with Brugada pattern was 7/10,000. None of the subjects with a Brugada-pattern ECG died suddenly during follow-up. CONCLUSION The Brugada-type ECG pattern is rare in the general Danish population. None of the subjects with a Brugada-type ECG died suddenly during a follow-up of 6-33 years.

Extracellular signal‐regulated kinases control expression of G protein‐coupled receptor kinase 2 (GRK2)

G protein‐coupled receptor kinase 2 (GRK2) phosphorylates G protein‐coupled receptors resulting in uncoupling from G proteins. Receptors modulate GRK2 expression, however the mechanistic basis for this effect is largely unknown. Here we report a novel mechanism by which receptors use the extracellular signal‐regulated kinase (ERK) cascade to regulate GRK2 cellular levels. ERK activation by receptor stimulation elevated endogenous GRK2 while antagonist treatment decreased cellular GRK2. Activating ERK by overexpressing constitutive active MEK‐1 or Ras elevated GRK2 protein levels while blocking ERK using PD98059 or dominant negative Ras abolished this effect. These data suggest ERK is a critical regulator of GRK2 levels.

Sudden unexpected death in infancy in Denmark

Abstract Background. Incidence of sudden unexpected death in infancy (SUDI) and sudden infant death syndrome (SIDS) differs among studies and non-autopsied cases are difficult to assess. Objectives. To investigate causes of sudden death in infancy in a nationwide setting. Validate the use of the ICD-10 code for SIDS (R95) in the Danish Cause of Death registry. Design. A retrospective analysis of all infant deaths (< 1 year of age) in Denmark in 2000–2006. All death certificates and autopsy reports were read. Results. We identified 192 SUDI cases (10% of total deaths, 0.42 per 1000 births) with autopsy performed in 87% of cases. In total, 49% of autopsied SUDI cases were defined as SIDS (5% of all deaths, 0.22 per 1000 births); Cardiac cause of death was denoted in 24% of cases. The Danish Cause of Death Registry misclassified 30% of SIDS cases. Conclusions. A large proportion of infant deaths are SUDI, and the majority of these are caused by cardiac disease or SIDS. Autopsy is not always performed and valuable information is subsequently lost. Cause of Death registry data is not accurate in describing SIDS.

Cascade screening in families with inherited cardiac diseases driven by cardiologists: feasibility and nationwide outcome in long QT syndrome

Objectives: We assessed the outcome of cascade screening of families with congenital long QT syndrome (LQTS) in Danish heart centers. Methods: Affected family members were identified through systematic family screening. Results: In total, 228 affected relatives were identified from 90 families. A disease-causing mutation useful for presymptomatic genetic testing was found in 82% of probands. Two-thirds of affected relatives fulfilled electrocardiographic criteria for the diagnosis, whereas diagnosis was based on genetic findings in only one-third. The majority of affected relatives were asymptomatic. Symptomatic relatives and probands most often presented with syncope, followed by aborted cardiac arrest and sudden cardiac death. A serious cardiac event (SCE, such as syncope, aborted cardiac arrest or cardiac arrest) was reported by 32% of affected relatives and 87% of probands (p < 0.0001). Fifty-two percent of affected relatives were on β-blockers and 11% had an implantable cardioverter defibrillator (ICD), as compared to 88 and 49% of probands (p < 0.0001). Appropriate ICD therapy was given to 13% of affected relatives and to 27% of probands (p = 0.1). Conclusions: Clinically driven cascade screening of Danish LQTS families identified 2-3 affected relatives per proband. Affected relatives had milder disease courses, but SCEs in a subset strongly support screening. Danish cardiologists have adopted cascade screening of LQTS families according to specific Danish guidelines.

A nationwide, retrospective analysis of symptoms, comorbidities, medical care and autopsy findings in cases of fatal pulmonary embolism in younger patients

Summary.  Objective: Our objective was to provide a comprehensive description of fatal pulmonary embolism (PE) in younger persons. Specifically, we recorded information on symptoms, comorbidity, medical contact, if this had been required, and subsequent autopsy findings. Methods: We reviewed all death certificates from persons aged 0–35 years who had died between 1 January 2000 and 31 December 2006, and retrospectively identified all cases of fatal PE. Additional information was retrieved from the National Patient Registry, autopsy reports, and clinical charts. Results: Sixty‐one cases of fatal PE were included; 38% of these were in males. The median age was 29 years. The predominant symptoms were dyspnea, syncope, leg pains, and chest pains. Sixty‐three per cent of patients reportedly experienced symptoms for days, weeks, or months. More than half of the patients had sought medical care, and at the time of medical evaluation the majority of the patients were not hemodynamically compromised. In 21% cases, the correct diagnosis was reached before death; however, in only 5% of cases was this accomplished before clinical deterioration. Furthermore, clinical history and subsequent postmortem examinations showed that approximately half of younger persons dying from PE were otherwise healthy, and in no case was occult cancer diagnosed. Conclusions: Our data show that a substantial proportion of younger victims of fatal PE had experienced symptoms for an extended period of time. Furthermore, the correct diagnosis remained elusive in the majority of cases, even though approximately half of the subjects had sought medical evaluation for symptoms that, in retrospect, were most likely caused by a venothrombotic event.

Mutations in Danish patients with long QT syndrome and the identification of a large founder family with p.F29L in KCNH2

BackgroundLong QT syndrome (LQTS) is a cardiac ion channelopathy which presents clinically with palpitations, syncope or sudden death. More than 700 LQTS-causing mutations have been identified in 13 genes, all of which encode proteins involved in the execution of the cardiac action potential. The most frequently affected genes, covering > 90% of cases, are KCNQ1, KCNH2 and SCN5A.MethodsWe describe 64 different mutations in 70 unrelated Danish families using a routine five-gene screen, comprising KCNQ1, KCNH2 and SCN5A as well as KCNE1 and KCNE2.ResultsTwenty-two mutations were found in KCNQ1, 28 in KCNH2, 9 in SCN5A, 3 in KCNE1 and 2 in KCNE2. Twenty-six of these have only been described in the Danish population and 18 are novel. One double heterozygote (1.4% of families) was found. A founder mutation, p.F29L in KCNH2, was identified in 5 “unrelated” families. Disease association, in 31.2% of cases, was based on the type of mutation identified (nonsense, insertion/deletion, frameshift or splice-site). Functional data was available for 22.7% of the missense mutations. None of the mutations were found in 364 Danish alleles and only three, all functionally characterised, were recorded in the Exome Variation Server, albeit at a frequency of < 1:1000.ConclusionThe genetic etiology of LQTS in Denmark is similar to that found in other populations. A large founder family with p.F29L in KCNH2 was identified. In 48.4% of the mutations disease causation was based on mutation type or functional analysis.

Cardiac magnetic resonance imaging after ventricular tachyarrhythmias increases diagnostic precision and reduces the need for family screening for inherited cardiac disease

AIMS Guidelines recommend evaluation of family members of sudden cardiac death victims. However, initiation of cascade screening in families with uncertain diagnoses is not cost-effective and may cause unnecessary concern. For these reasons, we set out to assess to what extent cardiac magnetic resonance imaging (CMR) would increase the diagnostic precision and thereby possibly change the indication for family screening in patients with ventricular tachyarrhythmias. METHODS AND RESULTS We retrospectively collected data from 79 patients hospitalized with aborted cardiac arrest (resuscitated from a cardiac arrest), ventricular tachycardia (VT), or syncope who underwent a CMR at the Copenhagen University Hospital, Rigshospitalet, Denmark. Besides CMR, the patients were evaluated with an electrocardiogram, echocardiogram (both 100%), coronary angiogram (CAG)/coronary computed tomography scan (CT-CAG) (81%), exercise stress test (47%), late potentials (54%), electrophysiological study (44%), pharmacological provocation (44%), and/or myocardial biopsy (16%). Family screening was indicated for 53 probands (67%) prior to CMR. After full workup, only 43 cases (54%) warranted evaluation of relatives (19% decrease, P = 0.034). The full evaluation changed whether family screening was indicated in 18 probands (14/18 moved to no indication for family screening). In the 18 where recommendations on family screening changed, CMR findings were the major driver for re-classification in 17 cases. CONCLUSION Cardiac magnetic resonance imaging re-defines the cardiac diagnoses in a significant proportion of cases and reduces the number of patients in whom family screening is warranted. Cardiac magnetic resonance imaging is highly relevant for optimal care and resource allocation when an inherited heart disease is the presumed cause of life-threatening arrhythmias.

Genetic variation in the inwardly rectifying K channel subunits KCNJ3 (GIRK1) and KCNJ5 (GIRK4) in patients with sinus node dysfunction.

Background: Sinus node dysfunction (SND) is a heterogeneous disorder of unknown etiology characterized by a variety of supraventricular arrhythmias with symptoms of syncope, palpitations, and dizziness. The mechanism underlying the abnormal rhythm is incompletely understood. Objective: Because vagal stimulation and acetylcholine (ACh) affect the function of pacemaker cells, we hypothesized that genetic variation in the genes encoding the ACh-activated K+ channels, the KACh channels, could be involved in the pathogenesis of SND. Methods and Results: We screened 184 patients listed in the pacemaker registry of the Copenhagen University Hospital aged <60 years at pacemaker implantation for SND in the period 1982–2005. Forty-three patients fulfilled the following inclusion criteria: documented sinus arrest, asystole, or extreme sinus bradycardia. The coding sequences of KCNJ3 and KCNJ5, encoding the main subunits of the KACh channels, were re-sequenced. We identified several known single nucleotide polymorphisms in KCNJ3 and KCNJ5, but no mutations in either of the genes. Conclusions: Genetic variation in KCNJ3 and KCNJ5 encoding the subunits of the KACh channels is apparently not involved in the pathogenesis of SND.