Clinical evaluation of unselected cardiac arrest survivors in a tertiary center over a 1-year period (the LAZARUZ study).

OBJECTIVES: When the cause of an aborted cardiac arrest is unclear the initiation of therapy, counseling and family screening is challenging. METHODS: We included 43 unselected, prospectively identified cardiac arrest survivors with or without a diagnosis. Family history for cardiac disease and supplemental electrocardiograms were evaluated for additional diagnostic information. RESULTS: 43 cardiac arrest survivors were included, 34 (79%) were male and the average age was 48years (range 23-64, SD 13.0). The most common etiologies identified in cardiac arrest survivors were ischemic heart disease (33%), cardiomyopathies (14%), miscellaneous (e.g. drug induced arrhythmias, coronary spasms) (12%) and channelopathies (5%). Family history of cardiac disease - even inheritable conditions - was not indicative of etiology in cardiac arrest survivors. Supplemental ECGs were abnormal in 10 of 43 patients; in the majority of these patients (7) no conclusive diagnosis was reached. CONCLUSIONS: In this study 16/43 (37%) of unselected, prospectively included cardiac arrest survivors remained without a diagnosis despite exhaustive investigations. We may extract additional diagnostic information from simple maneuvers during the recording of the electrocardiogram. We suggest that these ECG derived clues be investigated in future studies including genetic test results and data from relatives.

High Lipoprotein(a) May Explain One-Quarter of Clinical Familial Hypercholesterolemia Diagnoses in Danish Lipid Clinics.

CONTEXT: Cholesterol carried in lipoprotein(a) adds to measured low-density lipoprotein cholesterol (LDL-C) and may therefore drive some diagnoses of clinical familial hypercholesterolemia (FH). OBJECTIVE: We investigated plasma lipoprotein(a) in individuals referred to Danish lipid clinics and evaluated the effect of plasma lipoprotein(a) on a diagnosis of FH. METHODS: Individuals referred to 15 Danish lipid clinics who were suspected of having FH according to nationwide referral criteria were recruited between September 1, 2020 and November 30, 2021. All individuals were classified according to the Dutch Lipid Clinical Network criteria for FH before and after LDL-C was adjusted for 30% cholesterol content in lipoprotein(a). We calculated the fraction of individuals fulfilling a clinical diagnosis of FH partly due to elevated lipoprotein(a). RESULTS: We included a total of 1166 individuals for analysis, of whom 206 fulfilled a clinical diagnosis of FH. Median lipoprotein(a) was 15 mg/dL (29 nmol/L) in those referred and 28% had lipoprotein(a) greater than or equal to 50 mg/dL (105 nmol/L), while 2% had levels greater than or equal to 180 mg/dL (389 nmol/L). We found that in 27% (55/206) of those fulfilling a clinical diagnosis of FH, this was partly due to high lipoprotein(a). CONCLUSION: Elevated lipoprotein(a) was common in individuals referred to Danish lipid clinics and in one-quarter of individuals who fulfilled a clinical diagnosis of FH, this was partly due to elevated lipoprotein(a). These findings support the notion that the LPA gene should be considered an important causative gene in patients with clinical FH and further support the importance of measuring lipoprotein(a) when diagnosing FH as well as for stratification of cardiovascular risk.

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 ß-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.

Genetic testing increases the likelihood of a diagnosis of familial hypercholesterolaemia among people referred to lipid clinics: Danish national study.

BACKGROUND AND AIMS: It is unclear to what extent genetic testing improves the ability to diagnose familial hypercholesterolaemia (FH). We investigated the percentage with FH among individuals referred to Danish lipid clinics, and evaluated the impact of genetic testing for a diagnosis of FH. METHODS: From September 2020 through November 2021, all patients referred for possible FH to one of the 15 Danish lipid clinics were invited for study participation and >97% (n = 1488) accepted. The Dutch Lipid Clinical Network criteria were used to diagnose clinical FH. The decision of genetic testing for FH was based on local practice. RESULTS: A total of 1243 individuals were referred, of whom 25.9% were diagnosed with genetic and/or clinical FH. In individuals genetically tested (n = 705), 21.7% had probable or definite clinical FH before testing, a percentage that increased to 36.9% after genetic testing. In individuals with unlikely and possible FH before genetic testing, 24.4% and 19.0%, respectively, had a causative pathogenic variant. CONCLUSIONS: In a Danish nationwide study, genetic testing increased a diagnosis of FH from 22% to 37% in patients referred with hypercholesterolaemia suspected of having FH. Importantly, approximately 20% with unlikely or possible FH, who without genetic testing would not have been considered having FH (and family screening would not have been undertaken), had a pathogenic FH variant. We therefore recommend a more widespread use of genetic testing for evaluation of a possible FH diagnosis and potential cascade screening.

Low disease prevalence and inappropriate implantable cardioverter defibrillator shock rate in Brugada syndrome: a nationwide study.

AIMS: Brugada syndrome (BrS) is an inherited channelopathy that predisposes to malignant ventricular arrhythmias and thereby syncope and sudden cardiac death. Prior studies characterizing BrS patients have used highly selected referral populations from tertiary centres and prevalence estimates have been carried out using electrocardiogram (ECG) surveys only. We aimed to identify and characterize all diagnosed BrS patients in Denmark (population 5.4 million). METHODS AND RESULTS: Brugada syndrome patients were identified using several modalities including identification in all Danish tertiary referral centres, search in public health registries, contact to all cardiology departments in Denmark, and searching in a pedigree database for inherited heart disease used nationwide in Denmark. We identified 43 definite diagnosed BrS patients and 25 possible BrS patients, corresponding to a prevalence of 1.1 definite BrS cases per 100 000 inhabitants. Most definite BrS patients were men (86%) and the median age at diagnosis was 48 years. A total of 35 definite BrS patients (81%) had an implantable cardioverter defibrillator (ICD) implanted and of these 9 (26%) experienced appropriate shocks and 3 (8%) experienced inappropriate shocks during a median follow-up of 47 months. No patient died or experienced aborted sudden cardiac death during follow-up. CONCLUSIONS: We report the first nationwide study of BrS patients. We found a low incidence of diagnosed definite BrS compared with estimates from ECG surveys. Follow-up data show a lower rate of inappropriate therapies in ICD carriers than that reported in previous studies.

Longer retrieval distances to the automated external defibrillator reduces survival after out-of-hospital cardiac arrest.

AIMS: To evaluate and compare survival after out-of-hospital (OHCA), where an automated external defibrillator (AED) was used, in densely, moderately and thinly populated areas. Also, to evaluate the association between AED retrieval distance and survival after OHCA. METHODS: From 2014 to 2018, AEDs used during OHCA in the region of Southern Denmark were systematically collected. OHCAs were included if the OHCA address was known. OHCAs at nursing homes were excluded. To evaluate population density, a map with 1000 × 1000 meter grid cells was used with each cell color-graded according to the number of inhabitants. Densely, moderately and thinly populated areas were defined as ≥200 inhabitants, 20-199 inhabitants and 0-19 inhabitants per km2, respectively. Primary outcome was 30-day survival. RESULTS: A total of 423 cases of OHCA were included, of which 207 (49%) occurred in densely populated areas, while 78 (18%) and 138 (33%) occurred in moderately and thinly populated areas, respectively. AED retrieval distances were: densely populated 105 m (IQR 5-450), moderately populated 220 m (IQR 5-450) and thinly populated 350 m (IQR 5-1500) (P < 0.001). Thirty-day survival was 40%, 31% and 34%, respectively (P = 0.3). In a multivariable regression analysis, mortality increased with 10% per 100 m an AED was placed further away from the site of OHCA. CONCLUSION: Survival after OHCA, where an AED was used, did not seem to differ in thinly, moderately and densely populated areas. The length of the AED retrieval distance, however, was correlated with reduced survival after adjusting for other potentially explanatory variables.

Electrocardiographic Findings, Arrhythmias, and Left Ventricular Involvement in Familial ST-Depression Syndrome.

BACKGROUND: Familial ST-depression syndrome is an inherited disease characterized by persistent, nonischemic ST-deviations, and risk of arrhythmias and heart failure. We aimed at further characterizing the ECG, arrhythmias, and structural characteristics associated with this novel syndrome. METHODS: Retrospective analysis of data from consecutive families with familial ST-depression Syndrome in Denmark. ECG features, prevalence and type of arrhythmias, occurrence of systolic dysfunction, and medium-term outcome were analyzed. RESULTS: Forty affected individuals (43% men; mean age at diagnosis 49.1 years) from 14 apparently unrelated families with ≥2 affected members were included. Autosomal dominant inheritance was observed in all families. The ECG phenotype seemed to develop in prepuberty and the ST-deviations were persistent and most pronounced in leads V4/V5/II, respectively. Serial ECG analyses showed stable to slow progression of the ECG phenotype. Exercise accentuated the ST-deviations with a maximum difference between rest/stress (mean) of -117 µV in lead V5. During a mean follow-up of 9.3±7.1 years 5 (13%) patients developed sustained ventricular arrhythmias or (aborted) sudden cardiac death, 10 (25%) developed atrial fibrillation, 2 (5%) other supraventricular arrhythmias, and 10 (25%) were diagnosed with left ventricular ejection fraction ≤50%. The ventricular arrhythmias were polymorphic with relatively short-coupled premature ventricular contractions at onset (300-360 ms); no QT prolongation was observed. Seven patients had at least one catheter ablation; 5 for supraventricular arrhythmias and 2 for ventricular arrhythmias. Males experienced more arrhythmic end points than females (P<0.01). CONCLUSIONS: The familial ST-depression ECG phenotype is stable to slowly progressive after medium-term follow-up. Clinically, both supra- and ventricular arrhythmias are common; as are some degree of left ventricular systolic dysfunction. Familial ST-depression represent a novel inherited cause of polymorphic ventricular tachycardia.

Diagnostic Yield of Genetic Testing in Young Patients With Atrioventricular Block of Unknown Cause.

Background The cause of atrioventricular block (AVB) remains unknown in approximately half of young patients with the diagnosis. Although variants in several genes associated with cardiac conduction diseases have been identified, the contribution of genetic variants in younger patients with AVB is unknown. Methods and Results Using the Danish Pacemaker and Implantable Cardioverter Defibrillator (ICD) Registry, we identified all patients younger than 50 years receiving a pacemaker because of AVB in Denmark in the period from January 1, 1996 to December 31, 2015. From medical records, we identified patients with unknown cause of AVB at time of pacemaker implantation. These patients were invited to a genetic screening using a panel of 102 genes associated with inherited cardiac diseases. We identified 471 living patients with AVB of unknown cause, of whom 226 (48%) accepted participation. Median age at the time of pacemaker implantation was 39 years (interquartile range, 32-45 years), and 123 (54%) were men. We found pathogenic or likely pathogenic variants in genes associated with or possibly associated with AVB in 12 patients (5%). Most variants were found in the LMNA gene (n=5). LMNA variant carriers all had a family history of either AVB and/or sudden cardiac death. Conclusions In young patients with AVB of unknown cause, we found a possible genetic cause in 1 out of 20 participating patients. Variants in the LMNA gene were most common and associated with a family history of AVB and/or sudden cardiac death, suggesting that genetic testing should be a part of the diagnostic workup in these patients to stratify risk and screen family members.

Use and coverage of automated external defibrillators according to location in out-of-hospital cardiac arrest.

AIMS: To evaluate 1) the relative use of automated external defibrillators (AEDs) at different types of AED locations 2) the percentage of AEDs crossing location types during OHCA before use 3) the AED coverage distance at different types of AED locations, and 4) the 30-day-survival in different subgroups. METHODS: From 2014-2018, AEDs used by bystanders during out-of-hospital cardiac arrest (OHCA) in the Region of Southern Denmark were collected. Data regarding registered AEDs was retrieved from the national AED-network. The OHCA site and AED placement was categorized into; 1) Residential; 2) Public; 3) Nursing home, 4) Company/workplace; 5) Institution; 6) Health clinic and 7) Sports facility/recreational. To evaluate 30-day-survival, groups 4-7 were pooled into one Mixed group. RESULTS: In total 509 OHCAs were included. There was high relative usage of AEDs from public places, nursing homes, health clinics and sports facilities, and low relative usage from companies/workplaces, residential areas and institutions. Of AEDs used during residential OHCAs 39% were collected from public places. AEDs placed in residential areas and public places had a coverage of 575 m (IQR 130-1300) and 270 m (IQR5-550), respectively. Thirty-day- survival in public, residential and mixed groups were 49%, 14% and 67%, respectively. CONCLUSION: The relative use of AEDs from public places, nursing homes, sports facilities and health clinics was high, and AEDs used during OHCA in residential areas were most frequently collected from public places. AEDs placed in both residential areas and public places may have a wider coverage area than proposed in current literature.

Global positioning system alerted volunteer first responders arrive before emergency medical services in more than four out of five emergency calls.

AIM: To evaluate response rates for volunteer first responders (VFRs) activated by use of a smartphone GPS-tracking system and to compare response times of VFRs with those of emergency medical services (EMS). Furthermore, to evaluate 30-day-survival after out-of-hospital cardiac arrest (OHCA) on a rural island. METHODS: Since 2012 a GPS-tracking system has been used on a rural island to activate VFRs during all emergency calls requesting an EMS. When activated, three VFRs were recruited and given distinct roles, including collection of the nearest automatic external defibrillator (AED). We retrospectively investigated EMS response data from April 2012 to December 2017. These were matched with VFR response times from the GPS-tracking system. The 30-day survival in OHCA patients was also assessed. RESULTS: In 2266 of 2662 emergency calls (85%) at least one VFR arrived to the site before EMS. Median response times for VFRs (n = 2662) was 4:46 min:sec (IQR 3:16-6:52) compared with 10:13 min:sec (6:14-13:41) for EMS (p < 0.0001). A total of 17 OHCAs took place in public locations and 65 in residential areas. Thirty-day survival in these were 24% and 15%, respectively. CONCLUSION: Use of a smartphone GPS-tracking system to dispatch VFRs ensures that in more than four of five cases, a VFR arrives to the site before EMS. Response times for VFRs were also found to be lower than EMS response times. Finally, the 30-day survival of OHCA patients in a rural area, based on these results, surpass our expectations.

[Hypertriglyceridaemia-induced pancreatitis during pregnancy caused by a genetic defect].

This is a case report of a 35-year-old secundigravida woman with recurrent episodes of hypertriglyceridaemia-induced acute pancreatitis during pregnancy, which is a rare but serious complication in pregnancy. The woman was normal weight, and she was not known with any metabolic disorders, but she had idiopathic splenomegaly, which might be explained by the high triglyceride levels. Later genetic analysis revealed a lipoprotein lipase gene mutation known to cause hypertriglyceridaemia. This shows, that it is important to consider genetic aetiology in normal weight pregnant women with hypertriglyceridaemia and pancreatitis.

Nationwide experience of catecholaminergic polymorphic ventricular tachycardia caused by RyR2 mutations.

OBJECTIVE: The aim of this study was to characterise disease penetrance, course of disease and use of antiarrhythmic medication and implantable cardioverter-defibrillator (ICD) therapy in a Danish nationwide cohort of patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) due to mutations in the ryanodine receptor-2 (RyR2) gene. METHODS: The study population was identified through the national hereditary heart disease database (Progeny). The study population was divided into three groups: probands, symptomatic and asymptomatic relatives. RESULTS: We identified 23 symptomatic probands, 18 symptomatic and 10 asymptomatic relatives with a RyR2 mutation. Twenty (87%) probands and 10 (36%) relatives had severe presenting symptoms (sudden cardiac death (SCD), aborted SCD (ASCD) or syncope).As compared with symptomatic relatives, probands had lower age at onset of symptoms (16 years (IQR, 10-33) vs 43 years (IQR, 25-54), p<0.0001) and were more prone to fatal or near-fatal events (ASCD, SCD) (16vs5, p<0.0001). Twenty-eight patients had an ICD implanted, and eight experienced appropriate ICD therapy during follow-up (65 months (IQR, 43-175)). Electrical storm was seen in two of the 28 ICD treated patients (7%). No patients receiving treatment died during follow-up (57 months (IQR, 32-139)). Multifocal atrial tachycardia was the predominant symptom in five patients. CONCLUSIONS: In a national cohort of RyR2 mutation-positive CPVT patients, SCD, ASCD and syncope were presenting events in the majority of probands and also occurred in 36% of relatives identified through family screening. Probands were younger at disease onset and more prone to fatal or near-fatal events than relatives.

[Liquorice consumption may induce torsades de pointes ventricular tachycardia].

This case report describes an often forgotten cause of hypokalaemia resulting in electrocardiograpic changes in a 75-year-old man known with hypertension, atrial fibrillation and ischaemic heart disease. A detailed anamnesis, a prompt replacement of potassium and cessation of liquorice consumption resulted in a favourable outcome.

Newly detected abnormal glucose regulation and long-term prognosis after acute myocardial infarction: Comparison of an oral glucose tolerance test and glycosylated haemoglobin A1c.

BACKGROUND: An oral glucose tolerance test (OGTT) and/or glycosylated haemoglobin A1c (HbA1c) in patients with acute myocardial infarction (AMI) identify patients with increased mortality risk, but no comparison of the long-term prognostic values has yet been investigated. METHODS: This study was a prospective cohort enrolling patients with AMI between 2002 until 2008 and follow-up until 1st October, 2012. Patients without known diabetes mellitus (DM) underwent an OGTT. Seventy-nine patients with known DM did not have an OGTT performed. Primary endpoint was all-cause mortality. We included 548 patients with AMI, of whom 469 underwent a standardized OGTT and were stratified according to OGTT and HbA1c. RESULTS: During 9.8years of follow-up, 179 (33%) patients died. In patients having increased HbA1c ≥6.5%, a significantly increased mortality was observed (Hazard Ratio (HR) 1.60 [1.09-2.34]). However, when adjusting for known DM, no significance was detected. An OGTT did not show a significantly increased mortality, if used separately. A combined estimate showed a significantly increased mortality in patients categorized as newly diagnosed DM by OGTT and HbA1c<6.5% (HR 1.56 [95% CI 1.07-2.30]) compared to patients categorized as normal/impaired fasting glycaemia/impaired glucose tolerance by OGTT and HbA1c <6.5%. Approximately 50% of the patients with newly diagnosed DM by OGTT were only detected due to 2-hour post-load glucose values. CONCLUSION: An OGTT is recommended in AMI patients without known DM and HbA1c<6.5%. Patients categorized as newly diagnosed DM by OGTT although HbA1c <6.5% share the same high risk of mortality as patients with HbA1c≥6.5%.

[The genome and cardiology].

Several cardiac diseases are autosomal dominantly inherited. This includes cardiomyopathies, primary arrhythmias (channelopathies), dyslipidaemias, premature ischaemic heart diseases and diseases of the thoracic aorta. Sudden cardiac death in the young is also often due to one of the inherited cardiac diseases. Clinical and genetic cascade family screening of the relatives to patients with inherited cardiac diseases is now organized in a national network of centres of cardiology, sharing pedigrees, clinical and genetic information. This gives unique opportunities for offering focused prophylaxis in the group of high-risk relatives.

[Prevalence and prognostic significance of pathological glucose metabolism in acute myocardial infarction]. / Forekomst og prognostisk betydning af patologisk glukosemetabolisme ved akut myokardieinfarkt.

Individuals with diabetes are at increased risk of developing acute myocardial infarction (AMI) and recent investigations have shown that impaired glucose tolerance (IGT) contributes to a comparable increased risk of AMI. Studies in which oral glucose tolerance test (OGTT) has been used to diagnose IGT/diabetes report a prevalence of unrecognized pathological glucose metabolism in 54-66% of admitted patients. Newly detected diabetes by OGTT, but not IGT, also correlates strongly with prognosis after AMI even after adjusting for traditional risk factors.

[Prevalence of glucometabolic abnormalities in connection with myocardial infarction in a Danish coronary care unit]. / Forekomsten af patologisk glukosemetabolisme ved akut myokardieinfarkt på et dansk koronarafsnit.

BACKGROUND: The prevalence of previously undiscovered glucometabolic abnormalities such as diabetes and impaired glucose tolerance (IGT) has been shown to be high among selected groups with myocardial infarction. The aim of this study was to establish the prevalence of known diabetes and undiagnosed glucometabolic abnormalities in an unselected population with myocardial infarction (MI) at admission and after 3 months by use of oral glucose tolerance testing (OGTT). MATERIALS AND METHODS: During an 18-month period patients consecutively admitted with acute MI in a Danish coronary care unit were included. Out of the 218 patients included, 44 had known diabetes. Using the results of OGTT and fasting venous plasma glucose measures, the remaining 174 patients were classified in glucometabolic categories. 80 out of 111 invited patients were classified by OGTT after 3 months. RESULTS: 71% of the cohort had abnormal glucose metabolism, 29% IGT, 22% newly detected diabetes and 20% established diabetes. There were no significant differences in body mass index, blood pressure, cholesterol, HDL, LDL or triglycerides in the groups without known diabetes. Patients with abnormal glucose metabolism were older than their normal glucose tolerance counterparts. There was a trend towards normalization of glucometabolism after 3 months. CONCLUSION: The prevalence of abnormal glucose metabolism in MI-populations is high. Among individuals with presumably normal glucose tolerance 37% were classified as IGT and 27% as diabetics. Association between common risk factors for both abnormal glucose regulation and MI could not explain these findings. OGTT is probably required for correct diagnosis of abnormal glucose regulation in patients with MI.