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.

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.

Protocol for EXICODE: the EXIstential health COhort DEnmark-a register and survey study of adult Danes.

INTRODUCTION: We established the EXIstential health COhort DEnmark (EXICODE) to examine how existential and spiritual needs, practices and orientations in a secular culture are linked to health outcomes, illness trajectory and overall cost of care in patients. Substantial literature demonstrates that existential and spiritual well-being has positive effects on health. While people turn to existential and spiritual orientations and practices during ageing, struggle with illness and approaching death, patients with severe illnesses like, for example, cancer similarly experience existential and spiritual needs. These needs are often unmet in secular societies leading to spiritual pain, unnecessary suffering, worse quality of life and higher medical costs of care. METHODS AND ANALYSIS: EXICODE is a national cohort comprising a 10% random sample of the adult Danish population with individual-level register and survey data. Specific patient subgroups are oversampled to ensure diseased respondents. The questionnaire used in the survey consists of a collection of validated instruments on existential and spiritual constructs suited for secular culture as well as some ad hoc questions compiled in the comprehensive EXICODE Questionnaire. ETHICS AND DISSEMINATION: The project is registered for legal and GDPR concerns by the University of Southern Denmark, journal number: 10.367. Ethical approval was not required by Danish law since EXICODE collects only interview, survey and register data, but due to institutional best-practice policy an ethical evaluation and approval were nevertheless obtained from the University of Southern Denmark Research Ethics Committee (institutional review board), journal number: 20/39546. The project follows The Danish Code of Conduct for Research Integrity and is carried out in accordance with the Helsinki Declaration. Results will be disseminated widely through publications in peer-reviewed scientific journals, international conferences, patient societies as well as mass and social media.

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.

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.

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.

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.

Post-Hypoxic Myoclonus Status following Out-of-Hospital Cardiac Arrest-Does It still Predict a Poor Outcome? A Retrospective Study.

In patients with out-of-hospital cardiac arrest (OHCA), the initial prehospital treatment and transfer of patients directly to intervention clinics-bypassing smaller hospitals-have improved outcomes in recent years. Despite the improved treatment strategies, some patients develop myoclonic status following OHCA, and this phenomenon is usually considered an indicator of poor outcome. With this study, we wanted to challenge this perception. The regional prehospital database in Odense in the Region of Southern Denmark was searched for patients with OHCA from the period of 2011-2016. All 900 patients presenting with a diagnosis of OHCA were included in the study. Patients surviving to the hospital and presenting with myoclonic status were followed for up to one year. Only 2 out of 38 patients with myoclonic status and status epilepticus verified by an EEG survived more than one year. Eleven out of 36 patients with myoclonic status but without status epilepticus survived for more than one year. We found no evidence that myoclonic status is an unmistakable sign of poor outcome when not associated with EEG-verified status epilepticus. The conclusion for clinicians involved in post-resuscitation care is that myoclonic status is uncomfortable to witness but does not necessarily indicate that further treatment is futile.

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.

The Danish in-hospital cardiac arrest registry (DANARREST).

Aim of database: The aim of DANARREST is to collect data on processes of care and outcomes for patients with in-hospital cardiac arrest in Denmark, and thereby facilitate and monitor quality and quality improvement initiatives. Study population: In-hospital cardiac arrest patients with a clinical indication for cardiopulmonary resuscitation in Denmark. Main variables: DANARREST includes a number of descriptive variables as well as seven quality of care indicators; four related to processes of care and three related to clinical outcomes. The four process measures are related to whether the cardiac arrest was witnessed, whether the cardiac arrest was ECG-monitored, the timing of cardiopulmonary resuscitation, and the timing of the first rhythm analysis. The three outcomes measures include return of spontaneous circulation, 30-day survival, and 1-year survival. Database status: DANARREST started in 2013, and the coverage has increased steadily since. As of 2017, 95% of relevant hospitals are reporting data with an estimated coverage rate of approximately 80%. Conclusion: DANARREST is a relatively new national registry of in-hospital cardiac arrests in Denmark, with a high coverage rate. The registry provides an opportunity to monitor and improve quality of care for patients with in-hospital cardiac arrest.

[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.

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.

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.

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

BACKGROUND: Long 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. METHODS: We 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. RESULTS: Twenty-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. CONCLUSION: The 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.

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.