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Background Electrocardiographic abnormalities are common in arrhythmogenic right ventricular cardiomyopathy and are included in the 2010 Task Force Criteria. Their time course, however, remains uncertain. In this retrospective observational study, we aimed to assess the long‐term evolution of electrocardiographic characteristics and their relation to ventricular arrhythmias. Methods and Results Three hundred fifty‐three patients with arrhythmogenic right ventricular cardiomyopathy as per the 2010 Task Force Criteria with 6871 automatically processed 12‐lead digital ECGs were included. The relationship between the electrocardiographic parameters and the risk of ventricular arrhythmias was assessed at 10 years from the first ECG. Electrocardiographic parameters were compared between the first contact ECG, the ECG at diagnosis, and the most recent ECG. Median time between the first and the latest ECG was 6 [interquartile range, 1–14] years. Reductions of QRS voltage, R‐ and T‐wave amplitudes between the first, diagnostic, and the latest ECGs were observed across precordial and extremity leads. Mean QRS duration increased from 96 to 102 ms (P

Background Individuals with both atrial fibrillation (AF) and myocardial infarction (MI) have higher mortality compared with individuals with only 1 condition. Whether mortality differs according to the temporal order of AF and MI is unclear. Methods and Results We included participants from the FHS (Framingham Heart Study) from 1960 and onwards. We assessed the hazard ratio (HR) of new‐onset AF and MI, and mortality according to MI and AF status (prevalent and interim) using multivariable‐adjusted Cox proportional hazards models. Interim diseases were modeled as time‐varying variables. For the analysis of new‐onset AF, 10 923 participants (55% women; mean±SD age, 54±8 years) were included. For new‐onset MI, 10 804 participants (55% women; mean±SD age, 54±8 years) were included. Compared with no MI, the hazard of new‐onset AF was higher in participants with prevalent (HR, 1.60 [95% CI, 1.32–1.94]) and interim MI (HR, 3.96 [95% CI, 3.18–4.91]). Both ST‐segment–elevation MI and non–ST‐segment–elevation MI were associated with new‐onset AF. Interim AF, not prevalent AF, was associated with higher hazard rate of new‐onset MI (HR, 2.21 [95% CI, 1.67–2.92]). Interim AF was associated with both ST‐segment–elevation MI and non–ST‐segment–elevation MI. Mortality was significantly greater among participants with AF and MI compared with participants with 1 of the 2, regardless of temporal order. Conclusions We report a bidirectional association between AF and MI, which was observed for both non–ST‐segment–elevation MI and ST‐segment–elevation MI. Participants with both AF and MI had considerably higher mortality compared with participants with only 1 of the 2 conditions, regardless of order.

In the past 20 years, genetic variants in SCN5A encoding the cardiac voltage-gated sodium channel Nav1.5 have been linked to a range of inherited cardiac arrhythmias: variants resulting in loss-of-function of Nav1.5 have been linked to sick sinus syndrome, atrial stand still, atrial fibrillation (AF) impaired pulse generation, progressive and non-progressive conduction defects, the Brugada Syndrome (BrS), and sudden cardiac death. SCN5A variants causing increased sodium current during the plateau phase of the cardiac action potential is associated with Long QT Syndrome type 3 (LQTS3), Torsade de Pointes ventricular tachycardia and SCD. Recently, gain-of-function variants have been linked to complex electrical phenotypes, such as the Multifocal Ectopic Purkinje-related Premature Contractions (MEPPC) syndrome. MEPPC is a rare condition characterized by a high burden of premature atrial contractions (PACs) and/or premature ventricular contractions (PVCs) often accompanied by dilated cardiomyopathy (DCM). MEPPC is inherited in an autosomal dominant fashion with an almost complete penetrance. The onset is often in childhood. The link between SCN5A variants, MEPPC and DCM is currently not well understood, but amino acid substitutions resulting in gain-of-function of Nav1.5 or introduction of gating pore currents potentially play an important role. DCM patients with a MEPPC phenotype respond relatively poorly to standard heart failure medical therapy and catheter ablation as the PVCs originate from all parts of the fascicular Purkinje fiber network. Class 1c sodium channel inhibitors, notably flecainide, have a remarkable positive effect on the ectopic burden and the associated cardiomyopathy. This highlights the importance of genetic screening of DCM patients to identify patients with SCN5A variants associated with MEPPC. Here we review the MEPPC phenotype, MEPPC-SCN5A associated variants, and pathogenesis as well as treatment options.

Abstract Background Heterozygous familial hypercholesterolemia (HeFH) due to low-density lipoprotein receptor (LDLR) mutations predisposes patients to highly elevated levels of cholesterol, and patients are at increased risk of adverse cardiovascular events and other morbidities. Whether the LDLR mutation and high cholesterol levels affect the risk of cancer remains unknown. The purpose of the present study was to assess the long-term cancer risk in HeFH relatives. Methods Study participants were identified by cascade screening during 1992–1994. A comparison cohort was matched 10:1 to the relatives from the Danish general population based on birth year, gender and address. All participants were followed until a cancer diagnosis, migration, death, or end of follow-up as of December 31, 2019. The primary endpoint was any incident cancer diagnosis. Results In total, we included 221 relatives with a median age of 37 years (interquartile range: 27–53 years). A total of 117 (53%) of the relatives carried a LDLR gene mutation. The crude hazard ratio of our primary endpoint did not reveal any differences in cancer incidence in mutation-carrying relatives compared with the general population cohort (1.18; 95% CI, 0.81–1.71). Nonmutation-carrying relatives however had a lower cancer incidence than the general population (0.45: 95% CI, 0.26–0.80). Thus, the risk among mutation-carrying HeFH relatives compared with nonmutation-carrying HeFH relatives was increased (HR: 2.39; 95% CI, 1.24–4.61). Conclusion In Denmark, LDLR mutation-carrying HeFH relatives did not have a different cancer risk than the general population. In contrast, nonmutation-carrying relatives had a lower risk of cancer.

Objective To examine workforce attachment among patients with congenital long QT syndrome (cLQTS) following diagnosis and identify factors associated with workforce attachment.Methods and results In this nationwide cohort study, all patients diagnosed with cLQTS in Denmark between 1996 and 2016 aged 18–60 years at diagnosis were identified using nationwide registries. Patients attached to the workforce at diagnosis were included. Attachment to the workforce 1 year after cLQTS diagnosis was examined and compared with a background population matched 1:4 on age, sex and employment status. Multiple logistic regression was performed to identify factors associated with 1-year workforce detachment among patients with cLQTS. 298 patients fulfilled the inclusion criteria. Six months after cLQTS diagnosis, 90.9% of patients with cLQTS were attached to the workforce compared with 95.0% in the background population (p=0.006 for difference). One year after diagnosis, 93.3% of patients with cLQTS were attached to the workforce compared with 93.8% in the background population (p=0.26). Among patients with cLQTS, a severe cLQTS disease manifestation was associated with workforce detachment 1 year after diagnosis (compared with asymptomatic patients; aborted cardiac arrest OR 20.4 (95% CI, 1.7 to 249.9); ventricular tachycardia/syncope OR 10.9 (95% CI, 1.1 to 110.5)). No other associated factors were identified.Conclusions More than 90% of patients with cLQTS remained attached to the workforce 1 year after diagnosis, which was similar to a matched background population. Patients with a severe cLQTS disease manifestation were less likely to be attached to the workforce 1 year after diagnosis.

Background: Mortality following out-of-hospital cardiac arrest (OHCA) is high, and studies on return to work show varying results. It remains uncertain whether mortality and return to work differs between patients with ischaemic heart disease (IHD) and non-ischaemic heart disease (non-IHD). Aim: To investigate all-cause mortality, cardiac death, and return to work among patients admitted after OHCA with IHD and non-IHD. Methods: We included 234 consecutive patients admitted to Aarhus University Hospital with OHCA, who were not declared dead in the prehospital setting or upon arrival. Patients were divided into an IHD and a non-IHD group based on history of myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, or signs of obstructive IHD on the admission coronary angiography. Outcome in terms of all-cause mortality, cardiac death, and return to work was evaluated. Results: All-cause mortality after one month, one year, and five years was 41.9%, 49.1%, and 54.3%. There was no difference in all-cause mortality or cardiac death between IHD and non-IHD patients (all-cause mortality: adjusted HR 0.78, 95% CI, 0.53–1.14; P = 0.19) and cardiac death: adjusted HR 0.93, 95% CI, 0.60–1.43; P = 0.73). Among patients working prior to OHCA the cumulative incidence of patients returning to work was 62.3% after five years with no statistically significant difference between groups. Conclusion: A favourable outcome was observed in patients admitted after OHCA with a non-significant trend toward a higher mortality in non-IHD patients, possibly indicating that IHD is a favourable cause of cardiac arrest.

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.

AimsPersistent cardiac symptoms are an increasingly reported phenomenon following COVID-19. However, the underlying cause of cardiac symptoms is unknown. This study aimed to identify the underlying causes, if any, of these symptoms 1 year following acute COVID-19 infection.Methods and Results22 individuals with persistent cardiac symptoms were prospectively investigated using echocardiography, cardiovascular magnetic resonance (CMR), 6-min walking test, cardio-pulmonary exercise testing and electrocardiography. A median of 382 days (IQR 368, 442) passed between diagnosis of COVID-19 and investigation. As a cohort their echocardiography, CMR, 6-min walking test and exercise testing results were within the normal ranges. There were no differences in left ventricular ejection fraction (61.45 ± 6.59 %), global longitudinal strain (19.80 ± 3.12 %) or tricuspid annular plane systolic excursion (24.96 ± 5.55 mm) as measured by echocardiography compared to a healthy control group. VO2 max (2045.00 ± 658.40 ml/min), % expected VO2 max (114.80 ± 23.08 %) and 6-minute distance walked (608.90 ± 54.51 m) exceeded that expected for the patient cohort, whilst Troponin I (5.59 ± 6.59 ng/l) and Nt-proBNP (88.18 ± 54.27 ng/l) were normal.ConclusionAmong a cohort of 22 patients with self-reported persistent cardiac symptoms, we identified no underlying cardiac disease or reduced cardiopulmonary fitness 1 year following COVID-19.

Abstract Introduction The risk of cardiovascular death is increased in patients with eating disorders (ED), but the background for this is unknown. Early repolarization pattern (ERP) on the electrocardiogram (ECG) has been associated with increased risk of sudden cardiac death. Methods We investigated the prevalence of ERP in 233 female patients with anorexia nervosa (AN) and bulimia nervosa (BN) (age 18–35 years) compared with 123 healthy female controls. Results Early repolarization pattern was present in 52 (22%) of ED patients (16 (15%) AN patients and 36 (29%) BN patients) and 17 (14%) of healthy controls. When adjusting for age, BMI, heart rate, use of selective serotonin reuptake inhibitors (SSRI), and potassium level, the odds ratio (OR) for ERP was 2.1 (95% CI 1.1–4.2, p = .03). There was an increased prevalence of inferolateral ERP in patients with ED compared with healthy controls (OR = 4.3, 95% CI 1.7–11.3, p = .003) as well as ERP with a downward/horizontal sloping ST segment (OR = 3.1, 95% CI 1.3–7.6, p = .01). Additionally, J‐point elevation >0.2 mV was more prevalent in patients with ED (OR = 3.3, 95% CI 1.1–9.7, p = .03). Conclusion The prevalence of ERP was increased in patients with ED compared with healthy controls. This finding may provide a possible explanation for the increased cardiovascular mortality in ED patients.

Abstract It is important to consider calcium and parathyroid hormone levels in patients with recurrent VT/VF without any obvious cause of arrhythmia. In similar cases to gain rhythm control using isoprenaline and do comprehensive molecular‐genetic. Diagnosis and surgery in case of parathyroid adenoma may be needed to obtain definite arrhythmia control.

Background Polygenic risk scores (PRSs) based on risk variants from genome‐wide association studies predict coronary artery disease (CAD) risk. However, it is unknown whether the PRS is associated with specific CAD characteristics. Methods and Results We consecutively included 1645 patients with suspected stable CAD undergoing coronary computed tomography angiography. A multilocus PRS was calculated as the weighted sum of CAD risk variants. Plaques were evaluated using an 18‐segment model and characterized by stenosis severity and composition (soft [0%‐19% calcified], mixed‐soft [20%‐49% calcified], mixed‐calcified [50%‐79% calcified], or calcified [≥80% calcified]). Coronary artery calcium score and segment stenosis score were used to characterize plaque burden. For each standard deviation increase in the PRS, coronary artery calcium score increased by 78% (P=4.1e‐26) and segment stenosis score increased by 16% (P=2.4e‐29) in the fully adjusted model. The PRS was associated with a higher prevalence of obstructive plaques (odds ratio [OR]: 1.78, P=5.6e‐16), calcified (OR: 1.69, P=6.5e‐17), mixed‐calcified (OR: 1.67, P=7.3e‐9), mixed‐soft (OR: 1.45, P=1.6e‐6), and soft plaques (OR: 1.49, P=2.5e‐6), and a higher prevalence of plaque in each coronary vessel (all P0.05). Conclusions Our results suggest that polygenic risk based on large genome‐wide association studies increases CAD risk through an increased burden of coronary atherosclerosis rather than promoting specific plaque features. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT02264717.

BackgroundHeterozygous familial hypercholesterolemia increases the risk of adverse cardiovascular events. Whether affected relatives of probands are at increased risk remains unknown. We aimed to evaluate the long‐term cardiovascular risk in heterozygous familial hypercholesterolemia relatives with a low‐density lipoprotein receptor (LDLR) mutation who were all recommended statin therapy. Methods and ResultsParticipants were identified by cascade screening at Aarhus University Hospital during 1992–1994. A comparison cohort from the Danish general population was matched 10:1 to relatives by birth year and sex. Using medical registries, participants were followed until the event of interest, migration, death, or end of follow‐up on December 31, 2014. The primary end point was all‐cause mortality and major adverse cardiovascular events comprising myocardial infarction, ischemic stroke, transient ischemic attack, peripheral artery disease, and coronary revascularization. We included 220 relatives. Median age was 37 years (interquartile range: 27–52 years) of which 118 (54%) had an LDLR mutation. By 2004, when prescription data became available, 89% of mutation‐carrying participants were taking statins during their follow‐up period. Despite frequent use of lipid‐lowering medication, the adjusted hazard ratio of the primary end point was 1.65 (95% confidence interval, 1.17–2.33) in mutation‐carrying relatives compared with the general population cohort. The risk in non–mutation‐carrying relatives was not different from that of the general population cohort (adjusted hazard ratio: 0.85; 95% confidence interval, 0.56–1.29). Comparing mutation‐carrying relatives with non–mutation‐carrying relatives, the adjusted hazard ratio was 1.94 (95% confidence interval, 1.14–3.31). Results were driven by nonfatal events. ConclusionHeterozygous familial hypercholesterolemia relatives with an LDLR mutation had an increased long‐term risk of adverse cardiovascular events.

Genetic constitution and inflammation both contribute to development of coronary artery disease (CAD). Several CAD-associated single-nucleotide polymorphisms (SNPs) have recently been identified, but their functions are largely unknown. We investigated the associations between CAD-associated SNPs and five CAD-related inflammatory biomarkers.We genotyped 45 CAD-associated SNPs in 701 stable CAD patients in whom levels of high-sensitivity C-reactive protein (hsRCP), interleukin-6, calprotectin, fibrinogen and complement component 3 levels had previously been measured. A genetic risk score was calculated to assess the combined risk associated with all the genetic variants. A multiple linear regression model was used to assess associations between the genetic risk score, single SNPs, and the five inflammatory biomarkers.The minor allele (G) (CAD risk allele) of rs2075650 (TOMM40/APOE) was associated with lower levels of high-sensitivity C-reactive protein (effect per risk allele: -0.37 mg/l [95%CI -0.56 to -0.18 mg/l]). The inflammatory markers tested showed no association with the remaining 44 SNPs or with the genetic risk score.In stable CAD patients, the risk allele of a common CAD-associated marker at the TOMM40/APOE locus was associated with lower hsCRP levels. No other genetic variants or the combined effect of all variants were associated with the five inflammatory biomarkers.

Brugada syndrome (BrS) is a primary electrical heart disease, which can lead to sudden cardiac death. In older patients with BrS, the disease may coexist with ischaemic heart disease (IHD) and recent studies support a synergistic proarrhythmic effect of the two disease entities. We report a case that illustrates this. The index patient was a middle-aged patient with BrS traits, IHD, and aborted sudden cardiac death. Mutation analysis discovered a novel mutation P468L in the NaV1.5 sodium channel. Surprisingly, voltage-clamp experiments on the wild-type and mutant NaV1.5 channels expressed in HEK cells revealed no functional effect of the mutation. In a patient like ours, the distinction between IHD and BrS as the cause of an aborted sudden cardiac death is hard to establish and mounting evidence shows that coexistence of the two may have a synergistic proarrhythmic effect.