Bidirectional Association Between Atrial Fibrillation and Myocardial Infarction, and Relation to Mortality in the Framingham Heart Study.

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.

Five-year changes in weight and risk of atrial fibrillation in the Danish Diet, Cancer, and Health Cohort.

AIMS: Obesity is a major risk factor for atrial fibrillation (AF). Compared with stable weight, gaining weight was associated with a higher risk of incident AF in observational studies. The results, however, are conflicting regarding weight loss and risk of AF. This study aimed to assess the association between 5-year weight changes and risk of incident AF. METHODS AND RESULTS: The study was based on participants from the Danish Diet, Cancer, and Health Cohort. Body mass index (BMI) was assessed at a baseline examination and at a second examination 5 years later. Diagnoses of AF and co-morbidities were retrieved from the Danish National Patient Registry. In total, 43 758 participants without prior AF were included. The median age was 61 years and 54% were female. During a median follow-up of 15.7 years, 5312 individuals had incident AF (incidence rate 8.6/1000 person-years). Compared with stable weight, weight gain between 2.5 and 5 BMI units (kg/m2) was associated with a higher risk of AF [hazard ratio (HR) 1.24, 95% confidence interval (CI) 1.09-1.41]. Weight gain of 5 or more BMI units (kg/m2) was associated with a HR of 1.95 (95% CI 1.48-2.56) of incident AF. However, there was no statistically significant association between weight loss and risk of AF. CONCLUSION: Five-year weight gain was associated with greater risk of AF compared with stable weight in the Danish Diet, Cancer, and Health Cohort. There was no statistically significant association between weight loss and risk of AF.

We sought to understand the association between 5-year changes in weight and the future risk of atrial fibrillation, a common heart rhythm disturbance. Overweight, obesity, and underweight were associated with a higher risk of atrial fibrillation compared with normal weight.Gaining weight over a period of 5 years was associated with a higher risk of atrial fibrillation compared with maintaining a stable weight.

Interaction of genetic risk and lifestyle on the incidence of atrial fibrillation.

BACKGROUND: The relationship between combined genetic predisposition and lifestyle and the risk of incident atrial fibrillation (AF) is unclear. Therefore, we aimed to assess a possible interaction between lifestyle and genetics on AF risk. METHODS: We included AF cases and a randomly drawn subcohort of 4040 participants from the Danish Diet, Cancer and Health cohort. Lifestyle risk factors were assessed, a score was calculated, and participants were categorised as having a poor, intermediate, or ideal lifestyle. We calculated a genetic risk score comprising 142 variants, and categorised participants into low (quintile 1), intermediate (quintiles 2-4) or high (quintile 5) genetic risk of AF. RESULTS: 3094 AF cases occurred during a median follow-up of 12.9 years. Regardless of genetic risk, incidence rates per 1000 person-years were gradually higher with worse lifestyle. For participants with high genetic risk, the incidence rates of AF per 1000 person-years were 5.0 (95% CI 3.4 to 7.3) among individuals with ideal lifestyle, 6.6 (95% CI 5.4 to 8.1) among those with intermediate lifestyle and 10.4 (95% CI 9.2 to 11.8) among participants with poor lifestyle. On an additive scale, there was a positive statistically significant interaction between genetic risk and lifestyle (relative excess risk due to interaction=0.86, 95% CI 0.68 to 1.03, p<0.001). CONCLUSIONS: The rates of AF increased gradually with worse lifestyle within each category of genetic risk. We found a positive interaction on an additive scale between genetic risk and lifestyle, suggesting that risk factor modification is especially important in individuals with a high genetic risk of AF.

The bidirectional association between atrial fibrillation and myocardial infarction.

Atrial fibrillation (AF) is associated with an increased risk of myocardial infarction (MI) and vice versa. This bidirectional association relies on shared risk factors as well as on several direct and indirect mechanisms, including inflammation, atrial ischaemia, left ventricular remodelling, myocardial oxygen supply-demand mismatch and coronary artery embolism, through which one condition can predispose to the other. Patients with both AF and MI are at greater risk of stroke, heart failure and death than patients with only one of the conditions. In this Review, we describe the bidirectional association between AF and MI. We discuss the pathogenic basis of this bidirectional relationship, describe the risk of adverse outcomes when the two conditions coexist, and review current data and guidelines on the prevention and management of both conditions. We also identify important gaps in the literature and propose directions for future research on the bidirectional association between AF and MI. The Review also features a summary of methodological approaches for the study of bidirectional associations in population-based studies.

Five-year changes in alcohol intake and risk of atrial fibrillation: a Danish cohort study.

AIMS: Alcohol intake is a well-established risk factor for atrial fibrillation (AF). However, evidence on the effects of changes in alcohol intake to primary AF prevention is sparse. The aim of this study was to examine the association between 5-year changes in alcohol intake and the risk of incident AF. METHODS AND RESULTS: This study was based on the Danish cohort study Diet, Cancer and Health. Lifestyle factors were assessed using questionnaires at a recruitment research examination and a second examination 5 years later. Diagnoses of AF and comorbidities were retrieved from the Danish National Patient Registry. 43 758 participants without prior AF were included. The median age was 61 (25th-75th percentile 58-66) years and 54% were female. Over a median follow-up time of 15.7 years, 5312 participants had incident AF (incidence rate 8.6/1000 person-years). Compared with stable intake, increases in alcohol intake to ≥21 drinks/week from ≤6.9 drinks/week (HR: 1.38, 95% CI: 1.09-1.72) or 14-20.9 drinks/week (HR: 1.27, 95% CI: 1.01-1.59) at baseline were associated with a higher risk of AF. In contrast, we did not observe a statistically significant association between reductions in alcohol intake and the risk of AF. CONCLUSION: A 5-year increase in alcohol intake was associated with a greater risk of AF compared with a stable low/moderate intake.

Outcome after out-of-hospital cardiac arrest in patients with ischaemic and non-ischaemic heart disease: A Danish tertiary-center cohort study.

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.

Arrhythmic risk prediction in arrhythmogenic right ventricular cardiomyopathy: external validation of the arrhythmogenic right ventricular cardiomyopathy risk calculator.

AIMS: Arrhythmogenic right ventricular cardiomyopathy (ARVC) causes ventricular arrhythmias (VAs) and sudden cardiac death (SCD). In 2019, a risk prediction model that estimates the 5-year risk of incident VAs in ARVC was developed (ARVCrisk.com). This study aimed to externally validate this prediction model in a large international multicentre cohort and to compare its performance with the risk factor approach recommended for implantable cardioverter-defibrillator (ICD) use by published guidelines and expert consensus. METHODS AND RESULTS: In a retrospective cohort of 429 individuals from 29 centres in North America and Europe, 103 (24%) experienced sustained VA during a median follow-up of 5.02 (2.05-7.90) years following diagnosis of ARVC. External validation yielded good discrimination [C-index of 0.70 (95% confidence interval-CI 0.65-0.75)] and calibration slope of 1.01 (95% CI 0.99-1.03). Compared with the three published consensus-based decision algorithms for ICD use in ARVC (Heart Rhythm Society consensus on arrhythmogenic cardiomyopathy, International Task Force consensus statement on the treatment of ARVC, and American Heart Association guidelines for VA and SCD), the risk calculator performed better with a superior net clinical benefit below risk threshold of 35%. CONCLUSION: Using a large independent cohort of patients, this study shows that the ARVC risk model provides good prognostic information and outperforms other published decision algorithms for ICD use. These findings support the use of the model to facilitate shared decision making regarding ICD implantation in the primary prevention of SCD in ARVC.

The G213D variant in Nav1.5 alters sodium current and causes an arrhythmogenic phenotype resulting in a multifocal ectopic Purkinje-related premature contraction phenotype in human-induced pluripotent stem cell-derived cardiomyocytes.

AIMS: Variants in SCN5A encoding Nav1.5 are associated with cardiac arrhythmias. We aimed to determine the mechanism by which c.638G>A in SCNA5 resulting in p.Gly213Asp (G213D) in Nav1.5 altered Na+ channel function and how flecainide corrected the defect in a family with multifocal ectopic Purkinje-related premature contractions (MEPPC)-like syndrome. METHODS AND RESULTS: Five patients carrying the G213D variant were treated with flecainide. Gating pore currents were evaluated in Xenopus laevis oocytes. The 638G>A SCN5A variant was introduced to human-induced pluripotent stem cell (hiPSC) by CRISPR-Cas9 gene editing and subsequently differentiated to cardiomyocytes (hiPSC-CM). Action potentials and sodium currents were measured in the absence and presence of flecainide. Ca2+ transients were measured by confocal microscopy. The five patients exhibited premature atrial and ventricular contractions which were suppressed by flecainide treatment. G213D induced gating pore current at potentials negative to -50 mV. Voltage-clamp analysis in hiPSC-CM revealed the activation threshold of INa was shifted in the hyperpolarizing direction resulting in a larger INa window current. The G213D hiPSC-CMs had faster beating rates compared with wild-type and frequently showed Ca2+ waves and alternans. Flecainide applied to G213D hiPSC-CMs decreased window current by shifting the steady-state inactivation curve and slowed the beating rate. CONCLUSION: The G213D variant in Nav1.5 induced gating pore currents and increased window current. The changes in INa resulted in a faster beating rate and Ca2+ transient dysfunction. Flecainide decreased window current and inhibited INa, which is likely responsible for the therapeutic effectiveness of flecainide in MEPPC patients carrying the G213D variant.

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.

Genotype-phenotype correlation in arrhythmogenic right ventricular cardiomyopathy-risk of arrhythmias and heart failure.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is predominantly caused by desmosomal genetic variants, and clinical hallmarks include arrhythmias and systolic dysfunction. We aimed at studying the impact of the implicated gene(s) on the disease course. METHODS: The Nordic ARVC Registry holds data on a multinational cohort of ARVC families. The effects of genotype on electrocardiographic features, imaging findings and clinical events were analysed. RESULTS: We evaluated 419 patients (55% men), with a mean follow-up of 11.2±7.4 years. A pathogenic desmosomal variant was identified in 62% of the 230 families: PKP2 in 41%, DSG2 in 13%, DSP in 7% and DSC2 in 3%. Reduced left ventricular ejection fraction (LVEF) ≤45% on cardiac MRI was more frequent among patients with DSC2/DSG2/DSP than PKP2 ARVC (27% vs 4%, p<0.01). In contrast, in Cox regression modelling of patients with definite ARVC, we found a higher risk of arrhythmias among PKP2 than DSC2/DSG2/DSP carriers: HR 0.25 (0.10-0.68, p<0.01) for atrial fibrillation/flutter, HR 0.67 (0.44-1.0, p=0.06) for ventricular arrhythmias and HR 0.63 (0.42-0.95, p<0.05) for any arrhythmia. Gene-negative patients had an intermediate risk (16%) of LVEF ≤45% and a risk of the combined arrhythmic endpoint comparable with DSC2/DSG2/DSP carriers. Male sex was a risk factor for both arrhythmias and reduced LVEF across all genotype groups (p<0.01). CONCLUSION: In this large cohort of ARVC families with long-term follow-up, we found PKP2 genotype to be more arrhythmic than DSC2/DSG2/DSP or gene-negative carrier status, whereas reduced LVEF was mostly seen among DSC2/DSG2/DSP carriers. Male sex was associated with a more severe phenotype.

Complications of implantable cardioverter-defibrillator treatment in arrhythmogenic right ventricular cardiomyopathy.

AIMS: Treatment with implantable cardioverter-defibrillators (ICD) is a cornerstone for prevention of sudden cardiac death in arrhythmogenic right ventricular cardiomyopathy (ARVC). We aimed at describing the complications associated with ICD treatment in a multinational cohort with long-term follow-up. METHODS AND RESULTS: The Nordic ARVC registry was established in 2010 and encompasses a large multinational cohort of ARVC patients, including their clinical characteristics, treatment, and events during follow-up. We included 299 patients (66% males, median age 41 years). During a median follow-up of 10.6 years, 124 (41%) patients experienced appropriate ICD shock therapy, 28 (9%) experienced inappropriate shocks, 82 (27%) had a complication requiring surgery (mainly lead-related, n = 75), and 99 (33%) patients experienced the combined endpoint of either an inappropriate shock or a surgical complication. The crude rate of first inappropriate shock was 3.4% during the first year after implantation but decreased after the first year and plateaued over time. Contrary, the risk of a complication requiring surgery was 5.5% the first year and remained high throughout the study period. The combined risk of any complication was 7.9% the first year. In multivariate cox regression, presence of atrial fibrillation/flutter was a risk factor for inappropriate shock (P < 0.05), whereas sex, age at implant, and device type were not (all P > 0.05). CONCLUSION: Forty-one percent of ARVC patients treated with ICD experienced potentially life-saving ICD therapy during long-term follow-up. A third of the patients experienced a complication during follow-up with lead-related complications constituting the vast majority.

Seventeen years of misdiagnosis in rare dyslipidaemia: a case report of sitosterolaemia in a young female.

BACKGROUND: Sitosterolaemia is a rare, autosomal recessive dyslipidaemia with increased absorption of dietary plant sterol and often presents with hypercholesterolaemia, xanthomas, and haematologic manifestations. If left untreated, sitosterolaemia can lead to high symptomatic burden and coronary artery disease (CAD). CASE SUMMARY: We describe a case of a young female who initially presented at 4 years of age with classic manifestations of sitosterolaemia. She was misdiagnosed and treated for both juvenile arthritis and later familial hypercholesterolaemia until adulthood, when venous blood samples showed significantly elevated concentrations of plant sterols. DNA analyses showed that the patient was homozygous for a mutation in the ABCG5 gene, [c.1336C>T, p.(Arg446*)], which is known to be associated with sitosterolaemia. DISCUSSION: Sitosterolaemia presents with multiple manifestations, which can initially be misinterpreted leading to prolonged misdiagnosis. Early diagnosis is key in order to relieve symptoms and prevent CAD.

Early repolarization pattern in adult females with eating disorders.

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.

QTc Interval and Risk of Cardiac Events in Adults With Anorexia Nervosa: A Long-Term Follow-Up Study.

BACKGROUND: The literature contains several cases of anorexia nervosa (AN) patients with prolonged QTc interval. However, the risk of prolonged QTc interval is controversial and the risk of cardiac events in AN patients has yet to be investigated. METHODS: We estimated the difference in mean QTc interval and relative risk of borderline prolonged QTc (>440 ms) and prolonged QTc (>460 ms) between 430 adult women AN patients and 123 healthy controls using 3 correction formulas. In a follow-up study, we estimated the risk of a primary end point (a composite of ventricular tachycardia, aborted cardiac arrest, and cardiac arrest) in AN patients compared with a population-based cohort derived from the Danish Civil Register. RESULTS: Mean QTc for AN patients was 408 ms (Hodges), 402 ms (Fridericia), and 399 ms (Bazett). Hodges' found a slightly increased mean QTc (6.8 ms, 95% confidence interval, 1.6-12.0; P=0.01) and percentage with QTc >440 ms in AN patients (relative risk, 3.7, 95% confidence interval, 1.4-10.3; P=0.01), not observed with Fridericia's and Bazett's formulas. There was no difference in the risk of QTc >460 ms between AN patients and healthy controls. During a median follow-up of 10.1 years, AN patients had an increased risk of the primary end point compared with the population-based cohort (hazard ratio, 10.4, 95% confidence interval, 2.6-41.6; P=0.001). However, absolute numbers were small with cumulative incidences of 0.5% and 0.07%, respectively, after 10 years. No events occurred in any AN patient with QTc >440 ms. All-cause mortality was also significantly increased in AN patients compared with the population-based cohort (hazard ratio, 11.2, 95% confidence interval, 5.1-24.5; P<0.001). CONCLUSIONS: Overall, there was no difference in mean QTc interval or risk of prolonged QTc between AN patients and healthy controls. However, AN patients had a notably increased all-cause mortality, as well as an increased risk of cardiac events, which was not related to the baseline QTc interval.