Smoking is a major risk factor for cardiovascular disease, but the long-term relationship between cumulative smoking exposure, smoking cessation, and sudden cardiac death (SCD) remains incompletely understood. We investigated these associations in 10,038 participants from the Copenhagen City Heart Study who were followed for a median of 28.6 years. Smoking exposure was assessed using smoking status, cumulative pack-years, and years since smoking cessation, and SCD events were identified using standardized adjudication criteria. Cause-specific Cox proportional hazards models accounting for competing risks were used to estimate associations with SCD. During 188,870 person-years of follow-up, 890 participants experienced SCD. Compared with never smokers, the adjusted hazard ratio for SCD was 1.88 (95% confidence interval [CI] 1.54–2.29) among current smokers and 1.34 (95% CI 1.09–1.66) among former smokers. A clear dose–response relationship was observed, with progressively higher SCD risk across increasing categories of cumulative smoking exposure, reaching a hazard ratio of 2.50 (95% CI 1.89–3.32) in the highest exposure category. Among former smokers, SCD risk declined with increasing time since smoking cessation and approached that of never smokers only after prolonged abstinence. These findings provide long-term population-based evidence that cumulative smoking exposure is strongly associated with SCD risk and that smoking cessation is associated with gradual but prolonged risk reduction. The results reinforce the importance of smoking prevention and early smoking cessation to reduce the burden of SCD.

Background:Sudden cardiac death (SCD) remains a major public health challenge, yet the long-term association of leisure-time physical activity with SCD risk is not well established. We examined whether self-reported leisure-time physical activity is associated with SCD incidence over 28 years, accounting for competing risks from non-SCD mortality and time-updated changes in leisure-time physical activity. Methods:We included 10,100 participants from the Copenhagen City Heart Study, examined in 1991-1994 and followed until 31 December 2021. SCD events were identified from Danish death certificates using a standardized protocol. Leisure-time physical activity was self-reported at baseline and at 10-year follow-up and incorporated as a time-updated exposure, categorized as low, moderate, or high. Cause-specific Cox models estimated associations with SCD, adjusting for age, sex, smoking, alcohol, and socioeconomic factors. Cumulative incidence was standardized to the Danish population, and population attributable risk for low activity was calculated. This study is registered at ClinicalTrials.gov (NCT02993172). Findings:During a median follow-up of 28.6 years, 897 SCD events occurred among 10,100 participants (mean age 60.8 years; 56% women). Twenty-year standardized cumulative incidence rose with lower activity. In time-updated analyses, moderate and high leisure-time physical activity were associated with lower SCD risk compared with low activity (hazard ratio (HR) of 0.60, 95% confidence interval (CI) 0.50-0.72; and HR 0.50, 95% CI 0.41-0.62, respectively). After 25 years, 33% (95% CI 21-46%) of SCD could be attributed to low activity. Interpretation:Higher leisure-time physical activity is associated with lower long-term risk of SCD in this observational cohort. These findings support the potential public health relevance of promoting leisure-time physical activity, although causality cannot be established. Funding:Research Fund of Tokai University Educational System, Asahikawa Medical University Alumni Fund, Danish Heart Foundation, Birthe and John Meyer Family Foundation, Novo Nordisk Foundation.

INTRODUCTION:The incidence, risk and resuscitation characteristics of out-of-hospital cardiac arrest (OHCA) in the non-ischaemic dilated cardiomyopathy (NIDCM) population have not been analysed before in an unselected nationwide population, and could provide insight into risk stratification and prevention of sudden cardiac death in this unique heart failure cohort. METHODS:We conducted an observational, register-based study with cohort and nested case-control analyses using Denmark's healthcare registers between 1 June 2001 to 31 December 2022. DCM was classified as non-ischaemic using validated methods combined with exclusion of other causes of ischaemia or abnormal loading conditions. Incidence rates and hazard ratios were calculated in the general population. Absolute risk was determined using the Aalen-Johansen estimator in an exposure-matched cohort including incident NIDCM patients and matched controls. Resuscitation characteristics were determined in a nested case-control study. RESULTS:The incident rate of OHCA was approximately 12 times higher in NIDCM patients compared with the general population (incidence rate 532 vs 45 per 100 000 person years). The 5- and 10-year risk of OHCA for male de novo NIDCM patients was 2% and 3.4%, respectively (vs 0.6% and 1.1% for non-NIDCM) and 1.4% and 2.1% for female de novo NIDCM patients (vs 0.4 and 0.5% for non-NIDCM). NIDCM OHCAs had higher rates of initial shockable rhythm than non-NIDCM OHCAs (48.5% vs 22.3%, P < .001) but no significant differences in 30 day and 1-year mortality (79% vs 84% and 82% vs 84, respectively). CONCLUSIONS:The Danish NIDCM population has a significantly increased incidence of OHCA compared to the general population but a comparable mortality despite multiple positive resuscitation characteristics.

BACKGROUND AND AIMS:Diabetes mellitus is associated with increased risk of sudden cardiac death (SCD). However, nationwide, unselected studies are lacking. Therefore, this study aimed to estimate the incidence rates of SCD among individuals with Type 1 diabetes (T1D) and Type 2 diabetes (T2D) and to quantify the shortened life expectancy that can be attributed to SCD. METHODS:The study included the entire Danish population in 2010. Sudden cardiac death cases were identified through the detailed Danish death certificates, and discharge summaries, and if performed, autopsy reports. Cox proportional hazards models were used to estimate risk of SCD in diabetes patients. Loss of life years was estimated for both T1D and T2D patients. RESULTS:Among the identified 6862 SCD cases, 97 were diagnosed with T1D and 1149 with T2D. Incidence rates of SCD were 3.7 times higher for T1D and 6.5 times higher for T2D compared with the general population. After multivariable adjustment, both T1D and T2D were independently associated with SCD. The greatest risk difference was observed in younger individuals with diabetes. Life-years lost were on average 14.2 and 7.9 years shorter for patients with T1D and T2D, respectively. A reduced life expectancy of 3.4 and 2.7 years was found to be attributed to SCD for T1D and T2D, respectively. CONCLUSIONS:Individuals with diabetes displayed consistently elevated incidence rates of SCD across age groups. Further, the elevated risk of SCD in individuals with diabetes diminished with increasing age. For both T1D and T2D, SCD was an important contributing factor to shortened life expectancy.

Importance:Hypertrophic cardiomyopathy (HCM) is associated with an elevated risk of sudden cardiac death, often preceded by an out-of-hospital cardiac arrest (OHCA). However, population-based estimates of OHCA risk in patients with HCM are limited. Objective:To estimate the risk of OHCA in patients with HCM and identify characteristics associated with OHCA. Design, Setting, and Participants:This cohort study used multiple Danish registers during an observation period ranging from June 1, 2001, to December 31, 2022, and included a nested case-control study. All Danish residents aged 18 to 85 years during the study period constituted the source population. Patients with HCM were identified using codes from the International Statistical Classification of Diseases, Tenth Revision. The cohort included patients with a first-time HCM diagnosis and exposure-matched controls. In the nested case-control study, patients with HCM who experienced OHCA were risk-set matched with controls with HCM and no OHCA at the index time. Analyses were performed between September 1 and November 30, 2025. Exposure:First-time diagnosis of HCM. Main Outcomes and Measures:Time to OHCA from exposure or the matching date was the primary outcome. Risk estimates were determined using the Aalen-Johansen estimator. Association between covariates and OHCA was determined by conditional logistic regression. Results:The cohort included a total of 29 240 individuals: 5901 patients with HCM (median age, 65 [IQR, 54-75] years; 3277 male [55.5%]) and 23 339 matched controls (median age, 65 [IQR, 55-75] years; 12 982 male [55.6%]). In the group aged 61 to 85 years, the 10-year risk of OHCA was 4.3% (95% CI, 3.4%-5.1%) in patients and 3.3% (95% CI, 3.0%-3.7%) in controls. In the group aged 18 to 60 years, the 10-year risk was 2.8% (95% CI, 1.9%-3.7%) in patients and 1.5% (95% CI, 1.2%-1.8%) in controls. The nested case-control study included 250 cases with HCM and OHCA (167 male [66.8%]; median age, 68 [IQR, 59-76] years) and 1000 controls with HCM and no OHCA (668 male [66.8%]; median age, 68 [IQR, 59-76] years). Heart failure, both recent and longer term, was associated with an increased rate of OHCA (hazard ratio, 3.63 [95% CI, 1.55-8.50] and 2.82 [95% CI, 1.88-4.22], respectively). Conclusions and Relevance:The findings of this cohort study suggest that HCM was associated with an increased risk of OHCA in people aged 18 to 85 years. The rate of OHCA was associated with heart failure, underscoring the need for improved risk stratification to optimize primary prevention.

BACKGROUND:Antidepressants (ADs) are among the most widely prescribed medications worldwide. Although previous studies suggest associations between AD use and adverse cardiovascular outcomes, the impact of treatment duration and recency on sudden cardiac death (SCD) risk remains unclear, limiting clinical risk stratification. OBJECTIVE:This study aimed to investigate whether cumulative duration and recency of AD treatment are associated with SCD risk and whether associations differ across drug classes. METHODS:We conducted a nationwide cohort study of 4.3 million Danish residents aged 18-90 years during 2010. AD exposure was ascertained from the national prescription registry (1999-2009). Deaths were adjudicated as SCD or non-SCD. Multivariable Cox models estimated hazard ratios (HRs). AD use was defined as ≥2 prescriptions within 1 calendar year and categorized by cumulative duration (1-5 years vs ≥6 years) and recency (remote, recent, or current). RESULTS:Among 6002 SCDs, 1907 (32%) occurred in AD users. Adjusted HRs were 1.41 (95% confidence interval [CI] 1.31-1.51) for 1-5 years and 1.74 (95% CI 1.59-1.90) for ≥6 years of use. A temporal gradient emerged: current users showed the highest risk (HR 1.71; 95% CI 1.59-1.83) vs recent (HR 1.24; 95% CI 1.09-1.42) and remote users (HR 1.11; 95% CI 0.97-1.27). Associations were consistent across drug classes: selective serotonin reuptake inhibitors (HR 1.38; 95% CI 1.28-1.49; HR 1.57; 95% CI 1.42-1.75) and tricyclic ADs (HR 1.24; 95% CI 1.09-1.42; HR 1.40; 95% CI 1.15-1.71) for 1-5 and ≥6 years, respectively. CONCLUSION:Long-term AD treatment was associated with increased SCD risk in a duration- and recency-dependent manner across major drug classes. Although causality cannot be inferred, these findings identify patients receiving prolonged AD therapy as a population at elevated cardiovascular risk, warranting further investigation.

Aim: How a family history of cardiovascular disease (CVD) or death influences the risk of out-of-hospital cardiac arrest (OHCA) is unknown. This study examined the prevalence of family histories of CVD and death in patients with OHCA and if these factors were associated with OHCA. Methods: Patients (<70 years) with OHCA’s of presumed cardiac origin and available kinship information were identified from the Danish Cardiac Arrest Register (2001–2014). Patients with OHCA were matched 1:4 (age, sex, and number of identifiable parents) with individuals from the background population (controls) to compare family histories (events in first-degree relatives before OHCA) of CVD, all-cause death, cardiovascular death, and premature death (death <60 years). In conditional multivariable logistic regressions, we examined associations between parental history and offspring OHCA risk. Results: Of 45,293 patients with OHCA 4,994, were eligible for inclusion (median age 50 years at OHCA, 76% male). Of these 47.7% had a family history of CVD (vs. 42.1% of controls), 68.2% of all-cause death (vs. 60.9%), 23% of premature death (vs. 15.8%) and 33.3% of cardiovascular death (vs. 27%) (p < 0.001 for all). A family history of a single parent with CVD (OR: 1.13, 95%CI: 1.05,1.23), all-cause death (OR: 1.42, 95%CI: 1.29,1.56), cardiovascular death (OR: 1.35, 95%CI: 1.24, 1.47), and premature death (OR: 1.45, 95%CI: 1.32,1.59) were all associated with OHCA (p < 0.001 for all). Conclusion: A family history of CVD and death is more common among patients with OHCA compared to a matched background population, as well as being significantly associated with OHCA.

Patients with psychiatric disorders have an increased all-cause mortality as well as an increased risk for sudden cardiac death (SCD) across all age groups. We have previously shown that patients with depressive disorders had a 2-fold increased risk of SCD compared to the general population. However, the impact of antidepressants (AD) exposure on SCD risk is unclear. To investigate the association between length of antidepressant use and SCD in patients aged 18-90 years in the Danish population in one year. We examined all deaths in Denmark among residents aged 18-90 years in 2010 by reviewing all death certificates and autopsy reports. Deaths were categorized as non-SCD or SCD based on the available information. Exposure to AD was defined by redemption of a prescription for AD-medication at least 2 times in one year over a period of 12 years before the year of follow-up (2010). Furthermore, exposure time was categorized into two groups: 1-5 years and 6+ years. Of 4.3 million residents in 2010 aged 18-90 years, there was a total of 45 701 deaths and 6 002 cases of SCD. 643 999 inhabitants were exposed to AD-medication prior to the year of follow up. The total amount of SCD in the AD cohort was 1 981 individuals. The incidence rate of SCD was significantly higher in the exposed groups compared to the general population across all age groups bar the age group 18-29 years (Figure 1). Adjusting for age, sex, and comorbidities the hazard ratio for SCD was 1.56 (1.46-1.67 p<0.001) for 1-5 years of exposure to AD, and 2.17 (2.01-2.31 p<0.001) for 6+ years of exposure of AD. In individuals ages 40-79 years, the SCD incidence rate ratio was significantly higher among persons with 6+ exposure of AD compared to persons with 1-5 years exposure (Figure 2). Exposure time to antidepressants was associated with a higher risk of SCD. Adjusted HR was 1.56 for 1-5 years of AD exposure and 2.17 for 6+ years (p-value <0.001). The risk was notably higher among individuals aged 40-79 years with longer exposure time.Figure 1 Figure 2

BACKGROUND:Sudden cardiac death (SCD) is a significant public health problem. Knowledge on SCD victims without a history of cardiovascular disease (CVD) is limited, presenting challenges for future prevention efforts. OBJECTIVES:This study aims to examine the differences between SCD cases with and without a known history of CVD. METHODS:All Danish citizens were followed from January 1, 2010, until death or the end of the year. All deaths in Denmark during this period were reviewed by ≥1 medical doctor to identify cases of SCD. Data were analyzed from March 2023 until March 2024. RESULTS:A total of 6,851 SCD cases were identified, of which 3,046 (44.5%) had no history of CVD. Incidence rates of SCD increased with age and were higher in cases with a history of CVD across all age groups. The difference in SCD incidence between individuals with and without a history of CVD decreased with age, with incidence rate ratios ranging from 21.6 (95% CI: 5.2-66.7) in those aged 0 to 19 years to 1.8 (95% CI: 1.7-1.9) in those aged >90 years. Female sex and living alone were associated with a lower odds of having a CVD before SCD with ORs of 0.66 and 0.75, respectively. CONCLUSIONS:The distribution of SCD cases is nearly equal between individuals with and without a history of CVD, although the risk remains higher in those with prior CVD. Future research should aim to uncover the distinct causes and mechanisms driving SCD in populations with a known CVD, as well as the general population.

BACKGROUND:Most of sudden cardiac death in the adult population is caused by ventricular fibrillation (VF) in the setting of acute myocardial ischemia. The assessment of risk factors for VF in this setting may point to novel causal pathways or new targets for intervention and risk prediction of sudden cardiac death. OBJECTIVE:This study aimed to evaluate the effect of family history of sudden death (SD), history of atrial fibrillation (AF), and anterior infarct location on the electrocardiogram on the development of VF during the first ST-elevation myocardial infarction (STEMI). METHODS:We performed an individual participant data meta-analysis of 3 European case-control studies including patients with a first STEMI (aged 18-80 years) with VF (cases) or without VF (controls) before revascularization. RESULTS:We included 1807 cases and 2923 controls (median age 59 years, 20% women) in the analyses. After adjusting for potential confounding, we found an independent association between the 3 risk factors and VF: family history of SD (odds ratio [OR] 1.61, 95% confidence interval 1.38-1.87), previous AF (OR 1.95, 1.22-3.11), and anterior myocardial infarction (OR 1.55, 1.36-1.75). Further investigation indicated increased effect of family history with multiple SDs in the family, a stronger effect of AF on VF developing within the first minutes of symptoms, and the effect of anterior infarctions being modified by enzymatically determined infarct size. CONCLUSION:Family history of SD, history of AF, and anterior infarct location were all independently and additively associated with an increased risk of VF in patients with a first STEMI.

Atrial fibrillation (AF) is the most common heart rhythm disorder and cardiac arrest (CA) is one of the leading causes of death. Growing evidence indicates an association between AF and CA.[1-2] However, research into the correlation between AF and CA has so far been challenged by shared risk factors between AF and ischemic heart disease and heart failure - two prevalent conditions commonly associated with CA in elderly.[3] The aim was to investigate whether AF is associated with a higher risk of CA, independent of risk factors such as ischemic heart disease and heart failure. This study was performed as a Danish register-based nationwide cohort study. The Danish National Population Register was employed to identify all individuals aged 18-85 years and present in Denmark from 1st June 2001 to 31st December 2021. The Danish Cardiac Arrest Registry was used to identify all out-of-hospital CAs (OHCA) receiving resuscitation efforts during this time period. Follow-up began at the latest of 1st June 2001 (study start), immigration date, or 18th birthday and ended at the first of OHCA, death, emigration date, 85th birthday, or 31st December 2021 (study end). Exposure was defined as presence of an AF diagnosis at start of follow-up, defined using ICD-codes and the Danish National Patient Register (DNPR). Comorbidities and medications were defined using respectively the DNPR and ICD-codes and Danish National Prescription Register and ATC-codes, and considered present if so at start of follow-up. Primary outcomes were OHCA and all-cause mortality (ACM). Analyses were performed using multivariable cox regression models using age as a time scale and results are presented as hazard ratios with death as a competing risk. The study included 6.2 million individuals, of which 51,964 (0.8%) had AF by start of follow-up. The average age was 38 years in non-AF patients (50% male) versus 69 years in AF patients (59% male). Compared with non-AF patients, AF patients had a significantly higher hazard of OHCA (HR 1.89, CI: 1.82-1.97) and ACM (1.66, 1.64-1.68). After adjusting for sex, heart failure, ischemic heart disease, myocardial infarction, chronic obstructive pulmonary disorder, peripheral arterial disease, stroke, hypertension, diabetes, cancer, statin usage, and betablocker usage, the hazard for OHCA (1.06, 1.01-1.10) and ACM (1.13, 1.12-1.14) remained significantly higher in AF patients. This study suggests that AF is a risk factor for OHCA, even after adjusting for ischemic heart disease and heart failure. Future studies should explore which subsets of AF patients are at highest risk and examine potential genetic, molecular, or structural mechanisms underlying this link. This could lead to more targeted OHCA prevention and determine whether AF in combination with other risk factors warrants inclusion in sudden cardiac death risk assessment for implantable cardioverter defibrillator implantation.Table 1– Baseline characteristics Cox Regression Models

AbstractAimsSocioeconomic deprivation is a risk marker for worse prognosis in patients with heart failure (HF), and a potential barrier to referral for advanced HF evaluation. The relationship between socioeconomic status (SES) and invasive haemodynamics in patients undergoing evaluation for advanced HF therapies is unknown.MethodsWe combined a consecutive clinical registry of patients evaluated for advanced HF with patient‐level data on SES (household income, education, workforce status, cohabitant status and distance from home to tertiary HF centre) derived from nationwide registries. Using this information, the cohort was divided into groups of low‐, medium‐ and high degree of socioeconomic deprivation. The associations between SES and invasive haemodynamics were explored with multiple linear regression adjusted for age and sex.ResultsA total of 631 patients were included. The median age was 53 years, and 23% were women. Patients in the highest income quartile versus the lowest (Q4 vs. Q1) were older (median age 57 vs. 50 years) and more often male (83% vs. 67%), both P < 0.001. Increasing household income (per 100 000 Danish kroner,1 EUR = 7.4 DKK) was associated with lower pulmonary capillary wedge pressure (PCWP) [−0.18 mmHg, 95% confidence interval (CI) −0.36 to −0.01, P = 0.036] but not significantly associated with central venous pressure (CVP) (−0.07 mmHg, 95% CI −0.21 to 0.06, P = 0.27), cardiac index (−0.004 L/min/m2, 95% CI −0.02 to 0.01, P = 0.60), or pulmonary vascular resistance (PVR) (−0.003 Wood units, 95% CI −0.37 to 0.16, P = 0.84). Comparing the most deprived with the least deprived group, adjusted mean PVR was higher (0.35 Wood units, 95% CI 0.02 to 0.68, P = 0.04), but PCWP (0.66 mmHg, 95% CI −1.49 to 2.82, P = 0.55), CVP (−0.26 mmHg, 95% CI −1.76 to 1.24, P = 0.73) and cardiac index (−0.03 L/min/m2, 95% CI −0.22 to 0.17, P = 0.78) were similar.ConclusionsMost haemodynamic measurements were similar across layers of SES. Nevertheless, there were some indications of worse haemodynamics in patients with lower household income or a high accumulated burden of socioeconomic deprivation. Particular attention may be warranted in socioeconomically deprived patients to ensure timely referral for advanced HF evaluation.

Abstract Background and objective Sudden cardiac death (SCD) is a leading cause of death and previous studies have shown that approximately half of all cases have no known history of cardiovascular disease (CVD). Epidemiological studies of SCD cases of all ages are sparse. The aim of this study was to examine differences in incidence rates, clinical characteristics, comorbidities, and socioeconomic status between SCD cases with and without a known history of cardiovascular disease. Methods All 54,028 deaths in Denmark in 2010 were reviewed. Autopsy reports, death certificates, discharge summaries, and nationwide health and social registries were reviewed to identify cases of SCD. Information on previous history of CVD was extracted from the comprehensive Danish nationwide health and social registries. Results A total of 6,867 SCD cases were identified, of which 3,056 (44.5%) had no history of cardiovascular disease and 3,811 (55.5 %) had a history of CVD. Incidence rates of SCD increased with age and were higher in cases of SCD with a history of CVD across all age groups. The difference in incidence of SCD between persons with and without history of cardiovascular disease decreased with increasing age with incidence rate ratios ranging from 11.7 (95 % CI: 5.51 – 25.00) to 3.19 (95 % CI: 2.79-3.64) in those age 0-29 years and >90 years, respectively. Persons living in a low-income household (OR: 0.76, 95 % CI: 0.58-0.98, p=0.037), persons living in rural municipalities (OR: 0.87, 95 % CI: 0.78-0.98, p=0.021), and persons living in single-person households (OR: 0.73, 95 % CI: 0.66-0.82, p=0.037) had a lower likelihood of having a CVD prior to SCD. Conclusion This is the first nationwide study of SCD cases with and without history of CVD across all ages. SCD cases with no known CVD were significantly younger, more female and had less comorbidities. Although a substantial amount of SCD cases occur in persons with no known CVD, SCD is more common in the populations of persons with a history of CVD. Socioeconomic factors such as low income, living alone and living in rural communities were associated with a lower risk of having a cardiovascular diagnosis prior to SCD.Crude numbers and incidence rates of SCDIncidence rate ratios

BACKGROUND: Socioeconomic deprivation is associated with a lower likelihood of referral for advanced heart failure (HF) evaluation, but it is not known whether it influences rates of advanced HF therapies independently of key hemodynamic measures and comorbidity following advanced HF evaluation in a universal healthcare system. METHODS: We linked data from a single-center Danish clinical registry of consecutive patients evaluated for advanced HF with patient-level information on socioeconomic status. Patients were divided into groups based on the level of education (low, medium, and high), combined degree of socioeconomic deprivation (low, medium, and high), and household income quartiles. Rates of the combined outcome of left ventricular assist device implantation or heart transplantation (advanced HF therapy) with death as a competing risk were estimated with cumulative incidence functions, and Cox proportional hazards models adjusted for age, sex, central venous pressure, cardiac index, and comorbidities. RESULTS: We included 629 patients, median age 53 years, of whom 77% were men. During a median follow-up of 5 years, 179 (28%) underwent advanced HF therapy. The highest level of education was associated with higher rates (high vs low, adjusted HR 1.81 95% CI 1.14-2.89, p = 0.01), whereas household income quartile groups (Q4 vs Q1, adjusted HR 1.37 95% CI 0.76-2.47, p = 0.30) or groups of combined socioeconomic deprivation (high vs low degree of deprivation, adjusted HR 0.86 95% CI 0.50-1.46, p = 0.56) were not significantly associated with rates of advanced HF therapy. CONCLUSIONS: Patients with a lower level of education might be disfavored for advanced HF therapies and could require specific attention in the advanced HF care center. (c) 2024 International Society for Heart and Lung Transplantation. All rights reserved.

Aims The underlying biological mechanisms of ventricular fibrillation (VF) during acute myocardial infarction are largely unknown. To our knowledge, this is the first proteomic study for this trait, with the aim to identify and characterize proteins that are associated with VF during first ST-elevation myocardial infarction (STEMI).Methods and results We included 230 participants from a Danish ongoing case-control study on patients with first STEMI with VF (case, n = 110) and without VF (control, n = 120) before guided catheter insertion for primary percutaneous coronary intervention. The plasma proteome was investigated using mass spectrometry-based proteomics on plasma samples collected within 24 h of symptom onset, and one patient was excluded in quality control. In 229 STEMI patients {72% men, median age 62 years [interquartile range (IQR): 54-70]}, a median of 257 proteins (IQR: 244-281) were quantified per patient. A total of 26 proteins were associated with VF; these proteins were involved in several biological processes including blood coagulation, haemostasis, and immunity. After correcting for multiple testing, two up-regulated proteins remained significantly associated with VF, actin beta-like 2 [ACTBL2, fold change (FC) 2.25, P < 0.001, q = 0.023], and coagulation factor XIII-A (F13A1, FC 1.48, P < 0.001, q = 0.023). None of the proteins were correlated with anterior infarct location.Conclusion Ventricular fibrillation due to first STEMI was significantly associated with two up-regulated proteins (ACTBL2 and F13A1), suggesting that they may represent novel underlying molecular VF mechanisms. Further research is needed to determine whether these proteins are predictive biomarkers or acute phase response proteins to VF during acute ischaemia.

Introduction: The documented treatment-induced excess mortality in Hodgkin lymphoma (HL) has led to significant changes in treatment regimens aimed at maintaining efficacy while reducing toxicity. These modifications include the replacement of alkylator-based regimens with anthracycline-based combinations and the adoption of highly conformal radiotherapy. Danish and Nordic radiation oncologists were pioneers in implementing these changes nationwide 10-15 years earlier than most other nations. These early adaptations make Danish HL data uniquely valuable for assessing long-term mortality in a cohort where modern treatment regimens have been implemented nationwide throughout the entire study period. The impact of these treatment modifications on mortality risk in HL survivors remains unclear, therefore, this study aims to assess cause-specific mortality among HL patients treated with contemporary strategies. Methods: This nationwide, unselected study included all HL patients in Denmark aged 15-40 years at diagnosis and treated between 1995 and 2015. Patients were followed from diagnosis until emigration, death, or the study end. HL cases were identified through meticulous individual record reviews of medical records, national registries, and pathology data. Disease-specific death due to HL was the primary outcome, with other cause-specific mortality as a competing risk. Cox proportional hazard models assessed factors influencing overall survival and cause-specific survival. A landmark analysis was conducted to compare the risk of death between the study population and the national background population. Results: Among 1,348 included HL patients, 66.5% had Ann Arbor stage I-II at the time of diagnosis. During 18,731 person-years of follow-up, 139 deaths occurred, resulting in a 5-year overall survival rate of 94.6% (95% CI 93.4-95.8). Factors associated with higher overall mortality risk included older age, advanced disease stage at diagnosis, earlier treatment periods, and exposure to intensive treatment regimens. Causes of death included: HL (71 cases), cardiovascular disease (9 cases), second malignancies (19 cases including 3 hematologic malignancies), bone-marrow transplant-related complications (9 cases), acute treatment-related toxicity (<5 cases), pulmonary diseases (<5 cases), other diseases not related to HL (11 cases), and deaths related to accidents, poisoning or suicide (7 cases). The cumulative risk of mortality due to HL steeply increased over the first 10 years, reaching a plateau at 5.3% at the 10-year mark. Cumulative risk of death due to cardiovascular or pulmonary disease and second cancers had a gradual increase around 10 years after HL diagnosis, but only reached 1.2% and 2.0%, respectively, at the 20-year mark. The cumulative risk of death due to other causes had a slower rise, reaching 2.5% 15 years after diagnosis. Stratifying the cumulative cause-specific risk of death into HL and other causes, we found an initial sharp increase in cumulative risk of death due to HL in the first year after diagnosis, which was surpassed by the risk of death from other causes by 17.8 years of follow-up, with a cumulative risk of death of 5.72%. HL cases had a 7.5-fold higher hazard of mortality compared to the background population. Conclusion: Despite the implementation of contemporary treatment regimes, HL patients still face higher mortality compared to the general population. In the initial years after diagnosis, most deaths are disease-specific, while the risk of mortality due to possible treatment-related late effects gradually increases after 10 years. However, our findings demonstrate a markedly lower overall risk of mortality and cause-specific mortality among HL patients exposed to contemporary treatment, compared to the risk reported in earlier studies among patients from earlier treatment eras (Aleman, B. et al. Long-term cause-specific mortality of patients treated for Hodgkin's disease. J Clin Oncol21 2003, 3431-3439). Furthermore, we observe a remarkably low overall and cause-specific risk of death due to possible treatment-related late effects. The treatment of HL remains a balance between efficacy and toxicity in the individual patient, but our results suggest that recent changes in treatment strategies have led to a distinct reduction in the risk of fatal long-term toxicity and have improved HL-specific survival.

The documented treatment-induced excess mortality in Hodgkin lymphoma (HL) has spurred important treatment changes over recent decades. This study aimed to examine mortality among young HL patients treated with contemporary strategies, including historical data comparison. This nationwide study included 1348 HL patients, diagnosed in 1995–2015 and aged 15–40 at diagnosis. Among the patients, 66.5% had Ann Arbor stage I–II and 33.5% had stage III–IV disease. With a median follow-up of 14.76 years, 139 deaths occurred, yielding a 5-year overall survival of 94.6%. Older age, advanced disease, earlier treatment periods and extensive regimens were associated with higher overall mortality risk. The cumulative risk of HL-related death showed an initial sharp rise, with a plateau at 5.3% 10-year post-diagnosis. Deaths due to cardiovascular or pulmonary diseases and second cancers initially had minimal risk, gradually reaching 1.2% and 2.0% at the 20-year mark respectively. HL cases had a 7.5-fold higher mortality hazard than the background population. This study suggests that contemporary HL treatment still poses excess mortality risk, but recent changes have notably reduced overall and cause-specific mortality compared to earlier eras. Balancing treatment efficacy and toxicity remains crucial, but our findings highlight improved outcomes with modern treatment approaches.