Journal Article Corrected proof Forecasting cardiovascular risk reduction with semaglutide in overweight and obese with heart disease: a nationwide cohort study Get access Mats C Højbjerg Lassen, Mats C Højbjerg Lassen Department of Cardiology, Copenhagen University Hospital—Herlev and Gentofte, Gentofte Hospitalsvej 1, 2900 Copenhagen, DenmarkCenter for Translational Cardiology and Pragmatic Randomized Trials, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Gentofte Hospitalsvej 1, 2900 Hellerup, DenmarkDepartment of Medicine, Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA Corresponding author. Tel: +4538673867, Email: mats.christian.hoejbjerg.lassen@regionh.dk https://orcid.org/0000-0002-2255-582X Search for other works by this author on: Oxford Academic Google Scholar Kristoffer Grundtvig Skaarup, Kristoffer Grundtvig Skaarup Department of Cardiology, Copenhagen University Hospital—Herlev and Gentofte, Gentofte Hospitalsvej 1, 2900 Copenhagen, DenmarkCenter for Translational Cardiology and Pragmatic Randomized Trials, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Gentofte Hospitalsvej 1, 2900 Hellerup, Denmark Search for other works by this author on: Oxford Academic Google Scholar Muthiah Vaduganathan, Muthiah Vaduganathan Department of Medicine, Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA https://orcid.org/0000-0003-0885-1953 Search for other works by this author on: Oxford Academic Google Scholar John W Ostrominski, John W Ostrominski Department of Medicine, Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USADepartment of Medicine, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA https://orcid.org/0000-0002-2866-9414 Search for other works by this author on: Oxford Academic Google Scholar Jens Ulrik Stæhr Jensen, Jens Ulrik Stæhr Jensen Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, DenmarkDepartment of Medicine, Respiratory Medicine Section, Copenhagen University Hospital—Herlev and Gentofte, 2900 Copenhagen, Denmark Search for other works by this author on: Oxford Academic Google Scholar Tor Biering-Sørensen, Tor Biering-Sørensen Department of Cardiology, Copenhagen University Hospital—Herlev and Gentofte, Gentofte Hospitalsvej 1, 2900 Copenhagen, DenmarkCenter for Translational Cardiology and Pragmatic Randomized Trials, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Gentofte Hospitalsvej 1, 2900 Hellerup, DenmarkDepartment of Cardiology, Copenhagen University Hospital—Rigshospitalet, 2100 Copenhagen, DenmarkSteno Diabetes Center Copenhagen, University of Copenhagen, 2730 Herlev, Denmark https://orcid.org/0000-0003-4209-2778 Search for other works by this author on: Oxford Academic Google Scholar Niklas Dyrby Johansen Niklas Dyrby Johansen Department of Cardiology, Copenhagen University Hospital—Herlev and Gentofte, Gentofte Hospitalsvej 1, 2900 Copenhagen, DenmarkCenter for Translational Cardiology and Pragmatic Randomized Trials, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Gentofte Hospitalsvej 1, 2900 Hellerup, Denmark Search for other works by this author on: Oxford Academic Google Scholar European Journal of Preventive Cardiology, zwae224, https://doi.org/10.1093/eurjpc/zwae224 Published: 18 July 2024 Article history Received: 20 March 2024 Revision received: 20 June 2024 Accepted: 25 June 2024 Corrected and typeset: 18 July 2024 Published: 18 July 2024

BackgroundB-lines on lung ultrasound (LUS) are nonspecific signs of increased lung density, which can be secondary to pulmonary congestion, pneumonia, or fibrosis. While its use is recommended in acute heart failure (HF), its value in non-HF populations is less clear.MethodsWe prospectively analyzed hospitalized non-ICU patients ≥18 years old with confirmed laboratory diagnoses of COVID-19. We aimed to identify associations between 8-zone LUS findings and clinical, laboratory, and echocardiographic data, and 30-day mortality using trend and regression analyses.ResultsAmong 270 patients (mean age 69 ± 14 years, 58% male, and 11% with prior HF) the median time from hospital admission to LUS was 4 days [interquartile range (IQR) 2–8]. In total, 263 (97%) had ≥1 B-line [median B-line number 13 (IQR 9–22)], and the median left ventricular ejection fraction (LVEF) was 59 (IQR 54–63). In adjusted models, having more B-lines was associated with higher levels of C-reactive protein, with an incidence rate ratio (IRR) of 16% (95%CI: 8%–24%) per log-unit increase (P < 0.001) and higher Early Warning Score [IRR 5% (95%CI: 2%–8%) per point, P = 0.003]. Higher tricuspid regurgitation gradient was associated with more B-lines: IRR 2% (95%CI: 1%–3%) per mmHg, P = 0.001). However, left ventricular function measures and NT-proBNP concentrations showed no significant association with B-lines. Furthermore, B-lines were not associated with 30-day mortality.ConclusionsAmong patients with COVID-19, B-lines on LUS are associated with markers of infectious disease severity and pulmonary hypertension, but not with markers of left-sided HF.

BACKGROUND:Influenza vaccination reduces the risk of adverse outcomes in patients with cardiovascular disease (CVD). We sought to evaluate whether the presence of CVD modified the relative effectiveness of the high-dose quadrivalent influenza vaccine (QIV-HD) versus standard-dose quadrivalent influenza vaccine (QIV-SD) in this prespecified analysis of the DANFLU-1 trial (Feasibility of Randomizing Danish Citizens Aged 65-79 Years to High-Dose Quadrivalent Influenza Vaccine Versus Standard-Dose Quadrivalent Influenza Vaccine in a Pragmatic Registry-Based Setting).METHODS:DANFLU-1 was a pragmatic, open-label, randomized feasibility trial of QIV-HD versus QIV-SD in adults aged 65 to 79 years during the 2021/2022 influenza season in Denmark. Vaccines were allocated in a 1:1 ratio. Baseline and follow-up data regarding diagnoses and mortality were obtained from Danish national registers. The trial is registered at Clinicaltrials.gov: NCT05048589. The CVDs assessed included heart failure, ischemic heart disease, atrial fibrillation, and a combined group denoted chronic CVD consisting of the aforementioned diseases, among others. Prespecified outcomes included hospitalizations for pneumonia or influenza, respiratory disease, CVD, cardiorespiratory disease, all-cause hospitalizations, and mortality. Effect modification was tested using interaction terms.RESULTS:The final study population included 12 477 participants (mean age of 71.7 +/- 3.9 years and 5877 [47.1%] were female), of whom 2540 (20.4%) had chronic CVD. QIV-HD versus QIV-SD was associated with a lower incidence of hospitalizations for pneumonia or influenza (incidence rate ratio [IRR], 0.30 [95% CI, 0.14-0.64]) and all-cause mortality (IRR, 0.51 [95% CI, 0.30-0.86]) regardless of chronic CVD (Pinteraction=0.57 and 0.49, respectively). The relative effectiveness of QIV-HD versus QIV-SD against all-cause hospitalizations was modified in participants with chronic CVD (overall: IRR, 0.87 [95% CI, 0.76-0.99]; no chronic CVD: IRR, 0.79 [95% CI, 0.67-0.92]; chronic CVD: IRR, 1.11 [95% CI, 0.88-1.39]; Pinteraction=0.026). No other effect modification was observed by the presence of chronic CVD, heart failure, ischemic heart disease, or atrial fibrillation.CONCLUSIONS:The relative effectiveness of QIV-HD versus QIV-SD was consistent against hospitalizations for pneumonia or influenza and all-cause mortality regardless of chronic CVD. However, the relative effectiveness against all-cause hospitalizations was modified by the presence of chronic CVD. These results should be considered hypothesis generating.REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT05048589.

IMPORTANCE Influenza vaccination in patients with acute myocardial infarction (AMI) reduces major adverse cardiac events and is strongly recommended in clinical practice guidelines. Effective strategies to improve vaccination are needed in these high-risk patients. OBJECTIVE To evaluate whether electronically delivered behavioral nudges improve influenza vaccine uptake in patients with AMI across 3 nationwide implementation randomized clinical trials (RCTs). DESIGN, SETTING, AND PARTICIPANTS Nationwide Utilization of Danish Government Electronic Letter System for Increasing Influenza Vaccine Uptake (NUDGE-FLU), Nationwide Utilization of Danish Government Electronic Letter System for Confirming the Effectiveness of Behavioral Nudges in Increasing Influenza Vaccine Uptake Among Older Adults (NUDGE-FLU-2), and Nationwide Utilization of Danish Government Electronic Letter System for Increasing Influenza Vaccine Uptake Among Adults With Chronic Disease (NUDGE-FLU-CHRONIC) were RCTs conducted during the 2022 to 2023 and 2023 to 2024 influenza seasons in Denmark. Participants were randomized to either usual care or various behaviorally informed, electronically delivered, letter-based nudges. In a prespecified participant-level pooled meta-analysis, interaction of AMI status on the effects of letter-based nudges vs usual care was examined. Pooled treatment effects were estimated using binomial regression models with identity link, adjustment for trial, and 2-way clustered SEs at the household and participant levels. Effect modification by recency of AMI as a continuous variable was assessed using restricted cubic spline modeling in NUDGE-FLU-CHRONIC. INTERVENTIONS Behaviorally informed, electronically delivered, letter-based nudges or usual care. MAIN OUTCOME AND MEASURES The primary end point was influenza vaccination receipt. RESULTS Of 2146124 individual randomizations (mean [SD] age, 71.1 [11.6] years; 1114725 female [51.9%]) across all 3 trials, 59458 (2.8%) had a history of AMI. Improvement in vaccine uptake was similar in patients with vs without a history of AMI who received any nudge letter compared with usual care (+1.81 vs +1.32 percentage points; P for interaction by AMI status = .09). A letter highlighting the cardiovascular benefits of vaccination (ie, cardiovascular-gain frame) resulted in larger improvements in vaccine uptake among patients with (vs without) a history of AMI (+3.91 vs +2.03 percentage points; P for interaction by AMI status = .002). Among patients with AMI, the benefits of the cardiovascular-gain frame letter were more pronounced in those not vaccinated in the prior season (+13.7 vs +1.48 percentage points; P for interaction <.001). Among younger participants with chronic disease, the cardiovascular-gain frame letter was particularly effective in patients with more recent AMI (P for interaction by continuous recency of AMI <.001). CONCLUSIONS and Relevance Across 3 nationwide RCTs of Danish citizens, messaging emphasizing the cardiovascular benefits of vaccination improved influenza vaccination uptake, with greater benefits observed in patients with a history of AMI. This low-cost, scalable implementation strategy should be considered to encourage influenza vaccination in high-risk patients.

BACKGROUND:Influenza infection has been associated with multiple cardiac complications including acute heart failure and myocardial infarction. The FluHeart study aims to uncover the potential effect of influenza infection on cardiac structure and function as assessed by echocardiography during hospitalization. METHODS:This prospective cohort study included hospitalized influenza patients of the 2021-2022 influenza season. Participants underwent echocardiography using a prespecified protocol. Participants were successfully matched 1:1:1 on age, sex, and heart failure status with controls from the general population and controls hospitalized with COVID-19. RESULTS:This interim analysis involved 108 participants (36 influenza patients, 36 general population controls, and 36 COVID-19 patients). Mean age was 72 ± 18 years and 58% were male. Median time from admission to echocardiography was 1 day (IQI: 1:1) for influenza patients. The prevalence of left ventricular (LV) dysfunction was 75%, and right ventricular (RV) dysfunction was observed in 20% of influenza patients. N-terminal pro-brain natriuretic peptide levels were elevated ≥ 300 pg/mL in 62%, and 19% exhibited myocardial injury with elevated high-sensitivity troponin I levels. RV tricuspid annular plane systolic excursion and LV early diastolic peak mitral inflow to early diastolic tissue velocity were significantly worse in influenza patients compared to general population controls. Echocardiographic measures did not significantly differ between patients hospitalized with influenza and COVID-19. CONCLUSION:In this interim analysis of the FluHeart study, both RV and LV function measures were significantly impaired in hospitalized influenza patients compared with matched general population controls. The extent of impairment resembled that observed in hospitalized COVID-19 patients.

Abstract Background Emerging evidence suggests that the pathogenesis of atrial fibrillation (AF) is affected by inflammatory processes which contribute to structural and electrical remodeling of the atria, creating a substrate for arrythmia. Aim To assess whether inflammation measured by C-reactive protein (CRP) is associated with readmission for direct current (DC) cardioversion, ablation, heart failure or stroke after discharge from 1st time DC cardioversion. Methods This nationwide retrospective cohort study included patients undergoing 1st DC cardioversion between 2011 and 2018. Exclusion criteria were death within one day of cardioversion and no available CRP at baseline. Primary outcome was readmission for DC cardioversion of AF. Secondary outcomes were AF ablation, new admission of stroke, new admission of heart failure (HF), and all-cause death. Absolute risk rates (ARR) of outcomes were calculated for patients with available 1-year follow-up data. CRP 20 mg/L was chosen as cutoff to establish a clinically relevant borderline for inflammation. The association between baseline CRP and outcome was assessed in Cox proportional hazards regression models with a follow-up period starting from 1st DC cardioversion, ending no later than 31st of December 2018, for the entire study population (n=9,977). Results After exclusion criteria the study population consisted of 9,977 patients Mean age for CRP > 20mg/L: 66.8 (IQR: 60.5-74.2). Mean age for CRP < 20mg/L 68.9 (IQR: 62.9-75.9)(p<0.001). In total, 68.9% were male and the most frequent comorbidities included hypertension (57.3%), ischemic heart disease (25.1%), HF (20.6%), and history of stroke (7.1%). Patients with available CRP measurement and 1yr follow up was 7,764. Compared to patients with low CRP (<20 mg/L), patients with elevated CRP (>20mg/L) had a higher 1-year ARR of HF, and all cause death (p<0.001). Compared to patients with low CRP, patients with elevated CRP had a lower 1-year ARR of all-ablation and new DC cardioversion (p<0.001), (Table 1). CRP > 20mg/L was associated with lower risk for new DC cardioversion (HR 0.72, 95% CI: 0.64-0.82, p<0.001). However, in patients <75 years of age with CRP > 20mg/L at baseline had an increased risk of stroke after multivariable adjustments (HR 1.92, 95% CI: 1.10-3.35; p = 0.02) (Fig.1), while CRP > 20 mg/L was not associated with an increased risk of stroke in patients > 75yrs of age (Cox regressions estimates) (p for interaction = 0.03). Conclusion However, elevated CRP was associated with an increased risk of stroke in patients <75 years of age, even after multivariable adjustments. These results suggest that CRP may not be a reliable predictor of readmission for DC-cardioversion, especially in older individuals, but might be a potential risk stratification tool in identifying AF patients at higher risk of stroke in young individuals. We suspect this is due to the population with elevated CRP has more comorbidities and are older.

Abstract Background Inflammation is increasingly recognized as a risk factor for cardiac morbidity in the general population. Biomarkers like high-sensitivity C-reactive protein (hs-CRP) can aid in the detection of adverse systemic inflammation. The relationship between hs-CRP and cardiac structure and function is therefore a target of interest. Purpose The purpose of this study was to investigate the association of inflammation with cardiac structure and function in individuals free of overt cardiac disease. In addition, we examined if hs-CRP provided prognostic information regarding incident heart failure and myocardial infarction independent of echocardiographic measures. Methods In a community-based cohort study, participants were randomly selected for invitation from the Capital Region of Denmark. Echocardiography was performed on all the participants and measures of cardiac structure and function were obtained by blinded investigators. Participants with a history of cardiac disease were excluded from the analysis. Associations between log-transformed hs-CRP and echocardiographic measures were analyzed through uni- and multivariable linear regressions. Results A total of 3,379 individuals were included. Mean age was 55 years, 42% were female and the median hs-CRP was 1.13 (interquartile range: 0.65 - 1.47) mg/L. In the univariable analyses, increasing levels of hs-CRP were associated with worse left ventricular (LV) function including LV ejection fraction, global longitudinal strain (GLS), worse diastolic function (E/e’), worse right heart function (tricuspid regurgitation (TR) velocity and tricuspid annular plane systolic excursion (TAPSE)) and higher left ventricular (LV) mass index (p < 0.001 for all measures) (figure). When adjusting for sex, age, physical activity, smoking status, body mass index, blood pressure, hypercholesterolemia, diabetes, hypertension, creatinine, and heart rate, only LVEF (p < 0.001), GLS, (p < 0.001), E/e’ (p = 0.027), TAPSE (p = 0.008) and peak TR velocity (p = 0.015) remained significantly associated with increasing hs-CRP levels. In multivariable Cox regression adjusting for clinical characteristics and echocardiographic measures including LV ejection fraction, LV mass index, E/e’, TAPSE and GLS, higher hs-CRP was significantly associated with both heart failure and myocardial infarction (table) (HR for heart failure: 1.30, 95% CI: 1.03–1.66 p = 0.030; HR for acute myocardial infarction: 1.40, 95% CI: 1.04 – 1.89, p = 0.028, per doubling of hs-CRP). We did not find any interactions between hs-CRP and outcome among different types of echocardiographic phenotypes. Conclusion In the general population, higher levels of hs-CRP were associated with declining systolic, diastolic and right heart function. The associations persisted when adjusting for clinical characteristics. In addition, hs-CRP was associated with cardiac events independent of cardiac function as assessed by echocardiography.Linear regression splinesCox regressions

Abstract Background Human Immunodeficiency Virus (HIV) has become a treatable, chronic condition, but people with HIV still face an elevated risk of cardiovascular disease, including heart failure. Purpose To assess echocardiographic alterations in left ventricular (LV) function in a contemporary cohort of well-treated people with HIV compared to the general population. Methods We included 744 people with HIV frequency matched 1:1 on age and sex with controls from the general population. Both people with HIV and controls underwent echocardiography, physical examination, questionnaires and blood sampling according to similar study protocols. LV systolic dysfunction was defined as LV ejection fraction (LVEF) <50% or absolute global longitudinal strain (GLS) <16%. LV diastolic function was defined as abnormal if the following was true for half or more available parameters: (1) average E/e’>14, (2) septal e’ velocity < 7 cm/s or lateral e’ velocity <10cm/s, (3) tricuspid regurgitation velocity >2.8 m/s, (4) left atrial volume index >34ml/m2. Associations between HIV status and LV function were assessed using linear and logistic regression models adjusted for age, sex, smoking, hypertension, diabetes mellitus, total cholesterol and high-sensitivity C-reactive protein. Among people with HIV, the association between HIV-specific characteristics and LV function were assessed using logistic regression models with adjustment for the same potential confounders. Results Mean age was 53.4 years and 88% were male. For people with HIV, median time since HIV diagnosis was 18 years and 99% received antiretroviral therapy. People with HIV had lower adjusted mean absolute GLS [17.6 vs. 18.5%, p<0.001], E/A ratio [1.0 vs. 1.2, p<0.001] and average e’ [9.5 vs. 10.5 cm/s, p<0.001] than controls, while LVEF and E/e’ were not significantly different between people with HIV and controls (Figure 1). HIV was associated with impaired systolic function as assessed by GLS [odds ratio 1.70, 95% CI: 1.17-2.46, p=0.005], but not when assessed by LVEF [odds ratio 1.06, 95% CI: 0.78-1.45, p=0.69](Figure 2). Living with HIV was not associated with diastolic dysfunction compared to controls [odds ratio 0.97, 95% CI: 0.61-1.52, p=0.88], but longer HIV-duration was associated with higher odds of diastolic dysfunction among people with HIV (odds ratio 1.06, 95% CI: 1.02-1.10 per year, p=0.004). Current antiretroviral medication type, previous AIDS defining conditions, current CD4+ count and detectable viral load were not associated with LV dysfunction. Conclusion People with HIV show signs of early impairments in longitudinal LV systolic function compared to the general population. These subclinical changes may underlie the increased risk of heart failure observed in PWH.

BACKGROUND:Left atrial (LA) strain by three-dimensional echocardiography (3DE), has been proposed as a more accurate measure of LA function, providing incremental prognostic benefits over traditional two-dimensional approaches. OBJECTIVES:Our aim was to evaluate the prognostic value of LA strain by 3DE in predicting incident atrial fibrillation (AF) in the general population. METHODS:The study included 4466 participants from a prospective longitudinal cohort study in the general population, among these 3DE LA strain was analysed in 1935 participants. The endpoint was incident AF. Adjustments were made for the CHARGE-AF clinical risk score. RESULTS:Mean age was 54 ± 17 years, 43 % were male. During a median follow-up time of 4.8 years (interquartile range 4.3-5.5 years) 59 participants (3.0 %) developed AF. In univariable analysis, all three parameters were associated with incident AF (p value for all <0.01). After multivariable adjustments, only LA reservoir strain (LASr) and LA contractile strain (LASct) were associated with incident AF (LASr: HR 1.12 (1.07-1.17), p < 0.001, per 1 % decrease; LASct: HR 1.16 (1.09-1.24), p < 0.001, per 1 % decrease), whereas LA conduit strain (LAScd) was not (HR 1.04 (0.98-1.10), p = 0.17, per 1 % decrease). Both LASr (continuous net reclassification index 0.37 ± 0.14; p = 0.003) and LASct (continuous net reclassification index 0.41 ± 0.14; p = 0.002) provided incremental prognostic information beyond the CHARGE-AF risk score. CONCLUSION:LASr and LASct measured by 3DE are independently associated with incident AF and provided incremental prognostic information beyond existing risk scores.

Background The extent of cardiac involvement in cystic fibrosis (CF) remains to be determined. The remarkable therapeutic advancements with new highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator treatment and subsequent increase in life expectancy substantiates further research. We aimed to explore the prevalence of cardiac alterations in people with CF (pwCF) compared to matched controls and investigate potential cardiovascular risk factors. Methods In this cross-sectional study, 104 pwCF underwent clinical and echocardiographic assessment. All participants were matched 1:1 with controls from the general population. Results Of 104 pwCF, 44 % were female, mean age was 34 years, and 93 % received CFTR modulator treatment. The prevalence of abnormal cardiac function in pwCF was 44 %, more than double the prevalence in controls. PwCF were found to have smaller left ventricular (LV) dimensions, worse LV diastolic function, and reduced right ventricle (RV) as well as LV systolic function. After multivariable adjustment, LV diastolic function as well as LV and RV systolic function remained poorer in pwCF as compared to controls. Male sex and decreasing FEV1/FVC ratio remained independently associated with abnormal cardiac function in pwCF (male sex: OR 3.94 (1.56; 9.95), p = 0.004 and FEV1/FVC ratio: OR 2.05 per 0.1 unit decrease (1.21; 3.52), p = 0.008, respectively). Conclusions Both left- and right-sided cardiac alterations were found in pwCF. After adjustments for risk factors, both RV and LV systolic measures remained altered in pwCF, compared to controls. Male sex and decreasing pulmonary function evaluated by FEV1/FVC-ratio were associated with abnormal cardiac function in pwCF.

Abstract Background Cystic fibrosis (CF) is an autosomal recessive disease affecting multiple organs. Emerging evidence indicates an elevated risk of cardiovascular complications in people with CF (pwCF), with some studies implicating CF-related cardiomyopathy as an underlying mechanism. Whether screening for cardiac symptoms and N-terminal pro B-type natriuretic peptide (NT-proBNP) levels may aid in identifying cardiac impairment in pwCF remains unknown. Purpose To assess prevalence of dyspnea and chest pain in pwCF and investigate whether symptoms and NT-pro-BNP are predictive of cardiac impairment. Methods We interviewed 104 adult pwCF and 104 age- and sex-matched controls from the general population about symptoms of dyspnea and chest pain. All participants were examined with transthoracic echocardiography and NT-proBNP. Cardiac impairment was defined as left ventricular (LV) ejection fraction (LVEF) <50%, LV global longitudinal strain (GLS) < 16% or presence of diastolic dysfunction. Results Chest pain was more frequent in pwCF than in controls: (29% vs. 1%, p<0.001), although primarily characterized as atypical and non-exertional chest pain (27%). PwCF also suffered more from dyspnea than controls (89% vs. 18%, p<0.001) (Figure 1) and more pwCF had abnormal cardiac function compared to controls (44% versus 22%, p<0.001). Median NT-proBNP in pwCF was 50.0 pg/ml (40.7; 100.8) and increasing NT-proBNP level was associated with decreasing FEV1 (L) (estimate: -0.008, p<0.001). NT-proBNP level was not associated with neither dyspnea nor chest pain (p=0.60 and p=0.15, respectively). PwCF with dyspnea did not differ from those without on clinical or echocardiographic parameters. However, pwCF with chest pain had lower absolute GLS compared to pwCF without (17.4% vs.18.5%, p=0.026). Neither dyspnea nor chest pain was more frequent in pwCF with cardiac impairment versus normal cardiac function (54% vs. 39%, p=0.17 and 29% vs. 28%, p=0.91, respectively). Decreasing absolute GLS was associated with increased odds of chest pain (OR 1.25, 95% CI 1.02; 1.53, p=0.030) (Figure 2). Neither dyspnea or chest pain alone, nor in combination with NT-proBNP were able to predict abnormal cardiac function. While dyspnea and chest pain combined showed a slight improvement in sensitivity and positive predictive value for diagnosing cardiac impairment, the combination of symptoms and increased NT-proBNP did not enhance diagnostic accuracy. Conclusions In this cross-sectional study, dyspnea and atypical, non-exertional chest pain were common symptoms in adult pwCF. While abnormal cardiac function was prevalent in pwCF, neither symptoms, NT-proBNP nor a combination of these were associated with increased odds of cardiac impairment. Dyspnea and chest pain, though prevalent, are multifactorial in pwCF and do not seem to serve as sensitive markers of cardiac impairment, even when combined with NT-proBNP level.

ImportanceDespite strong worldwide guideline recommendations, influenza vaccination rates remain suboptimal among young and middle-aged patients with chronic diseases. Effective scalable strategies to increase vaccination are needed.ObjectiveTo investigate whether electronically delivered letter-based nudges informed by behavioral science could increase influenza vaccination uptake among patients aged 18 to 64 years with chronic diseases.Design, Setting, and ParticipantsNationwide pragmatic registry-based randomized clinical implementation trial conducted between September 24, 2023, and May 31, 2024, enrolling all Danish citizens aged 18 to 64 years who met criteria for free-of-charge influenza vaccination in light of preexisting chronic disease. All trial data were sourced from nationwide administrative health registries.InterventionRandomized in 2.45:1:1:1:1:1:1 ratio to no letter (usual care) or 6 different behaviorally informed electronic letters.Main Outcomes and MeasuresThe primary end point was receipt of influenza vaccination on or before January 1, 2024, assessed in 7 prespecified coprimary comparisons (all intervention groups pooled vs usual care and each individual intervention group vs usual care). Absolute risk difference in proportions and a crude relative risk were calculated for each comparison.ResultsA total of 299 881 participants (53.2% [159 454] female, median age, 52.0 [IQR, 39.8-59.0] years) were randomized. Compared with usual care, influenza vaccination rates were higher among those receiving any intervention letter (any intervention letter, 39.6% vs usual care, 27.9%; difference, 11.7 percentage points; 99.29% CI, 11.2-12.2 percentage points; P < .001). Each individual letter type significantly increased influenza vaccination with the largest effect sizes observed with a repeated letter sent 10 days after the initial letter (repeated letter, 41.8% vs usual care, 27.9%; difference, 13.9 percentage points; 99.29% CI, 13.1-14.7 percentage points; P < .001) and a letter emphasizing potential cardiovascular benefits of vaccination (cardiovascular gain, 39.8% vs usual care, 27.9%; difference, 11.9 percentage points; 99.29% CI, 11.1-12.7 percentage points; P < .001). Vaccination rates were improved across major subgroups.Conclusions and RelevanceIn a nationwide randomized clinical implementation trial, electronically delivered letter-based nudges markedly increased influenza vaccination compared with usual care among young and middle-aged patients with chronic diseases. The results of this study suggest that simple, scalable, and cost-efficient electronic letter strategies may have substantial public health implications.Trial RegistrationClinicalTrials.gov Identifier: NCT06030739

AIMS:Pressure-strain loop (PSL) analysis is a novel echocardiographic tool capable of assessing myocardial work non-invasively. In this study, we aim to evaluate the prognostic value of myocardial work indices in the general population. METHODS AND RESULTS:This was a prospective community-based cohort study (n = 4466). PSL analyses were performed to acquire global work index (GWI), global constructive work (GCW), global wasted work, and global work efficiency (GWE). The endpoint was a composite of heart failure or cardiovascular death (HF/CVD). Survival analysis was applied. A total of 3932 participants were included in this analysis (median age: 58 years, 43% men). Of these, 124 (3%) experienced the outcome during a median follow-up period of 3.5 years [interquartile range (IQR): 2.6-4.4 years]. Hypertension significantly modified the association between all work indices and outcome (P for interaction < 0.05), such that work indices posed a higher risk of outcome in non-hypertensive than in hypertensive participants. After adjusting for Atherosclerosis Risk in Communities (ARIC)-HF risk variables, all work indices predicted outcome in non-hypertensive participants, but only GWI, GCW, and GWE predicted outcome in hypertensive participants [GWI: hazard ratio (HR) = 1.12 (1.07-1.16), per 100 mmHg% decrease; GCW: HR = 1.12 (1.08-1.17), per 100 mmHg% decrease; GWE: HR = 1.08 (1.04-1.12), per 1% decrease]. Only GWE significantly increased C-statistics when added to ARIC-HF risk variables in hypertensive participants (C-stat 0.865 vs. 0.877, P for increment = 0.003). CONCLUSION:Hypertension modifies the association between myocardial work indices and HF/CVD in the general population. All work indices are associated with outcome in normotensive participants. GWI, GCW, and GWE are independently associated with outcome in hypertension, but only GWE improves risk prediction.

Abstract Background The use of glucagon-like peptide-1 receptor agonsists (GLP-1 RA) continues to rise and is increasingly important in the treatment of type-2 diabetes mellitus (T2DM). Though the use of GLP-1 RA continues to increase, persistence and adherence to therapy remains suboptimal. Purpose We aimed to assess the level of adherence and persistence to GLP-1 RA using real-world data and to investigate sociodemographic and clinical factors associated with discontinuation of GLP-1 RA therapy. Methods In this retrospective cohort study, all first-time users of GLP-1 RA with T2DM ≥18 years from 2007-2020 were identified using the Danish registries (Figure 1A-1B). All participants had 18 months of follow-up. Medication possession ratio (MPR) was calculated by summing days of medication supply from all dispensed prescription made during the study period divided by number of days in study period. MPR ≥0.80 was used to define adherence. Discontinuation was defined as >90 days between the last day of prescription coverage and the first day of a new dispensed prescription. Adherence to GLP-1 RA therapy and the risk of discontinuing therapy was estimated at 6- and 12-months of follow-up. Multivariable logistic regression was used to identify sociodemographic and clinical factors associated with discontinuing GLP-1 RA therapy. Results In total, 44,343 first-time users of GLP-1 RA with T2DM were identified (mean age: 58.6 years, 42.7% female, 21.3% had cardiovascular disease, median duration of T2DM was 6.8 years, median HbA1c was 65 mmol/mol). The absolute risk of discontinuing GLP-1 RA at 6 and 12 months was 14.2% (95%CI: 13.9-14.6) and 21.4% (95%CI: 21.1-21.8), respectively (Figure 2A). Of the 9,520 (21.5%) who discontinued therapy during the 12-month follow-up, 1,947 (20.5%) occurred within the first 31 days of treatment. At 6 months, 58.5% were adherent to GLP-1 RA therapy with a median MPR of 0.84 [IQR: 0.70-0.95]. At 12 months, 61.1% were adherent to therapy with a median MPR of 0.85 [IQR: 0.71, 0.94]. In the multivariable model, low (<40 years) and high age (>75 years), lower household income, educational level, longer diabetes duration, and higher comorbidity burden were associated with a higher risk of discontinuing GLP-1 RA whereas baseline HbA1c was not (Figure 2B-2E). Conclusion Approximately one in five patients discontinued therapy within 12 months and a little over 60% were adherent. Sociodemographic factors, including household income, age, and comorbidity burden were associated with risk of discontinuing GLP-1 RA therapy. Given the changing landscape of who should be treated with GLP-1 RA, the cardio-renal benefits reported in recent trials, and the ongoing trials in the field, future research into adherence and persistence to GLP-1 RA and possible interventions to improve these, are needed.

Abstract Background Lipoprotein(a) [Lp(a)] is a genetically determined risk factor for myocardial infarction and aortic valve stenosis, and elevated Lp(a) levels are associated with increased risk of heart failure. While part of this heart failure risk is mediated through atherosclerotic and valvular disease, other pathological pathways may also contribute to the association between Lp(a) and heart failure. Purpose To assess if Lp(a) levels and corresponding LPA genotypes are associated with echocardiographic measures of left ventricular structure and function in the general population. Methods We included 3,427 participants from an observational general population study who underwent protocol echocardiography between 2011-15 and had an available measurement of Lp(a) and LPA genotypes. Lp(a) was measured in 1991-94 and 2001-03 using well-validated assays with the most recent measurement used for the present analysis. Participants were divided into groups based on quartiles of Lp(a) with the top quartile further stratified to capture those above the 90th percentile. For genetic analysis, participants were grouped based on kringle IV type 2 [KIV-2] repeat corresponding to plasma Lp(a) percentile groups. Linear regression models were used to estimate β-coefficients for echocardiographic measures associated with Lp(a) levels and genotypes, while logistic regression models were used to estimate odds ratios for cardiac dysfunction or remodeling. All models were adjusted for age and sex. Results Mean age was 63±14 years and 44% were male. Median plasma Lp(a) was 18 mg/dL [IQR 10-40], median number of KIV-2 repeats were 36 [30-40], 102 (3%) were rs3798220 minor allele carriers and 467 (14%) were rs10455872 carriers. Mean left ventricular ejection fraction [LVEF] was 56.0±6.6% and we had 99% power to detect an absolute LVEF difference of 2% between those with Lp(a) levels above the 90th percentile (corresponding to >75 mg/dL) compared with those below the 25th percentile (<10 mg/dL). Mean absolute global longitudinal strain (GLS) was 19.2±2.7% and we had 99% power to detect an absolute difference of 1%. However, we found no statistically significant differences in echocardiographic measures according to Lp(a) levels or LPA genotypes (Table 1). The prevalence of impaired LVEF was 16%, and we had <20% power to detect an odds ratio of 1.2 for those with Lp(a) above the 90th percentile compared with those below the 25th percentile. We found no significant associations between odds for cardiac dysfunction or left ventricular hypertrophy and Lp(a) levels or LPA genotypes (Table 2). Conclusion Elevated Lp(a) levels and corresponding LPA genotypes were not associated with echocardiographic measures of left ventricular structure and function in this general population cohort. While we did not have sufficient power to detect associations between Lp(a) and cardiac dysfunction, our findings do not support a substantial effect of Lp(a).

Aims It is unclear how serial high-sensitivity troponin-I (hsTnI) concentrations affect long-term prognosis in individuals with suspected acute coronary syndrome (ACS). Methods and results Subjects who underwent two hsTnI measurements (Siemens TnI Flex (R) Reagent) separated by 1-7 h, during a first-time hospitalization for myocardial infarction, unstable angina, observation for suspected myocardial infarction, or chest pain from 2012 through 2019, were identified through Danish national registries. Individuals were stratified per their hsTnI concentration pattern (normal, rising, persistently elevated, or falling) and the magnitude of hsTnI concentration change (<20%, >20-50%, or >50% in either direction). We calculated absolute and relative mortality risks standardized to the distributions of risk factors for the entire study population. A total of 20 609 individuals were included of whom 2.3% had died at 30 days, and an additional 4.7% had died at 365 days. The standardized risk of death was highest among persons with a persistently elevated hsTnI concentration (0-30 days: 8.0%, 31-365 days: 11.1%) and lowest among those with two normal hsTnI concentrations (0-30 days: 0.5%, 31-365 days: 2.6%). In neither case did relative hsTnI concentration changes between measurements clearly affect mortality risk. Among persons with a rising hsTnI concentration pattern, 30-day mortality was higher in subjects with a >50% rise compared with those with a less pronounced rise (2.2% vs. <0.1%). Conclusion Among individuals with suspected ACS, those with a persistently elevated hsTnI concentration consistently had the highest risk of death. In subjects with two normal hsTnI concentrations, mortality was very low and not affected by the magnitude of change between measurements. Lay summary In this Danish study of >20 000 individuals with suspected heart attack, we confirmed the clinical importance of drawing two consecutive blood samples for measurement of high-sensitivity troponin-I concentrations (a marker of damage to the heart): center dot The risk of death was highest in persons with two elevated high-sensitivity troponin-I concentrations and lowest in those with two normal concentrations. center dot Among persons who had a first normal and a subsequently elevated high-sensitivity troponin-I concentration, a >50% relative rise was associated with significantly higher risk of death at 30 days. [GRAPHICS] .