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Christian Kjer Heerfordt,1 Christian Rønn,1 Josefin Eklöf,1 Pradeesh Sivapalan,1 Zitta Barrella Harboe,2,3 Charlotte Hyldgaard,4 Andreas Fløe,5 Alexander G Mathioudakis,6,7 Mats Christian Højbjerg Lassen,8 Tor Biering-Sørensen,8,9 Jens-Ulrik Stæhr Jensen1,3,10 1Section of Respiratory Medicine, Department of Medicine, Copenhagen University Hospital Herlev and Gentofte, Hellerup, Denmark; 2 Department of Respiratory Medicine and Infectious Diseases, Copenhagen University Hospital, North Zealand, Hillerød, Denmark; 3Department of Clinical Medicine Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 4Diagnostic Centre, University Research Clinic for Innovative Patient Pathways, Silkeborg Regional Hospital, Silkeborg, Denmark; 5Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark; 6Division of Immunology, Immunity to Infection and Respiratory Medicine, School of Biological Sciences, The University of Manchester, Manchester, UK; 7North West Lung Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK; 8Department of Cardiology, Herlev & Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark; 9Faculty of Biomedical Sciences, Copenhagen University, Copenhagen, Denmark; 10PERSIMUNE & CHIP: Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, DenmarkCorrespondence: Jens-Ulrik Stæhr Jensen, Email jens.ulrik.jensen@regionh.dkBackground: Extra-fine particle inhaled corticosteroids (ICS) improve peripheral airway distribution, but their effect on risk of exacerbations and all-cause mortality in patients with chronic obstructive pulmonary disease (COPD) is unclear.Methods: This observational cohort study compares patients with COPD who received extra-fine particle ICS to those who received standard particle size ICS from 2010 to 2017 while followed in outpatient clinics. The primary outcome was the time to a COPD exacerbation that required hospitalization, with all-cause mortality as a secondary outcome. Data were analyzed using an adjusted Cox proportional hazards model and a competing risk analysis. Two predefined subgroup analyses of patients treated with pressurised metered dose inhalers (pMDIs) and patients with a previous exacerbation history, was carried out. Lastly, we created a propensity score matched cohort as a sensitivity analysis.Results: Of the 40,489 patients included, 38,802 (95.8%) received stand particle size ICS and 1,687 (4.2%) received extra-fine particle ICS. In total 7,058 were hospitalized with a COPD exacerbation, and 4,346 died. No significant protective effect of extra-fine particle ICS against hospitalization due to COPD exacerbations (HR 0.93, 95% CI 0.82– 1.05, p=0.23) or all-cause mortality (HR 1.00, 95% CI 0.85– 1.17, p=0.99) was found when compared to standard particle size ICS. However, in the subgroup analysis of patients treated with pMDIs, extra-fine particle ICS was associated with reduction in risk of exacerbations (HR 0.72, 95% CI 0.63– 0.82, p< 0.001) and all-cause mortality (HR 0.72, 95% CI 0.61– 0.86, p< 0.001).Conclusion: The administration of extra-fine particle ICS was not associated with reduced risk of exacerbations or all-cause mortality in our primary analysis. A subgroup consisting of patients treated with pMDIs suggested potential protective benefits.Keywords: COPD, Inhaled Corticosteroids, Particle size, COPD exacerbations

Aims: To assess the level of adherence to glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment using real-world data and to investigate the sociodemographic and clinical factors associated with discontinuation of GLP-1RAs., Methods: First-time users of GLP-1RAs with type 2 diabetes mellitus (T2DM), aged ≥18 years, in the period 2007 to 2020, were identified using Danish registries, allowing all participants a minimum of 18 months' follow-up. Adherence to GLP-1RA therapy (medication possession ratio >0.80) and discontinuation of GLP-1RA therapy was estimated at 6- and 12-month follow-ups. Multivariable cause-specific Cox regression was used to identify sociodemographic and clinical factors associated with risk of discontinuation., Results: In total, 44 343 first-time users of GLP-1RAs with T2DM were identified (mean age 58.6 years, 42.7% female, median duration of T2DM 6.8 years, median glycated haemoglobin level 65 mmol/mol). The absolute risk of discontinuing GLP-1RA treatment within 6 months was 14.2% (95% confidence interval [CI] 13.9-14.6) and 21.2% (95% CI 20.8-21.5) within 12 months. At 6 months, 50.4% were adherent to GLP-1RA therapy and at 12 months, 48.6% remained adherent. In the multivariable model, younger (<40 years) and older age (>75 years), higher Charlson Comorbidity Index score, lower household income, high school and longer university degree as educational attainment level, and longer diabetes duration were associated with a higher risk of discontinuing GLP-1RA treatment., Conclusion: Approximately one in five patients discontinued GLP-1RA therapy within the first 12 months and only half were adherent. Overall, lower socioeconomic status and higher comorbidity burden were associated with higher risk of discontinuing GLP-1RA treatment., (© 2024 John Wiley & Sons Ltd.)

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., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: RFT reports: Travel grant from Gilead. SDN reports: Advisory Board: Gilead, Takeda and GSK; Speaker honorarium: Gilead, Merck and GSK; Research grant: Novo Nordisk Foundation. KGS reports: Advisory Board: Sanofi Pasteur. TBS reports: Advisory Board: Sanofi Pasteur, Amgen, CSL Seqirus and GSK; Speaker honorarium: Bayer, Novartis, Sanofi Pasteur, GE healthcare and GSK; Research grants: Boston Scientific, GE Healthcare, AstraZeneca, Novo Nordisk and Sanofi Pasteur; Consultant appointments: Novo Nordisk, IQVIA and Parexel., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Global longitudinal strain (GLS) is recognized as a powerful predictor of heart failure (HF). However, the entire strain curve may entail important prognostic information regarding HF risk that might be undiscovered by only focusing on the peak strain value., Objective: The hypothesis of the present study was, that analysis of the entire strain curve using unsupervised machine learning (uML) would reveal novel ventricular deformation patterns capable of predicting incident HF independently of GLS., Methods: Longitudinal strain curves from 3710 subjects from the general population without prevalent HF were analyzed using uML., Results: Mean age was 56 years and 43 % were male. During a median follow-up of 5.3 years, 92 subjects (2.5 %) developed HF. The uML algorithm generated a hierarchical clustering tree (HCT) resulting in 10 different clusters. Generally, the strain curves displayed reduced early diastolic strain to peak-strain ratio with an increasing incidence rate of HF. In multivariable Cox regressions, cluster 9 was significantly associated with increased risk of HF when compared to cluster 2-5, and 7-8 [For cluster 3: HR 8.95, 95 %CI: 2.08;38.48, P = 0.003] even though the subjects of cluster 9 were younger, displayed healthier clinical baseline characteristics, and only had slightly reduced GLS. The mean strain curve of cluster 9 displayed an early systolic lengthening followed by a late and reduced contraction specifically related to the basal lateral segment., Conclusion: The unsupervised machine learning algorithm identified unknown strain patterns beyond GLS presumably related to increased risk of HF., Competing Interests: Declaration of competing interest Nothing to Disclose., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: Whether vaginal estradiol use is associated with an increased risk of recurrent venous thromboembolism (VTE) in women with prior VTE is unknown. We sought to evaluate the association between vaginal estradiol use and recurrent VTE in women with prior VTE., Methods: We performed a nationwide nested case-control study among 44 024 women aged ≥45 years who developed a first VTE without a history of vaginal estrogen use prior to VTE diagnosis. Cases with recurrent VTE were matched 1:2 on birth year with controls using incidence density sampling. Exposure to vaginal estradiol tablets was categorized into current use (0-2 months before index), prior use (2-24 months before index) and past use (more than 24 months prior to index)., Results: We identified 5066 cases and 10 127 age-matched controls. In fully adjusted analysis vaginal estrogen was not associated with recurrent VTE with a hazard ratio of 0.75, p = .07 for current use, 0.83, p = .13 for prior use, and 1.24, p = .06 for past use., Conclusion: Use of vaginal estradiol tablets in women with prior VTE was not associated with an increased rate of recurrent VTE. Our study indicates that vaginal estradiol therapy is unlikely to increase risk of recurrent VTE in women with prior VTE., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aims: Cardiovascular-kidney-metabolic (CKM) multimorbidity is prevalent among individuals with heart failure (HF), but whether cardiac structure and function, clinical outcomes, and treatment response to sacubitril/valsartan vary in relation to CKM status is unknown., Methods and Results: In this PARAGON-HF post-hoc analysis, we evaluated the impact of CKM multimorbidity (atherosclerotic cardiovascular [CV] disease, chronic kidney disease, and type 2 diabetes) on cardiac structure and function, clinical outcomes, and treatment effects of sacubitril/valsartan versus valsartan. The primary outcome was a composite of total HF hospitalizations and CV death. Secondary outcomes included the individual components of the primary outcome and a composite kidney outcome (sustained estimated glomerular filtration rate reduction of ≥50%, end-stage kidney disease, or kidney-related death). At baseline, 35.2% had one CKM condition, 33.3% had two, 15.9% had three, and only 15.6% had HF alone. CKM multimorbidity was associated with higher septal and posterior wall thickness, lower global longitudinal strain, higher E/e', and worse right ventricular function. Total HF hospitalizations or CV death increased with greater CKM multimorbidity, with the highest relative risk observed with three CKM conditions (rate ratio 3.06, 95% confidence interval 2.33-4.03), compared with HF alone. Treatment effects of sacubitril/valsartan were consistent irrespective of the number of CKM conditions for the primary endpoint (p interaction  = 0.75), CV death (p interaction  = 0.82), total HF hospitalizations (p interaction  = 0.67), and the composite kidney endpoint (p interaction  = 0.99)., Conclusions: Cardiovascular-kidney-metabolic multimorbidity was common in PARAGON-HF and associated with adverse changes in cardiac structure and function and with a stepwise increase in risk of clinical outcomes. Treatment effects of sacubitril/valsartan were consistent irrespective of CKM burden., Clinical Trial Registration: ClinicalTrials.gov NCT01920711., (© 2024 European Society of Cardiology.)

Competing Interests: Conflict of interest: K.G.S.: advisory board: Sanofi; T.B.-S. is a chief investigator of the Boston Scientific financed ‘DANLOGIC-HF’ trial; chief investigator of the Sanofi Pasteur financed ‘NUDGE-FLU’ trial; chief investigator of the Sanofi Pasteur financed ‘DANFLU-1’ trial; chief investigator of the Sanofi Pasteur financed ‘DANFLU-2’ trial; steering committee member of the Boston Scientific sponsored ‘LUX-Dx TRENDS Evaluates Diagnostics Sensors in Heart Failure Patients Receiving Boston Scientific’s Investigational ICM System’ trial; steering committee member of the Amgen sponsored GALACTIC-HF trial; and steering committee member of the Boehringer Ingelheim financed EASi-KIDNEY trial; advisory board: Sanofi Pasteur, Amgen, CSL Seqirus, and GSK; speaker honorarium: Bayer, Novartis, Sanofi Pasteur, GE HealthCare, and GSK; research grants: Boston Scientific, GE HealthCare, AstraZeneca, Novo Nordisk, and Sanofi Pasteur; and consultant appointments: Novo Nordisk, IQVIA, and Parexel. M.V. has received research grant support, served on advisory boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, BMS, Boehringer Ingelheim, Chiesi, Cytokinetics, Lexicon Pharmaceuticals, Merck, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health, and participates on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. All other authors have nothing to disclose.

Aims: Type 2 diabetes (T2D) and heart failure (HF) frequently coexist, but whether clinical outcomes and treatment effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) vary in relation to background glucose-lowering therapy (GLT) in this population is uncertain., Methods and Results: DELIVER randomized patients with HF and left ventricular ejection fraction (LVEF) >40% to dapagliflozin or placebo. The primary outcome was a composite of worsening HF (HF hospitalization or urgent HF visit) or cardiovascular death. In this pre-specified analysis of participants with T2D, treatment effects were assessed by number and class of background GLT(s). Of 3150 participants with T2D at baseline, 22.9% were on no GLT, 36.5% were treated with 1 GLT, and 40.6% with ≥2 GLTs. During follow-up (median: 2.3 years), treatment benefits of dapagliflozin (vs. placebo) on the primary outcome were consistent irrespective of the number of background GLTs (0 GLTs: hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.50-1.00; 1 GLT: HR 1.04, 95% CI 0.80-1.34; ≥2 GLTs: HR 0.71, 95% CI 0.56-0.90; p interaction  = 0.59). Similar findings were observed among participants with (HR 0.73, 95% CI 0.59-0.92) and without background metformin use (HR 0.89, 95% CI 0.72-1.11; p interaction  = 0.22) and in participants with (HR 0.89, 95% CI 0.69-1.16) and without background insulin use (HR 0.78, 95% CI 0.65-0.95; p interaction  = 0.45). Dapagliflozin was well-tolerated irrespective of the number of background GLTs., Conclusions: Dapagliflozin safely and consistently improved clinical outcomes among individuals with T2D and HF with LVEF >40% irrespective of the number and class of background GLTs, and the benefits were not influenced by concomitant metformin or insulin use. These data bolster contemporary guidelines supporting first-line SGLT2i among individuals with T2D and HF, irrespective of background GLT., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Objectives: To summarize current evidence of high-dose influenza vaccine (HD-IV) vs standard-dose (SD-IV) regarding severe clinical outcomes., Methods: A prespecified meta-analysis was conducted to assess relative vaccine effectiveness (rVE) of HD-IV vs SD-IV in reducing the rates of (1) pneumonia and influenza (P&I) hospitalization, (2) all hospitalizations, and (3) all-cause death in adults ≥ 65 years in randomized controlled trials. Pooled effect sizes were estimated using fixed-effects models with the inverse variance method., Results: Five randomized trials were included encompassing 105,685 individuals. HD-IV vs SD-IV reduced P&I hospitalizations (rVE: 23.5 %, [95 %CI: 12.3 to 33.2]). HD-IV vs SD-IV also reduced rate of all-cause hospitalizations (rVE: 7.3 %, [95 %CI: 4.5 to 10.0]). No significant differences were observed in death rates (rVE = 1.6 % ([95 %CI: -2.0 to 5.0]) in HD-IV vs SD-IV. Sensitivity analyses omitting trials with participants sharing the same comorbidity, trials with ≥ 100 events, and random-effects models provided comparable estimates for all outcomes., Conclusions: HD-IV reduced the incidence of P&I and all-cause hospitalization vs SD-IV in adults ≥ 65 years in randomized trials, through no significant difference was observed in all-cause death rates. These findings, supported by evidence from several randomized studies, can benefit from replication in a fully powered, individually randomized trial., Competing Interests: Declaration of Competing Interest KGS has served on advisory boards for Sanofi. MML, RH, and MD are full-time employees of Sanofi and may hold stocks and/or shares in the company. SDS has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi, Theracos, US2. AI and consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Puretech Health. TBS is chief investigator of the Boston Scientific financed ”DANLOGIC-HF” trial, the Sanofi financed “NUDGE-FLU” trial, the Sanofi financed “DANFLU-1″ trial, the Sanofi financed “DANFLU-2″ trial and steering committee member of the Boston Scientific sponsored “LUX-Dx TRENDS Evaluates Diagnostics Sensors in Heart Failure Patients Receiving Boston Scientific's Investigational ICM System” trial, the Amgen sponsored GALACTIC-HF trial, the Boehringer Ingelheim financed EASi-KIDNEY trial and served on advisory boards for Sanofi, Amgen, CSL Seqirus and GSK and received speaker honorariums from Bayer, Novartis, Sanofi, GE Healthcare and GSK and received research grants from Boston Scientific, GE Healthcare, AstraZeneca, Novo Nordisk, and Sanofi and consulted for Novo Nordisk, IQVIA and Parexel. The remaining authors have nothing to disclose., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aim: High-dose quadrivalent influenza vaccine (QIV-HD) has been shown to be more effective than standard-dose (QIV-SD) in reducing influenza infection, but whether diabetes status affects relative vaccine effectiveness (rVE) is unknown. We aimed to assess rVE on change in glycated haemoglobin [HbA1c (∆HbA1c)], incident diabetes, total all-cause hospitalizations (first + recurrent), and a composite of all-cause mortality and hospitalization for pneumonia or influenza., Methods: DANFLU-1 was a pragmatic, open-label trial randomizing adults (65-79 years) 1:1 to QIV-HD or QIV-SD during the 2021/22 influenza season. Cox proportional hazards regression was used to estimate rVE against incident diabetes and the composite endpoint, negative binomial regression to estimate rVE against all-cause hospitalizations, and ANCOVA when assessing rVE against ∆HbA1c., Results: Of the 12 477 participants, 1162 (9.3%) had diabetes at baseline. QIV-HD, compared with QIV-SD, was associated with a reduction in the rate of all-cause hospitalizations irrespective of diabetes [overall: 647 vs. 742 events, incidence rate ratio (IRR): 0.87, 95% CI (0.76-0.99); diabetes: 93 vs. 118 events, IRR: 0.80, 95% CI (0.55-1.15); without diabetes: 554 vs. 624 events, IRR: 0.88, 95% CI (0.76-1.01), p interaction  = 0.62]. Among those with diabetes, QIV-HD was associated with a lower risk of the composite outcome [2 vs. 11 events, HR: 0.18, 95% CI (0.04-0.83)] but had no effect on ∆HbA1c; QIV-HD adjusted mean difference: ∆ + 0.2 mmol/mol, 95% CI (-0.9 to 1.2). QIV-HD did not affect the risk of incident diabetes [HR 1.18, 95% CI (0.94-1.47)]., Conclusions: In this post-hoc analysis, QIV-HD versus QIV-SD was associated with an increased rVE against the composite of all-cause death and hospitalization for pneumonia/influenza, and the all-cause hospitalization rate irrespective of diabetes status., (© 2024 John Wiley & Sons Ltd.)

Aims: 3D echocardiographic (3DE) assessment of the left atrium (LA) is a new modality of potential clinical value. Age- and sex-based normative values are needed to benchmark these parameters for clinical use., Methods and Results: Of 4466 participants in the 5th Copenhagen City Heart Study, a prospective longitudinal cohort study on the general population, 2082 participants underwent 3DE of the LA. Healthy participants were included to establish normative values for LA strain, volume, and function by 3DE. The effects of age and sex were also evaluated. After excluding participants with comorbidities, 979 healthy participants (median age 44 years, 39.6% males) remained. The median and limits of normality (2.5th and 97.5th percentiles) for functional and volumetric measures were as follows: LA reservoir strain (LASr) 30.8% (18.4-44.2%), LA conduit strain (LAScd) 19.1% (6.8-32.0%), LA contractile strain 11.7% (4.3-22.2%), total LA emptying fraction (LAEF) 61.4% (47.8-71.0%), passive LAEF 37.7% (17.4-53.9%), active LAEF 37.4% (22.2-52.5%), LA minimum volume index (LAVimin) 10.2 (5.9-18.5) mL/m2, and LA maximum volume index (LAVimax) 26.8 (16.5-40.1) mL/m2. All parameters changed significantly with increasing age (P value for all <0.001). Significant sex-specific differences were observed for all parameters except active LAEF and LAVimax. Sex significantly modified the association between age and LASr (P for interaction < 0.001), LAScd (P for interaction < 0.001), LAVimin (P for interaction = 0.037), and total LAEF (P for interaction = 0.034) such that these parameters deteriorated faster with age in females than males., Conclusion: We present age- and sex-specific reference material including limits of normality for LA strain, volume, and function by 3DE., Competing Interests: Conflict of interest: M.Y.: none; F.J.O.: none; K.G.S.: advisory board: Sanofi Pasteur; M.C.H.L.: none; N.D.J.: none; F.L.L.: none; G.B.J.: none; P.Sc.: none; R.M.: none; P.Sø.: advisory board: Biotronik; and T.B.-S.: Steering Committee member of the Amgen-financed GALACTIC-HF trial; Steering Committee member of the Boehringer Ingelheim–financed SHARP3 trial; chief investigator of the Sanofi Pasteur–financed ‘NUDGE-FLU’ trial; chief investigator of the Sanofi Pasteur–financed ‘DANFLU-1’ trial; chief investigator of the Sanofi Pasteur–financed ‘DANFLU-2’ trial; Steering Committee member of ‘LUX-Dx TRENDS Evaluates Diagnostics Sensors in Heart Failure Patients Receiving Boston Scientific’s Investigational ICM System’ trial; advisory board: Sanofi Pasteur, Amgen, and GSK; speaker honorarium: Bayer, Novartis, Sanofi Pasteur, and GSK; and research grants: GE Healthcare, AstraZeneca, Novo Nordisk, and Sanofi Pasteur., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: Mitral regurgitation (MR) can be difficult to quantify. We sought to investigate whether the MR jet area to left atrial (LA) area ratio (MR/LA ratio) method for quantifying MRs can be used to predict incident atrial fibrillation (AF) in the general population., Methods and Results: The study included 4466 participants from the 5th Copenhagen City Heart Study, a prospective general population study, who underwent transthoracic echocardiography. MR jet area was measured and indexed to LA area. The endpoint was incident AF. MR was quantified in 4042 participants (mean age: 57 years, 43% men). Of these, 198 (4.9%) developed AF during a median follow-up period of 5.3 years (interquartile range: 4.4-6.1 years). MR was present in 1938 participants (48%) including 1593 (39%) trace/mild MRs (MR/LA ratio ≤ 20% and ≤4 cm2). In unadjusted analysis, MR/LA ratio was associated with incident AF [HR: 1.06 (1.00-1.13), P = 0.042 per 5% increase] but not after adjusting for CHARGE-AF score. However, the association was modified by age (P for interaction = 0.034), such that MR/LA ratio was associated with AF only in participants ≤ 73 years. In these participants, MR/LA ratio 'was' independently associated with AF after adjusting for CHARGE-AF score [HR: 1.14 (1.06-1.24), P = 0.001, per 5% increase]. This finding persisted when restricting the analysis to participants without moderate or severe MR and normal LA size [HR: 1.35 (1.09-1.68), P = 0.005, per 5% increase]., Conclusion: MR, including even trace regurgitations quantified by MR/LA ratio, is independently associated with incident AF in individuals ≤ 73 years of age., Competing Interests: Conflict of interest: M.Y.: none. F.J.O.: none. A.S.: none. K.G.S.: advisory board: Sanofi Pasteur. M.C.H.L.: none. N.D.J.: none. M.T.J.: none. G.B.J.: none. P.S.: none. R.M.: none. T.B.-S.: Steering Committee member of the Amgen financed GALACTIC-HF trial. Chief investigator of the Sanofi Pasteur financed ‘NUDGE-FLU’ trial. Chief investigator of the Sanofi Pasteur financed ‘DANFLU-1’ trial. Chief investigator of the Sanofi Pasteur financed ‘DANFLU-2’ trial. Steering Committee member of ‘LUX-Dx TRENDS Evaluates Diagnostics Sensors in Heart Failure Patients Receiving Boston Scientific’s Investigational ICM System’ trial. Advisory board: Sanofi Pasteur, Amgen, and GSK. Speaker honorarium: Bayer, Novartis, Sanofi Pasteur, and GSK. Research grants: GE Healthcare, Sanofi Pasteur, Novo Nordisk, and AstraZeneca., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

To investigate the long-term prognostic value of the left atrial (LA) strain indices - peak atrial longitudinal strain (PALS), peak conduit strain (PCS), and peak atrial contractile strain (PACS) in acute coronary syndrome (ACS) patients in relation to all-cause mortality. This retrospective study included ACS patients treated with percutaneous coronary intervention (PCI) and examined with echocardiography. Exclusion criteria were non-sinus rhythm during echocardiography, missing images, and inadequate image quality for 2D speckle tracking analysis of the LA. The endpoint was all-cause death. Multivariable Cox regression which included relevant clinical and echocardiographic measures was utilized to assess the relationship between LA strain parameters and all-cause mortality. A total of 371 were included. Mean age was 64 years and 76% were male. Median time to echocardiography was 2 days following PCI. During a median follow-up of 5.7 years, 83 (22.4%) patients died. Following multivariable analysis, PALS (HR 1.04, 1.01-1.06, p = 0.002, per 1% decrease) and PCS (HR 1.05, 1.01-1.09, p = 0.006, per 1% decrease) remained significantly associated with all-cause mortality. PALS and PCS showed a linear relationship with the outcome whereas PACS was associated with the outcome in a non-linear fashion such that the risk of death increased when PACS < 18.22%. All LA strain parameters remained associated with worse survival rate when restricting analysis to patients with left atrial volume index < 34 ml/m 2 . Reduced LA function as assessed by PALS, PCS, and PACS were associated with an increased risk of long-term mortality in patients with ACS., (© 2024. The Author(s).)

Aim: To promote the implementation of right ventricular (RV) longitudinal strain in clinical practice, we sought to propose normal values for RV free wall (RVFWLS) and four-chamber longitudinal strain (RV4CLS) and investigate the association with clinical and echocardiographic parameters in participants from the general population., Methods and Results: Participants from the 5th Copenhagen City Heart Study (2011-2015)-a prospective cohort study-with available RV longitudinal strain measurements were included. RVFWLS and RV4CLS were assessed using two-dimensional speckle-tracking echocardiography. In total, 2951 participants were included. Amongst 1297 participants without cardiovascular disease or risk factors (median age 44, 63% female), mean values of RVFWLS and RV4CLS were - 26.7% ± 5.2 (95% prediction interval (PI) - 36.9, - 16.5) and - 21.7% ± 3.4 (95%PI - 28.4, - 15.0), respectively. Women had significantly higher absolute values of RVFWLS and RV4CLS than men (mean - 27.5 ± 5.5 vs. - 25.4 ± 4.5, p < 0.001 and - 22.3 ± 3.5 vs. - 20.6 ± 3.0, p < 0.001, respectively). Absolute values of RVFWLS but not RV4CLS decreased significantly with increasing age in unadjusted linear regression. Tricuspid annular plane systolic excursion, RV s' and left ventricular global longitudinal strain were the most influential parameters associated with both RVFWLS and RV4CLS in multiple linear regression. Participants with cardiovascular disease (n = 1531) had a higher proportion of abnormal values of RVFWLS and RV4CLS compared to the healthy population (8% vs. 4%, p < 0.001 and 8% vs. 3%, p < 0.001, respectively)., Conclusion: This study proposed normal age- and sex-based values of RVFWLS and RV4CLS in a healthy population sample and showed significant sex differences in both measurements across ages., (© 2023. The Author(s).)

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., Competing Interests: Conflict of interest: T.B.-S.: Steering Committee member of the Amgen financed GALACTIC-HF trial; Steering Committee of the Boston Scientific financed LUX-Dx TRENDS trial; Advisory Board: Sanofi Pasteur. Advisory Board: Amgen; Speaker Honorarium: Novartis; Speaker Honorarium: Sanofi Pasteur; Research grant: GE Healthcare; Research grant: Sanofi Pasteur. O.A.S.: co-inventor of ‘Method for myocardial segment work analysis’, which was used to calculate myocardial work indices. J.H.S.: advisory board member for Medtronic and unrestricted research grants from Medtronic outside this work. The organizations had no role in any aspect of the study. The remaining authors do not have any potential conflicts of interest to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: Right ventricular free wall (RVFWLS) and four-chamber longitudinal strain (RV4CLS) are associated with adverse events in various patient populations including patients with heart failure (HF). We sought to investigate the prognostic value of RVFWLS and RV4CLS for the development of incident HF in participants from the general population., Methods and Results: Participants from the 5th Copenhagen City Heart Study (2011-2015) without known chronic ischaemic heart disease or HF at baseline were included. RVFWLS and RV4CLS were obtained using two-dimensional speckle-tracking echocardiography from the right ventricular (RV)-focused apical four-chamber view. The primary endpoint was incident HF. Among 2740 participants (mean age 54 ± 17 years, 42% male), 43 (1.6%) developed HF during a median follow-up of 5.5 years (IQR 4.5-6.3). Both RVFWLS and RV4CLS were associated with an increased risk of incident HF during follow-up independent of age, sex, hypertension, diabetes, body mass index and tricuspid annular plane systolic excursion (TAPSE), (HR 1.06, 95%CI 1.00-1.11, P = 0.034, per 1% absolute decrease and HR 1.14, 95%CI 1.05-1.23, P = 0.001, per 1% absolute decrease, respectively). Left ventricular ejection fraction (LVEF) modified the association between RV4CLS and incident HF (P for interaction = 0.016) such that RV4CLS was only of prognostic importance among those with LVEF < 55% (HR 1.21, 95%CI 1.11-1.33, P < 0.001 vs. HR 0.94, 95%CI 0.80-1.10, P = 0.43 in patients with LVEF ≥ 55%)., Conclusion: In participants from the general population, both RVFWLS and RV4CLS were associated with a greater risk of incident HF independent of important baseline characteristics and TAPSE, and LVEF modified the relationship between RV4CLS and incident HF., Competing Interests: Conflict of interest: T.B.S.: Steering Committee member of the Amgen financed GALACTIC-HF trial, the Boehringer Ingelheim financed EASi-KIDNEY trial, and the ‘LUX-Dx TRENDS Evaluates Diagnostics Sensors in Heart Failure Patients Receiving Boston Scientific’s Investigational ICM System’ trial. Chief investigator of the Sanofi Pasteur financed ‘NUDGE-FLU’ trial, the Sanofi Pasteur financed ‘DANFLU-1’ trial, and the Sanofi Pasteur financed ‘DANFLU-2’ trial, and the Boston Scientific financed “DANLOGIC-HF” trial., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Impaired diastolic function is a hallmark of diabetic cardiomyopathy and a common feature in type 1 diabetes mellitus (T1DM). The ratio of transmitral early filling velocity to early diastolic strain rate (E/e'sr) has in recent studies proved to have strong prognostic value. This study aimed to investigate the prognostic value of E/e'sr compared to E/e' in T1DM without known heart disease., Methods: In this prospective cohort of T1DM patients, echocardiography was performed including two-dimensional speckle tracking. Follow-up was performed using nationwide registries. Outcomes were all-cause mortality and major cardiovascular events (MACE)., Results: In total 1079 patients (age: 49.6 ± 14.5 years, 52.5% male, duration of diabetes 25.8 ± 14.6 years) were included in the study. During follow-up (median 6.3 years, IQR:5.7-6.9) 13.2% experienced MACE and 5.8% died. Following multivariable adjustment, both E/e'sr and E/e' was significantly associated with both MACE (E/e'sr: HR 1.16 CI95%:[1.05-1.29], p = 0.005, per 10 cm increase) vs. (E/e': HR 1.09 CI95%:[1.03-1.15], p = 0.001, per 1 unit increase) and all-cause mortality (E/e'sr: HR 1.20 [1.03-1.40], p = 0.016) vs. (E/e': HR: 1.11 [1.02-1.20], p = 0.016). Sex modified the association between E/e'sr and MACE (p for interaction = 0.008) such that E/e'sr after multivariable adjustment only remained significantly associated with MACE in females (HR: 1.41 [1.19-1.67], p < 0.001) but not in males (HR: 1.06 [0.93-1.20], p = 0.42). In females, E/e'sr provided incremental information beyond the Steno T1 Risk Engine (Harrell's C-statistic: 0.78 (0.72-0.83) vs. 0.81 (0.75-0.86), p = 0.007)., Conclusion: In patients with T1DM, both E/e'sr and E/e' provides independent prognostic information regarding prognosis. E/e'sr seems to have stronger prognostic value in females with T1DM., Competing Interests: Declaration of Competing Interest PR reports grants from and shares in Novo Nordisk, advisory boards in Astra Zeneca, Bayer, Boehringer, Eli Lilly, Mundi, Novo Nordisk, Sanofi, Astellas, Abbvie (all fees to institution). PGJ reports lecture fees from Novo Nordisk and Astra Zeneca. TBS: Steering Committee member of the Amgen financed GALACTIC-HF trial and the Boston Scientific financed LUX-Dx TRENDS trial; Advisory Board: Sanofi Pasteur and Amgen; Speaker Honorarium: Novartis and Sanofi Pasteur; Research grant: GE Healthcare and Sanofi Pasteur. MTJ has served as consultant, on advisory boards, or invited speaker for Astra Zeneca, Novo Nordisk, Novartis, and GE. The other authors report no conflicts., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Layer-specific global longitudinal strain (GLS) may provide important insights in patients with suspected coronary artery disease (CAD). We aimed to investigate the association between layer-specific GLS and coronary artery calcium score (CACS) in patients suspected of CAD., Methods: We performed a retrospective study of patients suspected of CAD who underwent both an echocardiogram and cardiac computed tomography (median 42 days between). Layer-specific (endocardial-, whole-layer-, and epicardial-) GLS was measured using speckle tracking echocardiography. We assessed the continuous association between layer-specific GLS and CACS by negative binomial regression, and the association with high CACS (≥400) using logistic regression., Results: Of the 496 patients included (mean age 59 years, 56% male), 64 (13%) had a high CACS. Those with high CACS had reduced GLS in all layers compared to those with CACS < 400 (endocardial GLS: -20.5 vs. -22.7%, whole-layer GLS: -17.7 vs. -19.4%, epicardial GLS: -15.3 vs. -16.9%, p < .001 for all). Negative binomial regression revealed a significant continuous association showing increasing CACS with worsening GLS in all layers, which remained significant after multivariable adjustment including SCORE chart risk factors. All layers of GLS were associated with high CACS in univariable analyses, which was consistent after multivariable adjustment (endocardial GLS: OR = 1.11 (1.03-1.20); whole-layer GLS: OR = 1.14 (1.04-1.24); epicardial GLS: OR = 1.16 (1.05-1.29), per 1% absolute decrease)., Conclusion: In this study population with patients suspected of CAD and normal systolic function, impaired layer-specific GLS was continuously associated with increasing CACS, and decreasing GLS in all layers were associated with presence of high CACS., (© 2024 Wiley Periodicals LLC.)

The ratio of early transmitral filling velocity to early diastolic strain rate (E/SRe) has been proposed as a new non-invasive measurement of left ventricular filling pressure. We aimed to investigate the ability of E/SRe to predict atrial fibrillation (AF) after ST-elevation myocardial infarction (STEMI). This was a prospective cohort study of patients (n = 369) with STEMI. Patients underwent an echocardiographic examination a median of two days after pPCI. By echocardiography, transmitral early filling velocity (E) was measured by pulsed-wave Doppler, and early diastolic strain rate (SRe) was measured by speckle tracking of the left ventricle. E was indexed to SRe and the early myocardial relaxation velocity (e') to obtain the E/SRe and E/e', respectively. The endpoint was new-onset AF. During follow-up (median 5.6 years, IQR: 5.0-6.1 years), 23 (6%) of the 369 patients developed AF. In unadjusted analyses, both E/SRe and E/e' were significantly associated with AF [E/SRe: HR = 1.06; (1.03-1.10); p < 0.001, per 10 increase] and [E/e': HR = 1.11 (1.05-1.17); p < 0.001, per 1 increase] and had equal Harrell's C-statistic of 0.71. However, only E/SRe remained an independent predictor after multivariable adjustments for clinical and echocardiographic parameters [E/SRe: HR = 1.06 (1.00-1.11); p = 0.044, per 10 increase]. E/SRe was further significantly associated with AF in patients with E/e' < 14 HR = 1.09 (1.01-1.17); p = 0.030, per 10 increase), also after multivariable adjustments. E/SRe is an independent predictor of AF in STEMI patients, even in subjects with seemingly normal filling pressure., (© 2023. The Author(s).)

Arrhythmogenic right ventricular cardiomyopathy is an inherited cardiomyopathy, characterized by abnormal cell adhesions, disrupted intercellular signaling, and fibrofatty replacement of the myocardium. These changes serve as a substrate for ventricular arrhythmias, placing patients at risk of sudden cardiac death, even in the early stages of the disease. Current echocardiographic criteria for diagnosing arrhythmogenic right ventricular cardiomyopathy lack sensitivity, but novel markers of cardiac deformation are not subject to the same technical limitations as current guideline-recommended measures. Measuring cardiac deformation using speckle tracking allows for meticulous quantification of global systolic function, regional function, and dyssynchronous contraction. Consequently, speckle tracking to quantify myocardial strain could potentially be useful in the diagnostic process for the determination of disease progression and to assist risk stratification for ventricular arrhythmias and sudden cardiac death. This narrative review provides an overview of the potential use of different myocardial right ventricular strain measures for characterizing right ventricular dysfunction in arrhythmogenic right ventricular cardiomyopathy and its utility in assessing the risk of ventricular arrhythmias.

Background: The effect of trastuzumab therapy on left atrial (LA) function remains largely unknown. Our aim was to assess the changes in LA strain parameters longitudinally in patients treated with trastuzumab., Methods: We retrospectively studied 170 patients with stage I-IV HER2+ breast cancer. All patients had baseline echocardiograms and repeat echocardiograms at 3 months and after 1 year. We measured LA strain at all three time points. Changes in LA strain and strain rate (sr) parameters were evaluated using repeated-measures mixed-effects models. The cohort was stratified according to development of cancer therapeutics-related cardiac dysfunction (CTRCD) during follow-up., Results: The mean age was 52.7 ± 13.8 years, 25.3% had hypertension and 16.0% had metastatic disease. Multiple LA strain parameters (predicted delta value, [95%CI]) showed statistically significant declines in patients who developed CTRCD from baseline to the 3-month follow-up after multivariable adjustment; LA reservoir strain (LAε res ): -4.7%; [-8.1% to -1.3%], p = .007; LA conduit strain (LAε con ): -2.8%; [-5.3% to -.4%], p = .021); and LAε res sr: -.2/s; [-.3/s to -.09/s], p < .001). In patients who did not develop CTRCD, LA strain parameters declined significantly but to a smaller degree than in the CTRCD group (LAε res : -1.7%; [-3.1% to -.3%], p = .020, LAε con : -2.2%; [-3.3% to -1.1%], p < .001, and LA booster pump strain : -2.4%; [-3.5% to -1.4%], p < .001). LA strain rates did not decline significantly in the non-CTRCD group., Conclusion: Trastuzumab treatment was associated with declines in LA strain parameters in patients with breast cancer. The largest declines were observed in patients who developed CTRCD during treatment., (© 2024 Wiley Periodicals LLC.)

Importance: Influenza vaccination is associated with a reduced risk of mortality in patients with diabetes, but vaccination rates remain suboptimal., Objective: To assess the effect of electronic nudges on influenza vaccination uptake according to diabetes status., Design, Setting, and Participants: The NUDGE-FLU (Nationwide Utilization of Danish Government Electronic Letter System for Increasing Influenza Vaccine Uptake) trial was a nationwide clinical trial of Danish citizens 65 years or older that randomized participants at the household level to usual care or 9 different electronic nudge letters during the 2022 to 2023 influenza season. End of follow-up was January 1, 2023. This secondary analysis of the NUDGE-FLU trial was performed from May to July 2023., Intervention: Nine different electronic nudge letters designed to boost influenza vaccination were sent in September to October 2022. Effect modification by diabetes status was assessed in a pooled analysis of all intervention arms vs usual care and for individual letters., Main Outcomes and Measures: The primary end point was receipt of a seasonal influenza vaccine., Results: The trial included 964 870 participants (51.5% female; mean [SD] age, 73.8 [6.3] years); 123 974 had diabetes. During follow-up, 83.5% with diabetes vs 80.2% without diabetes received a vaccine (P < .001). In the pooled analysis, nudges improved vaccination uptake in participants without diabetes (80.4% vs 80.0%; difference, 0.37 percentage points; 99.55% CI, 0.08 to 0.66), whereas there was no evidence of effect in those with diabetes (83.4% vs 83.6%; difference, -0.19 percentage points; 99.55% CI, -0.89 to 0.51) (P = .02 for interaction). In the main results of NUDGE-FLU, 2 of the 9 behaviorally designed letters (cardiovascular benefits letter and a repeated letter) significantly increased uptake of influenza vaccination vs usual care; these benefits similarly appeared attenuated in participants with diabetes (cardiovascular gain letter: 83.7% vs 83.6%; difference, 0.04 percentage points; 99.55% CI, -1.52 to 1.60; repeated letter: 83.5% vs 83.6%; difference, -0.15 percentage points; 99.55% CI, -1.71 to 1.41) vs those without diabetes (cardiovascular gain letter: 81.1% vs 80.0%; difference, 1.06 percentage points; 99.55% CI, 0.42 to 1.70; repeated letter: 80.9% vs 80.0%; difference, 0.87 percentage points; 99.55% CI, 0.22 to 1.52) (P = .07 for interaction)., Conclusions and Relevance: In this exploratory subgroup analysis, electronic nudges improved influenza vaccination uptake in persons without diabetes, whereas there was no evidence of an effect in persons with diabetes. Trials are needed to investigate the effect of digital nudges specifically tailored to individuals with diabetes., Trial Registration: ClinicalTrials.gov Identifier: NCT05542004.

Background: The ratio of transmitral early filling velocity to early diastolic strain rate (E/e'sr) has recently emerged as a measure of left ventricular filling pressure. Reference values are needed for this new parameter for it to be used clinically., Methods: Healthy participants from a prospective general population study, the Fifth Copenhagen City Heart Study, were assessed to establish reference values for E/e'sr derived from two-dimensional speckle-tracking echocardiography. The prevalence of abnormal E/e'sr was assessed in participants with cardiovascular risk factors or specific diseases., Results: The population comprised 1,623 healthy participants (median age, 45; interquartile range, 32-56; 61% female). The upper reference limit for E/e'sr in the population was 79.6 cm. Following multivariable adjustment, male participants exhibited significantly higher E/e'sr than female participants (upper reference limit for male participants, 83.7 cm; for female participants, 76.5 cm). For both sexes, E/e'sr increased in a curvilinear fashion with age such that the largest increases in E/e'sr were observed in participants >45 years. In the entire CCHS5 population with E/e'sr available (n = 3,902), increasing age, body mass index, systolic blood pressure, male sex, estimated glomerular filtration rate, and diabetes were associated with E/e'sr (all P < .05). Total cholesterol was associated with a less steep increase in E/e'sr. Abnormal E/e'sr was seldomly observed in participants with normal diastolic function but became more frequent in participants with increasing grades of diastolic dysfunction (normal, mild, moderate, severe [abnormal E/e'sr for each grade: 4.4% vs 20.0% vs 16.2% vs 55.6%, respectively])., Conclusion: The E/e'sr differs between sexes and is age dependent such that E/e'sr increases with advancing age. Therefore, we established sex- and age-stratified reference values for E/e'sr., (Copyright © 2023 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Background: The cardiac time intervals include the isovolumic contraction time (IVCT), the left ventricular ejection time (LVET), the isovolumic relaxation time (IVRT) and the combination of all the cardiac time intervals in the myocardial performance index (MPI) (defined as [(IVCT+IVRT)/LVET)]. Whether the cardiac time intervals change over time and which clinical factors that accelerate these changes is not well-established. Additionally, whether these changes are associated with subsequent heart failure (HF), remains unknown., Methods: We investigated participants from the general population (n = 1064) who had an echocardiographic examination including color tissue Doppler imaging performed in both the 4th and 5th Copenhagen City Heart Study. The examinations were performed 10.5 years apart., Results: The IVCT, LVET, IVRT and MPI increased significantly over time. None of the investigated clinical factors were associated with increase in IVCT. Systolic blood pressure (standardized β= - 0.09) and male sex (standardized β= - 0.08) were associated with an accelerated decrease in LVET. Age (standardized β=0.26), male sex (standardized β=0.06), diastolic blood pressure (standardized β=0.08), and smoking (standardized β=0.08) were associated with an increase in IVRT, while HbA1c (standardized β= - 0.06) was associated with a decrease in IVRT. Increasing IVRT over a decade was associated with an increased risk of subsequent HF in participants aged <65 years (per 10 ms increase: HR 1.33; 95%CI (1.02-1.72), p = 0.034)., Conclusion: The cardiac time increased significantly over time. Several clinical factors accelerated these changes. An increase in IVRT was associated with an increased risk of subsequent HF in participants aged <65 years., Competing Interests: Declaration of Competing Interest Tor Biering-Sørensen reports receiving research grants from Sanofi Pasteur and GE Healthcare, being a Steering Committee member of an Amgen financed and a Boston Scientific financed trial, on advisory boards for Sanofi Pasteur and Amgen, and speaker honorariums from Novartis, Sanofi Pasteur, and GSK. The remaining authors have nothing to disclose., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aim: Randomized controlled trials (RCTs) enrolling patients at high cardiovascular risk have found that influenza vaccination may reduce the incidence of cardiovascular events. We performed an updated meta-analysis assessing the effect of influenza vaccination on the incidence of cardiovascular events in patients with ischaemic heart disease or heart failure., Methods and Results: We searched PubMed, EMBASE and other sources to identify RCTs examining the effect of influenza vaccination on the incidence of cardiovascular events assessed as efficacy outcomes in patients with ischaemic heart disease or heart failure. Eligible studies followed patients for at least one influenza season, defined as a minimum duration of 6 months. The primary endpoint was a composite of cardiovascular death, acute coronary syndrome, stent thrombosis or coronary revascularization, stroke or heart failure hospitalization. The secondary endpoints were cardiovascular death and all-cause death. Two investigators independently identified and extracted data from studies. Results were compared using hazard ratios (HRs) in both random effects and fixed effects models. We included five peer-reviewed and one non peer-reviewed RCTs for a total of 9340 patients. Five trials included patients with ischaemic heart disease (n = 4211) and one trial included patients with heart failure (n = 5129). Influenza vaccination was associated with a reduced incidence of the primary composite endpoint (random effects HR [rHR] 0.74, 95% confidence interval [CI] 0.63-0.88, p < 0.001, I 2  = 52%), cardiovascular death (rHR 0.63, 95% CI 0.42-0.95, p = 0.028, I 2  = 58%) and all-cause death (rHR 0.72, 95% CI 0.54-0.95, p = 0.0227, I 2  = 52%). Results were similar when non peer-reviewed data were excluded., Conclusion: In this meta-analysis of available RCTs in patients at high cardiovascular risk, influenza vaccination was associated with a reduced incidence of cardiovascular events, cardiovascular death and all-cause death as compared to placebo or no treatment., (© 2023 European Society of Cardiology.)

Background: Color tissue Doppler imaging (TDI) M-mode can be used to measure the cardiac time intervals including the isovolumic contraction time (IVCT), the left ventricular ejection time (LVET), the isovolumic relaxation time (IVRT), and the combination of all the cardiac time intervals in the myocardial performance index (MPI) defined as [(IVCT + IVRT)/LVET]. The aim of this study was to establish normal age- and sex-based reference ranges for the cardiac time intervals., Methods and Results: A total of 1969 participants free of cardiovascular diseases and risk factors from the general population with limited age range underwent an echocardiographic examination including TDI. The median age was 46 years (25th-75th percentile: 33-58 years), and 61.5% were females. In the entire study population, the IVCT was observed to be 40 ± 10 ms [95% prediction interval (PI) 20-59 ms], the LVET 292 ± 23 ms (95% PI 248-336 ms), the IVRT 96 ± 19 ms (95% PI 59-134 ms) and MPI 0.47 ± 0.09 (95% PI 0.29-0.65). All the cardiac time intervals differed significantly between females and males. With increasing age, the IVCT increased in females, but not in males. The LVET did not change with age in both sexes, while the IVRT increased in both sexes with increasing age. Furthermore, we developed regression equations relating the heart rate to the cardiac time intervals and age- and sex-based normal reference ranges corrected for heart rate., Conclusion: In this study, we established normal age- and sex-based reference ranges for the cardiac time intervals. These normal reference ranges differed significantly with sex., (© 2023. The Author(s).)

Aims: Left ventricular (LV) systolic deformation is altered early in the ventricular disease process despite normal LV ejection fraction (LVEF). These alterations seem to be characterized by decreased global longitudinal strain (GLS) and augmented global circumferential strain (GCS). This study aimed to investigate the link between myocardial deformation phenotyping using longitudinal and circumferential strain and risk of incident heart failure (HF) and cardiovascular death (CD)., Methods and Results: The study sample was based on the prospective cohort study the 5th Copenhagen City Heart Study (2011-15). All participants were examined with echocardiography following a pre-defined protocol. A total of 2874 participants were included. Mean age was 53±18 years and 60% were female. During a median follow-up of 3.5 years, a total of 73 developed HF/CD. A U-shaped relationship between GCS and HF/CD was observed. LVEF significantly modified the association between GCS and HF/CD (P for interaction <0.001). The optimal transition point for the effect modification was LVEF < 50%. In multivariable Cox regressions, increasing GCS was significantly associated with HF/CD in participants with LVEF ≥ 50% (hazard ratio [HR]=1.12 [95% confidence interval (CI): 1.02; 1.23] per 1% increase), while decreasing GCS was associated with a higher risk of HF/CD in individuals with LVEF < 50% [HR=1.18 (95% CI: 1.05; 1.31) per 1% decrease]., Conclusions: The prognostic utility of GCS is modified by LVEF. In participants with normal LVEF, higher GCS was associated with increased risk of HF/CD, while the opposite was observed in participants with abnormal LVEF. This observation adds important information to our understanding of the pathophysiological evolution of myocardial deformation in cardiac disease progression., Competing Interests: Conflict of interest: K.G.S is a member of an advisory board in Sanofi Pasteur. T.B.S. is a steering committee member of the Amgen-financed GALACTIC-HF trial, chief investigator and steering committee chair of the Sanofi Pasteur–financed ‘NUDGE-FLU’ trial, chief investigator and steering committee chair of the Sanofi Pasteur–financed ‘DANFLU-1’ trial, chief investigator and steering committee chair of the Sanofi Pasteur–financed ‘DANFLU-2’ trial, and steering committee member of the ‘LUX-Dx TRENDS Evaluates Diagnostics Sensors in Heart Failure Patients Receiving Boston Scientific’s Investigational ICM System’ trial. He is a member of an advisory board in Sanofi Pasteur, Amgen, and GSK and has received speaker honorarium from Novartis, Sanofi Pasteur, and GSK and research grants from GE Healthcare and Sanofi Pasteur. The remaining authors have nothing to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: Hypertensive heart disease (HHD) is recognized as a key clinical precursor to heart failure with preserved ejection fraction (HFPEF). However, pathophysiological transition from HHD to HFPEF is not well understood. We sought determine whether regional differences in impaired myocardial function may underlie the greater mechanical dysfunction seen in HFPEF compared to HHD., Methods and Results: We used standardized echocardiography to assess regional myocardial deformation in a cohort of n = 327 adults with preserved left ventricular (LV) ejection fraction (≥45%), including: n = 129 with HFPEF, n = 158 with HHD and no heart failure, and n = 40 normotensive controls. From detailed measurements of LV systolic strain performed in multiple views, we derived and then compared regional measures of basal, mid-ventricular, and apical longitudinal strains. In models adjusting for clinical covariates, basal and mid-ventricular LV myocardial deformation was more impaired in HHD than in controls (P ≤ 0.003), whereas apical deformation was more impaired in HFPEF than in HHD (P = 0.005). In multivariable-adjusted analyses, only apical strain remained independently associated with HFPEF vs. HHD status [odds ratio 1.18 (1.02-1.37), P = 0.030 per 1% decrease in apical strain]. Compared to other regional strains, apical longitudinal strain optimally differentiated HFPEF from HHD (area under the receiver operating curve: apical longitudinal strain = 0.67; mid-ventricular longitudinal strain = 0.59; basal longitudinal strain = 0.60)., Conclusion: We found that while apical mechanical function is preserved in HHD, it was impaired in HFPEF and may contribute to the transition from an asymptomatic heart disease to a symptomatic heart disease., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Global longitudinal strain (GLS) and global circumferential strain (GCS) have been shown to be impaired in heart failure with preserved ejection fraction. We sought to assess whether treating patients with heart failure with preserved ejection fraction with sacubitril/valsartan would significantly improve GLS and GCS compared with valsartan alone., Methods and Results: PARAMOUNT (Prospective Comparison of ARNI With ARB on Management of Heart Failure With Preserved Ejection Fraction Trial) was a phase II, randomized, parallel-group, double-blind multicenter trial in 301 patients with New York Heart Association functional class II-III heart failure, a left ventricular ejection fraction of 45%, and an N-terminal pro-B-type natriuretic peptide of ≥400 pg/mL. Participants were randomly assigned (1:1) to sacubitril/valsartan titrated to 200 mg twice daily or valsartan titrated to 160 mg twice daily for 36 weeks. We assessed changes in the GLS and the GCS from baseline to 36 weeks, adjusting for baseline value, in patients with sufficient imaging quality for 2-dimensitonal speckle tracking analysis at both timepoints (n = 60 sacubitril/valsartan, n = 75 valsartan only). GCS was significantly improved at 36 weeks in the sacubitril/valsartan group when compared with the valsartan group (Δ4.42%, 95% confidence interval [CI] 0.67-8.17, P = .021), with no significant difference observed in GLS (Δ0.25%, 95% CI, -1.19 to 1.70, P = .73). Patients with a history of hospitalization for heart failure had a differentially greater improvement in GCS when treated with sacubitril/valsartan., Conclusions: In patients with heart failure with preserved ejection fraction, sacubitril/valsartan improved GCS but not GLS when compared with valsartan during a 36-week period. This trial is registered at ClinicalTrials.gov, NCT00887588., Competing Interests: Declaration of Competing Interest T.B.S. has received speaker honorarium from Novartis; M.H.L., A.S., B.C., and E.K.-K. declare that they have no conflicts of interest. M.Z., B.P., A.V., A.S., M.P., J.J.V.M., and S.D.S. have received research support and have consulted for Novartis. M.P. has not consulted for Novartis recently. V.S. and M.L. are employees of Novartis., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Ventricular arrhythmia is one of the main causes of sudden cardiac death. Hence, identifying patients at risk of ventricular arrhythmias and sudden cardiac death is important but can be challenging. The indication for an implantable cardioverter defibrillator as a primary preventive strategy relies on the left ventricular ejection fraction as a measure of systolic function. However, ejection fraction is flawed by technical constraints and is an indirect measure of systolic function. There has, therefore, been an incentive to identify other markers to optimize the risk prediction of malignant arrhythmias to select proper candidates who could benefit from an implantable cardioverter defibrillator. Speckle-tracking echocardiography allows for a detailed assessment of cardiac mechanics, and strain imaging has repeatedly been shown to be a sensitive technique to identify systolic dysfunction unrecognized by ejection fraction. Several strain measures, including global longitudinal strain, regional strain, and mechanical dispersion, have consequently been proposed as potential markers of ventricular arrhythmias. In this review, we will provide an overview of the potential use of different strain measures in the context of ventricular arrhythmias.

Background: 2-dimensional Speckle-Tracking Echocardiography, to obtain longitudinal layer specific strain (LSS), has recently emerged as a novel and accurate non-invasive imaging technique for diagnosis as well as for prediction of adverse cardiac events. This systematic review and meta-analysis aimed to give an overview of the possible clinical implication and significance of longitudinal LSS., Methods: We conducted a systematic review and meta-analysis with all the studies involving layer specific strain in patients with ischemic heart disease (IHD). Of 40 eligible studies, 9 met our inclusion criteria. Studies that were included either investigated the prognostic value ( n  = 3) or the diagnostic value ( n  = 6) of longitudinal LSS., Results: The pooled meta-analysis showed that longitudinal LSS is a significant diagnostic marker for coronary artery disease (CAD) in patients with IHD. Endocardial LSS was found to be a good diagnostic marker for CAD in IHD patients (OR: 1.28, CI95% [1.11-1.48], p  < 0.001, per 1% decrease). Epicardial (OR: 1.34, CI95% [1.14-1.56], p  < 0.001, per 1% decrease), Mid-Myocardial (OR: 1.24, CI95% [1.12-1.38], p  < 0.001, per 1% decrease) and endocardial (OR: 1.21, CI95% [1.09-1.35], p  < 0.001, per 1% decrease) LSS all entailed diagnostic information regarding CAD, with epicardial LSS emerging as the superior diagnostic marker for CAD in patients with SAP. Endocardial LSS proved to be the better diagnostic marker of CAD in patients with non-ST elevation acute coronary syndrome (NSTE-ACS). LSS was shown to be a good prognostic maker of adverse cardiac events in IHD patients. Two studies found endocardial circumferential strain to be the good predictor of outcome in CAD patients and when added to baseline characteristics. Epicardial LSS emerged as best predictor in acute coronary syndrome (ACS) patients., Conclusion: In patients with SAP, epicardial LSS was the stronger diagnostic marker while in NSTE-ACS patients, endocardial LSS was the stronger diagnostic marker. In addition, endocardial circumferential strain is the better predictor of adverse outcome in CAD patients whilst in ACS patients, epicardial LSS was found to be a better predictor of outcome., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Sharma, Lassen, Nielsen, Skaarup and Biering-Sørensen.)

Aims: Valvular event timing is an integral part of echocardiographic pressure-strain loop (PSL) analyses. The impact that different event timing modalities may have on myocardial work indices is unknown., Methods and Results: A methodological study was performed on 200 subjects, including 50 healthy subjects, 50 with aortic valve sclerosis, 50 with atrial fibrillation, and 50 with reduced left ventricular ejection fraction. Valvular event timing was estimated by visual assessment, spectral Doppler, and colour tissue Doppler imaging (TDI) M-mode. These valvular event timings were added to the same PSL analyses sequentially to acquire myocardial work indices, including global work index (GWI). For the 200 participants, the median age was 72 years, 50% were men, and mean blood pressure was 143/80 mmHg. Valvular event timings differed between all three modalities and so did all myocardial work indices. Compared with visual assessment, spectral Doppler resulted in a significantly higher GWI (mean difference: 114 ± 93 mmHg%, P < 0.001), and so did TDI (mean difference: 83 ± 90 mmHg%, P < 0.001). A higher GWI by spectral Doppler than by TDI was also observed (mean difference: 30 ± 53 mmHg%, P < 0.001). In the healthy subgroup, a systematic bias was observed for spectral Doppler compared with visual assessment (mean difference: 160 ± 77 mmHg%, P < 0.001), and a similar trend was noted for TDI vs. visual assessment (mean difference: 124 ± 74 mmHg%, P < 0.001)., Conclusion: Myocardial work indices differ depending on the event timing modality used, with visual assessment yielding lower GWI values compared with Doppler-based methods. Serial PSL analyses should apply the same event timing method., Competing Interests: Conflict of interest: B.-S.: Steering Committee: Amgen financed GALACTIC-HF trial; the Boston Scientific financed LUX-Dx TRENDS trial; Advisory Board: Sanofi Pasteur; Amgen; Speaker Honorarium: Novartis; Sanofi Pasteur; GSK; research grant: GE Healthcare; Sanofi Pasteur. J.H.S.: advisory board, speaker fee, and research grant: Medtronic. P.S.: consulting fees and speaker honoraria for Biotronic. Remaining others: none., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: COVID-19 is associated with subclinical myocardial injury. Exogenous ketone esters acutely improve left myocardial function in healthy participants and patients with heart failure, but the effects have not been investigated in participants previously hospitalized for COVID-19., Methods: This is a randomized placebo-controlled double-blind crossover study comparing a single oral ketone ester dose of 395 mg/kg with placebo. Fasting participants were randomized to either placebo in the morning and oral ketone ester in the afternoon or vice versa. Echocardiography was performed immediately after intake of the corresponding treatment. Primary outcome was left ventricular ejection fraction (LVEF). Secondary outcomes were absolute global longitudinal strain (GLS), cardiac output and blood oxygen saturation. Linear mixed effects models were used to assess differences., Results: We included 12 participants previously hospitalized for COVID-19 with a mean (±SD) age of 60 ± 10 years. The mean time from hospitalization was 18 ± 5 months. Oral ketone esters did not increase LVEF between placebo and oral ketone ester [mean difference: -0.7% (95% CI -4.0 to 2.6%), p = 0.66], but increased GLS [1.9% (95% CI: 0.1 to 3.6%), p = 0.04] and cardiac output [1.2 L/min (95% CI: -0.1 to 2.4 L/min), p = 0.07], although non-significant. The differences in GLS remained significant after adjustment for change in heart rate ( p = 0.01). There was no difference in blood oxygen saturation. Oral ketone esters increased blood ketones over time (peak level 3.1 ± 4.9 mmol/L, p < 0.01). Ketone esters increased blood insulin, c-peptide, and creatinine, and decreased glucose and FFA (all p ≤ 0.01) but did not affect glucagon, pro-BNP, or troponin I levels (all p > 0.05)., Conclusion: In patients previously hospitalized with COVID-19, a single oral dose of ketone ester had no effect on LVEF, cardiac output or blood oxygen saturation, but increased GLS acutely., Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT04377035., Competing Interests: FD reports having served as a consultant for Bayer. TB-S reports serving as steering committee member of the Amgen financed GALACTIC-HF trial, chief investigator and steering committee chair of the Sanofi Pasteur financed “NUDGE-FLU” trial, chief investigator and steering committee chair of the Sanofi Pasteur financed “DANFLU-1” trial, chief investigator and steering committee chair of the Sanofi Pasteur financed “DANFLU-2” trial, steering committee member of “LUX-Dx TRENDS Evaluates Diagnostics Sensors in Heart Failure Patients Receiving Boston Scientific’s Investigational ICM System” trial. Being on the advisory board for Sanofi Pasteur, Amgen, and GSK. Receiving speaker honorarium from Bayer, Novartis, Sanofi Pasteur, and GSK and research grants from GE HealthCare and Sanofi Pasteur. PR reports having received research grants from AstraZeneca and Novo Nordisk and given lectures for AstraZeneca, Mundipharma, and Boehringer Ingelheim and has served as a consultant for AstraZeneca, Bayer, Eli Lilly, Boehringer Ingelheim, Astellas, Gilead, Sanofi Aventis Vifor, and Novo Nordisk, all fees given to Steno Diabetes Center Copenhagen. JL reports receiving a speaker honorarium from Boehringer Ingelheim, all fees given to Steno Diabetes Centre Copenhagen. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wodschow, Davidovski, Christensen, Lassen, Skaarup, Nygaard, Møller, Rungby, Biering-Sørensen, Rossing, Jensen and Laursen.)

Introduction: COVID-19 has spread globally in waves, and Danish treatment guidelines have been updated following the first wave. We sought to investigate whether the prognostic values of echocardiographic parameters changed with updates in treatment guidelines and the emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, 20E (EU1) and alpha (B.1.1.7), and further to compare cardiac parameters between patients from the first and second wave., Methods: A total of 305 patients hospitalized with COVID-19 were prospectively included, 215 and 90 during the first and second wave, respectively. Treatment in the study was defined as treatment with remdesivir, dexamethasone, or both. Patients were assumed to be infected with the dominant SARS-CoV-2 variant at the time of their hospitalization., Results: Mean age for the first versus second wave was 68.7 ± 13.6 versus 69.7 ± 15.8 years, and 55% versus 62% were males. Left ventricular (LV) systolic and diastolic function was worse in patients hospitalized during the second wave (LV ejection fraction [LVEF] for first vs. second wave = 58.5 ± 8.1% vs. 52.4 ± 10.6%, p < 0.001; and global longitudinal strain [GLS] = 16.4 ± 4.3% vs. 14.2 ± 4.3%, p < 0.001). In univariable Cox regressions, reduced LVEF (hazard ratio [HR] = 1.07 per 1% decrease, p = 0.002), GLS (HR = 1.21 per 1% decrease, p < 0.001), and tricuspid annular plane systolic excursion (HR = 1.18 per 1 mm decrease, p < 0.001) were associated with COVID-related mortality, but only GLS remained significant in fully adjusted analysis (HR = 1.14, p = 0.02)., Conclusion: Reduced GLS was associated with COVID-related mortality independently of wave, treatment, and the SARS-CoV-2 variant. LV function was significantly impaired in patients hospitalized during the second wave., (© 2022 S. Karger AG, Basel.)

Background: In this study we aimed to assess if a focused lung ultrasound examination predicts the need for mechanical ventilation, admission to an intensive care unit, high-flow oxygen treatment, death from COVID-19 within 30 days and 30-day all-cause mortality in patients with clinical suspicion of COVID-19 or PCR-verified SARS-CoV-2 infection., Methods: A multicentre prospective cohort trial was performed. Film clips from focused lung ultrasound examinations were recorded and rated by blinded observers using different scoring systems. A prediction model was built and used to test relationship between lung ultrasound scores and clinical outcomes. Diagnostic performance of scoring systems was analysed., Results: A total of 3889 film clips of 398 patients were analysed. Patients who had any of the outcomes of interest had a significantly higher ultrasound score than those who did not. Multivariable logistic regression analyses showed that lung ultrasound predicts mechanical ventilation (relative risk 2.44, 95% CI 1.32-5.52), admission to intensive care (relative risk 2.55, 95% CI 1.41-54.59) and high-flow oxygen treatment (relative risk 1.95, 95% CI 1.5-2.53) but not survival when adjusting for sex, age and relevant comorbidity. There was no diagnostic difference in area under the receiver operating characteristic curve between a scoring system using only anterolateral thorax zones and a scoring system that also included dorsal zones., Conclusion: Focused lung ultrasound in patients with clinical suspicion of COVID-19 predicts respiratory failure requiring mechanical ventilation, admission to intensive care units and the need for high-flow oxygen treatment. Thus, focused lung ultrasound may be used to risk stratify patients with COVID-19 symptoms., Competing Interests: Conflict of interest: None of the authors have any conflicts of interest to report., (Copyright ©The authors 2022.)

Aims: A pattern of reduced basal longitudinal strain (BLS) is often observed with left ventricular (LV) hypertrophy (LVH). Whether this pattern is associated with poor outcome is unclear. We aimed to evaluate the prognostic value of regional longitudinal strain according to LV geometry., Methods and Results: We investigated participants in the 4th Copenhagen City Heart Study who had an echocardiogram with speckle tracking performed. Participants were stratified according to the presence of LVH (LV mass index ≥116 g/m2 for men and ≥96 g/m2 for women). The outcome was major adverse cardiovascular events (MACE) defined as a composite of myocardial infarction, heart failure, and/or cardiovascular death. The study population consisted of 1090 participants. Mean LVEF was 60% and 160 (15%) had LVH. During a median follow-up of 14.7 years, there were 137 events. Both BLS and midventricular strain, but not apical strain, became incrementally impaired in the spectrum from normal to hypertensives subjects without LVH, and to participants with hypertension and LVH. After multivariable adjustment, BLS and midventricular strain were independently associated with MACE in participants with LVH (BLS: HR 1.08, 95% CI 1.00-1.17, P = 0.041; midventricular strain: HR 1.10, 95% CI 1.00-1.21, P = 0.041) but not in participants without LVH (BLS: HR 0.96, 95% CI 0.90-1.01, P = 0.13; midventricular strain: HR 0.97, 95% CI 0.91-1.03, P = 0.36)., Conclusion: BLS and midventricular strain, but not apical strain, become incrementally impaired in the spectrum from normal geometry to LVH, and are independently associated with MACE in participants with LVH., Competing Interests: Conflict of interest: K.E.F.-M. was supported by a travel grant from the William Demant Foundation. F.J.O was funded by a research grant from the Danish Heart Foundation (Grant no.: 18-R125-A8534-22083). T.B.-S. was supported by grants from the Fondsbørsvekselerer Henry Hansen og Hustrus Hovedlegat and the Lundbeck Foundation. All other authors declared no conflict of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background COVID-19 infection has been hypothesized to affect left ventricular function; however, the underlying mechanisms and the association to clinical outcome are not understood. The global work index (GWI) is a novel echocardiographic measure of systolic function that may offer insights on cardiac dysfunction in COVID-19. We hypothesized that GWI was associated with disease severity and all-cause death in patients with COVID-19. Methods and Results In a multicenter study of patients admitted with COVID-19 (n=305), 249 underwent pressure-strain loop analyses to quantify GWI at a median time of 4 days after admission. We examined the association of GWI to cardiac biomarkers (troponin and NT-proBNP [N-terminal pro-B-type natriuretic peptide]), disease severity (oxygen requirement and CRP [C-reactive protein]), and all-cause death. Patients with elevated troponin (n=71) exhibited significantly reduced GWI (1508 versus 1707 mm Hg%; P =0.018). A curvilinear association to NT-proBNP was observed, with increasing NT-proBNP once GWI decreased below 1446 mm Hg%. Moreover, GWI was significantly associated with a higher oxygen requirement (relative increase of 6% per 100-mm Hg% decrease). No association was observed with CRP. Of the 249 patients, 37 died during follow-up (median, 58 days). In multivariable Cox regression, GWI was associated with all-cause death (hazard ratio, 1.08 [95% CI, 1.01-1.15], per 100-mm Hg% decrease), but did not increase C-statistics when added to clinical parameters. Conclusions In patients admitted with COVID-19, our findings indicate that NT-proBNP and troponin may be associated with lower GWI, whereas CRP is not. GWI was independently associated with all-cause death, but did not provide prognostic information beyond readily available clinical parameters. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04377035.

Background: Chronic low-grade inflammation as in asthma may lead to a higher risk of cardiovascular events. We evaluated whether patients with COPD and asthma have a higher risk of acute cardiovascular events than patients with COPD without asthma., Methods: Nationwide multicentre retrospective cohort study of Danish outpatients with a specialist diagnosis of COPD with or without asthma. Patients with both COPD and asthma were propensity-score matched 1:2 to patients with COPD without asthma. The primary end-point was severe major adverse cardiac events (MACE), defined as mortal cardiovascular events and events requiring revascularisation or hospitalisation., Results: A total of 52 386 Danish patients with COPD were included; 34.7% had pre-existing cardiovascular disease, and 20.1% had asthma in addition to their COPD. Patients with pre-existing cardiovascular disease were then propensity-score matched: 3690 patients with COPD and asthma versus 7236 patients with COPD without asthma, and similarly, for patients without pre-existing cardiovascular disease (6775 matched with 13 205). The risk of MACE was higher among patients with asthma and COPD versus COPD without asthma: hazard ratio (HR) 1.25 (95% CI 1.13-1.39, p<0.0001) for patients with pre-existing cardiovascular disease and HR 1.22 (95% CI 1.06-1.41, p=0.005) for patients without pre-existing cardiovascular disease., Conclusion: Among patients with COPD, asthma as a comorbid condition is associated with substantially increased risk of cardiovascular events. The signal was an increased risk of 20-25%. Based on our study and other smaller studies, asthma can be considered a risk factor for cardiovascular events among COPD patients., Competing Interests: Conflict of interest: B. Bonnesen has nothing to disclose. Conflict of interest: P. Sivapalan has nothing to disclose. Conflict of interest: A.K. Kristensen has nothing to disclose. Conflict of interest: M.C.H. Lassen has nothing to disclose. Conflict of interest: K.G. Skaarup has nothing to disclose. Conflict of interest: E. Rastoder has nothing to disclose. Conflict of interest: R. Sørensen has nothing to disclose. Conflict of interest: J. Eklöf has nothing to disclose. Conflict of interest: T. Biering-Sørensen has nothing to disclose. Conflict of interest: J-U. Stæhr Jensen has nothing to disclose., (Copyright ©The authors 2022.)

Purpose: Several studies have reported thromboembolic events to be common in severe COVID-19 cases. We sought to investigate the relationship between lung ultrasound (LUS) findings in hospitalized COVID-19 patients and the development of venous thromboembolic events (VTE)., Methods: A total of 203 adults were included from a COVID-19 ward in this prospective multi-center study (mean age 68.6 years, 56.7% men). All patients underwent 8-zone LUS, and all ultrasound images were analyzed off-line blinded. Several LUS findings were investigated (total number of B-lines, B-line score, and LUS-scores)., Results: Median time from admission to LUS examination was 4 days (IQR: 2, 8). The median number of B-lines was 12 (IQR: 8, 18), and 44 (21.7%) had a positive B-line score. During hospitalization, 17 patients developed VTE (4 deep-vein thrombosis, 15 pulmonary embolism), 12 following and 5 prior to LUS. In fully adjusted multivariable Cox models (excluding participants with VTE prior to LUS), all LUS parameters were significantly associated with VTE (total number of B-lines: HR = 1.14, 95% CI (1.03, 1.26) per 1 B-line increase), positive B-line score: HR = 9.79, 95% CI (1.87, 51.35), and LUS-score: HR = 1.51, 95% CI (1.10, 2.07), per 1-point increase). The B-line score and LUS-score remained significantly associated with VTE in sensitivity analyses., Conclusion: In hospitalized COVID-19 patients, pathological LUS findings were common, and the total number of B-lines, B-line score, and LUS-score were all associated with VTE. These findings indicate that the LUS examination may be useful in risk stratification and the clinical management of COVID-19. These findings should be considered hypothesis generating., Gov Id: NCT04377035., (© 2021. Società Italiana di Ultrasonologia in Medicina e Biologia (SIUMB).)

Background: Pressure-strain loop analyses is a noninvasive technique capable of evaluating myocardial work. Reference values are needed to benchmark these myocardial work indices for clinical practice., Methods: Healthy participants from a general population study were used to establish reference values for global work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE) measured by pressure-strain loop analyses. The relation to age and sex was examined. We furthermore examined the proportion of abnormal work indices according to low, intermediate, and high cardiovascular risk by the Framingham risk score., Results: The healthy sample consisted of 1827 participants (median age, 45 years; 39% men). Lower reference values were GWI, 1576 mm Hg%; GCW, 1708 mm Hg%; and GWE, 93.0% and upper reference value for GWW was 159 mm Hg%. Women exhibited significantly higher GWI, GCW, and GWW and lower GWE. Sex significantly modified the association between all indices and age ( P for interaction: 0.001 for GWI, 0.009 for GCW, 0.003 for GWW, and 0.009 for GWE). For men, only GCW increased with age, whereas the other indices did not change with age. For women, GCW increased linearly with increasing age, whereas GWI, GWW, and GWE changed in a curvilinear fashion with age such that GWI increased in younger participants, GWW increased in elderly, and GWE declined concordantly. Abnormalities in myocardial work indices became more frequent with increasing Framingham risk score category (abnormal GWI: 2% versus 4% versus 5%, P =0.001; abnormal GCW: 2% versus 3% versus 4%, P =0.006; abnormal GWW: 3% versus 6% versus 11%, P <0.001; abnormal GWE: 3% versus 4% versus 11%, P <0.001)., Conclusions: Myocardial work indices differ between sexes and change with age in a sex-dependent manner. Accordingly, we established age- and sex-specific reference values from a general population sample. Abnormal work indices become more frequent with higher clinical risk., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT02993172.

Aims: Technical advancements in 2D-speckle tracking echocardiography (2DSTE) have allowed for quantification of layer-specific global longitudinal strain (GLS) and circumferential strain (GCS) of the left ventricle (LV). The aim of this study was to establish age- and sex-based reference ranges of peak systolic layer-specific GLS and GCS and to assess normal values of regional strain., Methods and Results: We performed 2DSTE analysis of 1997 members of the general population from the fifth round of the Copenhagen City Heart Study, who were free of cardiovascular disease and risk factors. The mean age was 46 ± 16 years (range 21-97) and 62% were female. Mean values for peak systolic whole wall GLS (GLSWW.Sys), endomycardial (GLSEndo.Sys), and epimyocardial (GLSEpi.Sys) were 19.9 ± 2.1% (prediction interval [PI]: 15.8-24.0%), 23.5 ± 2.5% (PI: 18.6-28.4%), and 17.3 ± 1.9% (PI: 13.6-21.1%), respectively. Mean peak systolic whole wall GCS (GCSWW.Sys), was 21.6 ± 3.7% (PI: 14.3-28.9%), endomyocardial (GCSEndo.Sys) was 31.9 ± 4.7% (PI: 22.7-41.1%), and epimyocardial (GCSEpi.Sys) was 14.3 ± 3.8% (PI: 6.8-21.8%). A significant discrepancy in normal strain values between males and females was observed. Men had lower mean values and lower reference limits for all strain parameters. Furthermore, GLS and GCS changed differently with age in males and females. Finally, regional LS decreased from the apical to the basal LV region in both sexes, and regional CS varied significantly by LV segment., Conclusion: In this study, we reported age- and sex-based reference ranges of layer-specific GLS and GCS. These reference ranges varied significantly with sex and age., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Background: Adverse events in COVID-19 are difficult to predict. Risk stratification is encumbered by the need to protect healthcare workers. We hypothesize that artificial intelligence (AI) can help identify subtle signs of myocardial involvement in the 12-lead electrocardiogram (ECG), which could help predict complications., Objective: Use intake ECGs from COVID-19 patients to train AI models to predict risk of mortality or major adverse cardiovascular events (MACE)., Methods: We studied intake ECGs from 1448 COVID-19 patients (60.5% male, aged 63.4 ± 16.9 years). Records were labeled by mortality (death vs discharge) or MACE (no events vs arrhythmic, heart failure [HF], or thromboembolic [TE] events), then used to train AI models; these were compared to conventional regression models developed using demographic and comorbidity data., Results: A total of 245 (17.7%) patients died (67.3% male, aged 74.5 ± 14.4 years); 352 (24.4%) experienced at least 1 MACE (119 arrhythmic, 107 HF, 130 TE). AI models predicted mortality and MACE with area under the curve (AUC) values of 0.60 ± 0.05 and 0.55 ± 0.07, respectively; these were comparable to AUC values for conventional models (0.73 ± 0.07 and 0.65 ± 0.10). There were no prominent temporal trends in mortality rate or MACE incidence in our cohort; holdout testing with data from after a cutoff date (June 9, 2020) did not degrade model performance., Conclusion: Using intake ECGs alone, our AI models had limited ability to predict hospitalized COVID-19 patients' risk of mortality or MACE. Our models' accuracy was comparable to that of conventional models built using more in-depth information, but translation to clinical use would require higher sensitivity and positive predictive value. In the future, we hope that mixed-input AI models utilizing both ECG and clinical data may be developed to enhance predictive accuracy., (© 2021 Heart Rhythm Society.)

To investigate cross-sectional associations between heavy occupational lifting and cardiac structure and function. Participants from the 5th round of the Copenhagen City Heart Study, aged < 65 years old, answering a questionnaire regarding occupational physical activity, heavy occupational lifting, use of anti-hypertensive and heart medication, and data on blood pressure, cardiac structure and function, from an echocardiographic examination, were included. Adjusted linear regressions and logistic regressions were applied to estimate the cross-sectional association between heavy occupational lifting and cardiac structure and function across all included participants and in groups stratified by hypertension status, and the risk for having abnormal values of cardiac structure and function. 2511 participants were included. The cross-sectional standardized associations between heavy occupational lifting and measures of cardiac structure and function showed a trends for raised left ventricular mass index (LVMi) (β 0.14, 99% CI - 0.03 to 0.31). The standardized associations stratified by hypertensive status showed significant associations between exposure to heavy occupational lifting and LVMi (β 0.20, 99% CI - 0.002 to 0.40) and a trend of a raised end-diastolic interventricular septal thickness (IVSd) (β 0.15, 99% CI - 0.03 to 0.33) among normotensives. Exposure to heavy occupational lifting increased the odds for an abnormal IVSd (OR 1.42, 99% CI 1.07-1.89). This cross-sectional study shows heavy occupational lifting to associate with indices of abnormal cardiac structure and function among normotensives, indicating an increased risk for cardiovascular disease., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)