Effects of high-dose versus standard-dose quadrivalent influenza vaccine among patients with diabetes: A post-hoc analysis of the DANFLU-1 trial.

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), pinteraction = 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.

Clinical Outcomes With Electronic Nudges to Increase Influenza Vaccination : A Prespecified Analysis of a Nationwide, Pragmatic, Registry-Based, Randomized Implementation Trial.

BACKGROUND: In the NUDGE-FLU (Nationwide Utilization of Danish Government Electronic letter system for increasing inFLUenza vaccine uptake) trial, electronic letters incorporating cardiovascular (CV) gain-framing and repeated messaging increased influenza vaccination by approximately 1 percentage point. OBJECTIVE: To evaluate the effects of the successful nudging interventions on downstream clinical outcomes. DESIGN: Prespecified exploratory analysis of a nationwide randomized implementation trial. (ClinicalTrials.gov: NCT05542004). SETTING: The 2022 to 2023 influenza season. PARTICIPANTS: 964 870 Danish citizens aged 65 years or older. INTERVENTION: Usual care or 9 different electronically delivered behavioral nudging letters. MEASUREMENTS: Cardiovascular, respiratory, and other clinical end points during follow-up from intervention delivery (16 September 2022) through 31 May 2023. RESULTS: The analysis set included 691 820 participants. Hospitalization for pneumonia or influenza occurred in 3354 of 346 327 (1.0%) participants in the usual care group, 396 of 38 586 (1.0%) in the CV gain-framing group (hazard ratio [HR], 1.06 [95% CI, 0.95 to 1.18]; versus usual care), and 403 of 38 231 (1.1%) in the repeated letter group (HR, 1.09 [CI, 0.98 to 1.21]; versus usual care). In the usual care group, 44 682 (12.9%) participants were hospitalized for any cause, compared with 5002 (13.0%) in the CV gain-framing group (HR, 1.00 [CI, 0.97 to 1.03]; versus usual care) and 4965 (13.0%) in the repeated letter group (HR, 1.01 [CI, 0.98 to 1.04]; versus usual care). A total of 6341 (1.8%) participants died in the usual care group, compared with 721 (1.9%) in the CV gain-framing group (HR, 1.02 [CI, 0.94 to 1.10]; versus usual care) and 646 (1.7%) in the repeated letter group (HR, 0.92 [CI, 0.85 to 1.00]; versus usual care). LIMITATION: Prespecified but exploratory analysis, potential misclassification of events in routinely collected registry data, and results may not be generalizable to other health systems or countries with other racial compositions and/or cultural or societal norms. CONCLUSION: In a prespecified exploratory analysis, modest increases in influenza vaccination rates seen with electronic nudges did not translate into observable improvements in clinical outcomes. Seasonal influenza vaccination should remain strongly recommended. PRIMARY FUNDING SOURCE: Sanofi.

Rationale and design of NUDGE-FLU-CHRONIC and NUDGE-FLU-2: Two nationwide randomized trials of electronic nudges to increase influenza vaccination among patients with chronic diseases and older adults during the 2023/2024 influenza season.

BACKGROUND: Yearly influenza vaccination is strongly recommended for older adults and patients with chronic diseases including cardiovascular disease (CVD); however, vaccination rates remain suboptimal, particularly among younger patients. Electronic letters incorporating behavioral nudges are highly scalable public health interventions which can potentially increase vaccination, but further research is needed to determine the most effective strategies and to assess effectiveness across different populations. The purpose of NUDGE-FLU-CHRONIC and NUDGE-FLU-2 are to evaluate the effectiveness of electronic nudges delivered via the Danish governmental electronic letter system in increasing influenza vaccination among patients with chronic diseases and older adults, respectively. METHODS: Both trials are designed as pragmatic randomized implementation trials enrolling all Danish citizens in their respective target groups and conducted during the 2023/2024 influenza season. NUDGE-FLU-CHRONIC enrolls patients aged 18-64 years with chronic diseases. NUDGE-FLU-2 builds upon the NUDGE-FLU trial conducted in 2022/2023 and aims to expand the evidence by testing both previously successful and new nudges among adults ≥65 years during a subsequent influenza season. Persons with exemptions from the electronic letter system are excluded from both trials. In both trials, participants are randomized in a 2.45:1:1:1:1:1:1 ratio to either receive no electronic letter (usual care) or to receive one of 6 different behaviorally informed electronic letters. NUDGE-FLU-CHRONIC has randomized 299,881 participants with intervention letters delivered on September 24, 2023, while NUDGE-FLU-2 has randomized 881,373 participants and delivered intervention letters on September 13, 2023. Follow-up is currently ongoing. In both trials, the primary endpoint is receipt of influenza vaccination on or before January 1, 2024, and the secondary endpoint is time to vaccination. Clinical outcomes including respiratory and cardiovascular hospitalizations, all-cause hospitalization, and mortality are included as prespecified exploratory endpoints. Prespecified individual-level pooled analyses will be conducted across NUDGE-FLU, NUDGE-FLU-CHRONIC, and NUDGE-FLU-2. DISCUSSION: NUDGE-FLU-CHRONIC is the first nationwide randomized trial of electronic nudges to increase influenza vaccination conducted among 18-64-year-old high-risk patients with chronic diseases. NUDGE-FLU-2 will provide further evidence on the effectiveness of electronic nudges among older adults ≥65 years. Collectively, the NUDGE-FLU trials will provide an extensive evidence base for future public health communications. TRIAL REGISTRATION: NUDGE-FLU-CHRONIC: Clinicaltrials.gov: NCT06030739, registered September 11, 2023, https://clinicaltrials.gov/study/NCT06030739. NUDGE-FLU-2: Clinicaltrials.gov: NCT06030726, registered September 11, 2023, https://clinicaltrials.gov/study/NCT06030726.

Right Ventricular Function in Arrhythmogenic Right Ventricular Cardiomyopathy: Potential Value of Strain Echocardiography.

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.

Nudging a Nation - The Danish NUDGE Trial Concept.

Danish NUDGE Trial ConceptRandomized encouragement trials randomize to an opportunity to receive treatment instead of to the treatment. Here, Johansen and colleagues combine randomized encouragement trials with several advantages inherent in the Danish health system.

Effectiveness of high-dose versus standard-dose quadrivalent influenza vaccine against recurrent hospitalizations and mortality in relation to influenza circulation: A post-hoc analysis of the DANFLU-1 randomized clinical trial.

OBJECTIVES: To evaluate the relative effectiveness of high-dose quadrivalent influenza vaccine (QIV-HD) versus standard-dose quadrivalent influenza vaccine (QIV-SD) against recurrent hospitalizations and its potential variation in relation to influenza circulation. METHODS: We did a post-hoc analysis of a pragmatic, open-label, randomized trial of QIV-HD versus QIV-SD performed during the 2021-2022 influenza season among adults aged 65-79 years. Participants were enrolled in October 2021-November, 2021 and followed for outcomes from 14 days postvaccination until 31 May, 2022. We investigated the following outcomes: Hospitalizations for pneumonia or influenza, respiratory hospitalizations, cardio-respiratory hospitalizations, cardiovascular hospitalizations, all-cause hospitalizations, and all-cause death. Outcomes were analysed as recurrent events. Cumulative numbers of events were assessed weekly. Cumulative relative effectiveness estimates were calculated and descriptively compared with influenza circulation. The trial is registered at Clinicaltrials.gov: NCT05048589. RESULTS: Among 12,477 randomly assigned participants, receiving QIV-HD was associated with lower incidence rates of hospitalizations for pneumonia or influenza (10 vs. 33 events, incidence rate ratio [IRR] 0.30 [95% CI, 0.14-0.64]; p 0.002) and all-cause hospitalizations (647 vs. 742 events, IRR 0.87 [95% CI, 0.76-0.99]; p 0.032) compared with QIV-SD. Trends favouring QIV-HD were consistently observed over time including in the period before active influenza transmission; i.e. while the first week with a ≥10% influenza test positivity rate was calendar week 10, 2022, the first statistically significant reduction in hospitalizations for pneumonia or influenza was already observed by calendar week 3, 2022 (5 vs. 15 events, IRR 0.33 [95% CI, 0.11-0.94]; p 0.037). DISCUSSION: In a post-hoc analysis, QIV-HD was associated with lower incidence rates of hospitalizations for pneumonia or influenza and all-cause hospitalizations compared with QIV-SD, with trends evident independent of influenza circulation levels. Our exploratory results correspond to a number needed to treat of 65 (95% CI 35-840) persons vaccinated with QIV-HD compared with QIV-SD to prevent one additional all-cause hospitalization per season. Further research is needed to confirm these hypothesis-generating findings.

Normal values for left atrial strain, volume, and function derived from 3D echocardiography: the Copenhagen City Heart Study.

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.

Serial troponin-I and long-term outcomes in subjects with suspected acute coronary syndrome.

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

In this Danish study of >20 000 individuals with suspected heart attack, we confirmed the clinical importance of drawing two consecutive blood samples for measurement of high-sensitivity troponin-I concentrations (a marker of damage to the heart): The risk of death was highest in persons with two elevated high-sensitivity troponin-I concentrations and lowest in those with two normal concentrations.Among persons who had a first normal and a subsequently elevated high-sensitivity troponin-I concentration, a >50% relative rise was associated with significantly higher risk of death at 30 days.

Right ventricular free wall and four-chamber longitudinal strain in relation to incident heart failure in the general population.

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.

Association between myocardial work indices and cardiovascular events according to hypertension in the general population.

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.

Normal age- and sex-based values of right ventricular free wall and four-chamber longitudinal strain by speckle-tracking echocardiography: from the Copenhagen City heart study.

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.

Even Mild Mitral Regurgitation is Associated with Incident Atrial Fibrillation in the General Population.

BACKGROUND: 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 AF in the general population. METHODS: The study included 4,466 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. RESULTS: MR was quantified in 4,042 participants (mean age: 57 years, 43% men). Of these, 198 (4.9%) developed AF during a median follow-up period of 5.3 years (IQR: 4.4-6.1 years). MR was present in 1,938 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: Mitral regurgitation, including even trace regurgitations quantified by MR/LA-ratio is independently associated with incident AF in individuals ≤73 years of age.

Electronically Delivered Nudges to Increase Influenza Vaccination Uptake in Older Adults With Diabetes: A Secondary Analysis of the NUDGE-FLU Trial.

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.

Age- and sex-based normal reference ranges of the cardiac time intervals: the Copenhagen City Heart Study.

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.

Normal Values and Reference Ranges for the Ratio of Transmitral Early Filling Velocity to Early Diastolic Strain Rate: The Copenhagen City Heart Study.

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.

Influenza vaccination and cardiovascular events in patients with ischaemic heart disease and heart failure: A meta-analysis.

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, I2 = 52%), cardiovascular death (rHR 0.63, 95% CI 0.42-0.95, p = 0.028, I2 = 58%) and all-cause death (rHR 0.72, 95% CI 0.54-0.95, p = 0.0227, I2 = 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.

Left atrial reservoir strain predicts ischaemic stroke after coronary artery bypass grafting independent of postoperative atrial fibrillation.

Aims: Measures of left atrial (LA) function are known to predict both ischaemic stroke and atrial fibrillation in specific patient groups. The aim of this study was to investigate the value of LA reservoir strain for predicting ischaemic stroke in patients undergoing coronary artery bypass grafting (CABG) and investigate whether the presence of postoperative atrial fibrillation (POAF) modified this relationship. Methods and results: Patients undergoing isolated CABG were included. The primary endpoint was ischaemic stroke. The association between LA reservoir strain and ischaemic stroke was investigated in uni- and multivariable Cox proportional hazards regression models including adjustment for POAF.We included 542 patients (mean age 67.3±8.9 years, 16.4% female). During a median follow-up period of 3.9 years, 21 patients (3.9%) experienced an ischaemic stroke. In total, 96 patients (17.7%) developed POAF during the index hospitalization. In a multivariable-adjusted Cox proportional hazards regression model, LA reservoir strain was significantly associated with the development of ischaemic stroke [HR (hazard ratio) 1.09 (95% CI 1.02-1.17) per 1% decrease, P = 0.011]. The presence of POAF did not modify this association (p for interaction = 0.07). The predictive value of the LA reservoir strain persisted in multiple sensitivity analyses including restricting the analysis to patients with normal left atrial volumes (LAV<34 ml/m2), patients without POAF, patients without prior stroke, and when excluding patients who developed atrial fibrillation at any time during follow-up. Conclusion: LA reservoir strain was independently associated with ischaemic stroke in CABG patients. The predictive value of LA reservoir strain was unaffected by the presence of POAF. Prospective studies are warranted to validate the potential usefulness of LA reservoir strain to predict postoperative ischaemic stroke in the setting of CABG.