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Background: Cardiac troponins (cTns) are the cornerstone of diagnosing acute myocardial infarction. There is limited knowledge on the duration of ischemia necessary to induce a measurable release of cTns or the very-early-release kinetics of cTns after an ischemic event. Copeptin may have a supplementary role in ruling out myocardial infarction early. We investigated the release of cTns and copeptin in the first hours after experimental balloon-induced ischemia in humans. Methods: Thirty-four patients (median age, 60 years [interquartile range, 51–64]; 15 men, 43%) with angiographically normal coronary arteries were randomly assigned into 4 groups with different durations of induced myocardial ischemia (0, 30, 60, 90 s). Ischemia was induced by inflating a balloon in the left anterior descending artery between the first and second diagonal branch. Blood was collected before balloon inflation (baseline) every 15 minutes for the first 3 hours, and every 30 minutes for the next 3 hours. The cTns were analyzed by 3 high-sensitivity (hs) cTn assays: hs-cTnT (Roche), hs-cTnI (Siemens), and hs-cTnI (Abbott). Copeptin was analyzed by a sandwich immunoluminometric assay. Results: None of the patients had any complications. Increased cTn concentrations were detected by all 3 assays, and the magnitude of the increase was associated with the duration of ischemia. Increased hs-cTnI (Siemens) concentrations were first detectable 15 minutes after 90-s ischemia (median 43.7% increase) and increased more steeply and had a higher peak than the other assays. Copeptin levels did not significantly change. Using the cTnT, hs-cTnI (Siemens), and hs-cTnI (Abbott) concentrations at 0 and 180 minutes, 1 (11%), 0, and 0 patients from the 60-s ischemia group and 5 (63%), 2 (25%), and 1 (11%) from the 90-s ischemia group, respectively, fulfilled criteria for a biochemical myocardial infarction. Conclusions: This study is the first to report the early-release kinetics of cTn concentrations after different durations of experimental coronary balloon occlusion in humans. All assays detected a cTn increase after only 30 s of ischemia. hs-cTnI (Siemens) rose faster and reached a higher peak. Copeptin levels did not change significantly. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03203057.

Background When the left ventricle pressure rises during early systole, myocardial fibres with reduced contractility tend to stretch instead of shortening. This interval is known as duration of early systolic lengthening (DESL). We sought to investigate if DESL provides prognostic information on cardiovascular events. Methods and results In this prospective study we included 1210 participants from a low-risk general population who underwent speckle tracking echocardiography (men 41%, mean age 56 years, SD 16). Primary endpoints were incident heart failure (HF), myocardial infarction (MI), and cardiovascular death (CVD). We defined DESL as time from onset of Q-wave on the electrocardiogram to peak positive systolic strain. In addition, we assessed the ratio between DESL and duration of cardiac systole, DESLsystole. During median follow-up of 16 years, 90 (7%) developed HF, 50 (4%) MI, and 70 (6%) experienced CVD. Both DESL [hazard ratio (HR) 1.58 95%CI 1.16–2.15, P = 0.004 per 10 ms increase] and DESLsystole (HR 1.74 95%CI 1.24–2.47, P = 0.001 per 1% increase) were predictors of HF. Similarly, DESL (HR 1.40 95%CI 1.09–1.78, P = 0.007 per 10 ms increase) and DESLsystole (HR 1.58 95%CI 1.01–2.49, P = 0.047 per 1% increase) were predictors of MI. No associations were found with CVD. After adjusting for clinical and echocardiographic parameters, the associations remained significant. DESLsystole was superior to systolic echocardiographic parameters for predicting HF (P = 0.012). Conclusion DESL and the novel index of DESLsystole provide independent and novel prognostic information on the risk of HF and MI in the general population. Evaluation of DESL should be explored in future echocardiographic studies.

Objectives This study sought to investigate whether left atrial (LA) functional measures predict atrial fibrillation (AF) in the general population. Background Increasing evidence suggests LA functional measures are predictors of AF in several patient groups. Methods In a community-based cohort study, approximately 2,000 individuals underwent a transthoracic echocardiogram. Conventional echocardiographic measures and extended LA measures, including the minimal and maximal LA volumes (LAVmin and LAVmax, respectively) and left atrial emptying fraction (LAEF), were performed. The endpoint was incident AF, and participants with known AF were excluded, which left 1,951 for inclusion. Results Over 11.0 years of follow-up, 184 (9.4%) developed AF. Those who developed AF had significantly larger LA volumes and lower LAEF than participants free of AF. These LA measures were univariable predictors of AF (LAVmax hazard ratio [HR]: 1.10 [95% confidence interval (CI): 1.08 to 1.12] per 1-ml increase, p Conclusions LA functional measures predict AF in the general population and provide prognostic information incremental to clinical risk scores. In individuals without hypertension and nondilated LA, these measures indicate an increased risk of AF.

Aims Colour tissue Doppler imaging (TDI) M-mode through the mitral leaflet is an easy and precise method to obtain cardiac time intervals including the isovolumic contraction time (IVCT), isovolumic relaxation time (IVRT), and ejection time (ET). The myocardial performance index (MPI) was defined as [(IVCT + IVRT)/ET]. Our aim was to investigate if cardiac time intervals can be used to predict atrial fibrillation (AF) in the general population. Methods and results A total of 1915 participants from the general population underwent a health examination including TDI echocardiography. The primary endpoint was AF, and the secondary endpoint was complicated AF as assessed by the occurrence of either stroke or heart failure (HF) after the diagnosis of AF. Participants with known AF were excluded (n = 54). During a median follow-up of 11 years, 166 participants (9%) were diagnosed with AF and of these 44 participants (27%) developed HF or stroke. Assessing the association between IVCT and incident AF, the risk increased with 27% per 10 ms increase in IVCT [per 10 ms increase: hazard ratio (HR) 1.27, 95% confidence interval (CI) (1.17–1.38); P Conclusion In the general population, the IVCT provides novel and independent prognostic information on the long-term risk of AF. Additionally, the IVCT can identify persons in risk of complicated AF.

Background: Influenza infection is a serious event for patients with heart failure (HF). Little knowledge exists about the association between influenza vaccination and outcome in patients with HF. This study sought to determine whether influenza vaccination is associated with improved long-term survival in patients with newly diagnosed HF. Methods: We performed a nationwide cohort study including all patients who were >18 years of age and diagnosed with HF in Denmark in the period of January 1, 2003, to June 1, 2015 (n=134 048). We collected linked data using nationwide registries. Vaccination status, number, and frequency during follow-up were treated as time-varying covariates in time-dependent Cox regression. Results: Follow-up was 99.8% with a median follow-up time of 3.7 years (interquartile range, 1.7–6.8 years). The vaccination coverage of the study cohort ranged from 16% to 54% during the study period. In unadjusted analysis, receiving ≥1 vaccinations during follow-up was associated with a higher risk of death. After adjustment for inclusion date, comorbidities, medications, household income, and education level, receiving ≥1 vaccinations was associated with an 18% reduced risk of death (all-cause: hazard ratio, 0.82; 95% CI, 0.81–0.84; P P Conclusions: In patients with HF, influenza vaccination was associated with a reduced risk of both all-cause and cardiovascular death after extensive adjustment for confounders. Frequent vaccination and vaccination earlier in the year were associated with larger reductions in the risk of death compared with intermittent and late vaccination.

Aims Left atrial (LA) enlargement predicts cardiovascular risk. The prognostic value of left atrial peak reservoir strain (LA RS) by two-dimensional speckle tracking in the general population is currently unknown. This study sought to determine the prognostic value of LA RS in the general population. Methods and results A total of 385 participants without atrial fibrillation, heart failure (HF), and ischaemic heart disease (IHD) had an echocardiogram including left ventricular and LA speckle-tracking analysis performed. LA RS was averaged from the three apical views. The endpoint was a composite of incident IHD, HF, or cardiovascular death. Median follow-up was 12.6 years (interquartile-range 11.5-12.8 years). Follow-up was 100%. Fifty-one participants (13.3%) reached the composite outcome. LA RS was a univariable predictor of outcome [hazard ratio (HR) 1.25, 95% confidence interval (95% CI) 1.09-1.43; P = 0.002]. However, LA RS did not remain an independent predictor of outcome after adjustment for clinical parameters. The prognostic value was modified by sex (P = 0.011). LA RS predicted the composite outcome in women but not in men when adjusting for clinical parameters (women: HR 1.46, 95% CI 1.05-2.02; P = 0.025) (men: HR 0.96, 95% CI 0.81-1.14; P = 0.65). Further adjustment for echocardiographic parameters did not significantly alter the results. LA RS added incremental prognostic information in addition to SCORE and the American Heart Association/American College of Cardiology Pooled Cohort Equation in women only. Conclusion LA RS is a univariable predictor of cardiovascular morbidity and mortality in the general population. However, the prognostic value of LA RS is modified by sex. LA RS is an independent predictor of outcome in women but not in men.

Background: The optimal timing of invasive coronary angiography (ICA) and revascularization in patients with non-ST-segment elevation acute coronary syndrome is not well defined. We tested the hypothesis that a strategy of very early ICA and possible revascularization within 12 hours of diagnosis is superior to an invasive strategy performed within 48 to 72 hours in terms of clinical outcomes. Methods: Patients admitted with clinical suspicion of non-ST-segment elevation acute coronary syndrome in the Capital Region of Copenhagen, Denmark, were screened for inclusion in the VERDICT trial (Very Early Versus Deferred Invasive Evaluation Using Computerized Tomography) ( ClinicalTrials.gov NCT02061891). Patients with ECG changes indicating new ischemia or elevated troponin, in whom ICA was clinically indicated and deemed logistically feasible within 12 hours, were randomized 1:1 to ICA within 12 hours or standard invasive care within 48 to 72 hours. The primary end point was a combination of all-cause death, nonfatal recurrent myocardial infarction, hospital admission for refractory myocardial ischemia, or hospital admission for heart failure. Results: A total of 2147 patients were randomized; 1075 patients allocated to very early invasive evaluation had ICA performed at a median of 4.7 hours after randomization, whereas 1072 patients assigned to standard invasive care had ICA performed 61.6 hours after randomization. Among patients with significant coronary artery disease identified by ICA, coronary revascularization was performed in 88.4% (very early ICA) and 83.1% (standard invasive care). Within a median follow-up time of 4.3 (interquartile range, 4.1–4.4) years, the primary end point occurred in 296 (27.5%) of participants in the very early ICA group and 316 (29.5%) in the standard care group (hazard ratio, 0.92; 95% CI, 0.78–1.08). Among patients with a GRACE risk score (Global Registry of Acute Coronary Events) >140, a very early invasive treatment strategy improved the primary outcome compared with the standard invasive treatment (hazard ratio, 0.81; 95% CI, 0.67–1.01; P value for interaction=0.023). Conclusions: A strategy of very early invasive coronary evaluation does not improve overall long-term clinical outcome compared with an invasive strategy conducted within 2 to 3 days in patients with non-ST-segment elevation acute coronary syndrome. However, in patients with the highest risk, very early invasive therapy improves long-term outcomes. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02061891.

The authors sought to perform a randomized controlled trial to evaluate the clinical efficacy of combined examination with coronary computed tomography angiography (CTA) and computed tomography perfusion imaging (CTP) compared to coronary CTA alone.Stress myocardial CTP may increase diagnostic specificity when added to coronary CTA in patients suspected of having ischemic heart disease.Patients recently hospitalized for acute-onset chest pain, who had acute coronary syndrome had been ruled out by normal electrocardiograms, normal troponin levels, and relief of symptoms, and who had a clinical indication for outpatient noninvasive testing, were screened for inclusion in the CATCH-2 (CArdiac cT in the treatment of acute CHest pain 2) trial (NCT02014311). Patients were randomized 1:1 to examination with coronary CTA or coronary CTA+CTP. The primary endpoint was the frequency of coronary revascularization among patients referred for invasive coronary angiography (ICA) based on index computed tomography evaluation. Secondary endpoints were invasive procedural complications at index-related ICA, post-index cardiac death, hospital admittance because of recurrence of chest pain, unstable angina pectoris, or acute myocardial infarction, ICA, and revascularization.Among 300 patients allocated to the coronary CTA+CTP group, 41 (14%) were referred for ICA compared with 89 (30%) allocated to coronary CTA (p 0.0001). The primary endpoint occurred in 50% of coronary CTA+CTP patients versus 48% of invasively examined patients (p = 0.85). The total number of revascularizations was significantly lower in the coronary CTA+CTP group compared to the coronary CTA group (n = 20 [7%] vs. n = 42 [14%]; p = 0.0045). At median follow-up of 1.5 years, the occurrence of secondary endpoints was similar in the 2 groups.A post-discharge diagnostic strategy of coronary CTA+CTP safely reduces the need for invasive examination and treatment in patients suspected of having ischemic heart disease. (CArdiac cT in the treatment of acute CHest pain 2-Myocardial CT Perfusion [CATCH2]; NCT02014311).

Background: Repolarization is impaired in patients with type 1 diabetes mellitus (T1DM), and repolarization disturbances are associated with an increased mortality. To study cardiac repolarization, we assessed T-wave morphology in patients with T1DM without known heart disease. Methods: 855 T1DM patients without known heart disease were matched 1:2 with 1710 people from a background population. Rate-corrected T-wave morphology markers were obtained. Patients were stratified by albuminuria. Results are mean ± standard deviation. Results: T-waves were flatter (0.398 ± 0.059 vs. 0.382 ± 0.062, p < 0.001) and more asymmetric (0.082 ± 0.068 vs. 0.071 ± 0.084, p = 0.001) in T1DM. Patients with albuminuria had an increased heart rate (normoalbuminuria: 71 ± 13 bpm, microalbuminuria: 75 ± 12 bpm, p < 0.001, macroalbuminuria: 78 ± 12 bpm, p < 0.001) and more asymmetric T-waves (normoalbuminuria: 0.079 ± 0.060, microalbuminuria: 0.094 ± 0.085, p < 0.01, macroalbuminuria: 0.101 ± 0.080, p < 0.01), but the QTc interval remained unchanged. Conclusions: T1DM is associated with changes in T-wave morphology. T-wave asymmetry but not QTc interval is associated with albuminuria in T1DM and may be used for stratification.

Post-systolic shortening (PSS) does not contribute to the ejection of blood and may inhibit diastolic filling. We determined normal values of PSS in healthy subjects and investigated associations with echocardiographic and invasive measures of systolic and diastolic function. We prospectively analyzed participants from the general population (n = 620, mean age 47 ± 14 years) with no cardiovascular disease. Participants underwent echocardiography, including speckle tracking assessment of the post-systolic index (PSI), strain and time. We defined the PSI as: 100 × [(peak global longitudinal strain − peak systolic longitudinal strain)/(peak global longitudinal strain)]. We also included stable patients (n = 44) referred for left ventricle (LV) catheterization and echocardiography. Normal values: median PSI 2.0% (IQR 0.7, 4.8), post-systolic strain 0.4% (IQR 0.2, 0.8) and post-systolic time 22.6 ms (IQR 10.7, 40.8). Sex modified the relationship between PSI and age (P interaction = 0.037), such that PSI increased with age in women but not in men. PSI was associated with diastolic function (e′, E/e′ and E/A) (P 5% had 82% specificity and 99% sensitivity for identifying impaired LV systolic and/or diastolic function. Normal values of PSS are modified by sex. The PSI is associated with most validated echocardiographic and invasive measures of cardiac systolic and diastolic function.

The aim of this study is to assess the prognostic value of mechanical dyssynchrony defined as the standard deviation of the time to peak longitudinal strain (SD T2P LS) in predicting the development of heart failure (HF) after an ST-segment elevation myocardial infarction (STEMI). Three hundred and seventy-three patients were admitted with STEMI and treated with primary percutaneous coronary intervention. Left ventricular (LV) mechanical dyssynchrony was examined through speckle tracking echocardiography and defined as SD T2P LS. The association with the outcome of HF hospitalization was assessed using Cox proportional hazard models. During a median follow-up of 5.12 years, 144 patients (38.6%) were admitted due to HF. Worse dyssynchrony was associated with the outcome in unadjusted and multivariable analysis (multivariable hazard ratio 1.05, 95% confidence interval 1.00-1.10, p-value 0.039, per 10 ms increase), but not after further adjustment for LV ejection fraction (LVEF), E/e' and global longitudinal strain (GLS) (hazard ratio 1.01, 95% confidence interval 1.00-1.07, p-value 0.71, per 10 ms increase), nor in a model only adjusting for GLS (hazard ratio 1.01, 95% confidence interval 1.00-1.06, p-value 0.61, per 10 ms increase). These findings were reproduced in a competing risk analysis treating all-cause mortality as a competing risk. LV mechanical dyssynchrony, as assessed by SD T2P LS is not an independent predictor of post-STEMI HF development and mechanical dyssynchrony does not provide independent prognostic information regarding HF when GLS is known.

Rationale Atrial fibrillation (AF) is the most common arrhythmia following acute myocardial infarction (AMI). Maximal left atrial (LA) volume is the only echocardiographic atrial parameter employed clinically to assess risk of AF development. Objective This study sought to determine the prognostic value of left atrial functional measures such as left atrial emptying fraction (LAEF) and left atrial expansion index (LAi) in predicting incident AF in the post-STEMI setting. Methods and results STEMI patients treated with primary percutaneous coronary intervention (pPCI) at Gentofte Hospital, Denmark were prospectively enrolled from September 2006 to December 2008 and had an echocardiogram performed a median 2 days (interquartile-range: 1-3 days) following pPCI. LA maximal volume, LA minimal volume, LAEF and LAi were measured from echocardiograms of 373 patients using the area-length method. End point was incident AF. Median follow-up time was 5.6 years (interquartile-range: 5.0-6.1 years), 24 patients (6%) developed incident AF, and follow-up was 100%. In multivariable Cox regression, LAEF and LAi but not maximal LA volume remained independent predictors of AF. Results were similar in competing risk analysis treating all–cause mortality as a competing risk. LAEF and LAi, but not maximal LA volume, added incremental prognostic information in predicting incident AF when added to the CHARGE-AF risk score and the CHA2DS2-VASc score. Conclusion LAEF and LAi independently predicted incident AF following STEMI and added incremental prognostic information in addition to established predictors of AF. Maximal LA volume was not an independent predictor of incident AF after multivariable adjustment.

It has previously been demonstrated that the ratio of early mitral inflow velocity to global diastolic strain rate (E/e'sr) is a significant predictor of cardiac events in specific patient populations. The utility of this measurement to predict cardiovascular events in a general population has not been evaluated.A total of 1238 participants in a general population study underwent a health examination including echocardiography where global longitudinal strain (GLS) and E/e'sr were determined. The primary endpoint was the composite of incident heart failure (HF), acute myocardial infarction (AMI) or cardiovascular death (CVD). During follow-up (median 11 years), 140 (11.3%) participants reached the composite endpoint. E/e'sr was associated with adverse outcome [HR 1.17 95% CI (1.13-1.21); P 0.001, per 10 cm increase]. After multivariable adjustment for echocardiographic and clinical parameters, E/e'sr remained an independent predictor of the composite endpoint [HR 1.08, 95% CI (1.02-1.13); P = 0.003] as opposed to E/e' [HR 1.03, 95% CI (0.99-1.06); P = 0.11 per 1 unit increase]. Global longitudinal strain modified the relationship between E/e'sr and outcome (P for interaction = 0.015). E/e'sr was a stronger predictor in participants with good systolic function as determined by GLS (GLS 18%) after multivariable adjustment, when compared to participants with reduced systolic function (GLS 18%) [HR 1.28 95% CI (1.06-1.54); P = 0.011, and HR 1.08 95% CI (1.02-1.14); P = 0.012, respectively). E/e'sr provided incremental information [Harrell's C-index: 0.839 (0.81-0.87) vs. 0.844 (0.82-0.87); P = 0.045] beyond the SCORE risk chart.In the general population, E/e'sr provides independent and incremental prognostic information regarding cardiovascular morbidity and mortality. Additionally, E/e'sr is a stronger predictor of cardiac events than E/e'.

AIMS Two-dimensional speckle tracking echocardiography (2DSTE) detects early signs of left ventricular dysfunction; however, it is unknown whether layer-specific global longitudinal strain (GLS) has incremental value in diagnosis of patients with reversible ischemia assessed by single photon emission computed tomography (SPECT). METHODS AND RESULTS Eighty patients with stable angina pectoris (SAP), normal left ventricular ejection fraction (LVEF), and no history of ischemic heart disease were retrospectively identified to have been examined by 2DSTE, SPECT, and coronary angiography (CAG). Patients with a normal SPECT constituted the control group, and patients with a positive SPECT were divided into patients with or without (true- or false- positive SPECT) significant stenosis assessed by CAG. GLS was measured for two myocardial layers (endocardial and epicardial) and as well as mid-myocardial GLS. Patients with reversible ischemia had significantly lower GLS compared to the control group (GLSEndocardial : -19.0 ± 4.4% vs -21.4 ± 3.7%, P = .011; GLSEpicardial : -14.3 ± 2.9% vs -16.3 ± 2.9%, P = .004); GLSMid-myocardial : -16.5 ± 3.6% vs -18.6 ± 3.2%, P = .006. This difference was even more evident in patients with a true-positive SPECT (GLSEndocardial : -18.0 ± 4.4% vs -21.4 ± 3.7%, P

Aims Quantification of systolic function in patients with atrial fibrillation (AF) is challenging. A novel approach, based on RR interval correction, to counteract the varying heart cycle lengths in AF has recently been proposed. Whether this method is superior in patients with systolic heart failure (HFrEF) with AF remains unknown. This study investigates the prognostic value of RR interval-corrected peak global longitudinal strain {GLSc = GLS/[RR^(1/2)]} in relation to all-cause mortality in HFrEF patients displaying AF during echocardiographic examination. Methods and results Echocardiograms from 151 patients with HFrEF and AF during examination were analysed offline. Peak global longitudinal strain (GLS) was averaged from 18 myocardial segments obtained from three apical views. GLS was indexed with the square root of the RR interval {GLSc = GLS/[RR^(1/2)]}. Endpoint was all-cause mortality. During a median follow-up of 2.7 years, 40 patients (26.5%) died. Neither uncorrected GLS (P = 0.056) nor left ventricular ejection fraction (P = 0.053) was significantly associated with all-cause mortality. After RR^(1/2) indexation, GLSc became a significant predictor of all-cause mortality (hazard ratio 1.16, 95% confidence interval 1.02-1.22, P = 0.014, per %/s^(1/2) decrease). GLSc remained an independent predictor of mortality after multivariable adjustment (age, sex, mean heart rate, mean arterial blood pressure, left atrial volume index, and E/e') (hazard ratio 1.17, 95% confidence interval 1.05-1.31, P = 0.005 per %/s^(1/2) decrease). Conclusions Decreasing {GLSc = GLS/[RR^(1/2)]}, but not uncorrected GLS nor left ventricular ejection fraction, was significantly associated with increased risk of all-cause mortality in HFrEF patients with AF and remained an independent predictor after multivariable adjustment.

Asymptomatic paroxysmal atrial fibrillation (PAF) is often assumed to be the cause of cryptogenic ischemic strokes (IS) and transient ischemic attacks (TIA). We examined the usefulness of measures obtained by 2D speckle tracking echocardiography and novel left atrial measurements, in the diagnosis of PAF in patients with IS and TIA. We retrospectively included 205 patients who after acute IS or TIA underwent an echocardiogram in sinus rhythm. Patients were designated as PAF-patients if they had one or more reported incidents of AF before or after their echocardiographic examination. None of the conventional echocardiographic parameters were significantly associated with PAF. Of the speckle tracking measurements, only early diastolic strain rate (0.7±0.2 s−1 vs. 0.8±0.3 s−1, p = 0.048) and global longitudinal displacement (GLD) (3.15 ± 1.40 mm vs. 3.87 ± 1.56 mm, p = 0.007) proved significantly different. Of the left atrial parameters both minimal and maximal left atrium volume divided by left ventricular length (min LAV/LVL and max LAV/LVL, respectively) were significantly impaired (min LAV/LVL: 3.7 ± 2.1 cm2 vs. 2.8 ± 1.11 cm2, p = 0.012; max LAV/LVL: 6.6 ± 3.1 cm2 vs. 5.6 ± 1.7 cm2, p = 0.012). GLD, min max LAV/LVL proved significant after adjustment for age, gender, CHA2DS2-VASc and NIHSS. By combining information regarding age, GLD, min and max LAV/LVL the diagnostic accuracy of PAF improved, resulting in a significantly increased area under the curve (p = 0.037). In patients with IS and TIA GLD, min and max LAV/LVL were independently associated with the presence of PAF.

Background Echocardiographic classification of DDF has been widely discussed. The aim of this study was to investigate the independent prognostic value of established echocardiographic measures in a community-based population and create a new classification of DDF. Methods Within the Copenhagen City Heart Study, a prospective, community-based study, 1851 participants were examined by echocardiography including Tissue Doppler Imaging (TDI) in 2001 to 2003 and followed with regard to MACE (median, 10.9 years). Results We found that persons with impaired myocardial relaxation as defined by low peak early diastolic mitral annular velocity e' by TDI had higher incidence of clinical and echocardiographic markers of cardiac dysfunction and increased risk of MACE. Among persons with impaired relaxation, only echocardiographic indices of increased filling pressures such as LAVi ≥34 mL/m 2 (HR 1.97 (1.13-3.45, P =.017), E/e′ ≥ 17 (HR 1.89 (1.34-2.65), P E/A >2 (HR 5.24 (1.91-14.42), P =.001) provided additional and independent prognostic information on MACE. Based on these findings, we created a new classification of DDF where all grades were significant predictors of MACE independently of age, sex, and cardiac clinical risk markers (Mild DDF: HR 1.99 (1.23-3.21), P =.005; Moderate DDF: HR 3.11 (1.81-5.34), P P Conclusions In the general population, the presence of echocardiographic markers of elevated filling pressures in persons with impaired relaxation increased the risk of MACE significantly. Based on this, we present a new, feasible, and unambiguous classification of DDF capable of accurate risk prediction in the community.

In patients with type 2 diabetes, both supervised exercise and treatment with the glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA) liraglutide may improve cardiac function. We evaluated cardiac function before and after 16 weeks of treatment with the GLP-1RA liraglutide or placebo, combined with supervised exercise, in 33 dysregulated patients with type 2 diabetes on diet and/or metformin. Early diastolic myocardial tissue velocity was improved by exercise in the placebo group (mean ± standard deviation [s.d.] -7.1 ± 1.6 to -7.7 ± 1.8 cm/s, P = .01), but not in the liraglutide group (-7.1 ± 1.4 to -7.0 ± 1.4 cm/s, P = .60; between groups, P = .02). Similarly, the mean ± s.d. ratio of early and atrial mitral annular tissue velocities improved in the placebo group (1.0 ± 0.4 to 1.2 ± 0.4, P = .003), but not in the liraglutide group (1.0 ± 0.3 to 1.0 ± 0.3, P = .87; between groups, P = .03). We found no significant differences in heart rate, left ventricular (LV) structure or function within or between the groups. In conclusion, the addition of liraglutide to exercise in sedentary patients with dysregulated type 2 diabetes may blunt the suggested beneficial effect of exercise on LV diastolic function.

AIMS: Vitamin B12 deficiency could be associated with cardiovascular autonomic neuropathy (CAN) in diabetes patients. We aim to investigate the association between serum levels of vitamin B12 and CAN in type 2 diabetes patients.METHODS: 469 ambulatory type 2 diabetes patients (mean diabetes duration 10.0years (IQR 5.0;17.0), mean age 59.0years (SD 11.6), 63% men, mean B12 289.0pmol/l (IQR 217;390)) were screened for CAN using three cardiovascular reflex tests, five minute resting heart rate (5min RHR) and heart rate variability indices.RESULTS: Serum levels of vitamin B12 were significantly lower in patients treated with metformin and/or proton pump inhibitors (PPIs) compared with patients not treated (pCONCLUSION: Vitamin B12 may be inversely associated with CAN in patients with type 2 diabetes. Confirmatory studies investigating a causal role of vitamin B12 for the development of diabetic CAN are warranted.

Introduction PCSK9 Inhibitors (PCSK9 I) are a new group of drugs for treatment of hyperlipidaemia. These drugs have been available in Denmark since October 2015. From the two existing major outcome studies (FOURIER and ODYSSEY OUTCOMES) it has been shown that there was no significant difference in the risk of serious adverse events, discontinuation due to adverse events, neurocognitive events, diabetes-related events, muscle-related events, or myalgia in the treatment group, compared with the control group. In FOUIRER 12.5% came of treatment; In ODYSSEY the rate was 10.2–14.8%. Although this highlights the efficacy and safety in patients with cardiovascular disease, we have little knowledge of the use, efficacy and safety with these drugs in real-life populations Purpose We aim to describe the demography, the treatment efficacy and the extent of adverse effects among patients treated in Danish lipid clinics. Methods Data on all patients treated with PCSK9 I between October 1st, 2015 and May 1st, 2018 were obtained from lipid clinics in Denmark. A database containing information on medications before treatment, adverse effects, plasma lipids (LDL-C, Triglyceride, High density lipoprotein cholesterol (HDL-C)) and supplementary blood tests was created. Levels of plasma lipids and organ markers (Creatinine, Hba1c or Alanine aminotransferase (ALAT)) at baseline and at follow up visits were analysed. Results Nationwide, 383 patients were included, an estimated 90% of all patients undergoing treatment with PCSK9 I in Denmark. A large proportion (n=243 - 63.4%) were described as statin intolerant and only 94 patients were receiving statins at baseline. Adverse effects (AE) were reported by 71 patients (18.5%) on PCSK9 I therapy and 50 patients (13.1%) stopped treatment. Most common AE were flu like symptoms and musculoskeletal aches. In two cases an increase in serum creatinine kinase was detected. One case of angioedema and three cases of local reactions to injections had been documented. No case of anaphylaxis was reported. Of the 71 patients with AEs 55 (77.5%) were statin intolerant. Of the 50, who came off treatment, 43 (86.0%) were statin intolerant. When treatment was stopped 15 patients (30.0%) tried the alternative PCSK9 Inhibitor (cross over). Of those, nine patients were able to tolerate the alternative PCSK9 I treatment. Conclusion Many patients (18.3%) reported AEs on a wide range of symptoms, but the rate of patients terminating PCSK9 I treatment was the same as found in the outcome studies (13.1% vs. 12.2 and 10.2–14.8%). Most of the patients who stopped treatment were statin intolerant and produced the same symptoms, as they had experienced with statins. Interestingly, nine of the 15 patients that were switched to the alternate PCSK9 I seems to tolerate this treatment.

Background: The prognostic value of LA functional measures in heart failure patients with reduced ejection fraction (HFrEF) is unclear. Therefore, this study investigated the prognostic value of left atrial (LA) functional measures such as the left atrial emptying fraction (LAEF) and the minimal LA volume compared with left atrial volume index (LAVI) in HFrEF patients. Methods and Results: A total of 818 HFrEF patients with left ventricular ejection fractions 2 increase; LAVI: HR 1.06 (P =.16) per 5 mL/m 2 increase. Conclusions: LAEF is an independent predictor of all-cause mortality in HFrEF patients after multivariable adjustment. LAEF provides incremental prognostic value over LAVI in risk stratification of HFrEF patients.

Aim To investigate the possible association between vitamin D deficiency and cardiovascular autonomic neuropathy in people with diabetes. Methods A total of 113 people with Type 1 or Type 2 diabetes [mean (interquartile range) diabetes duration 22.0 (12–31) years, mean (sd) age 56.2 (13.0) years, 58% men] underwent vitamin D (D2 and D3) assessment, and were screened for cardiovascular autonomic neuropathy using three cardiovascular reflex tests [heart rate response to deep breathing (E/I ratio), to standing (30/15 ratio) and to the Valsalva manoeuvre] and assessment of 5-min resting heart rate and heart rate variability indices. Results We found an inverse U-shaped association between serum vitamin D level and E/I ratio, 30/15 ratio and three heart rate variability indices (P

Aims Patients admitted with chest pain are a diagnostic challenge because the majority does not have coronary artery disease (CAD). Assessment of CAD with coronary computed tomography angiography (CCTA) is safe, cost-effective, and accurate, albeit with a modest specificity. Stress myocardial computed tomography perfusion (CTP) has been shown to increase the specificity when added to CCTA, without lowering the sensitivity. This article describes the design of a randomized controlled trial, CATCH-2, comparing a clinical diagnostic management strategy of CCTA alone against CCTA in combination with CTP. Methods Patients with acute-onset chest pain older than 50 years and with at least one cardiovascular risk factor for CAD are being prospectively enrolled to this study from 6 different clinical sites since October 2013. A total of 600 patients will be included. Patients are randomized 1:1 to clinical management based on CCTA or on CCTA in combination with CTP, determining the need for further testing with invasive coronary angiography including measurement of the fractional flow reserve in vessels with coronary artery lesions. Patients are scanned with a 320-row multidetector computed tomography scanner. Decisions to revascularize the patients are taken by the invasive cardiologist independently of the study allocation. The primary end point is the frequency of revascularization. Secondary end points of clinical outcome are also recorded. Discussion The CATCH-2 will determine whether CCTA in combination with CTP is diagnostically superior to CCTA alone in the management of patients with acute-onset chest pain.

Objectives: We aimed to determine the prevalence of echocardiographic abnormalities and their relation to clinical characteristics and cardiac symptoms in a large, contemporary cohort of patients with type 2 diabetes. Results: A total of 1030 patients with type 2 diabetes participated. Echocardiographic abnormalities were present in 513 (49.8%) patients, mainly driven by a high prevalence of diastolic dysfunction 178 (19.4%), left ventricular hypertrophy 213 (21.0%) and left atrial enlargement, 200 (19.6%). The prevalence increased markedly with age from 31.1% in the youngest group (75 years) ( p Conclusion: Echocardiographic abnormalities are very common in outpatients with type 2 diabetes, but neither cardiac symptoms nor clinical characteristics are effective to identify patients with echocardiographic abnormalities.

Identification of early signs and symptoms of heart disease is important in type 1 diabetes (T1DM). Global longitudinal strain (GLS) by speckle-tracking echocardiography can detect subtle impairments in myocardial function. We investigated the association between myocardial function and degree of dyspnea in patients with normal left ventricular ejection fraction (LVEF) and without known heart disease.Ambulatory patients from Steno Diabetes Center. Conventional echocardiography and GLS was performed. Patients reported degree of dyspnea according to the NYHA classification. Patients with LVEF≤45% were excluded. Data were analyzed in uni-and multivariable models.A total of 1075 T1DM patients were included. Mean age 49.5years, 52% men, mean diabetes duration 25.8years; 835 (77.7%) reported no dyspnea, 156 (14.5%) NYHA I, 68 (6.3%) NYHA II, and 16 (1.5%) NYHA III-IV. LVEF did not differ between groups of dyspnea in neither univariable nor multivariable models (p0.1). E/e' was associated with degree of dyspnea in both univariable (p0.001) and multivariable models (p=0.048). GLS was associated with degree of dyspnea in a dose-response relationship in both univariable (p0.001) and multivariable models (p0.001).Degree of dyspnea is independently associated with impaired myocardial function by GLS in T1DM patients with normal LVEF and without known heart disease.

Aim Heart disease is a common fatal diabetes-related complication. Early detection of patients at particular risk of heart disease is of prime importance. Soluble urokinase plasminogen activator receptor (suPAR) is a novel biomarker for development of cardiovascular disease. We investigate if suPAR is associated with early myocardial impairment assessed with advanced echocardiographic methods. Methods In an observational study on 318 patients with type 1 diabetes without known heart disease and with normal left ventricular ejection fraction (LVEF) (biplane LVEF >45%), we performed conventional, tissue Doppler and speckle tracking echocardiography, and measured plasma suPAR levels. Associations between myocardial function and suPAR levels were studied in adjusted models including significant covariates. Results Patients were 55±12 years (mean±s.d.) and 160 (50%) males. Median (interquartile range) suPAR was 3.4 (1.7) ng/mL and LVEF was 58±5%. suPAR levels were not associated with LVEF (P=0.11). In adjusted models, higher suPAR levels were independently associated with both impaired systolic function assessed with global longitudinal strain (GLS) and tissue velocity s′, and with impaired diastolic measures a′ and e′/a′ (all P=0.034). In multivariable analysis including cardiovascular risk factors and both systolic and diastolic measures (GLS and e′/a′), both remained independently associated with suPAR levels (P=0.012). Conclusions In patients with type 1 diabetes with normal LVEF and without known heart disease, suPAR is associated with early systolic and diastolic myocardial impairment. Our study implies that both suPAR and advanced echocardiography are useful diagnostic tools for identifying patients with diabetes at risk of future clinical heart disease, suited for intensified medical therapy.

It is often difficult to provide an exact echocardiographic measure of left ventricular systolic function in patients with atrial fibrillation, partly because of the varying cycle length affecting pre and afterload and partly because of the increased heart rate often accompanying this arrhythmia. We sought to elucidate two points: whether it would be possible to correct for the cyclic variance in systolic output, and if global longitudinal strain is preferable to the left ventricular ejection fraction at evaluating systolic function during atrial fibrillation.

Often the underlying cause of cerebral ischemia (CI) cannot be found during a routine diagnostic investigation, but paroxysmal atrial fibrillation (PAF) could be the culprit.The objective of the study is to investigate whether advanced echocardiography improves the diagnostic approach for PAF in CI.The study included 286 CI patients with an echocardiogram in sinus rhythm. Patients were divided by PAF occurrence (PAF: n = 86, non-PAF: n = 200). PAF was defined as 1 or more reported episodes of atrial fibrillation. Echocardiograms consisted of conventional measures, tissue Doppler imaging (TDI), and speckle tracking. TDI was performed to acquire myocardial peak velocities during systole/ventricular contraction (global s'), early diastole/ventricular filling (global e'), and late diastole/atrial contraction (global a'). Speckle tracking was performed for myocardial strain analysis, thereby retrieving global longitudinal strain and global strain rate (s, e, a) values.Patients with PAF exhibited significantly impaired atrial contractile measures: global a' (-7.0 cm/second versus -5.7 cm/second, P.001) and global strain rate a (.97 second(-1) versus .81 second(-1), P.001). Both were univariable markers of PAF, and along with age remained the only independent significant determinants of PAF after multivariable logistic regression. Area under the curve (AUC) for age, global a', and global strain rate a significantly exceeded AUC for age alone (.79 versus .76, P = .032). Cutoff values with the highest sensitivity and specificity for these 3 parameters improved the diagnostic accuracy (sensitivity = 97%, specificity = 32%, negative predictive value = 95%, and positive predictive value = 38%).Atrial contractile measures by advanced echocardiography are significant determinants of PAF in CI. However, there is no discriminatory power to make them clinically useful at the current moment.

Influenza infection is a serious event for patients with heart failure (HF). Little knowledge exists about the association between influenza vaccination and outcome in patients with HF. This study sought to determine whether influenza vaccination is associated with improved long-term survival in patients with newly diagnosed HF.We performed a nationwide cohort study including all patients who were18 years of age and diagnosed with HF in Denmark in the period of January 1, 2003, to June 1, 2015 (n=134 048). We collected linked data using nationwide registries. Vaccination status, number, and frequency during follow-up were treated as time-varying covariates in time-dependent Cox regression.Follow-up was 99.8% with a median follow-up time of 3.7 years (interquartile range, 1.7-6.8 years). The vaccination coverage of the study cohort ranged from 16% to 54% during the study period. In unadjusted analysis, receiving ≥1 vaccinations during follow-up was associated with a higher risk of death. After adjustment for inclusion date, comorbidities, medications, household income, and education level, receiving ≥1 vaccinations was associated with an 18% reduced risk of death (all-cause: hazard ratio, 0.82; 95% CI, 0.81-0.84; P0.001; cardiovascular causes: hazard ratio, 0.82; 95% CI, 0.81-0.84; P0.001). Annual vaccination, vaccination early in the year (September to October), and greater cumulative number of vaccinations were associated with larger reductions in the risk of death compared with intermittent vaccination.In patients with HF, influenza vaccination was associated with a reduced risk of both all-cause and cardiovascular death after extensive adjustment for confounders. Frequent vaccination and vaccination earlier in the year were associated with larger reductions in the risk of death compared with intermittent and late vaccination.

The optimal timing of invasive coronary angiography (ICA) and revascularization in patients with non-ST-segment elevation acute coronary syndrome is not well defined. We tested the hypothesis that a strategy of very early ICA and possible revascularization within 12 hours of diagnosis is superior to an invasive strategy performed within 48 to 72 hours in terms of clinical outcomes.Patients admitted with clinical suspicion of non-ST-segment elevation acute coronary syndrome in the Capital Region of Copenhagen, Denmark, were screened for inclusion in the VERDICT trial (Very Early Versus Deferred Invasive Evaluation Using Computerized Tomography) ( ClinicalTrials.gov NCT02061891). Patients with ECG changes indicating new ischemia or elevated troponin, in whom ICA was clinically indicated and deemed logistically feasible within 12 hours, were randomized 1:1 to ICA within 12 hours or standard invasive care within 48 to 72 hours. The primary end point was a combination of all-cause death, nonfatal recurrent myocardial infarction, hospital admission for refractory myocardial ischemia, or hospital admission for heart failure.A total of 2147 patients were randomized; 1075 patients allocated to very early invasive evaluation had ICA performed at a median of 4.7 hours after randomization, whereas 1072 patients assigned to standard invasive care had ICA performed 61.6 hours after randomization. Among patients with significant coronary artery disease identified by ICA, coronary revascularization was performed in 88.4% (very early ICA) and 83.1% (standard invasive care). Within a median follow-up time of 4.3 (interquartile range, 4.1-4.4) years, the primary end point occurred in 296 (27.5%) of participants in the very early ICA group and 316 (29.5%) in the standard care group (hazard ratio, 0.92; 95% CI, 0.78-1.08). Among patients with a GRACE risk score (Global Registry of Acute Coronary Events)140, a very early invasive treatment strategy improved the primary outcome compared with the standard invasive treatment (hazard ratio, 0.81; 95% CI, 0.67-1.01; P value for interaction=0.023).A strategy of very early invasive coronary evaluation does not improve overall long-term clinical outcome compared with an invasive strategy conducted within 2 to 3 days in patients with non-ST-segment elevation acute coronary syndrome. However, in patients with the highest risk, very early invasive therapy improves long-term outcomes.URL: https://www.clinicaltrials.gov . Unique identifier: NCT02061891.

Cardiovascular death (CVD) is a leading cause of death and constitutes a major burden on society. Left ventricular mechanical dyssynchrony (LVMD), evaluated as SD of time to peak regional longitudinal strain, is a capable predictor of many cardiovascular outcomes related to CVD, including ventricular arrhythmias, but the prognostic utility of LVMD in the general population is unknown. Hence, this study sought to determine the prognostic value of LVMD in the general population in predicting CVD.A total of 1138 participants underwent a general health examination and an echocardiographic examination including speckle tracking analysis with subsequent calculation of LVMD from time-to-peak regional strain. Primary end point was CVD, and secondary end point was noncardiovascular death. Follow-up was 100%. During a median follow-up of 11.1 years (interquartile range: 10.2-11.3 years), 62 participants suffered CVD (5.5%) while 131 participants experienced noncardiovascular death (11.5%). LVMD was an independent predictor of CVD (subdistribution hazard ratio, 1.04; 95% CI, 1.01-1.06; P=0.004, per 10-ms increase) in competing risk regression treating noncardiovascular death as a competing risk and retained prognostic capability after extensive multivariable adjustment. LVMD was not a significant predictor of noncardiovascular death. LVMD added incremental prognostic information in predicting CVD beyond the Systematic Coronary Risk Evaluation risk chart and a modified version of the American College of Cardiology/American Heart Association Pooled Cohort Equation.Left ventricular mechanical dyssynchrony adds incremental prognostic information in addition to established risk factors in prediction of CVD in individuals from the general population without atrial fibrillation and significant valvular disease.

There are 320,000 diabetes patients in Denmark. Heart failure (HF) is a major cardiovascular complication to diabetes mellitus with increasing prevalence. HF occurs 2-4 times more frequently in diabetes patients, but patients may go undiagnosed for years. Diabetes patients typically suffer from diastolic dysfunction caused by myocardial hyper-trophy and "stiffness" of the left ventricle. This frequent finding has prompted the term "diabetic cardiomyopathy". Echocardiography is a key examination in diagnosing HF and may be warranted to a greater degree in diabetes patients at particular risk.

Aims: The aim of the study was to determine whether patients treated with drug-eluting stents in the proximal left anterior descending artery (LAD) carried a different long-term prognosis from patients treated in other coronary artery segments. Methods and results: Ten-year clinical outcome expressed as all-cause mortality and major adverse cardiac events (MACE: Cardiac death, acute myocardial infarction, or target vessel revascularisation) was determined for 1,479 patients with a single non-left main coronary stenosis treated with a first-generation drug-eluting stent in the SORT OUT II trial. The outcome of patients treated with stents in the proximal LAD (n=365) was compared with that of patients treated in a non-proximal LAD segment (n=1,114). Follow-up was 99.3% complete. All-cause mortality was 24.9% in the proximal LAD group vs. 26.3% in the non-proximal LAD group (p=0.60). MACE occurred less frequently in the proximal LAD group, 24.6% vs. 31.0% with a hazard ratio of 0.77 (95% confidence interval [CI]: 0.61-0.97, p=0.024). After multivariate analysis which included baseline characteristics that were unevenly distributed between the groups, the hazard ratio for MACE was 0.82 (95% CI: 0.65-1.03, p=0.09). Conclusions: Patients treated with a drug-eluting stent in the proximal LAD have similar, if not better, long-term clinical outcome compared with patients stented in other coronary artery segments.

Background Type 2 diabetes mellitus is closely associated with metabolic risk factors that all contribute to impairment of the left ventricle. The implications of having type 2 diabetes mellitus with well‐controlled metabolic risk factors compared to an increasing burden of uncontrolled metabolic risk factors on left ventricular structure and function are not known. Methods and Results We compared patients with type 2 diabetes mellitus (n=751) with different degrees of uncontrolled metabolic risk factors present with a control group of individuals without present uncontrolled metabolic risk factors as recommended by the World Health Organization (n=80). In patients with well‐controlled metabolic risk factors, only diastolic but neither structural nor systolic measures were impaired compared to the control group: the (early diastolic mitral inflow velocity)/(atrial diastolic mitral inflow velocity) ratio (median 0.94 [interquartile range 0.80, 1.08] versus 1.11 [0.85, 1.38], P P P P 1c , and HDL ‐cholesterol. Conclusions In patients with type 2 diabetes mellitus, having well‐controlled metabolic risk factors was associated with only left ventricular diastolic impairment but not with either structural or even subtle measures of systolic function. Increasing burden of uncontrolled metabolic risk factors was associated with structural and functional impairments.