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Purpose: Tissue Doppler imaging (TDI) is a sensitive marker of impaired cardiac function and different phases of the TDI curve carry different prognostic information. It is not known how continuous TDI curves change with age in normal subjects, and whether these changes differ from changes seen in individuals at risk of future cardiac events., Methods: A total of 1,763 individuals from the general population were examined with color TDI at the septal and lateral mitral sites. A low-risk group was defined as without cardiac risk factors (hypertension, diabetes or ischemic heart disease) at baseline and without any cardiac events (cardiovascular death or admission due to either heart failure or acute myocardial infarction) during 10-years follow-up. All TDI curves were corrected for heart rate, and whole-cycle analysis of age-related changes to TDI velocities was performed in both low-risk ( n = 881) and high-risk individuals ( n = 882)., Results: In the low-risk population, four phases where myocardial velocity differed most ( p < 10 -10 ) according to age were identified [in a standardized cardiac cycle of 1 second (s)]: Systolic peak (0.09-0.13 s), systolic plateau (0.18-0.27 s), early diastole (0.43-0.54 s) and late diastole (0.88-0.95 s). With increasing age, systolic velocities decreased, early diastolic velocities decreased and had delayed peak, and late diastolic velocities increased until age 70 and then stopped increasing. In the high-risk population, comparison to corresponding age groups of the low-risk population showed: Lower early diastolic velocities in 20-40-year-olds; higher late diastolic velocities and lower peak systolic velocities in 40-60-year-olds; further decreased systolic velocities including the systolic plateau and decreased late diastolic velocities in 60-year-olds. The time segments around the systolic peak ( p = 0.002) and early diastole ( p < 0.001) differed significantly between the high-risk and low-risk population, thus making it possible to use the individual age gap between a TDI-derived biological age and the real chronological age as a tool to discriminate high-risk individuals from low-risk individuals., Conclusion: We found that individuals with cardiac risk factors display findings compatible with an accelerated aging of the heart and thus propose TDI-derived biological age as a tool to identify high-risk patients., 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., (Copyright © 2023 Wang, Olsen, Taraldsen and Mogelvang.)

Increased left ventricular mass (LVM) is a strong independent predictor for adverse cardiovascular events, but conventional echocardiographic methods are limited by poor reproducibility and accuracy. We developed a novel method based on adding the mean wall thickness from the parasternal short axis view, to the left ventricular end-diastolic volume acquired using the biplane model of discs. The participants (n = 85) had various left ventricular geometries and were assessed using echocardiography followed immediately by cardiac magnetic resonance, as reference. We compared our novel two-dimensional (2D) method to various conventional one-dimensional (1D) and other 2D methods as well as the three-dimensional (3D) method. Our novel method had better reproducibility in intra-examiner [coefficients of variation (CV) 9% vs. 11-14%] and inter-examiner analysis (CV 9% vs. 10-20%). Accuracy was similar to the 3D method (mean difference ± 95% limits of agreement, CV): Novel: 2 ± 50 g, 15% vs. 3D: 2 ± 51 g, 16%; and better than the "linear" 1D method by Devereux (7 ± 76 g, 23%). Our novel method is simple, has considerable better reproducibility and accuracy than conventional "linear" 1D methods, and similar accuracy as the 3D-method. As the biplane model forms part of the standard echocardiographic protocol, it does not require specific training and provides a supplement to the modern echocardiographic report., (© 2022. The Author(s).)

Introduction: Increased left ventricular mass (LVM) is one of the most powerful predictors of adverse cardiovascular events. Clinical evaluation requires reliable, accurate and reproducible echocardiographic LVM-quantification to manage patients. For this purpose, we have developed a novel two-dimensional (2D) method based on adding the mean wall thickness to the left ventricular volume acquired by the biplane method of disks, which has recently been validated in humans using cardiac magnetic resonance as reference value. We assessed the hypothesis that the novel method has better accuracy than conventional one-dimensional (1D) methods, when compared to necropsy LVM in pigs., Materials and Methods: Echocardiography was performed during anesthesia in 34 Danish Landrace pigs, weight 47-59 kg. All pigs were euthanized, cardiac necropsy was performed and the left ventricle was trimmed and weighed for necropsy LVM. Trans-thoracic echocardiography was applied for parasternal images. Transdiaphragmal echocardiography was applied for the apical images, which are otherwise difficult to obtain in pigs. We compared the conventional 1D- and 2D-methods and the novel 2D-method to the LVM from cardiac necropsy., Results: Necropsy LVM was 132 ± 11 g (mean ± SD). The novel method had better accuracy than other methods (mean difference ± 95% limits of agreement; coefficients of variation; standard error of the estimate, Pearson's correlation). Novel (-1 ± 20 g; 8%; 11 g; r = 0.70), Devereux (+26 ± 37 g; 15%; 33 g; r = 0.52), Area-Length (+27 ± 34 g; 13 %; 33 g; r = 0.63), Truncated Ellipsoid (+10 ± 30 g; 12%; 19 g; r = 0.63), biplane endo-/epicardial tracing (-3 ± 2 g; 10%; 14 g; r = 0.57). No proportional bias in linear regression was detected for any method, when compared to necropsy LVM., Conclusion: We confirm high accuracy of the novel 2D-based method compared to conventional 1D/2D-methods., 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., (Copyright © 2022 Kristensen, Sattler, Lubberding, Tfelt-Hansen, Jespersen, Hassager and Mogelvang.)

To assess if layer-specific longitudinal strain (LS) provides incremental diagnostic and prognostic value compared to global longitudinal strain (GLS) in patients with chronic severe aortic regurgitation (AR) scheduled for aortic valve surgery. Forty-one patients were examined with speckle tracking echocardiography before surgery along with 15 healthy age-matched controls. Paired strain analyses before and after surgery were available in 31 patients. Layer-specific LS analysis enabled assessment of epicardial GLS (GLS epi ), endocardial GLS (GLS endo ), and conventional GLS. Strain parameters were indexed to end-diastolic volume (EDV; GLS/EDV) to account for increased preload. The prognostic value of layer-specific LS was evaluated using the primary outcome of persistent LV dilatation (LVEDV ≥ 175 mL) three months after surgery. Absolute (GLS, GLS epi , GLS endo ) and EDV-indexed layer-specific LS (GLS/EDV, GLS epi /EDV, GLS endo /EDV) were impaired in severe AR compared to controls at baseline (GLS:17.0 ± 3.2 vs. 20.6 ± 2.0; GLS epi :14.6 ± 2.8 vs. 18.1 ± 1.9; GLS endo :20.2 ± 3.7 vs. 23.8 ± 2.2%; GLS/EDV:0.09 ± 0.05 vs. 0.21 ± 0.05; GLS epi /EDV:0.08 ± 0.04 vs. 0.18 ± 0.04; GLS endo /EDV:0.11 ± 0.06 vs. 0.24 ± 0.05%/mL; all p < 0.001). In severe AR, GLS, GLS epi and GLS endo decreased after surgery whereas GLS/EDV, GLS epi /EDV and GLS endo /EDV increased (all p < 0.001). Impaired absolute and EDV-indexed layer-specific LS were all associated with the primary outcome (all p ≤ 0.01). Area under the curve analysis revealed similar prognostic value of GLS epi , GLS endo and GLS (GLS:0.86; GLS epi :0.87; GLS endo :0.86; p = n.s.). EDV-indexed LS did not improve the predictive value significantly (GLS/EDV:0.93; GLS epi /EDV: 0.93; GLS endo /EDV:0.92; p = n.s.). Layer-specific LS detects transmural dysfunction in chronic severe AR and predicts persistent LV dilation after surgery. Layer-specific LS or EDV-indexed LS does not provide incremental prognostic value compared to conventional GLS., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Aims: This study investigated left atrial (LA) parameters as measured on transthoracic echocardiography as predictors of incident heart failure (HF) in a community cohort., Methods and Results: In a large general population study (n = 2221), participants underwent a health examination with echocardiography. The maximum and minimum LA volumes indexed to body surface area (LAVImax and LAVImin) were measured and the LA emptying fraction (LAEF) and LA expansion index (LAEI) were calculated. Among 1951 participants without atrial fibrillation or significant valve disease, the mean age was 59 ± 16 years and 58% were women. At baseline, 1% (n = 16) had a left ventricular ejection fraction of <50%, 44% had hypertension, and 10% had diabetes. During follow-up (median 15.8 years, interquartile range: 11.3-16.2 years), 187 (10%) participants were diagnosed with incident HF. Participants who were diagnosed with HF during follow-up had a larger LAVImax and LAVImin and a lower LAEF and LAEI compared to participants without HF. In unadjusted analysis, LAVImax, LAVImin, LAEF and LAEI were predictors of incident HF. After multivariable adjustment for clinical and echocardiographic parameters, only LAVImin remained an independent predictor of incident HF (hazard ratio per 1 standard deviation increase: 1.22 [95% confidence interval 1.01-1.47], p = 0.038)., Conclusion: In the general population, LAVImin is an independent predictor of incident HF. LAVImax, currently the only LA measure in a routine echocardiographic examination, was not an independent predictor of incident HF., (© 2021 European Society of Cardiology.)

Aims: Global longitudinal strain (GLS) is a strong predictor of adverse cardiovascular outcome in men. However, studies have indicated that GLS may not predict cardiovascular outcomes as effectively in women. The aim of this study was to identify echocardiographic predictors of cardiovascular morbidity and mortality in women from the general population., Methods and Results: A total of 1245 women from the general population free of heart failure (HF) and atrial fibrillation had an echocardiographic examination performed including tissue Doppler imaging. In this subset, 747 women had images eligible for strain analysis. Endpoint was a composite of acute myocardial infarction, HF, and cardiovascular death. During follow-up (median 12.5 years), 162 women (13.0%) reached the composite outcome. These women had higher left ventricular (LV) mass index (LVMI), more LV hypertrophy, lower E/A, higher E/e', larger LV dimensions, and longer deceleration time. LVMI and e' remained as significant predictors of the composite outcome [LVMI: hazard ratio (HR) 1.10, 95% confidence interval (CI) 1.03-1.17, P = 0.004, per 5 g/m2 increase] (e': HR 1.53, 95% CI 1.07-2.20, P = 0.020, per 1 cm/s decrease) after adjusting for age, hypertension, systolic blood pressure, diabetes mellitus, total cholesterol, smoking status, prevalent ischaemic heart disease, LV ejection fraction, E/e', E, E/A, interventricular septum thickness in diastole, left ventricular posterior wall in diastole, a', body surface area, and pro-brain natriuretic peptide. GLS was not an independent predictor of outcome after multivariable adjustment., Conclusion: The degree of LV hypertrophy assessed as LVMI and diastolic dysfunction evaluated by e' are associated with adverse cardiovascular outcome in women from the general population., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

To evaluate the impact of surgical aortic valve replacement (SAVR) on global (GLS) and regional longitudinal strain (RLS) across four flow-gradient patterns of severe aortic stenosis (AS) 3 months after surgery. A total of 103 patients with severe AS (aortic valve area < 1.0 cm 2 ) were examined by speckle tracking echocardiography the day before SAVR and at 3-months follow-up. Patients were stratified into four flow-gradient patterns by stroke volume index (>35 mL/m 2 vs. ≤35 mL/m 2 ) and mean transaortic gradients (>40 mmhg vs. ≤40 mmhg): normal-flow, high gradient (NF/HG); low-flow, high gradient (LF/HG); normal-flow, low gradient (NF/LG); low-flow, low gradient (LF/LG). Strain analysis comprised GLS and RLS at a basal (BLS), mid-ventricular (MLS) and apical level (ALS). Patients with high gradients improved GLS (NF/HG: 16.1 ± 3.5 % vs. 17.3 ± 3.4 %, p = 0.03 and LF/HG: 15.4 ± 3.6 % vs. 16.9 ± 3.1 %, p = 0.03), BLS (NF/HG: 12.7 ± 3.1 % vs. 14.2 ± 3.1 %, p = 0.003 and LF/HG: 11.4 ± 3.2 % vs. 13.8 ± 2.7 %, p = 0.005) and MLS (NF/HG: 15.4 ± 3.3 % vs. 16.5 ± 3.3 %, p = 0.04 and LF/HG: 14.5 ± 3.1 % vs. 16.2 ± 2.7 %, p = 0.01) whereas patients with low gradients showed no improvements three months after SAVR. ALS did not change significantly in any group. Patients with high gradients demonstrated a reduction in left ventricular (LV) mass index (p < 0.001) and N-terminal pro-Brain Natriuretic Peptide levels (p < 0.001) following SAVR in contrast to patients with low gradients. Patients with high gradient severe AS improve GLS and RLS three months after SAVR with concomitant reduction of LV mass and neurohormonal activation whereas patients with low gradients do not improve longitudinal strain, LV mass or neurohormonal activation., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V. part of Springer Nature.)

LA dyssynchrony is a predictor of cardiovascular morbidity in various patient populations. However, the prognostic value of LA dyssynchrony as evaluated by two-dimensional speckle tracking (2D-STE) in the general population is unknown. A cohort of 375 participants without atrial fibrillation (AF), ischemic heart disease (IHD), heart failure (HF) or previous ischemic stroke (IS) had an echocardiogram, including LA 2D-STE, performed. LA dyssynchrony was defined as the standard deviation of the time to peak regional LA reservoir strain values. The endpoints were all-cause mortality, a combined endpoint of AF and IS, and a combined endpoint of major adverse cardiovascular events (MACE) comprised of acute myocardial infarction (AMI), HF or cardiovascular death (CVD). During a median follow up of 16.1 years (IQR 15.0-16.3 years), 83 (22%) participants died, 60 (15%) reached the composite endpoint of AF and IS, and 38 (10%) reached the composite MACE endpoint. LA dyssynchrony was a univariable predictor of all-cause mortality (HR 1.07, 95% CI 1.02-1.11, p = 0.001) but was not significantly associated with the combined endpoint of AF and IS (HR 1.05, p = 0.064) nor MACE (HR 1.04, p = 0.22). However, when adjusted for age, LA dyssynchrony did not predict all-cause mortality (HR 1.03, p = 0.28). Similarly, after further adjustments for clinical and echocardiographic parameters LA dyssynchrony did not predict any of the study outcomes. In this general population study, LA dyssynchrony was not an independent predictor of all-cause mortality and did not predict MACE nor a composite outcome consisting of AF and IS.

Background: Speckle-tracking echocardiographic (STE) imaging and cardiac magnetic resonance feature-tracking (CMR-FT) are novel imaging techniques enabling layer-specific quantification of myocardial deformation. Conventional echocardiographic parameters are load dependent, but few studies have investigated the effects of loading conditions on STE and CMR-FT layer-specific strain and the interchangeability of the two modalities. The aim of this study was to evaluate the effects of acute preload augmentation by saline infusion on STE and CMR-FT longitudinal and circumferential layer-specific strain parameters and their intermodal agreement., Methods: A total of 80 subjects, including 41 control subjects (mean age, 40 ± 12 years; 49% men) and 39 patients with cardiac disease (mean age, 47 ± 15 years; 92% men) were examined using STE and CMR-FT layer-specific strain analysis before and after saline infusion (median, 2.0 L) with quantification of transmural global longitudinal strain (GLS), epicardial GLS, endocardial GLS, transmural global circumferential strain (GCS), epicardial GCS, and endocardial GCS in addition to epicardial-endocardial gradients. Bland-Altman plots and Pearson correlation coefficients were used to evaluate agreement between the two modalities across all strain parameters., Results: Acute saline infusion increased all STE and CMR-FT layer-specific strain parameters in both groups. STE and CMR-FT GLS increased by 1.4 ± 1.5% and 1.5 ± 2.0% (P < .001) in control subjects and by 0.9 ± 1.8% and 0.9 ± 1.9% (P < .001) in patients with cardiac disease. STE and CMR-FT GCS increased by 2.0 ± 2.2% and 1.8 ± 2.3% (P < .001) in control subjects and by 1.8 ± 2.3% and 1.7 ± 3.6% in patients with cardiac disease (P < .001 and P = .03). STE longitudinal strain correlated strongly with corresponding CMR-FT longitudinal strain (GLS, epicardial GLS, and endocardial GLS: r = 0.81, r = 0.82, and r = 0.81, respectively) despite poor intermodal agreement (bias ± limits of agreement, -2.84 ± 4.06%, 0.16 ± 3.68%, and 2.33 ± 3.52%, respectively) whereas GCS, epicardial GCS, and endocardial GCS correlated weakly between the two modalities (r = 0.28, r = 0.19, and r = 0.34, respectively) and displayed poor intermodal agreement (bias ± limits of agreement, -1.33 ± 6.86%, 4.43 ± 6.49%, and -9.92 ± 8.55%, respectively)., Conclusions: STE and CMR-FT longitudinal and circumferential layer-specific strain parameters are preload dependent in both control subjects and patients with cardiac disease. STE and CMR-FT longitudinal layer-specific strain parameters are strongly correlated, whereas circumferential layer-specific strain parameters are weakly correlated. STE and CMR-FT longitudinal and circumferential strain should not be used interchangeably, because of poor intermodal agreement., (Copyright © 2021 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Aims: The prognostic value of myocardial performance index (MPI) has not yet been assessed in patients with atrial fibrillation (AF). The aim of this study was to evaluate the prognostic value of MPI by tissue Doppler imaging (TDI) M-mode in AF patients., Methods and Results: Echocardiograms from 210 patients with AF during examination were analysed offline. Patients with known heart failure (HF) were excluded. Time intervals were measured using an M-mode line through the mitral valve leaflets to provide a colour diagram of the mitral leaflet movement so all time intervals could be measured from one cardiac cycle. MPI was calculated as the sum of isovolumic relaxation time and isovolumic contraction time divided by the ejection time [(IVRT+IVCT)/ET]. During a median follow-up of 2.4 years, 84 patients (40%) reached the combined endpoint of major adverse cardiovascular events (MACE), being all-cause mortality, HF, myocardial infarction, or stroke. Increasing MPI was significantly associated with an increased risk of MACE, and the risk increased with 20% per 0.1 increase in MPI [hazard ratio (HR) 1.20, 95% confidence interval (CI) 1.10-1.32; P < 0.001]. Increasing MPI was also significantly associated with a lower left ventricular ejection fraction (LVEF) (P < 0.001). Nevertheless, MPI remained an independent predictor even after adjustment for age, sex, diabetes mellitus, left atrial volume, and LVEF (HR 1.12, 95% CI 1.01-1.25; P = 0.038)., Conclusion: Increasing MPI was significantly associated with increased risk of MACE and remained an independent predictor after multivariable adjustment. This demonstrates that the MPI obtained by TDI M-mode might be useful in assessing cardiac function in AF patients with ongoing arrhythmia during examination., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Left ventricular hypertrophy is a strong predictor of prognosis in hypertension. Physical activity is associated with higher left ventricular mass but also reduced risk of cardiovascular outcomes. The aims were to explore whether (1) presence of hypertension modifies the association between physical activity and left ventricular mass; (2) the beneficial association between physical activity and prognostic outcome is modified by left ventricular hypertrophy. Randomly selected number of 3078 persons from the general population underwent echocardiogram. Left ventricular mass was indexed to body surface area. Level of physical activity was self-reported: inactivity, light activity, and moderate/high activity. Blood pressure was measured in rest: normal BP (<140/90 mm Hg) and hypertension (≥140/90 mm Hg or in pharmacological treatment for hypertension). Presence of hypertension modified the association between physical activity and left ventricular mass index significantly (test for interaction: P =0.01): in normal BP, higher levels of physical activity were associated with significantly higher left ventricular mass index ( P <0.001), but this was not present in hypertension ( P =0.90). Level of physical activity was associated with reduction in mortality and cardiovascular outcome independent of the presence of LVH (Persons with LVH: light activity HR, 0.77 [0.52-1.15], moderate/high activity HR, 0.61 [0.38-0.97]; test for interaction between LVH and level of physical activity P =0.71). In conclusion, persons with normal BP had higher left ventricular mass index at increased levels of physical activity, whereas this association was not present among persons with hypertension. Level of physical activity was associated with better prognosis independent of whether left ventricular hypertrophy was present or not.

It has been a challenge to verify the dose of exercise that will produce the maximum health benefits in hypertension. This study aimed to explore the association between level of daily physical activity, all-cause mortality and cardiovascular outcome at different blood pressure levels. A random sample of 18 974 white men and women aged 20 to 98 years were examined in a prospective cardiovascular population study. Self-reported activity level in leisure-time was drawn from the Physical Activity Questionnaire (level I: inactivity; II: light activity; and III: moderate/high-level activity). Blood pressure was defined as normal blood pressure: <120/<80 mm Hg; Prehypertension: 120-139/80-89 mm Hg; Stage I hypertension: 140-159/90-99 mm Hg; Stage II hypertension ≥160/≥100 mm Hg. The mean follow-up time was 23.4±11.7 years. At all levels of blood pressure, higher levels of physical activity were associated with lower all-cause mortality in a dose-response pattern. The pattern remained unchanged after adjustment for following confounders: sex, age, smoking status, education, diabetes mellitus, previous cardiovascular disease, body mass index, and calendar time. Compared with inactivity, following hazard ratios were found for stage I hypertension: light activity, hazard ratio 0.78 (0.72-0.84; P <0.001), moderate/high-level activity, hazard ratio 0.69 (0.63-0.75; P <0.001). At all levels of blood pressure, the risk of cardiovascular events was significantly reduced independent of the level of physical activity. In conclusion, the association between physical activity and all-cause mortality was present in an inverse dose-response pattern at all levels of blood pressure. Physical activity was associated with reduction in cardiovascular events independent of the level of physical activity.

Background: Dyspnea is a common clinical challenge in patients with type 2 diabetes and may be a sign of heart failure (HF). We sought to evaluate the predictive value dyspnea with and without an echocardiographic substrate in patients with type 2 diabetes without known heart disease., Methods: A total of 724 patients with type 2 diabetes followed at specialized clinics participated in this prospective cohort study. Clinical evaluation, comprehensive echocardiography and follow-up through national registers were performed. An echocardiographic substrate was either left ventricular hypertrophy, increased left atrial size, E/e' > 15, or LV ejection fraction<50%. The end-points were cardiovascular (CVD) events and all-cause mortality., Results: Median follow-up was 4.8 years [Interquartile range: 4.1, 5.3] for CVD event and 77 patients suffered a CVD event. Dyspnea was significantly associated with CVD event: Hazard ratio (HR): 1.58 (95% confidence interval: 1.01-2.48), p = 0.04. Stratifying by evidence of echocardiographic substrate revealed high risk individuals: CVD event: 0.71 (0.35-1.46), p = NS in patients with dyspnea and no echocardiographic substrate and 2.85 (1.74-4.67), p < 0.001 in patients with dyspnea with echocardiographic substrate). This pattern was similar in multivariable analyses. Also, C-statistics improved from 0.66 (0.60-0.72) to 0.69 (0.63-0.75), p < 0.001 and net reclassification index was 27.5%(5.0-50.0), p = 0.01 for CVD event. The results were similar for all-cause mortality except dyspnea was only a borderline significant predictor., Conclusion: In patients with type 2 diabetes complaining of dyspnea, identifying an echocardiographic substrate - thus indicating patients with HF - accurately stratifies patients with increased risk of CV events and all-cause mortality., (Copyright © 2019 Elsevier B.V. All rights reserved.)

This study aimed to test the hypothesis that regular physical activity is associated with improved cardiac function measured by tissue Doppler imaging (TDI) in the general population. Within a large prospective community-based population study, cardiac function was assessed in 2221 persons by TDI. Longitudinal displacement (LD), early diastolic velocity (e'), and myocardial performance index (MPI) was obtained by TDI. Linear univariable and multivariable regression analyses were performed in relation to age groups (< 50 years, 50-65 years, > 65 years) and self-reported level of physical activity: I (inactivity), II (light activity), III (moderate activity), and IV (high-level activity). Participants < 50 years in the most active group had significantly better cardiac performance when compared to all other activity levels (higher levels of e', LD, and lower levels of MPI). The findings remained with statistical significance after adjustment for sex, ischemic heart disease, diabetes, hypertension, and body mass index (e' = 11.0, 95% CI (10.4-11.6), p < 0.001; LD = 12.8 (12.3-13.4), p < 0.003; MPI: 0.40 (0.38-0.42), p = 0.02). In age > 65 years, there was a tendency of impaired cardiac function in higher levels of exercise. Interaction analysis revealed that age significantly modified the association between physical activity and cardiac function (p < 0.001). We found a positive association between higher level of physical activity and improved cardiac function in younger persons (< 50 years). In the general population, however, the association interacted with age and amongst persons above 65 years there was a negative association between higher level of physical activity and cardiac function.

Aims: Echocardiography is suggested in the diagnostic work-up of patients with Type 2 diabetes (T2D). We investigated which echocardiographic parameters that best predicted cardiovascular disease (CVD) and whether this was persistent in both genders in a large cohort of outpatients with T2D., Methods and Results: We performed comprehensive echocardiography in 933 patients with T2D followed at specialized out-patients clinics in Copenhagen, Denmark. Follow-up was performed using national registries and included admission with future CVD events and non-CVD death as competing risk. Median follow-up was 4.8 years and 138 CVD events occurred. In univariable and multivariable analyses, a wide range of structural, diastolic, and systolic measurements predicted CVD including mean E/e' [hazard ratio (HR) 1.06, 95% confidence interval: (1.03-1.10), P < 0.001, C-statistics 0.74 (0.70-0.78)] and global longitudinal strain (GLS) [1.10 (1.01-1.20), P = 0.03, C-statistics 0.73 (0.69-0.77)]. However, this was modified by gender. In men, mean E/e' remained the strongest predictor in multivariable analyses and performed best measured by highest C-statistics [HR 1.15, 95% confidence interval: (1.08-1.21), P < 0.001, C-statistics 0.75 (0.71-0.80)] whereas in women this was GLS [1.39 (1.14-1.70), P = 0.001, C-statistics 0.79 (0.70-0.87)]. These findings persisted when excluding patients with known heart disease and when regarding all-cause mortality as a competing risk., Conclusion: A range of echocardiographic parameters predicted CVD in patients with Type 2 diabetes, however, in multivariable analyses, mean E/e' was the strongest predictor and had the highest model performance. Importantly, this study identifies a hitherto undescribed gender interaction as mean E/e' performed best in men, whereas in women this was GLS., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)

Purpose: To compare two-dimensional (2D) and three-dimensional (3D) methods to estimate left ventricular ejection fraction (LVEF) with respect to feasibility, time consumption, and retest reproducibility., Methods: A total of 100 patients planned to undergo coronary artery bypass grafting and/or aortic valve replacement were included consecutively. 2D and 3D echocardiography was performed on all patients. Acquisition and analysis time as well as intra- and inter-examiner variability were assessed in 50 consecutive patients with 3 repeated echocardiographic examinations and analyses. LVEF was estimated by five different methods: uniplane, biplane, and single-beat triplane (SB3P), as well as semi-automated biplane (AutoEF) and 3D volumetric tracings (4D Auto LVQ). All methods were compared to Simpson's biplane method and feasibility was determined., Results: Feasibility of Simpson's uniplane method, Simpson's biplane method, AutoEF, SB3P, and 4D Auto LVQ was 97%, 92%, 86%, 70%, and 89%, respectively. All methods evaluated were 18%-33% faster (P < 0.001) than Simpson's biplane method (115 seconds, standard deviation 15 seconds). Compared to Simpson's biplane method mean LVEF was slightly underestimated by 4D Auto LVQ (-2 ± 8%, P = 0.02), but not significantly different when assessed by the other methods. AutoEF and 4D Auto LVQ showed the lowest test variability (intra-examiner coefficient of variation (CV) 10%-11%; inter-examiner CV 10%-12% vs intra-examiner CV 12%-18%; inter-examiner CV 12%-20%)., Conclusions: Estimation of LVEF by modern semi-automated 2D and 3D echocardiographic modalities is feasible, time-efficient, and reproducible., (© 2018 Wiley Periodicals, Inc.)

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<0.001), lateral early diastolic myocardial velocity at the level of the mitral annulus (mean 9.6 m/s [SD 2.5] versus 10.8 [3.5], P<0.001) and lateral (early diastolic mitral inflow velocity)/(early diastolic myocardial velocity at the level of the mitral annulus) (7.7 [6.5, 10.2] versus 6.3 [4.9, 7.8], P<0.001). With an increasing burden of uncontrolled metabolic risk factors, there were increased left ventricular mass index and wall thicknesses and impaired systolic function measured as global longitudinal strain: control group -15.9 (2.0); 0 uncontrolled risk factors -15.3 (2.4); 1 to 2 -14.6 (2.8); and ≥3 -14.0 (2.8), P<0.001. Within the diabetes mellitus group, there were uni- and multivariable associations of left ventricular measures and systolic blood pressure, body mass index, hemoglobin A 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.

Aims: Albuminuria-a marker of generalized vascular dysfunction-is a strong predictor of heart failure in patients with type 2 diabetes which may be caused by concomitant myocardial dysfunction reflecting the same underlying pathogenesis., Methods and Results: We included 915 patients with type 2 diabetes from two secondary care centres and stratified according to albuminuria status in normo-, micro-, and macroalbuminuria. We performed comprehensive echocardiography including conventional imaging, tissue Doppler imaging, and 2D speckle tracking. Cardiac remodelling occurred in patients with increasing left ventricular (LV) mass index and LV wall thicknesses with increasing severity of albuminuria. Diastolic measures worsened across groups of albuminuria severity (normo-, micro-, and macroalbuminuria, respectively): septal e' velocity [mean: 6.9 cm/s (SD 1.9), 6.4 (1.7), and 5.9 (1.7), P < 0.001], septal E/e' (median: 10.6 [interquartile range: 8.9-13.2], 12.1 [10.3-14.8], and 12.7 [10.4-16.6], P < 0.001), and left atrial volume index (24.3 mL/m2 [19.1-29.9], 25.7 [20.0-31.6], and 29.0 [22.2-34.9], P < 0.001) In contrast, systolic measures were only impaired in patients with macroalbuminuria: global longitudinal strain (GLS): [-14.6% (2.7) in normo- and -13.3 (2.9) in macroalbuminuria, P < 0.001] and GLS rate [mean: -0.79 s-1 (0.17) in normo- and -0.72 (0.16) in macroalbuminuria, P = 0.001]. The findings persisted in subgroup analyses of patients without known coronary heart disease and with normal ejection fraction and in multivariable adjusted analyses., Conclusion: In patients with type 2 diabetes, microalbuminuria is associated with decreased diastolic function whereas decreased systolic function was only associated with macroalbuminuria supporting the notion of similar pathogenic mechanisms of albuminuria and impaired myocardial function.

Hypertension may be the most significant cardiovascular risk factor. Few studies have assessed the prognostic value of echocardiography in hypertensive individuals. This study examines the incremental prognostic value of adding echocardiographic parameters to established risk factors in individuals from the general population with and without hypertension. A total of 1294 individuals from the general population underwent a health examination and an echocardiogram including 2-dimensional speckle tracking. Outcome was a composite of ischemic heart disease and heart failure. The prevalence of hypertension was 38.3%. During a median follow-up of 12.5 years (interquartile range, 9.4-12.8 years), 222 participants (17.2%) developed the outcome. Out of these 222 events, 145 (65%) occurred in hypertensive participants, whereas 77 (35%) occurred in nonhypertensive individuals, corresponding to an incidence rate of 32/(1000×person-years) and 8/(1000×person-years), respectively. Follow-up was 100%. After multivariable adjustment, only left ventricular mass index predicted the outcome in hypertensive individuals, whereas only global longitudinal strain predicted the outcome in nonhypertensive individuals. In hypertensive individuals the prognostic value of left ventricular mass index was incremental to SCORE and abnormal ECG status. In nonhypertensive individuals the prognostic value of global longitudinal strain was incremental to SCORE and abnormal ECG status. The prognostic value of echocardiography in predicting cardiovascular outcomes in the general population is altered by hypertension. In hypertensive individuals, left ventricular mass index added incremental prognostic value in addition to established risk factors. In nonhypertensive individuals, global longitudinal strain added incremental prognostic value in addition to established risk factors., (© 2018 American Heart Association, Inc.)

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<.001), and 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<.001; Severe DDF: HR 4.20 (1.81-9.73), P<.001). Increasing severity of DDF was linearly associated with increasing plasma proBNP concentrations., 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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: There exists no consensus on the site of E/e' measurement. This study aimed to evaluate the predictive value of septal and lateral E/e' along with the importance of their intra-individual difference., Methods: In 1775 persons from the general population, peak early diastolic velocity (e') was obtained by color tissue Doppler at the septal and lateral mitral annular sites. The endpoint was combined of cardiovascular death or admission due to heart failure or acute myocardial infarction., Results: During a median follow-up of 10.9 years, the endpoint occurred in 227 participants. E/e' septal and E/e' lateral were equally strong predictors of cardiac events; in age- and sex-adjusted models they did not differ in AUC (septal: 0.8385, lateral: 0.8389; p = 0.94) or in continuous NRI (p = 0.84). Models using E/e' average did not improve AUC or NRI, and the intra-individual difference between sites had no predictive value (p = 0.79). E/e' septal was generally higher than E/e' lateral , thus age- and sex-specific normal values were reported for both sites for a population free of cardiac events during 10 years of follow-up., Conclusions: Septal and lateral E/e' are equally useful in predicting cardiac events in the general population. Measuring both sites provides no further predictive value than measuring a single site.

Background: Fragments of insulin-like growth factor binding protein 4 (IGFBP-4) are potential new biomarkers for cardiac risk assessment. The fragments are generated on specific cleavage by pregnancy-associated plasma protein-A, which exerts proatherogenic activity. This study investigated the prognostic value of IGFBP-4 fragments in patients with ST-segment elevation myocardial infarction., Methods and Results: We prospectively included 656 patients with ST-segment elevation myocardial infarction treated with percutaneous coronary intervention from September 2006 to December 2008. Blood samples were drawn before percutaneous coronary intervention, and levels of intact IGFBP-4 and N-terminal and C-terminal IGFBP-4 fragments were measured by specific assays. End points were 5-year all-cause and cardiovascular mortality and the combined end point of major adverse cardiac events. Prognostic potential was evaluated on top of a clinical model in terms of discrimination, calibration, and reclassification analysis. During follow-up, 166 patients experienced a major adverse cardiac event and 136 patients died, of whom 69 died from cardiovascular causes. Both IGFBP-4 fragments were associated with all end points ( P <0.001). After multivariable adjustments, both N-terminal and C-terminal IGFBP-4 fragment levels remained associated with all end points, including cardiovascular mortality with hazard ratios per doubling in protein concentration of 2.54 (95% CI 1.59-4.07; P <0.001) and 2.07 (95% CI 1.41-3.04; P <0.001), respectively. Incorporation of IGFBP-4 fragments into a clinical model with 15 risk factors improved C-statistics and model calibration and provided incremental prognostic contribution, as assessed by net reclassification improvement and integrated discrimination improvement., Conclusions: IGFBP-4 fragments are associated with increased risk of all-cause mortality, cardiovascular mortality, and major adverse cardiac events in patients with ST-segment elevation myocardial infarction., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Global longitudinal strain (GLS) is prognostic of adverse cardiovascular outcomes in various patient populations, but the prognostic utility of GLS for long-term cardiovascular morbidity and mortality in the general population is unknown., Methods and Results: A total of 1296 participants in a general population study underwent a health examination, including echocardiography measurement of GLS. The primary end point was the composite of incident heart failure, acute myocardial infarction, or cardiovascular death. During a median follow-up of 11 years, 149 (12%) participants were diagnosed with heart failure, acute myocardial infarction, or cardiovascular death. Lower GLS was associated with a higher risk of the composite end point (hazard ratio, 1.12; 95% confidence interval, 1.08-1.17; P <0.001 per 1% decrease), an association that persisted after multivariable adjustment for age, sex, heart rate, hypertension, systolic blood pressure, left ventricular ejection fraction, left ventricular mass index, left ventricular dimension, deceleration time, left atrium dimension, E / e ', and pro B-type natriuretic peptide (hazard ratio, 1.05; 95% confidence interval, 1.00-1.11; P =0.045 per 1% decrease). GLS provided incremental prognostic information beyond the Framingham Risk Score, the Systemic Coronary Evaluation risk chart, and the modified American College of Cardiology/American Heart Association Pooled Cohort Equation for the composite outcome and incident heart failure. Sex modified the relationship between GLS and outcome such that after multivariable adjustment, GLS was an independent predictor of outcomes in men but not in women (hazard ratio, 1.14; 95% confidence interval, 1.06-1.24; P =0.001, and hazard ratio, 0.99; 95% confidence interval, 0.92-1.07; P =0.81, respectively; P for interaction =0.032)., Conclusions: In the general population, GLS provides independent and incremental prognostic information regarding long-term risk of cardiovascular morbidity and mortality. GLS seems to be a stronger prognosticator in men than in women., (© 2017 American Heart Association, Inc.)

Background: Contemporary treatment of type 2 diabetes (T2D) has improved patient outcome and may also have affected myocardial structure and function. We aimed to describe the effect of T2D and T2D duration on cardiac structure and function in a large outpatient population., Methods: We performed comprehensive echocardiography on a representative sample of 1004 persons including a representative sample of 770 patients with T2D without known heart disease and 234 age- and sex-matched controls., Results: T2D was associated with increased left ventricular (LV) wall thicknesses and decreased LV internal diameter and the changes were pronounced with increasing diabetes duration (P<0.01 for all) but not with increased LV mass (P=0.74). It was also significantly associated with the prevalence of diastolic dysfunction (16.5% vs. 4.0%; P<0.001), with indices of LV relaxation and elevated filling pressures expressed as e'septal (mean: 6.9 (SD: 1.9) cm/s vs. 7.5 (2.4); P<0.001) and E/e'septal (median: 10.8 (interquartile range (IQR): 9.1-13.3) vs. 9.1 (7.2-11.1); P<0.001) and global longitudinal strain (mean: -14.1 (SD: 2.4) vs. -15.0 (2.0), P<0.001) but not with LV ejection fraction (median: 60.8 (IQR: 56.5-65.1) vs. 62.1 (57.9-65.4), P=0.28). With the exception of global longitudinal strain, this was pronounced with increasing diabetes duration for all measures including increasing diastolic dysfunction (<10years: 10.8%, 10-20years: 18.5%, >20years: 24.8%; P<0.001). The increased risk of diastolic dysfunction persisted after multivariable adjustment (P=0.013)., Conclusions: In patients with T2D, LV structural and functional alterations persist and are accentuated with increasing diabetes duration despite reductions in overall risk of cardiovascular disease in this patient population., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Recently, genetic studies have suggested a causal relationship between cholesterol remnants and ischemic heart disease. We aimed to determine whether cholesterol remnants and its marker, triglyceride levels, are associated with cardiac function as determined by sensitive echocardiographic measures in a population of patients with type 2 diabetes., Methods: Comprehensive echocardiography including 2D-speckle tracking echocardiography was performed on a representative sample of 924 patients with type 2 diabetes-730 of whom were treated with statins. These were recruited from two large secondary care centers., Results: In multivariable analyses, triglycerides and cholesterol remnants were not associated with left ventricular ejection fraction, but with subtle measures of systolic function, including global longitudinal strain by speckle tracking and longitudinal displacement by tissue Doppler echocardiography: global longitudinal strain [0.33 % (0.14), p = 0.02 per doubling in cholesterol remnants and 0.28 % (0.13), p = 0.03 per doubling in triglyceride levels] and with longitudinal displacement [-0.25 mm (0.10), p = 0.01 per doubling in cholesterol remnants and -0.25 mm (0.09), p = 0.005 per doubling in triglyceride levels]. Subgroup analyses of patients receiving statin therapy and patients without known heart disease revealed similar results, but the association was not present in patients with known heart disease., Conclusion: In patients with type 2 diabetes, subtle decrease in left ventricular function is present with increasing levels of cholesterol remnants and triglyceride levels indicating an effect of these on cardiac function that is not detectable by conventional echocardiography.

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 (<55 years) to 73.9% in the oldest group (>75 years) (p < 0.001) and was equally distributed among the sexes (p = 0.76). In univariate analyses, electrocardiographic abnormalities, age, body mass index, known coronary heart disease, hypertension, albuminuria, diabetes duration and creatinine were associated with abnormal echocardiography along with dyspnoea and characteristic chest pain (p < 0.05 for all). Neither of the cardiac symptoms nor clinical characteristics had sufficient sensitivity and specificity to accurately identify patients with abnormal echocardiography., 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., (© The Author(s) 2016.)

Background: Global longitudinal systolic strain (GLS) has recently been demonstrated to be a superior prognosticator to conventional echocardiographic measures in patients after myocardial infarction (MI). The aim of this study was to evaluate the prognostic value of regional longitudinal myocardial deformation in comparison to GLS, conventional echocardiography and clinical information., Method: In total 391 patients were admitted with ST-Segment elevation myocardial infarction (STEMI), treated with primary percutaneous coronary intervention and subsequently examined by echocardiography. All patients were examined by tissue Doppler imaging (TDI) and two-dimensional strain echocardiography (2DSE)., Results: During a median-follow-up of 5.3 (IQR 2.5-6.1) years the primary endpoint (death, heart failure or a new MI) was reached by 145 (38.9%) patients. After adjustment for significant confounders (including conventional echocardiographic parameters) and culprit lesion, reduced longitudinal performance in the anterior septal and inferior myocardial regions (but not GLS) remained independent predictors of the combined outcome. Furthermore, inferior myocardial longitudinal deformation provided incremental prognostic information to clinical and conventional echocardiographic information (Harrell's c-statistics: 0.63 vs. 0.67, p = 0.032). In addition, impaired longitudinal deformation outside the culprit lesion perfusion region was significantly associated with an adverse outcome (p<0.05 for all deformation parameters)., Conclusion: Regional longitudinal myocardial deformation measures, regardless if determined by TDI or 2DSE, are superior prognosticators to GLS. In addition, impaired longitudinal deformation in the inferior myocardial segment provides prognostic information over and above clinical and conventional echocardiographic risk factors. Furthermore, impaired longitudinal deformation outside the culprit lesion perfusion region seems to be a paramount marker of adverse outcome.

Background/aims: Neutrophil gelatinase-associated lipocalin (NGAL) has emerged as a marker for acute kidney injury and cardiovascular outcome. However, the relative importance of inflammation versus kidney function on plasma NGAL levels is uncertain, making the interpretation of plasma NGAL unclear. Accordingly, we investigated the relationship between plasma NGAL, inflammation and kidney function in patients with myocardial infarction (MI)., Methods: We prospectively included 584 patients with acute ST-segment elevation MI (STEMI) treated with primary percutaneous coronary intervention (PCI) from 2006 to 2008. Blood samples were drawn immediately before PCI. Additionally, we included 42 patients who had 4 blood samples drawn before and after PCI. Plasma NGAL was measured using a time-resolved immunofluorometric assay. Cross-sectional analyses were performed in these two single-center, prospective study cohorts., Results: Estimated glomerular filtration rate (eGFR) was associated significantly more strongly with plasma NGAL when eGFR was abnormal compared to normal eGFR: a decrease in eGFR of 10 ml/min was associated with an increase in NGAL of 27% (18-36%) versus 4% (1-7%), respectively (p < 0.001). Leukocyte count and C-reactive protein were the main determinants of plasma NGAL in patients with normal eGFR, whereas eGFR was the main determinant at reduced kidney function., Conclusions: eGFR determines the association of NGAL with either inflammation or kidney function; in patients with normal eGFR, plasma NGAL reflects inflammation but when eGFR is reduced, plasma NGAL reflects kidney function, highlighting the dual perception of plasma NGAL. From a clinical perspective, eGFR may be used to guide the interpretation of elevated NGAL levels in patients with STEMI.

Purpose: To define normal values of the cardiac time intervals obtained by tissue Doppler imaging (TDI) M-mode through the mitral valve (MV). Furthermore, to evaluate the association of the myocardial performance index (MPI) obtained by TDI M-mode (MPITDI) and the conventional method of obtaining MPI (MPIConv), with established echocardiographic and invasive measures of systolic and diastolic function., Methods: In a large community based population study (n = 974), where all are free of any cardiovascular disease and cardiovascular risk factors, cardiac time intervals, including isovolumic relaxation time (IVRT), isovolumic contraction time (IVCT), and ejection time (ET) were obtained by TDI M-mode through the MV. IVCT/ET, IVRT/ET and the MPI ((IVRT+IVCT)/ET) were calculated. We also included a validation population (n = 44) of patients who underwent left heart catheterization and had the MPITDI and MPIConv measured., Results: IVRT, IVRT/ET and MPI all increased significantly with increasing age in both genders (p<0.001 for all). IVCT, ET, IVRT/ET, and MPI differed significantly between males and females, displaying that women, in general exhibit better cardiac function. MPITDI was significantly associated with invasive (dP/dt max) and echocardiographic measures of systolic (LVEF, global longitudinal strain and global strainrate s) and diastolic function (e', global strainrate e)(p<0.05 for all), whereas MPIConv was significantly associated with LVEF, e' and global strainrate e (p<0.05 for all)., Conclusion: Normal values of cardiac time intervals differed between genders and deteriorated with increasing age. The MPITDI (but not MPIConv) is associated with most invasive and established echocardiographic measures of systolic and diastolic function.

Aims: To evaluate the prognostic value of global longitudinal strain (GLS) and basal longitudinal strain (BLS) with the knowledge of coexisting coronary pathology evaluated by multi-detector computed tomography (MDCT) coronary angiography., Background: GLS and BLS are both sensitive markers of myocardial dysfunction and predictors of outcome in asymptomatic aortic stenosis. Aortic stenosis and ischaemic heart disease share risk factors and longitudinal function can be severely reduced in both conditions, why some of the previous findings of impaired regional longitudinal function in asymptomatic aortic stenosis could in fact be explained by silent ischaemic heart disease., Methods and Results: Prospective follow-up of 104 asymptomatic patients with moderate-severe aortic stenosis defined as an aortic valve area <1.5 cm(2). Patients underwent a thorough clinical work-up, advanced echocardiographic analysis and coronary angiography by MDCT. The combined endpoint was indication for aortic valve replacement (AVR) and sudden cardiac death. During a median follow-up of 2.3 years (interquartile range 1.7-3.6) 43 patients (41%) met the endpoint of indication for AVR. The basal (13.4 ± 3.1% vs. 15.7 ± 3.1%) and mid-ventricular segments (14.9 ± 2.7% vs. 16.2 ± 2.9%) were significantly reduced, but with sparing of the apical segments, in patients who later underwent AVR. In various multivariable Cox regression models, including only BLS, but not GLS, remained an independent predictor of AVR., Conclusion: In contrast to GLS, reduced BLS is a significant predictor of future AVR in asymptomatic patients with aortic stenosis, independently of clinical characteristics, conventional echocardiographic measures, and coronary pathology., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Background: We hypothesized that the cardiac time intervals reveal reduced myocardial function in persons with hypertension and are strong predictors of future ischemic cardiovascular diseases in the general population., Methods and Results: In a large community-based population study, cardiac function was evaluated in 1915 participants by using both conventional echocardiography and tissue Doppler imaging (TDI). The cardiac time intervals, including the isovolumic relaxation time (IVRT), isovolumic contraction time (IVCT), and ejection time (ET), were obtained by TDI M-mode through the mitral leaflet. IVCT/ET, IVRT/ET, and myocardial performance index [MPI=(IVRT+IVCT)/ET] were calculated. After multivariable adjustment for clinical variables the IVRT, IVRT/ET, and MPI, remained significantly impaired in persons with hypertension (n=826) compared with participants without hypertension (n=1082). Additionally, they displayed a significant dose-response relationship, between increasing severity of elevated blood pressure and increasing left ventricular mass index (P<0.001 for all). Further, during follow-up of a median of 10.7 years, 435 had an ischemic cardiovascular disease (ischemic heart disease, peripheral arterial disease, or stroke). The IVRT/ET and MPI were powerful and independent predictors of future cardiovascular disease, especially in participants with known hypertension. They provide prognostic information incremental to clinical variables from the Framingham Risk Score, the SCORE risk chart, and the European Society of Hypertension/European Society of Cardiology risk chart., Conclusion: The cardiac time intervals identify impaired cardiac function in individuals with hypertension, not only independent of conventional risk factors but also in participants with a normal conventional echocardiographic examination. The IVRT/ET and MPI are independent predictors of future cardiovascular disease especially in participants with known hypertension., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Though the electrocardiogram(ECG) and plasma pro-brain-natriuretic-peptide (pro-BNP) are widely used markers of subclinical cardiac injury and can be used to predict future cardiovascular disease(CVD), they could merely be markers of the same underlying pathology. We aimed to determine if ECG changes and pro-BNP are independent predictors of CVD and if the combination improves risk prediction in persons without known heart disease., Methods: Pro-BNP and ECG were obtained on 5454 persons without known heart disease from the 4th round of the Copenhagen City Heart Study, a prospective cohort study. Median follow-up was 10.4 years. High pro-BNP was defined as above 90th percentile of age and sex adjusted levels. The end-points were all-cause mortality and the combination of admission with ischemic heart disease, heart failure or CVD death., Results: ECG changes were present in 907 persons and were associated with high levels of pro-BNP. In a fully adjusted model both high pro-BNP and ECG changes remained significant predictors: all-cause mortality(high pro-BNP, no ECG changes: HR: 1.43(1.12-1.82);P=0.005, low pro-BNP, ECG changes: HR: 1.22(1.05-1.42);P=0.009, and both high pro-BNP and ECG changes: HR: 1.99(1.54-2.59);P<0.001), CVD event(high pro-BNP, no ECG changes: HR: 1.94(1.45-2.58);P<0.001, low pro-BNP, ECG changes: HR: 1.55(1.29-1.87);P<0.001, and both high pro-BNP and ECG changes: HR: 3.86(2.94-5.08);P<0.001). Adding the combination of pro-BNP and ECG changes to a fully adjusted model correctly reclassified 33.9%(26.5-41.3);P<0.001 on the continuous net reclassification scale for all-cause mortality and 49.7%(41.1-58.4);P<0.001 for CVD event., Conclusion: Combining ECG changes and pro-BNP improves risk prediction in persons without known heart disease., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Aims: To improve risk prediction of cardiovascular morbidity and mortality, we need sensitive markers of cardiac dysfunction; Echocardiographic Tissue Doppler Imaging (TDI) is feasible and harmless and may be ideal for this purpose., Methods and Results: Within the community-based Copenhagen City Heart Study, 2064 participants were examined by echocardiography including TDI and followed (median 10.9 years) with regard to cardiovascular death, heart failure, or acute myocardial infarction (n = 277). Impaired systolic (s') and diastolic (e' and a') function according to age and sex as assessed by TDI was associated with increased risk of the combined end point, even in the subgroup of persons with a normal conventional echocardiographic examination [per 1 cm/s decrease: s': HR 1.32 (1.12-1.57), P < 0.001; e': HR 1.17(1.04-1.31), P < 0.01; a': HR 1.17 (1.06-1.30), P < 0.005]. Interestingly, reduced early diastolic myocardial velocity (e') was associated with risk of acute myocardial infarction, whereas reduced systolic (s') or late diastolic function (a') was associated with heart failure and cardiovascular death independently of traditional risk factors, plasma proBNP, and conventional echocardiographic measures. Combining information on early and late diastolic function by TDI provided incremental prognostic information and improved risk classification (net reclassification improvement: 27%; P < 0.001) and remained a significant predictor of the combined end point even in the subgroup with a normal conventional echocardiographic examination [per cm/s decrease: HR 1.18 (1.08-1.28), P < 0.001]., Conclusion: In the general population, TDI identifies individuals with cardiac dysfunction and high risk of cardiovascular morbidity and mortality independently of traditional risk factors, even in persons with a normal conventional echocardiographic examination., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Natriuretic peptides (NPs) may regulate adipocyte metabolism including adiponectin. Infusion of atrial natriuretic peptide (ANP) increases plasma adiponectin in patients with heart failure. However, this relation has not been examined in a clinical setting or in myocardial infarction (MI). Accordingly, we investigated the interplay between proANP and adiponectin and the prognostic implications in patients with MI. We prospectively included 680 patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention from September 2006 to December 2008. Blood samples were drawn immediately before percutaneous coronary intervention. Additionally, we included 40 patients with 4 obtained blood samples during STEMI. Adiponectin and proANP were measured in all plasma samples. All patients were followed for 5 years. End points were all-cause mortality (n = 137) and the combined end point (n = 170) of major adverse cardiovascular events (MACEs). Plasma adiponectin and proANP were strongly associated at admission (r = 0.34, p <0.001). In patients with increasing proANP during STEMI, adiponectin also increased (0.5 ± 0.3 vs -0.1 ± 0.1 mg/L, p = 0.026). During follow-up, patients with higher adiponectin at admission had increased risk of all-cause mortality and MACE (both, p <0.001). After adjustment for confounding risk factors by Cox regression analysis, adiponectin remained an independent predictor of all-cause mortality and MACE: hazard ratio 1.31 (95% confidence interval 1.07 to 1.60; p = 0.009) and 1.31 (95% confidence interval 1.09 to 1.57; p = 0.004), respectively, for each SD increase. However, the association vanished when proANP was included in the analysis. In conclusion, adiponectin is associated with an increased risk of all-cause mortality and MACE. However, concomitantly elevated proANP levels appear to confound the association between adiponectin and worsened outcome., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Assessment of myocardial longitudinal function has proved to be a sensitive marker of deteriorating myocardial function in aortic stenosis, demonstrated by both color Doppler tissue imaging and recently by two-dimensional speckle-tracking echocardiography. The aim of this study was to compare velocity (color Doppler tissue imaging) and deformation (two-dimensional speckle-tracking echocardiography) in relation to global and regional longitudinal function in asymptomatic and severe symptomatic aortic stenosis., Methods: In a cross-sectional design, 231 patients with aortic stenosis were divided into four groups: asymptomatic moderate aortic stenosis (aortic valve area, 1.0-1.5 cm(2); n = 38), asymptomatic severe aortic stenosis (aortic valve area < 1.0 cm(2); n = 66), and symptomatic severe aortic stenosis with preserved (n = 68) and reduced (<50%) left ventricular ejection fraction (n = 59)., Results: Among all global (peak systolic s', diastolic e' and a', longitudinal displacement, and global longitudinal strain and strain rate) and regional longitudinal (basal, middle, and apical longitudinal strain and strain rate) parameters, only diastolic e', longitudinal displacement, and basal longitudinal strain (BLS) remained significantly associated with symptomatic status, independent of age, gender, heart rate, aortic valve area, stroke volume index, left ventricular mass index, left atrial volume index, and tricuspid annular systolic plane excursion. Furthermore, in a model with the aforementioned parameters, including e', longitudinal displacement, and BLS, only BLS remained significantly associated with symptomatic status in the entire study population (BLS per one-unit decrease: odds ratio, 1.23; 95% CI, 1.04-1.46; P = .017). Furthermore, patients with BLS < 13% were more likely to be symptomatic (odds ratio, 4.97; 95% CI, 2.6-9.4; P < .001), and no patients with asymptomatic severe aortic stenosis with BLS ≥ 13% were admitted with myocardial infarction or heart failure during follow-up of 1,462 days., Conclusions: Among the many echocardiographic measures of longitudinal velocity and deformation, BLS has the strongest association with symptomatic status in aortic stenosis, and BLS < 13% is related to adverse outcomes in severe asymptomatic aortic stenosis., (Copyright © 2015 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Aim: Tissue Doppler Imaging (TDI) detects early signs of left ventricular dysfunction. The prognostic potential of TDI in patients with atrial fibrillation (AF) has, however, not yet been clarified. This study evaluates the prognostic value of TDI in patients with atrial fibrillation., Methods and Results: In total, echocardiograms from 313 patients with AF during examination were analyzed offline. Longitudinal systolic velocity (s'), early diastolic velocity (e') and longitudinal displacement (LD) were measured by color TDI. During a median follow-up of 891 days, 64 patients (20%) died. TDI was significantly associated with all-cause mortality, and the risk of dying increased significantly per 1 cm/s decrease in s' (HR of 1.31, 95% CI 1.05-1.63; p=0.018) and e' (HR of 1.17, 95% CI 1.01-1.35; p=0.038) respectively, even after adjustment for age, gender, heart rate, aortic stenosis, DM and LVEF quartiles. LD also proved to be a significant predictor of outcome after multivariate adjustment (HR 1.23; 95% CI 1.05-1.44; p=0.012). The population was stratified according to high or low s' and e'. Patients with low s' and e' had more than three times the risk of mortality compared to the patients with high s' and e' (HR 3.64; 95% CI 1.83-7.26; p<0.001) and remained in significantly higher risk after adjustment for various risk factors., Conclusions: Both systolic and diastolic performance, as assessed by TDI, are strong predictors of mortality in patients with atrial fibrillation, and especially the combination of systolic and diastolic dysfunction is a significant prognostic marker.

Background: Atrial natriuretic peptide (ANP) is released from the atria (on cleavage of proANP) in response to elevated intra-atrial pressure and wall stretch. Clinical data on proANP are still limited, mainly due to limitations in assaying the protein, which recently have been solved. ProANP is elevated in cardiovascular disease and predicts outcome in heart failure. However, knowledge of the prognostic value in acute myocardial infarction remains limited., Methods: We prospectively included 680 patients with STEMI treated with primary-PCI, from September 2006 to December 2008. Blood samples were drawn immediately before PCI. Plasma MR-proANP was measured using an automated processing assay. Endpoints were all-cause mortality (n = 137) and the combined endpoint (n = 170) of major adverse cardiovascular events (MACE) defined as cardiovascular mortality and admission due to recurrent MI, ischaemic stroke or heart failure., Results: During 5-year follow-up, MR-proANP was associated with increased risk of all-cause mortality and MACE (both p < 0.001). After adjustment for confounding risk factors (age, gender, hypertension, diabetes, hypercholesterolaemia, smoking, previous MI, BMI, eGFR, CRP, peak-TnI, symptom-to-balloon time, multivessel disease, complex lesion, LAD-lesion and use of glycoprotein inhibitor), MR-proANP remained an independent predictor of all-cause mortality and MACE - hazard ratio: 1.68 (95% CI 1.35-2.10; p < 0.001) and 1.68 (95% CI 1.39-2.03; p < 0.001) per standard deviation increase in MR-proANP. MR-proANP significantly increased C-statistics and reclassified 26% of the patients for all-cause mortality and 34% for MACE into higher or lower risk categories, matching actual event rates more accurately., Conclusions: Plasma MR-proANP independently predicts all-cause mortality and MACE in patients with STEMI., (© The European Society of Cardiology 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

Objective: Tissue Doppler imaging (TDI) M-mode through the mitral leaflet is an easy and precise method to estimate the cardiac time intervals. The aim was to evaluate the usability of the cardiac time intervals in predicting major cardiovascular events (MACE) in the general population., Methods: In a large prospective community-based study, cardiac function was evaluated in 1915 participants by both conventional echocardiography and TDI. The cardiac time intervals, including the isovolumic relaxation time (IVRT), isovolumic contraction time (IVCT) and ejection time (ET), were obtained by TDI M-mode through the mitral leaflet. IVCT/ET, IVRT/ET and the myocardial performance index (MPI=(IVRT+IVCT)/ET) were calculated., Results: During follow-up (median 10.8 years), 383 (20%) participants reached the combined endpoint MACE (ischaemic heart disease, heart failure or cardiac death). After multivariable adjustment for clinical predictors and conventional echocardiography, only the combined indexes, including information on both systolic and diastolic performance (IVRT/ET and MPI), remained significant prognosticators (p<0.05 for both). Adding IVRT/ET or MPI to a model already including all other echocardiographic parameters resulted in a significant increase in the c-statistics (0.76 vs 0.75 p<0.01 for both). IVRT/ET or MPI improved reclassification significantly when added to the clinical predictors (p<0.05 for both)., Conclusions: In the general population, the combined cardiac time intervals that include information on both systolic and diastolic function in one index (IVRT/ET and MPI) are not only powerful and independent predictors of future MACE, but provide additional prognostic information to clinical and conventional echocardiographic measures of systolic and diastolic function., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Longitudinal deformation has been shown to deteriorate with progressive aortic stenosis as well as ischemic heart disease. Despite that both conditions share risk factors and are often coexisting, studies have not assessed the influence on longitudinal deformation for both conditions simultaneously. Thus the purpose of this study was to evaluate the association between subclinical ischemic heart disease and global and regional longitudinal strain in asymptomatic patients with significant aortic stenosis. Prevalent patients with a diagnosis of aortic stenosis at six hospitals in the Greater Copenhagen area were screened for inclusion. A total of 104 asymptomatic patients with moderate-severe aortic stenosis (aortic valve area ≤1.5 cm(2)) fulfilled study criteria and underwent advanced echocardiographic analysis and coronary angiography by multi-detector computed tomography. Angiography revealed coronary stenosis >50% in 31% (n = 32). All regional longitudinal strain measures (apical, mid and basal longitudinal strain) were significant predictors of significant coronary stenosis (>70% stenosis), but only apical and mid longitudinal strain were significant predictors in multivariable analyses independent of aortic valve area, stroke volume index, pro-BNP, valvulo-arterial impedance, body mass index and heart rate. In linear regression models with both aortic valve area and significant coronary stenosis, apical (p < 0.001) and mid (p < 0.01) longitudinal strain were associated to significant coronary stenosis but not aortic valve area. Conversely, basal longitudinal strain was significantly associated to aortic valve area (p = 0.001), but not to significant coronary stenosis. Subclinical coronary artery disease is frequent in moderate and severe aortic stenosis, and should be suspected when regional longitudinal dysfunction is predominant in the apical and mid ventricular segments.

Background: Adiponectin is viewed as an insulin-sensitizing hormone with anti-inflammatory effects. In accordance, plasma adiponectin is decreased in metabolic disorders including type 2 diabetes mellitus (T2DM). However, in spite of the apparently beneficially effects, recent data from large prospective studies have consistently linked high adiponectin levels with increased cardiovascular (CV) disease and mortality, thus questioning the positive view on adiponectin. Accordingly, we investigated the relationship between adiponectin, incident T2DM and subsequently CV events., Methods: We prospectively followed 5349 randomly selected men and women from the community, without T2DM or CV disease. Plasma adiponectin was measured at study entry. Median follow-up time was 8.5 years (IQR 8.0-9.1 years). During follow up, 136 participants developed T2DM. Following their diagnosis, 36 of the 136 participants experienced a CV event (myocardial infarction, ischaemic stroke, or CV death)., Results: Participants with increasing adiponectin had reduced risk of developing T2DM (p < 0.001). After adjustment for confounding risk factors (including age, gender, body mass index, physical activity, alcohol consumption, blood glucose, HbA1c, blood pressure, lipids, high-sensitivity C-reactive protein, estimated glomerular filtration rate, and plasma N-terminal pro-brain natriuretic peptide, competing risk Cox-regression analysis identified adiponectin as an independent predictor of T2DM: hazard ratio (HR) for each doubling of adiponectin 0.55 (95% CI 0.41-0.74; p < 0.001). After development of T2DM, the risk of a CV event more than doubled. Increasing adiponectin (adjusted for the confounding risk factors mentioned) was associated with reduced risk of CV events: HR 0.34 (95% CI 0.16-0.72; p = 0.005) for each doubling in plasma adiponectin., Conclusions: In conclusion, increasing plasma adiponectin is associated with decreased risk of T2DM and subsequently reduced risk of CV events., (© The European Society of Cardiology 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

Background: High levels of circulating osteoprotegerin (OPG) predicts long-term outcome in patients with ST-elevation myocardial infarction (STEMI), possibly because of increased vascular inflammation resulting in myocardial damage. In the present study we aimed at elucidating the dynamic progress of OPG levels during STEMI treated with percutaneous coronary intervention (PCI) and additionally, the effect of OPG levels on cardiac function., Methods: We prospectively included 42 patients with STEMI treated with primary PCI. Four consecutive blood samples were obtained before and after PCI treatment. Plasma OPG levels were determined using an in-house immunoassay. Cardiac function was increased according to echocardiography, estimating left ventricular ejection fraction (LVEF) 1-3 days after STEMI., Results: During STEMI, OPG levels peaked after PCI and then decreased; mean concentrations (95% confidence interval) before PCI, after PCI, and on day 1 and day 2 of 2650 ng/L (2315-3036 ng/L), 2778 ng/L (2442-3363 ng/L), 2024 ng/L (1775-230 6 ng/L), and 1808 ng/L (1551-2106 ng/L), respectively (P < 0.001). Interestingly, the OPG response was observed before the response in troponin I and C-reactive protein. Patients with reduced LVEF (< 40%) exhibited an increased OPG response before, during, and after PCI (mean increase, 38%; 9%-75%; repeated measures analysis of variance, P = 0.009). Adjustment for age, sex, body mass index, and cardiovascular risk factors did not significantly affect the association between reduced LVEF and increased OPG response (mean increase 33% (4%-70%; F = 5.784; P = 0.023)., Conclusions: Circulating OPG levels are altered during STEMI treated with primary PCI. A high OPG level is independently associated with impaired LVEF., (Copyright © 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Objective: Patients with acute myocardial infarction (MI) have increased risk of developing type 2 diabetes mellitus (T2DM). Adiponectin is an insulin-sensitizing hormone produced in adipose tissue, directly suppressing hepatic gluconeogenesis, stimulating fatty acid oxidation and glucose uptake in skeletal muscle and insulin secretion. In healthy humans, low plasma adiponectin levels associate with increased risk of T2DM; however, the relationship between adiponectin and T2DM in patients with MI has never been investigated., Research Design and Methods: We prospectively included 666 patients with ST-segment elevation MI, without diabetes, treated with percutaneous coronary intervention, from September 2006 to December 2008 at a tertiary cardiac center. Blood samples were drawn before intervention, and total plasma adiponectin was measured in all samples. During follow-up (median 5.7 years [interquartile range 5.3-6.1]) 6% (n = 38) developed T2DM. Risk of T2DM was analyzed using a competing risk analysis., Results: Low adiponectin levels were associated with increased risk of T2DM (P < 0.001). Even after adjustment for confounding risk factors (age, sex, hypertension, hypercholesterolemia, current smoking, previous MI, BMI, blood glucose, total cholesterol, HDL, LDL, triglyceride, estimated glomerular filtration rate, C-reactive protein, peak troponin I, and proatrial natriuretic peptide), low adiponectin levels remained an independent predictor of T2DM (hazard ratio [HR] 5.8 [2.3-15.0]; P < 0.001). Importantly, plasma adiponectin added to the predictive value of blood glucose, with the combination of high blood glucose and low plasma adiponectin, vastly increasing the risk of developing T2DM (HR 9.6 [3.7-25.3]; P < 0.001)., Conclusions: Low plasma adiponectin levels are independently associated with increased risk of T2DM in patients with MI and added significantly to the predictive value of blood glucose., (© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Background: Risk prediction in elderly patients is increasingly relevant due to longer life expectancy., Objectives: This study sought to examine whether electrocardiographic (ECG) changes provide prognostic information incremental to current risk models and to the conventional risk factors., Methods: In all, 6,991 participants from the Copenhagen Heart Study attending an examination at age ≥65 years were included. ECG changes were defined as Q waves, ST-segment depression, T-wave changes, ventricular conduction defects, and left ventricular hypertrophy based on the Minnesota code. The primary endpoint was fatal cardiovascular disease (CVD) event and the secondary was fatal or nonfatal CVD event. In our study, 2,236 fatal CVD and 3,849 fatal or nonfatal CVD events occurred during a median of 11.9 and 9.8 years of follow-up., Results: ECG changes were frequently present (30.6%) and associated with conventional risk factors. All ECG changes except 1 univariably predicted both endpoints. Event rates of ECG changes versus no ECG changes were respectively 41.4% versus 27.8% and 64.6% versus 50.8%. When added to existing risk scores, ECG changes independently increased the risk of both endpoints. Fatal CVD events: hazard ratio (HR): 1.33 (95% confidence interval [CI]: 1.29 to 1.36; p < 0.001) and fatal or nonfatal CVD events: HR: 1.21 (95% CI: 1.19 to 1.24; p < 0.001). When added to conventional risk factors, continuous net reclassification improvement was 42.3% (95% CI: 42.0 to 42.4; p < 0.001) for fatal and 29.2% (95% CI: 28.4 to 29.2; p < 0.001) for fatal or nonfatal events. Categorical net reclassification was 7.1% (95% CI: 6.7 to 9.0; p < 0.001) for fatal and 4.2% (95% CI: 3.5 to 5.6; p < 0.001) for fatal or nonfatal events., Conclusions: Simple assessment of the existence of ECG changes improves risk prediction in the general population of persons age ≥65 years., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objective: Neutrophil gelatinase-associated lipocalin (NGAL) is a glycoprotein stored in granules of neutrophil leukocytes participating in inflammatory and atherosclerotic processes and possibly plaque rupture. Despite the putative role of NGAL in atherosclerosis and acute myocardial infarction, human studies of plasma NGAL are still limited., Approach and Results: We prospectively followed 5599 randomly selected men and women from the community in the fourth Copenhagen Heart Study. Plasma NGAL was measured at study entry. Participants were followed for 10 years. During follow-up, 20% died (n=1120) and 15% (n=884) developed a major adverse cardiovascular event. Plasma NGAL associated strongly with all inflammatory markers (high-sensitivity C-reactive protein, total leukocyte count, neutrophil count) and inversely with estimated glomerular filtration rate (all, P<0.001). Multivariate analysis identified neutrophil leukocyte count as the main determinant of plasma NGAL. During follow-up, participants with increasing NGAL had increased risk of all-cause mortality and major adverse cardiovascular event (both, P<0.001). Even after adjustment for confounding risk factors by Cox regression analysis, NGAL remained an independent predictor of both all-cause mortality and major adverse cardiovascular event. When added to the Framingham risk score, NGAL improved c-statistics and correctly reclassified ≈15% into more appropriate risk groups. In comparison with high-sensitivity C-reactive protein, when both markers were added to the Framingham risk score, NGAL conferred 3× to 4× the risk., Conclusions: Plasma NGAL is strongly associated with inflammation in the general population. NGAL independently associated with 10-year outcome, and when added to the Framingham risk score, NGAL both improves c-statistics and correctly reclassifies participants into more accurate risk categories., (© 2014 American Heart Association, Inc.)

Aims: There is increasing evidence of cross-talk between the heart, body metabolism, and adipose tissue, but the precise mechanisms are poorly understood. Natriuretic peptides (NPs) have recently emerged as the prime candidate for a mediator. In patients with heart failure (HF), infusion of NPs increases adiponectin secretion, indicating that NPs may improve adipose tissue function and in this way function as a cardio-protective agent in HF. Accordingly we investigated the interplay between plasma adiponectin, plasma proBNP, and development of HF., Methods and Results: We prospectively followed 5574 randomly selected men and women from the community without ischaemic heart disease or HF. Plasma adiponectin and proBNP were measured at study entry. Median follow-up time was 8.5 years (interquartile range 8.0-9.1 years). During follow-up 271 participants developed symptomatic HF. Plasma adiponectin and proBNP were strongly associated (P < 0.001). Participants with increasing adiponectin had increased risk of incident HF (P < 0.001). After adjustment for confounding risk factors (including age, gender, smoking status, body mass ratio, waist-hip ratio, glucose, glycated haemoglobin, systolic and diastolic blood pressure, lipid profile, high sensitivity C-reactive protein, estimated glomerular filtration rate, and physical activity) by Cox regression analysis, adiponectin remained an independent predictor of HF: the hazard ratio (HR) per 1 standard deviation (SD) increase in adiponectin was 1.20 [95% confidence interval (CI) 1.06-1.30; P = 0.003]. However, the association vanished when plasma proBNP was included in the analysis, HR 1.08 (95% CI 0.95-1.23; P = 0.26)., Conclusions: In conclusion, plasma adiponectin and proBNP are strongly associated. Increasing plasma adiponectin is associated with increased risk of HF. However, concomitantly elevated proBNP levels appear to explain the positive association between adiponectin and risk of HF., (© 2014 The Authors. European Journal of Heart Failure © 2014 European Society of Cardiology.)

Background: Doppler tissue imaging (DTI) detects early signs of left ventricular (LV) dysfunction; however, the prognostic significance of DTI after ST-segment elevation myocardial infarction (STEMI) is unknown. The aim of this study was to evaluate the prognostic value of DTI after STEMI in patients treated with primary percutaneous coronary intervention., Method: In total, 391 patients who were admitted with STEMIs and treated with primary percutaneous coronary intervention were prospectively included. All participants were examined by echocardiography 2 days (interquartile range, 1-3 days) after STEMI. Longitudinal systolic (s'), early diastolic (e'), and late diastolic (a') myocardial velocities were measured using color DTI at six mitral annular sites and averaged to provide global estimates., Results: The median follow-up period was 25 months (interquartile range, 19-32 months). The primary end point was a composite of death, heart failure, or a new myocardial infarction. Patients with low global systolic function (s') or low global diastolic function (e') had >2 times greater risk for the combined end point compared with patients with high global s' (hazard ratio, 2.60; 95% confidence interval, 1.64-4.13; P < .001) or e' (hazard ratio, 2.26; 95% confidence interval, 1.44-3.55; P < .001), respectively. After adjustment for age, gender, peak troponin I, previous myocardial infarction, LV ejection fraction, LV mass index, and LV dimension in a multivariate Cox model, patients with low values of both global s' and e' remained at significantly higher risk than patients with high s' and/or e' (hazard ratio, 1.69; 95% confidence interval, 1.02-2.81; P = .043)., Conclusions: A pattern of low systolic and diastolic performance as assessed by DTI is a paramount marker of adverse prognosis for patients with STEMIs independent of conventional echocardiographic parameters. DTI velocities should be evaluated together as they interact with the prognosis., (Copyright © 2014 American Society of Echocardiography. Published by Mosby, Inc. All rights reserved.)

Background: Two-dimensional strain echocardiography detects early signs of left ventricular dysfunction; however, it is unknown whether myocardial strain analysis at rest in patients with suspected stable angina pectoris predicts the presence of coronary artery disease (CAD)., Methods and Results: In total, 296 consecutive patients with clinically suspected stable angina pectoris, no previous cardiac history, and normal left ventricular ejection fraction were included. All patients were examined by 2-dimensional strain echocardiography, exercise ECG, and coronary angiography. Two-dimensional strain echocardiography was performed in the 3 apical projections. Peak regional longitudinal systolic strain was measured in 18 myocardial sites and averaged to provide global longitudinal peak systolic strain. Duke score, including ST-segment depression, chest pain, and exercise capacity, was used as the outcome of the exercise test. Patients with an area stenosis≥70% in ≥1 epicardial coronary artery were categorized as having significant CAD (n=107). Global longitudinal peak systolic strain was significantly lower in patients with CAD compared with patients without (17.1±2.5% versus 18.8±2.6%; P<0.001) and remained an independent predictor of CAD after multivariable adjustment for baseline data, exercise test, and conventional echocardiography (odds ratio, 1.25 [P=0.016] per 1% decrease). Area under receiver operating characteristic curve for exercise test and global longitudinal peak systolic strain in combination was significantly higher than that for exercise test alone (0.84 versus 0.78; P=0.007). Furthermore, impaired regional longitudinal systolic strain identifies which coronary artery is stenotic., Conclusions: In patients with suspected stable angina pectoris, global longitudinal peak systolic strain assessed at rest is an independent predictor of significant CAD and significantly improves the diagnostic performance of exercise test. Furthermore, 2-dimensional strain echocardiography seems capable of identifying high-risk patients.

Aims: Mitral annular (MA) displacement reflects longitudinal left ventricular (LV) deformation and systolic velocity measurements reflect the rate of contraction; both are valuable in the diagnosis and prognosis of cardiac disease. The aim of this study was to test the agreement and reproducibility between motion mode (M-mode), colour tissue Doppler imaging (TDI), and two-dimensional strain imaging (2DSI) when measuring MA displacement and systolic velocity., Methods and Results: Using GE Healthcare Vivid 7 and E9 and Echopac BT11 software, MA displacement and velocity measurements by 2DSI, TDI, and M-mode determined in the septal and lateral walls in the apical four-chamber view were assessed in 50 control subjects and in 168 patients with various cardiac anomalies known to affect longitudinal displacement such as heart failure, mitral regurgitation, LV hypertrophy, and LV dilation. Intra- and inter-observer variability were tested using the Bland-Altman method in 125 patients. A relatively low bias between M-mode and TDI with respect to MA displacement (mean difference ± 1.96 standard deviation: 0.08 ± 0.35 cm) and a low bias between TDI and 2DSI with respect to MA peak systolic velocity (-0.13 ± 1.87 cm/s) were found. Reproducibility was acceptable for all methods with TDI having the lowest intra- and inter-observer variability., Conclusion: LV function could be assessed in terms of MA displacement and systolic velocity using M-mode, TDI, and 2DSI. None of the measurement techniques are, however, interchangeable. Overall, TDI seems to be the most robust method, having the lowest observer variability.

Background: Color tissue Doppler imaging M-mode through the mitral leaflet is an easy and precise method to estimate all cardiac time intervals from 1 cardiac cycle and thereby obtain the myocardial performance index (MPI). However, the prognostic value of the cardiac time intervals and the MPI assessed by color tissue Doppler imaging M-mode through the mitral leaflet in patients with ST-segment-elevation myocardial infarction (MI) is unknown., Methods and Results: In total, 391 patients were admitted with an ST-segment-elevation MI, treated with primary percutaneous coronary intervention, and examined by echocardiography a median of 2 days after the ST-segment-elevation MI. Outcome was assessed according to death (n=33), hospitalization with heart failure (n=53), or new MI (n=25). Follow-up time was a median of 25 months. The population was stratified according to tertiles of the MPI. The risk of new MI, being admitted with congestive heart failure or death, increased with increasing tertile of MPI, being ≈3 times as high for the third tertile compared with the first tertile (hazard ratio, 2.8; 95% confidence interval, 1.7-4.7; P<0.001). MPI provided independent prognostic information in a multivariable Cox regression model adjusted for age, sex, previous MI, peak troponin, and systolic and diastolic echocardiographic parameters, with a hazard ratio of 1.24 (P=0.005) for the combined end point per each 0.1 increase in MPI., Conclusions: MPI assessed by tissue Doppler imaging M-mode is a simple and reproducible measure that provides independent prognostic information, regardless of rhythm, incremental to conventional and novel echocardiographic parameters of systolic and diastolic function in patients with ST-segment-elevation MI treated with primary percutaneous coronary intervention.