Electrocardiographic markers in patients with type 2 diabetes and the role of diabetes duration.

BACKGROUND: The association between type 2 diabetes and electrocardiographic (ECG) markers are incompletely explored and the dependence on diabetes duration is largely unknown. We aimed to investigate the electrocardiographic (ECG) changes associated with type 2 diabetes over time. METHODS: In this cross-sectional study, we matched people with type 2 diabetes 1:1 on sex, age, and body mass index with people without diabetes from the general population. We regressed ECG markers with the presence of diabetes and the duration of clinical diabetes, respectively, adjusted for sex, age, body mass index, smoking, heart rate, diabetes medication, renal function, hypertension, and myocardial infarction. RESULTS: We matched 988 people with type 2 diabetes (332, 34% females) with as many controls. Heart rate was 8 bpm higher (p < 0.001) in people with vs. without type 2 diabetes, but the difference declined with increasing diabetes duration. For most depolarization markers, the difference between people with and without type 2 diabetes increased progressively with diabetes duration. On average, R-wave amplitude was 6 mm lower in lead V5 (p < 0.001), P-wave duration was 5 ms shorter (p < 0.001) and QRS duration was 3 ms (p = 0.03). Among repolarization markers, T-wave amplitude (measured in V5) was lower in patients with type 2 diabetes (1 mm lower, p < 0.001) and the QRS-T angle was 10 degrees wider (p = 0.002). We observed no association between diabetes duration and repolarization markers. CONCLUSIONS: Type 2 diabetes was independently associated with electrocardiographic depolarization and repolarization changes. Differences in depolarization markers, but not repolarization markers, increased with increasing diabetes duration.

Artificial intelligence enabled ECG screening for left ventricular systolic dysfunction: a systematic review.

Screening for left ventricular systolic dysfunction (LVSD), defined as reduced left ventricular ejection fraction (LVEF), deserves renewed interest as the medical treatment for the prevention and progression of heart failure improves. We aimed to review the updated literature to outline the potential and caveats of using artificial intelligence-enabled electrocardiography (AIeECG) as an opportunistic screening tool for LVSD.We searched PubMed and Cochrane for variations of the terms "ECG," "Heart Failure," "systolic dysfunction," and "Artificial Intelligence" from January 2010 to April 2022 and selected studies that reported the diagnostic accuracy and confounders of using AIeECG to detect LVSD.Out of 40 articles, we identified 15 relevant studies; eleven retrospective cohorts, three prospective cohorts, and one case series. Although various LVEF thresholds were used, AIeECG detected LVSD with a median AUC of 0.90 (IQR from 0.85 to 0.95), a sensitivity of 83.3% (IQR from 73 to 86.9%) and a specificity of 87% (IQR from 84.5 to 90.9%). AIeECG algorithms succeeded across a wide range of sex, age, and comorbidity and seemed especially useful in non-cardiology settings and when combined with natriuretic peptide testing. Furthermore, a false-positive AIeECG indicated a future development of LVSD. No studies investigated the effect on treatment or patient outcomes.This systematic review corroborates the arrival of a new generic biomarker, AIeECG, to improve the detection of LVSD. AIeECG, in addition to natriuretic peptides and echocardiograms, will improve screening for LVSD, but prospective randomized implementation trials with added therapy are needed to show cost-effectiveness and clinical significance.

The health consequences of informal employment among female workers and their children: a systematic review.

BACKGROUND: Informal employment is unprotected and unregistered and it is often characterized by precarious working arrangements. Although being a global phenomenon and the most common type of employment worldwide, scholarly attention to its health effects has only recently accelerated. While there is still some debate, informal employment is generally understood to be detrimental to workers' health. However, because women are more vulnerable to informality than men, attention is required to the health consequences of female workers specifically. We conducted a systematic review with the objective to examine the global evidence on the consequences of informal employment, compared to formal employment, on the health of female workers and their children. METHODS: We searched peer-reviewed literature in Embase, Medline, PsychInfo, Scopus and Web of Science up until November 11, 2022. No restrictions were applied in terms of year, language or country. Individual-level quantitative studies that compared women of reproductive age in informal and formal employment, or their children (≤ 5 years), were eligible for inclusion. If studies reported outcomes per subgroup level, these were included. Study quality was assessed using the Joanna Briggs Institute checklist and a narrative synthesis of the results were conducted. RESULTS: 13 articles were included in the review, looking at breastfeeding outcomes (n = 4), child nutritional status and low birthweight (n = 4), antenatal health (n = 3), and general health outcomes for women (n = 2). The overall evidence from the included studies was that compared to formal employment, there was an association between informal employment and worse health outcomes, especially on child nutritional status and antenatal health. The evidence for breastfeeding outcomes was mixed and showed that informal employment may be both protective and damaging to health. CONCLUSION: This review showed that informal employment is a potential risk factor for health among female workers and their children. Further research on the pathways between informal employment and health is needed to strengthen the understanding of the health consequences of informal employment.

Continuous monitoring is superior to manual measurements in detecting vital sign deviations in patients with COVID-19.

BACKGROUND: Patients admitted to the emergency care setting with COVID-19-infection can suffer from sudden clinical deterioration, but the extent of deviating vital signs in this group is still unclear. Wireless technology monitors patient vital signs continuously and might detect deviations earlier than intermittent measurements. The aim of this study was to determine frequency and duration of vital sign deviations using continuous monitoring compared to manual measurements. A secondary analysis was to compare deviations in patients admitted to ICU or having fatal outcome vs. those that were not. METHODS: Two wireless sensors continuously monitored (CM) respiratory rate (RR), heart rate (HR), and peripheral arterial oxygen saturation (SpO2 ). Frequency and duration of vital sign deviations were compared with point measurements performed by clinical staff according to regional guidelines, the National Early Warning Score (NEWS). RESULTS: SpO2 < 92% for more than 60 min was detected in 92% of the patients with CM vs. 40% with NEWS (p < .00001). RR > 24 breaths per minute for more than 5 min were detected in 70% with CM vs. 33% using NEWS (p = .0001). HR ≥ 111 for more than 60 min was seen in 51% with CM and 22% with NEWS (p = .0002). Patients admitted to ICU or having fatal outcome had longer durations of RR > 24 brpm (p = .01), RR > 21 brpm (p = .01), SpO2 < 80% (p = .01), and SpO2 < 85% (p = .02) compared to patients that were not. CONCLUSION: Episodes of desaturation and tachypnea in hospitalized patients with COVID-19 infection are common and often not detected by routine measurements.

Parental education and inequalities in child mortality: a global systematic review and meta-analysis.

BACKGROUND: The educational attainment of parents, particularly mothers, has been associated with lower levels of child mortality, yet there is no consensus on the magnitude of this relationship globally. We aimed to estimate the total reductions in under-5 mortality that are associated with increased maternal and paternal education, during distinct age intervals. METHODS: This study is a comprehensive global systematic review and meta-analysis of all existing studies of the effects of parental education on neonatal, infant, and under-5 child mortality, combined with primary analyses of Demographic and Health Survey (DHS) data. The literature search of seven databases (CINAHL, Embase, MEDLINE, PsycINFO, PubMed, Scopus, and Web of Science) was done between Jan 23 and Feb 8, 2019, and updated on Jan 7, 2021, with no language or publication date restrictions. Teams of independent reviewers assessed each record for its inclusion of individual-level data on parental education and child mortality and excluded articles on the basis of study design and availability of relevant statistics. Full-text screening was done in 15 languages. Data extracted from these studies were combined with primary microdata from the DHS for meta-analyses relating maternal or paternal education with mortality at six age intervals: 0-27 days, 1-11 months, 1-4 years, 0-4 years, 0-11 months, and 1 month to 4 years. Novel mixed-effects meta-regression models were implemented to address heterogeneity in referent and exposure measures among the studies and to adjust for study-level covariates (wealth or income, partner's years of schooling, and sex of the child). This study was registered with PROSPERO (CRD42020141731). FINDINGS: The systematic review returned 5339 unique records, yielding 186 included studies after exclusions. DHS data were compiled from 114 unique surveys, capturing 3 112 474 livebirths. Data extracted from the systematic review were synthesized together with primary DHS data, for meta-analysis on a total of 300 studies from 92 countries. Both increased maternal and paternal education showed a dose-response relationship linked to reduced under-5 mortality, with maternal education emerging as a stronger predictor. We observed a reduction in under-5 mortality of 31·0% (95% CI 29·0-32·6) for children born to mothers with 12 years of education (ie, completed secondary education) and 17·3% (15·0-18·8) for children born to fathers with 12 years of education, compared with those born to a parent with no education. We also showed that a single additional year of schooling was, on average, associated with a reduction in under-5 mortality of 3·04% (2·82-3·23) for maternal education and 1·57% (1·35-1·72) for paternal education. The association between higher parental education and lower child mortality was significant for both parents at all ages studied and was largest after the first month of life. The meta-analysis framework incorporated uncertainty associated with each individual effect size into the model fitting process, in an effort to decrease the risk of bias introduced by study design and quality. INTERPRETATION: To our knowledge, this study is the first effort to systematically quantify the transgenerational importance of education for child survival at the global level. The results showed that lower maternal and paternal education are both risk factors for child mortality, even after controlling for other markers of family socioeconomic status. This study provides robust evidence for universal quality education as a mechanism to achieve the Sustainable Development Goal target 3.2 of reducing neonatal and child mortality. FUNDING: Research Council of Norway, Bill & Melinda Gates Foundation, and Rockefeller Foundation-Boston University Commission on Social Determinants, Data, and Decision Making (3-D Commission).

The novel inflammatory biomarker GlycA and triglyceride-rich lipoproteins are associated with the presence of subclinical myocardial dysfunction in subjects with type 1 diabetes mellitus.

BACKGROUND: Subjects with Type 1 diabetes mellitus (T1DM) have an increased incidence of heart failure (HF). Several pathophysiological mechanisms have been involved in its development. The aim of this study was to analyze the potential contribution of the advanced lipoprotein profile and plasma glycosylation (GlycA) to the presence of subclinical myocardial dysfunction in subjects with T1DM. METHODS: We included subjects from a Danish cohort of T1DM subjects (Thousand & 1 study) with either diastolic and/or systolic subclinical myocardial dysfunction, and a control group without myocardial dysfunction, matched by age, sex and HbA1c. All underwent a transthoracic echocardiogram and an advanced lipoprotein profile obtained by using the NMR-based Liposcale® test. GlycA NMR signal was also analyzed. Systolic dysfunction was defined as left ventricular ejection fraction ≤ 45% and diastolic dysfunction was considered as E/e'≥12 or E/e' 8-12 + volume of the left atrium > 34 ml/m2. To identify a metabolic profile associated with the presence of subclinical myocardial dysfunction, a multivariate supervised model of classification based on least squares regression (PLS-DA regression) was performed. RESULTS: One-hundred forty-six subjects had diastolic dysfunction and 18 systolic dysfunction. Compared to the control group, patients with myocardial dysfunction had longer duration of diabetes (p = 0.005), and higher BMI (p = 0.013), serum NTproBNP concentration (p = 0.001), systolic blood pressure (p < 0.001), albuminuria (p < 0.001), and incidence of advanced retinopathy (p < 0.001). The supervised classification model identified a specific pattern associated with myocardial dysfunction, with a capacity to discriminate patients with myocardial dysfunction from controls. PLS-DA showed that triglyceride-rich lipoproteins (TGRLs), such as VLDL (total VLDL particles, large VLDL subclass and VLDL-TG content) and IDL (IDL cholesterol content), as well as the plasma concentration of GlycA, were associated with the presence of subclinical myocardial dysfunction. CONCLUSION: Proatherogenic TGRLs and the proinflammatory biomarker Glyc A are strongly associated to myocardial dysfunction in T1DM. These findings suggest a pivotal role of TGRLs and systemic inflammation in the development of subclinical myocardial dysfunction in T1DM.

Diagnostic and prognostic value of the electrocardiogram in stable outpatients with type 2 diabetes.

Aims. The European Society of Cardiology guidelines on diabetes and cardiovascular disease (CVD) recommend an electrocardiogram (ECG) in patients with diabetes and hypertension or with suspected CVD. We investigated whether ECG abnormalities can be used as a diagnostic and prognostic marker of heart failure (HF) in patients with type-2 diabetes (T2D) in secondary care diabetes-clinics. Methods. We included 722 patients with T2D in sinus rhythm. HF with preserved ejection fraction (HFpEF) was defined according to the European Society of Cardiology guidelines. Heart failure with mid-range ejection fraction (HFmrEF) was patients with dyspnoea and an LVEF 41-49%. Heart failure with reduced ejection fraction (HFrEF) or asymptomatic left ventricular systolic dysfunction (ALVSD) was defined as a LVEF ≤40%. Results. Overall, 24% patients had ECG abnormalities. A total of 15% had HF whereof 48% had ECG abnormalities. A normal ECG had a 99.3% negative predictive value (NPV) of ruling out HFrEF/ALVSD. In a sub-group with 0-1 simple clinical risk markers, the ECG ruled out both HFrEF/ALVSD, HFmrEF, and HFpEF with an NPV of 96.6%. The hazard-ratio (HR) of incident CVD or death in patients with HF and a normal ECG compared with patients without HF was 1.85 [95%CI 1.01-3.39], p = .05, while an abnormal ECG increased the HR to 3.84 [2.33-6.33], p < .001. Conclusion. HFrEF/ALVSD and HFmrEF were rare and HFpEF was frequent in this T2D population. A normal ECG ruled out HFrEF/ALVSD and in a sub-population with 0-1 simple clinical risk markers also both HFrEF/ALVSD, HFmrEF, and HFpEF.Key messagesWhat is already known about this subject?In early studies of unselected patients from primary care with suspected chronic heart failure, the presence of a normal ECG was found be useful to rule out heart failure with reduced ejection fraction.What does this study add?This study confirms that a standard electrocardiogram when normal in 722 stable outpatients with type 2 diabetes can be used to rule out HFrEF/ALVSD. Further, it adds knowledge about the risk of incident cardiovascular disease or death as a pathologic electrocardiogram increases the hazard ratio.How might this implicate clinical practice?With this study clinicians in secondary diabetes care clinics can use an electrocardiogram to select patients to undergo echocardiography when suspecting heart failure with reduced ejection fraction, as a normal electrocardiogram will rule out this diagnosis with a negative predictive value of >99%.

High-Throughput Molecular Imaging via Deep-Learning-Enabled Raman Spectroscopy.

Raman spectroscopy enables nondestructive, label-free imaging with unprecedented molecular contrast, but is limited by slow data acquisition, largely preventing high-throughput imaging applications. Here, we present a comprehensive framework for higher-throughput molecular imaging via deep-learning-enabled Raman spectroscopy, termed DeepeR, trained on a large data set of hyperspectral Raman images, with over 1.5 million spectra (400 h of acquisition) in total. We first perform denoising and reconstruction of low signal-to-noise ratio Raman molecular signatures via deep learning, with a 10× improvement in the mean-squared error over common Raman filtering methods. Next, we develop a neural network for robust 2-4× spatial super-resolution of hyperspectral Raman images that preserve molecular cellular information. Combining these approaches, we achieve Raman imaging speed-ups of up to 40-90×, enabling good-quality cellular imaging with a high-resolution, high signal-to-noise ratio in under 1 min. We further demonstrate Raman imaging speed-up of 160×, useful for lower resolution imaging applications such as the rapid screening of large areas or for spectral pathology. Finally, transfer learning is applied to extend DeepeR from cell to tissue-scale imaging. DeepeR provides a foundation that will enable a host of higher-throughput Raman spectroscopy and molecular imaging applications across biomedicine.

Echocardiographic predictors of long-term adverse cardiovascular outcomes in participants with and without diabetes mellitus: A follow-up analysis of the Copenhagen City Heart Study.

BACKGROUND: Previous studies have identified several echocardiographic markers of cardiac dysfunction in participants with diabetes mellitus, including E/e'. However, previous studies have been limited by short follow-up duration or low statistical power, and none have assessed whether echocardiographic predictors of adverse cardiovascular outcome differ between individuals with DM and individuals without DM. METHODS: A total of 1997 individuals from the general population without heart disease had an echocardiogram performed in 2001 to 2003. Diabetes was defined as HbA1c ≥6.5% (≥48 mmol/mol), non-fasted blood glucose ≥11.1 mmol/L or the use of glucose lowering medication. The end-point was a composite of heart failure (HF), ischemic heart disease (IHD) and cardiovascular death (CVD). RESULTS: At baseline, a total of 292 participants (15%) had diabetes. Median follow-up time was 12.4 years (interquartile-range: 9.8-12.8 years) and follow-up was 100%. During follow-up, 101 participants (35%) with diabetes and 281 participants without diabetes (16%) reached the composite end-point. The prognostic value of E/e' was significantly modified by diabetes (p for interaction: 0.003). In participants with diabetes, only E/e' remained an independent predictor of outcome in a final multivariable model adjusted for clinical and echocardiographic parameters (HR 1.08, 95% CI 1.00-1.17, p = 0.0041, per 1 increase). In participants without diabetes, left ventricular mass index (LVMI), left ventricular ejection fraction (LVEF) and a' remained independent predictors of outcome when adjusted for clinical and echocardiographic parameters. In individuals with diabetes, only E/e' added incremental prognostic value to risk factors from the SCORE risk chart and the ACC/AHA Pooled Cohort Equation. CONCLUSION: In individuals with diabetes from the general population, E/e' is a stronger predictor of cardiovascular mortality and morbidity than in individuals without diabetes and contributes with incremental prognostic value in addition to established cardiovascular risk factors.

Relationship between peripheral neuropathy, diastolic function and adverse cardiovascular outcome in individuals with type 1 diabetes mellitus without known cardiovascular disease: Results from the Thousand & 1 Study.

AIMS: To investigate the association between measures of peripheral neuropathy (PN) and impaired left ventricular diastolic function, and the prognosis in patients with type 1 diabetes (T1DM) and no known cardiovascular disease (CVD), and to test the incremental prognostic value of including measures of PN and diastolic function to the established Steno T1 Risk Engine. METHODS: Echocardiography and quantitative biothesiometry was performed to evaluate diastolic function and PN. The participants were categorized according to severity of diastolic function and PN. The study endpoint was combined cardiovascular (CV) events and all-cause death. Associations were analysed using multivariable regression models. The prognostic capability was assessed with Harrell's C-statistics and tested against the Steno T1 Risk Engine. RESULTS: A total of 946 individuals (51.5% men) were included. The mean (SD) follow-up was 6 (1.3) years. The total number of CV events and all-cause death were 100. In the multi-adjusted analysis, both PN and impaired diastolic function were associated with increased risk of CV events and all-cause death: severe PN versus no PN: hazard ratio (HR) 2.23 (95% confidence interval [CI] 1.06-4.68; P = 0.035); severe diastolic impairment versus normal function: HR 2.27 (95% CI 1.16-4.44; P = 0.016). Measures of diastolic function improved prognostic capability when added to the Steno T1 Risk Engine: C-statistic 0.797 (95% CI 0.793-0.817) versus 0.785 (95% CI 0.744-0.825; P = 0.006). CONCLUSION: Peripheral neuropathy and impaired diastolic function are associated with an increased risk of CV events and all-cause death in patients with T1DM. Measures of diastolic function improved prediction of prognosis by the Steno T1 Risk Engine.

Beta-blocker use and acute exacerbations of COPD following myocardial infarction: a Danish nationwide cohort study.

INTRODUCTION: Patients with chronic obstructive pulmonary disease (COPD) are undertreated with beta-blockers following myocardial infarction (MI), possibly due to fear for acute exacerbations of COPD (AECOPD). Is beta-blocker use associated with increased risk of AECOPD in patients following first-time MI? METHODS: Danish nationwide study of patients with COPD following hospitalisation for MI from 2003 to 2015. Multivariable, time-dependent Cox regression accounting for varying beta-blocker use based on claimed prescriptions during up to 13 years of follow-up. RESULTS: A total of 10 884 patients with COPD were discharged after first-time MI. The 1-year rate of AECOPD was 35%, and 65% used beta-blockers at 1 year. Beta-blocker use was associated with a lower risk of AECOPD (multivariable-adjusted HR 0.78, 95% CI 0.74-0.83). This association was independent of the type of MI (HR 0.70, 95% CI 0.59-0.83 in ST-elevation MI (STEMI) and HR 0.80, 95% CI 0.75-0.84 in non-STEMI), presence or absence of heart failure (HR 0.82, 95% CI 0.74-0.90 and HR 0.77, 95% CI 0.72-0.82, respectively), beta-blocker dosage and type, as well as exacerbation severity. Results were similar in 1118 patients with full data on COPD severity and symptom burden (median forced expiratory volume in 1 s as percentage of predicted was 46 and majority had moderate dyspnoea), and in 1358 patients with severe COPD and frequent AECOPD with a high 1-year rate of AECOPD of 70%. DISCUSSION: Beta-blocker use was not associated with increased risk of AECOPD following MI. This finding was independent of COPD severity, symptom burden and exacerbation history, and supports the safety of beta-blockers in patients with COPD, including high-risk patients with severe disease.

MR-proANP and incident cardiovascular disease in patients with type 2 diabetes with and without heart failure with preserved ejection fraction.

BACKGROUND: Mid-regional pro-atrial natriuretic peptide (MR-proANP) is a useful biomarker in outpatients with type 2 diabetes (T2D) to diagnose heart failure (HF). Elevated B-type natriuretic peptides are included in the definition of HF with preserved ejection fraction (HFpEF) but little is known about the prognostic value of including A-type natriuretic peptides (MR-proANP) in the evaluation of patients with T2D. METHODS: We prospectively evaluated the risk of incident cardiovascular (CV) events in outpatients with T2D (n = 806, mean ± standard deviation age 64 ± 10 years, 65% male, median [interquartile range] duration of diabetes 12 [6-17] years, 17.5% with symptomatic HFpEF) according to MR-proANP levels and stratified according to HF-status including further stratification according to a prespecified cut-off level of MR-proANP. RESULTS: A total of 126 CV events occurred (median follow-up 4.8 [4.1-5.3] years). An elevated MR-proANP, with a cut-off of 60 pmol/l or as a continuous variable, was associated with incident CV events (p < 0.001). Compared to patients without HF, patients with HFpEF and high MR-proANP (≥ 60 pmol/l; median 124 [89-202] pmol/l) and patients with HF and reduced ejection fraction (HFrEF) had a higher risk of CV events (multivariable model; hazard ratio (HR) 2.56 [95% CI 1.64-4.00] and 3.32 [1.64-6.74], respectively). Conversely, patients with HFpEF and low MR-proANP (< 60 pmol/l; median 46 [32-56] pmol/l) did not have an increased risk (HR 2.18 [0.78-6.14]). CONCLUSIONS: Patients with T2D and HFpEF with high MR-proANP levels had an increased risk for CV events compared to patients with HFpEF without elevated MR-proANP and compared to patients without HF, supporting the use of MR-proANP in the definition of HFpEF from a prognostic point-of-view.

Multiplexed polarized hypodermic Raman needle probe for biostructural analysis of articular cartilage.

In this Letter, we report a multiplexed polarized hypodermic Raman needle probe for the biostructural analysis of articular cartilage. Using a custom-developed needle probe with a sapphire ball lens, we measure polarized Raman spectra of cartilage. By imaging two polarizations simultaneously on the charge-coupled device (CCD) and binning them separately, we capture both biochemical and structural tissue information in real time. Here, we demonstrate that polarized Raman spectroscopy can distinguish between different collagen fibril alignment orientations in a cartilage explant model system, supporting its capacity for diagnosing the hallmark collagen alignment changes occurring in the early stages of osteoarthritis (OA). Accordingly, this work shows that needle-based polarized Raman spectroscopy has great potential for the monitoring and diagnosis of early OA.

Echocardiography improves prediction of major adverse cardiovascular events in a population with type 1 diabetes and without known heart disease: the Thousand & 1 Study.

AIMS/HYPOTHESIS: Cardiovascular disease is the most common comorbidity in type 1 diabetes. However, current guidelines do not include routine assessment of myocardial function. We investigated whether echocardiography provides incremental prognostic information in individuals with type 1 diabetes without known heart disease. METHODS: A prospective cohort of individuals with type 1 diabetes without known heart disease was recruited from the outpatient clinic. Follow-up was performed through Danish national registers. The association of echocardiography with major adverse cardiovascular events (MACE) and the incremental prognostic value when added to the clinical Steno T1D Risk Engine were examined. RESULTS: A total of 1093 individuals were included: median (interquartile range) age 50.2 (39.2-60.3) years and HbA1c 65 (56-74) mmol/mol; 53% men; and mean (SD) BMI 25.5 (3.9) kg/m2 and diabetes duration 25.8 (14.6) years. During 7.5 years of follow-up, 145 (13.3%) experienced MACE. Echocardiography significantly and independently predicted MACE: left ventricular ejection fraction (LVEF) <45% (n = 18) vs ≥45% (n = 1075), HR (95% CI) 3.93 (1.91, 8.08), p < 0.001; impaired global longitudinal strain (GLS), 1.65 (1.17, 2.34) (n = 263), p = 0.005; diastolic mitral early velocity (E)/early diastolic tissue Doppler velocity (e') <8 (n = 723) vs E/e' 8-12 (n = 285), 1.59 (1.04, 2.42), p = 0.031; and E/e' <8 vs E/e' ≥12 (n = 85), 2.30 (1.33, 3.97), p = 0.003. In individuals with preserved LVEF (n = 1075), estimates for impaired GLS were 1.49 (1.04, 2.15), p = 0.032; E/e' <8 vs E/e' 8-12, 1.61 (1.04, 2.49), p = 0.033; and E/e' <8 vs E/e' ≥12, 2.49 (1.41, 4.37), p = 0.001. Adding echocardiographic variables to the Steno T1D Risk Engine significantly improved risk prediction: Harrell's C statistic, 0.791 (0.757, 0.824) vs 0.780 (0.746, 0.815), p = 0.027; and net reclassification index, 52%, p < 0.001. CONCLUSIONS/INTERPRETATION: In individuals with type 1 diabetes without known heart disease, echocardiography significantly improves risk prediction over and above guideline-recommended clinical risk factors alone and could have a role in clinical care.

Midlife cardiorespiratory fitness and the long-term risk of chronic obstructive pulmonary disease.

BACKGROUND: Good midlife cardiorespiratory fitness (CRF) may reduce the risk of chronic obstructive pulmonary disease (COPD). Reverse causation may play a role if follow-up time is short. We examined the association between CRF and both incident COPD and COPD mortality in employed men with up to 46 years follow-up, which allowed us to account for reverse causality. METHODS: Middle-aged men (n=4730) were recruited in 1970-1971. CRF was determined as VO2max by ergometer test. Categories of CRF (low, normal, high) were defined as ± 1 Z-score (± 1 SD) above or below the age-adjusted mean. Endpoints were identified through national registers and defined as incident COPD, and death from COPD. Multi-adjusted Cox models and restricted mean survival times (RMST) were performed. RESULTS: Compared with low CRF, the estimated risk of incident COPD was 21% lower in participants with normal CRF (HR 0.79, 95% CI 0.63 to 0.99) and 31 % lower with high CRF (HR 0.69, 95% CI 0.52 to 0.91). Compared with low CRF, the risk of death from COPD was 35% lower in participants with normal CRF (HR 0.65, 95% CI 0.46 to 0.91) and 62% lower in participants with high CRF (HR 0.38, 95% CI 0.23 to 0.61). RMST showed a delay to incident COPD and death from COPD in the magnitude of 1.3-1.8 years in normal and high CRF vs low CRF. Test for reverse causation did not alter the results. CONCLUSION: In a population of healthy, middle-aged men, higher levels of CRF were associated with a lower long-term risk of incident COPD and death from COPD.

Biomarkers and clinical outcomes in COPD: a systematic review and meta-analysis.

BACKGROUND: Conventional measures to evaluate COPD may fail to capture systemic problems, particularly musculoskeletal weakness and cardiovascular disease. Identifying these manifestations and assessing their association with clinical outcomes (ie, mortality, exacerbation and COPD hospital admission) is of increasing clinical importance. OBJECTIVE: To assess associations between 6 min walk distance (6MWD), heart rate, fibrinogen, C reactive protein (CRP), white cell count (WCC), interleukins 6 and 8 (IL-6 and IL-8), tumour necrosis factor-alpha, quadriceps maximum voluntary contraction, sniff nasal inspiratory pressure, short physical performance battery, pulse wave velocity, carotid intima-media thickness and augmentation index and clinical outcomes in patients with stable COPD. METHODS: We systematically searched electronic databases (August 2018) and identified 61 studies, which were synthesised, including meta-analyses to estimate pooled HRs, following Meta-analysis of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: Shorter 6MWD and elevated heart rate, fibrinogen, CRP and WCC were associated with higher risk of mortality. Pooled HRs were 0.80 (95% CI 0.73 to 0.89) per 50 m longer 6MWD, 1.10 (95% CI 1.02 to 1.18) per 10 bpm higher heart rate, 3.13 (95% CI 2.14 to 4.57) per twofold increase in fibrinogen, 1.17 (95% CI 1.06 to 1.28) per twofold increase in CRP and 2.07 (95% CI 1.29 to 3.31) per twofold increase in WCC. Shorter 6MWD and elevated fibrinogen and CRP were associated with exacerbation, and shorter 6MWD, higher heart rate, CRP and IL-6 were associated with hospitalisation. Few studies examined associations with musculoskeletal measures. CONCLUSION: Findings suggest 6MWD, heart rate, CRP, fibrinogen and WCC are associated with clinical outcomes in patients with stable COPD. Use of musculoskeletal measures to assess outcomes in patients with COPD requires further investigation. TRIAL REGISTRATION NUMBER: CRD42016052075.

Epicardial adipose tissue predicts incident cardiovascular disease and mortality in patients with type 2 diabetes.

BACKGROUND: Cardiac fat is a cardiovascular biomarker but its importance in patients with type 2 diabetes is not clear. The aim was to evaluate the predictive potential of epicardial (EAT), pericardial (PAT) and total cardiac (CAT) fat in type 2 diabetes and elucidate sex differences. METHODS: EAT and PAT were measured by echocardiography in 1030 patients with type 2 diabetes. Follow-up was performed through national registries. The end-point was the composite of incident cardiovascular disease (CVD) and all-cause mortality. Analyses were unadjusted (model 1), adjusted for age and sex (model 2), plus systolic blood pressure, body mass index (BMI), low-density lipoprotein (LDL), smoking, diabetes duration and glycated hemoglobin (HbA1c) (model 3). RESULTS: Median follow-up was 4.7 years and 248 patients (191 men vs. 57 women) experienced the composite end-point. Patients with high EAT (> median level) had increased risk of the composite end-point in model 1 [Hazard ratio (HR): 1.46 (1.13; 1.88), p = 0.004], model 2 [HR: 1.31 (1.01; 1.69), p = 0.038], and borderline in model 3 [HR: 1.32 (0.99; 1.77), p = 0.058]. For men, but not women, high EAT was associated with a 41% increased risk of CVD and mortality in model 3 (p = 0.041). Net reclassification index improved when high EAT was added to model 3 (19.6%, p = 0.035). PAT or CAT were not associated with the end-point. CONCLUSION: High levels of EAT were associated with the composite of incident CVD and mortality in patients with type 2 diabetes, particularly in men, after adjusting for CVD risk factors. EAT modestly improved risk prediction over CVD risk factors.

Left ventricular concentric geometry predicts incident diabetes mellitus independent of established risk factors in the general population: the Copenhagen City Heart Study.

BACKGROUND: Subtle impairments in left ventricular (LV) function and geometry are common findings in individuals with diabetes. However, whether these impairments precede the development of diabetes mellitus (DM) is not entirely clear. METHODS: Echocardiograms from 1710 individuals from the general population free of prevalent diabetes mellitus were analyzed. Left ventricular (LV) concentric geometry was defined as either LV concentric remodeling or LV concentric hypertrophy as directed in contemporary guidelines. The severity of LV concentricity was assessed by relative wall thickness (RWT) calculated as posterior wall thickness (PWT) indexed to left ventricular internal diameter at end diastole (LVIDd) (RWT = 2 * PWT/LVIDd). End-point was incident DM. RESULTS: Median follow-up time was 12.6 years (IQR: 12.0-12.8 years). Follow-up was a 100%. A total of 55 participants (3.3%) developed DM during follow-up. At baseline, the prevalence of a concentric LV geometric pattern was significantly higher (41.8% vs 20.3%, p < 0.001) in individuals who developed DM during follow-up. In a final multivariable model adjusting for established DM risk factors including HbA1c, BMI and plasma glucose, LV concentric geometry and RWT remained significantly associated with incident DM (LV concentric geometry: HR 1.99, 95% CI 1.11-3.57, p = 0.021) (RWT: HR 1.41, 95% CI 1.06-1.86, p = 0.017, per 0.1 increase). This association remained despite adjustment for established risk factors for DM. CONCLUSION: Altered LV geometry may precede the development of DM. LV concentric geometry determined by echocardiography and the severity of LV concentricity evaluated as RWT are associated with incident DM in the general population.

Epicardial and pericardial adipose tissues are associated with reduced diastolic and systolic function in type 2 diabetes.

The aim of this study was to investigate the association of epicardial (EAT) and pericardial (PAT) adipose tissues with myocardial function in type 2 diabetes (T2D). EAT and PAT were measured by ultrasound in 770 patients with T2D and 234 age- and sex-matched non-diabetic controls. Echocardiography was performed, including tissue Doppler imaging and 2D speckle tracking. Patients with T2D versus controls had increased EAT (4.6 ± 1.8 mm vs. 3.4 ± 1.2 mm, P < 0.0001) and PAT (6.3 ± 2.8 mm vs. 5.3 ± 2.4 mm, P < 0.0001). EAT and PAT were associated with structural cardiac measures both in T2D patients and controls (all P < 0.043), but only in T2D patients with functional measures: PAT was associated with impaired global longitudinal strain [beta coefficient (SE)] [0.11% (0.04), P = 0.002], while EAT was associated with reduced diastolic function by lateral early diastolic myocardial velocity (e'lat ) [-0.31 (0.05) cm/s, P = 0.001], mitral inflow velocities: peak early (E)/peak atrial (A) ratio [-0.02 (0.01), P = 0.001] and lateral E/e'lat [0.36 (0.10), P < 0.001]. However, no interaction was found between diabetes status and PAT (P = 0.75) or EAT (P = 0.45). Adipose tissue in intimate relation to the myocardium is higher in patients with T2D versus controls and is associated with functional myocardial measures in T2D.