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Aims: Long-term sequelae may occur after SARS-CoV-2 infection. We comprehensively assessed organ-specific functions in individuals after mild to moderate SARS-CoV-2 infection compared with controls from the general population., Methods and Results: Four hundred and forty-three mainly non-hospitalized individuals were examined in median 9.6 months after the first positive SARS-CoV-2 test and matched for age, sex, and education with 1328 controls from a population-based German cohort. We assessed pulmonary, cardiac, vascular, renal, and neurological status, as well as patient-related outcomes. Bodyplethysmography documented mildly lower total lung volume (regression coefficient -3.24, adjusted P = 0.014) and higher specific airway resistance (regression coefficient 8.11, adjusted P = 0.001) after SARS-CoV-2 infection. Cardiac assessment revealed slightly lower measures of left (regression coefficient for left ventricular ejection fraction on transthoracic echocardiography -0.93, adjusted P = 0.015) and right ventricular function and higher concentrations of cardiac biomarkers (factor 1.14 for high-sensitivity troponin, 1.41 for N-terminal pro-B-type natriuretic peptide, adjusted P ≤ 0.01) in post-SARS-CoV-2 patients compared with matched controls, but no significant differences in cardiac magnetic resonance imaging findings. Sonographically non-compressible femoral veins, suggesting deep vein thrombosis, were substantially more frequent after SARS-CoV-2 infection (odds ratio 2.68, adjusted P < 0.001). Glomerular filtration rate (regression coefficient -2.35, adjusted P = 0.019) was lower in post-SARS-CoV-2 cases. Relative brain volume, prevalence of cerebral microbleeds, and infarct residuals were similar, while the mean cortical thickness was higher in post-SARS-CoV-2 cases. Cognitive function was not impaired. Similarly, patient-related outcomes did not differ., Conclusion: Subjects who apparently recovered from mild to moderate SARS-CoV-2 infection show signs of subclinical multi-organ affection related to pulmonary, cardiac, thrombotic, and renal function without signs of structural brain damage, neurocognitive, or quality-of-life impairment. Respective screening may guide further patient management., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

Aims: Evidence suggests that peripheral vascular function is related to cardiovascular disease (CVD) and mortality. We evaluated the associations of non-invasive measures of flow-mediated dilatation and peripheral arterial tonometry with incident CVD and mortality., Methods and Results: In a post-hoc analysis of the community-based Gutenberg Health Study, median age 55 years (25th/75th percentile 46/65) and 49.5% women, we measured brachial artery flow-mediated dilatation (N=12 599) and fingertip peripheral arterial tonometry (N=11 125). After a follow-up of up to 11.7 years, we observed 595 incident CVD events, 106 cardiac deaths, and 860 deaths in total. Survival curves showed decreased event-free survival with higher mean brachial artery diameter and baseline pulse amplitude and better survival with higher mean flow-mediated dilatation and peripheral arterial tonometry ratio (all Plog rank <0.05). In multivariable-adjusted Cox regression analyses only baseline pulse amplitude was inversely related to mortality [hazard ratio (HR) per standard deviation increase, 0.86, 95% confidence interval (95% CI), 0.79-0.94; P=0.0009]. After exclusion of individuals with prevalent CVD the association was no longer statistically significant in multivariable-adjusted models (HR 0.91, 95% CI 0.81-1.02; P=0.11). None of the vascular variables substantially increased the C-index of a model comprising clinical risk factors., Conclusions: In our cohort, non-invasive measures of peripheral vascular structure and function did not reveal clinically relevant associations with incident CVD or mortality. Whether determination of pulse amplitude by peripheral arterial tonometry improves clinical decision-making in primary prevention needs to be demonstrated., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

We report a family with heterozygous deletion of exons 3-6 of the LMNA gene. The main presentation of affected family members was characterized by ventricular and supraventricular arrhythmias, atrioventricular (AV) block and sudden cardiac death (SCD) but also by severe dilative cardiomyopathy (DCM). We report on two siblings, a 36-year-old female and her 40-year-old brother, who suffer from heart failure with mildly reduced ejection fraction, AV conduction delays and premature ventricular complexes. Their 65-year-old mother underwent heart transplantation at the age of 55 due to advanced heart failure. Originally, the LMNA mutation was detected in one of the uncles. This index patient and three of his brothers died of SCD as well as their father and aunt. The two siblings were treated with implanted defibrillators in our specialized tertiary heart failure center. This case report places this specific genetic variant in the context of LMNA-associated familial DCM.

Delta opioid receptor (DOR) agonists alleviate nociceptive behaviors in various chronic pain models, including neuropathic pain, while having minimal effect on sensory thresholds in the absence of injury. The mechanisms underlying nerve injury-induced enhancement of DOR function are unclear. We used a peripheral nerve injury (PNI) model of neuropathic pain to assess changes in the function and localization of DORs in mice and rats. Intrathecal administration of DOR agonists reversed mechanical allodynia and thermal hyperalgesia. The dose-dependent thermal antinociceptive effects of DOR agonists were shifted to the left in PNI rats. Administration of DOR agonists produced a conditioned place preference in PNI, but not in sham, animals, whereas the DOR antagonist naltrindole produced a place aversion in PNI, but not in sham, mice, suggesting the engagement of endogenous DOR activity in suppressing pain associated with the injury. GTPγS autoradiography revealed an increase in DOR function in the dorsal spinal cord, ipsilateral to PNI. Immunogold electron microscopy and in vivo fluorescent agonist assays were used to assess changes in the ultrastructural localization of DORs in the spinal dorsal horn. In shams, DORs were primarily localized within intracellular compartments. PNI significantly increased the cell surface expression of DORs within lamina IV-V dendritic profiles. Using neonatal capsaicin treatment, we identified that DOR agonist-induced thermal antinociception was mediated via receptors expressed on primary afferent sensory neurons but did not alter mechanical thresholds. These data reveal that the regulation of DORs following PNI and suggest the importance of endogenous activation of DORs in regulating chronic pain states., (© 2020 Wiley Periodicals LLC.)

Aim: Due to improved therapy in childhood, many patients with congenital heart disease reach adulthood and are termed adults with congenital heart disease (ACHD). ACHD often develop heart failure (HF) as a consequence of initial palliative surgery or complex anatomy and subsequently require advanced HF therapy. ACHD are usually excluded from trials evaluating heart failure therapies, and in this context, more data about heart failure trajectories in ACHD are needed to guide the management of ACHD suffering from HF., Methods and Results: The pAtients pResenTing with cOngenital heaRt dIseAse Register (ARTORIA-R) will collect data from ACHD evaluated or listed for heart or heart-combined organ transplantation from 16 countries in Europe and the Asia/Pacific region. We plan retrospective collection of data from 1989-2020 and will include patients prospectively. Additional organizations and hospitals in charge of transplantation of ACHD will be asked in the future to contribute data to the register. The primary outcome is the combined endpoint of delisting due to clinical worsening or death on the waiting list. The secondary outcome is delisting due to clinical improvement while on the waiting list. All-cause mortality following transplantation will also be assessed. The data will be entered into an electronic database with access to the investigators participating in the register. All variables of the register reflect key components important for listing of the patients or assessing current HF treatment., Conclusion: The ARTORIA-R will provide robust information on current management and outcomes of adults with congenital heart disease suffering from advanced heart failure., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Pregnancy may be associated with adverse outcome in women with congenital heart disease (CHD). However, data regarding the outcome of pregnancy in women with CHD who receive care in cardiac-obstetric expert units are limited., Methods: We retrospectively analyzed baseline characteristics and outcome of pregnancy in 67 females with CHD who received medical care in our tertiary center for 61 singleton and 6 twin pregnancies between 2009 and 2018., Results: According to the modified World Health Organization (mWHO) risk scale for pregnancy, CHD lesions in 39 enrolled women (58%) were classified as mWHO class I or II, and in 28 females (42%) as mWHO class III or IV. Preterm births were more frequent in mWHO classes III or IV (P=0.003). Cardiac signs and complications occurred more often in mWHO classes III or IV than in women with cardiac lesions assigned to mWHO classes I or II (42.9% vs . 7.7%, P=0.002). N-terminal pro B-type natriuretic peptide (NT-proBNP) levels during pregnancy were higher in mWHO classes III or IV than in mWHO classes I or II (median 269.0 vs . 115.5 pg/mL, P=0.019). Presence of functional NYHA class III [odds ratio (OR) per standard deviation (SD) 8.8, 95% confidence interval (CI): 2.2-57.2, P=0.008] and mWHO classes III/IV (OR per SD 3.4, 95% CI: 1.2-9.9, P=0.018) prior to pregnancy were identified as independent predictors of adverse cardiac outcome of pregnancy., Conclusions: Adverse cardiac events and preterm deliveries should be anticipated in pregnant women with CHD, especially in those with mWHO classes III or IV. Therefore, these pregnancies should be under close surveillance and managed in specialized, multidisciplinary tertiary referral centers. Preconception counseling including individualized risk assessment is strongly recommended in women with CHD., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/cdt-20-650). The series “Current Management Aspects in Adult Congenital Heart Disease (ACHD): Part IV” was commissioned by the editorial office without any funding or sponsorship. YvK serves as an unpaid editorial board member of Cardiovascular Diagnosis and Therapy from February 2018 to January 2022 and served as the unpaid Guest Editor of the series. Dr. SB reports grants and personal fees from Abbott Diagnostics, grants and personal fees from Bayer, grants from SIEMENS, grants from Singulex, grants and personal fees from Thermo Fisher, personal fees from Abott, personal fees from Astra Zeneca, personal fees from AMGEN, personal fees from Medtronic, personal fees from Pfizer, personal fees from Roche, personal fees from Novartis, personal fees from Siemens Diagnostics, outside the submitted work; Dr. PK reports non-financial support from the European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (UK), and German Centre for Heart Research, outside the submitted work; In addition, Dr. PK is listed as inventor on two patents held by University of Birmingham (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). He received research support for basic, translational and clinical research projects from several drug and device companies active in atrial fibrillation, and has received honoraria from several such companies in the past, but not in the last 3 years. The authors have no other conflicts of interest to declare., (2021 Cardiovascular Diagnosis and Therapy. All rights reserved.)

Aims: Despite signals from clinical trials and mechanistic studies implying different resilience to heart failure (HF) depending on gender, the impact of gender on presentation and outcomes in patients with HF remains unclear. This study assessed the impact of gender on clinical presentation and outcomes in patients with HF referred to a specialised tertiary HF service., Methods and Results: Consecutive patients with HF referred to a specialised tertiary HF service offering advanced therapy options including left ventricular assist devices (LVAD) and heart transplantation were prospectively enrolled from August 2015 until March 2018. We assessed clinical characteristics at baseline and performed survival analyses and age-adjusted Cox regression analyses in men vs. women for all-cause death and a combined disease-related endpoint comprising death, heart transplantation, and LVAD implantation. Analyses were performed for the overall study population and for patients with HF with reduced ejection fraction (HFrEF). Of 356 patients included, 283 (79.5%) were male. The median age was 58 years (interquartile range 50-67). Two hundred and fifty-one (74.5%) patients had HFrEF. HF aetiology, ejection fraction, functional status measures, and most of the cardiac and non-cardiac comorbidities did not differ between men and women. In a median follow-up of 3.2 years, 50 patients died (45 men, 5 women), 15 patients underwent LVAD implantation, and 8 patients heart transplantation. While all-cause death was not significantly different between both genders in the overall population [16.9 vs. 6.0%, P = 0.065, hazard ratio (HR) 2.29 (95% confidence interval 0.91-5.78), P = 0.078], in the HFrEF subgroup, a significant difference between men and women was observed [20.7% vs. 3.9%, P = 0.017, HR 3.67 (95% confidence interval 1.13-11.91), P = 0.031]. The combined endpoint was more often reached in men than in women in both the overall population [21.6% vs. 9.0%, P = 0.053, HR 2.51 (1.08-5.82), P = 0.032] and the HFrEF subgroup [27.1% vs. 7.7%, P = 0.015, HR 3.58 (1.29-9.94), P = 0.014]., Conclusions: Patients referred to a specialised tertiary HF service showed a similar clinical profile without relevant gender differences. In the mid-term follow-up, more male than female patients died or underwent heart transplantation and LVAD implantation. These findings call for independent validation and for further research into gender-specific drivers of HF progression., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Objectives: The 2014 Australian Physical Activity and Sedentary Behaviour Guidelines (Adults) recommend muscle-strengthening activities ≥2 days/week. This study aimed to identify factors associated with 5-year change and stability in adherence to these guidelines., Design: Two adult follow-ups of the Childhood Determinants of Adult Health (CDAH) Study. Participants (n = 1510) were 26-36 years (CDAH-1, 2004-06) and 31-41 years (CDAH-2, 2009-11)., Methods: Information on muscle-strengthening activities, sociodemographics, health, physical activity and sedentary behaviour was collected. Participants reporting muscle-strengthening activities ≥2 days/week 'met guidelines', with change and stability categorised as 'persistent adherence', 'increasing adherence', 'decreasing adherence' and 'persistent non-adherence'. Differences in sociodemographic, health and behavioural factors were analysed using log multinomial regression., Results: Between 15-21% of women (CDAH-1: 14.5%, 95% confidence interval = 12.5-16.9; CDAH-2: 20.7%, 95% confidence interval = 18.3-23.4) and ~21% of men (CDAH-1: 22.2%, 95% confidence interval = 19.0-26.0; CDAH-2: 21.0%, 95% confidence interval = 17.8-24.7) met muscle-strengthening guidelines, but only 8.5% (95% confidence interval = 7.2-10.1) of participants were persistently adherent. Remaining in or moving from a major city, CDAH-1 weight status, cumulative self-rated health and vigorous physical activity were positively associated with persistent adherence (relative risk range = 1.51-3.92), while female gender, becoming partnered and having children at any timepoint were negatively associated with persistent adherence (relative risk range = 0.38-0.58)., Conclusions: Adherence - particularly persistent adherence - to muscle-strengthening guidelines in this sample was low. Gender, marital status, weight status, BMI, self-rated health, urban-rural status, parental status, physical activity and sedentary behaviour were associated with adherence, and should be considered in intervention development to maximise effectiveness., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background and Aims: Indoleamine 2,3-dioxygenase (IDO) is an intracellular enzyme associated with artery wall inflammation. Previous studies have verified correlation between IDO activity and early signs of atherosclerosis especially in females. We aimed to elucidate the relationship between an estimate of IDO activity and atherosclerotic risk factors related to non-alchohol-fatty liver (NAFLD) in a 6- and 10-year follow-up., Methods: Estimates of IDO activity along with complete risk factor data were measured from females (n = 506; age 24-39) and males (n = 421; age 24-39) in 2001. Risk factor measurements were conducted again in 2007 and 2011. Statistical examinations were carried out by Pearson correlation and risk ratio analysis., Results: In females, age-adjusted IDO correlated with body mass index (BMI) (p = 0.0008), waist (p = 0.0009), C-reactive protein (CRP) (p = 0.0014) and logarithmically modified triglycerides (p = 0.0488) in 2007. Correlation remained significant with BMI (p = 0.0007) and waist (p = 0.0063) in 2011. In males, age-adjusted IDO correlated with waist (p = 0.0367) and high-density lipoprotein cholesterol (HDL-C) (p = 0.0489) in 2007. Correlation remained significant with HDL-C (p = 0.0348) in 2011. In risk ratio analysis, relationship between IDO and obesity was confirmed in females after 10 years (RR = 1.026, p = 0.0147, 95% CI) and in males after 6 and 10 years (RR = 1.019, p = 0.0091, 95% CI and RR = 1.015, p = 0.0404, 95% CI, respectively) when the data was adjusted for age and BMI., Conclusions: IDO activity correlated with obesity and factors related to NAFLD, namely obesity of visceral type, hypertriglyceridemia and CRP (in females), well-characterized risk factors for diabetes and atherosclerosis in 6- and 10-year follow-up in males and premenopausal females., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Right ventricular dysfunction is a major determinant of outcome in pulmonary arterial hypertension (PAH). We aimed to identify echocardiographic right heart parameters associated with adverse outcome and to develop a non-invasive, echocardiography-based risk score for PAH patients., Methods and Results: In 254 PAH patients we analyzed functional status, laboratory results, and echocardiographic parameters. We included these parameters to estimate all-cause death or lung transplantation using Cox regression models. The analyses included a conventional model using guideline-recommended variables and an extended echocardiographic model. Based on the final model a 12-point risk score was derived, indicating the association with the primary outcome within five years. During a median follow-up time of 4.2 years 74 patients died or underwent lung transplantation. The conventional model resulted in a C-Index of 0.539, whereas the extended echocardiographic model improved the discrimination (C-index 0.639, p -value 0.017). Ultimately, the newly developed risk score included WHO functional class, 6-min walking distance, N-terminal brain natriuretic peptide concentrations, pericardial effusion, right atrial area, tricuspid annular plane systolic excursion, and fractional area change., Conclusion: Integrating right heart function assessed by echocardiography improves prediction of death or lung transplantation in PAH patients. Independent validation of this finding is warranted.

Aims: Heart failure with preserved ejection fraction (HFpEF) is common in patients presenting with dyspnoea. Recently, clinical tools were developed to facilitate the diagnosis of HFpEF. Here, we apply the European Society of Cardiology (ESC) 2016 heart failure guidelines and the H 2 FPEF and HFA-PEFF scores to a middle-aged sample of the general population and compared the different groups with each other., Methods and Results: This study included the first 10 000 participants of the population-based Hamburg City Health Study. A total of 5613 subjects, aged 62 ± 8.7 years (51.1% women), qualified for the analysis. Unexplained dyspnoea was present in 407 (7.3%) subjects. In those, the estimated prevalence of HFpEF was 20.4% (ESC 2016), 12.3% (H 2 FPEF), and 7.6% (HFA-PEFF). The majority of subjects was classified as HFpEF not excludable according to the HFA-PEFF (57.7%) and H 2 FPEF (59.2%) scores. For all algorithms, subjects diagnosed with HFpEF showed elevated age and body mass index as well as a higher prevalence of atrial fibrillation, diabetes, and arterial hypertension compared with those without HFpEF or HFpEF not excludable. The distribution of those co-morbidities and risk factors varied between the differently diagnosed HFpEF groups with the highest burden in the HFpEF group defined by the H 2 FPEF score. The overlap of subjects diagnosed with HFpEF according to the different algorithms was very limited., Conclusions: Unexplained dyspnoea is common in the middle-aged general population. The ESC 2016 algorithm and the H 2 FPEF and HFA-PEFF scores detect different, discordant subpopulations of probands with breathlessness. Further classification of the HFpEF syndrome is desirable., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Even on optimal therapy, many patients with heart failure and atrial fibrillation experience cardiovascular complications. Additional treatments are needed to reduce these events, especially in patients with heart failure and preserved left ventricular ejection fraction., Methods: This prespecified subanalysis of the randomized EAST-AFNET4 trial (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial) assessed the effect of systematic, early rhythm control therapy (ERC; using antiarrhythmic drugs or catheter ablation) compared with usual care (allowing rhythm control therapy to improve symptoms) on the 2 primary outcomes of the trial and on selected secondary outcomes in patients with heart failure, defined as heart failure symptoms New York Heart Association II to III or left ventricular ejection fraction [LVEF] <50%., Results: This analysis included 798 patients (300 [37.6%] female, median age 71.0 [64.0, 76.0] years, 785 with known LVEF). The majority of patients (n=442) had heart failure and preserved LVEF (LVEF≥50%; mean LVEF 61±6.3%), the others had heart failure with midrange ejection fraction (n=211; LVEF 40%-49%; mean LVEF 44 ± 2.9%) or heart failure with reduced ejection fraction (n=132; LVEF<40%; mean LVEF 31±5.5%). Over the 5.1-year median follow-up, the composite primary outcome of cardiovascular death, stroke, or hospitalization for worsening of heart failure or for acute coronary syndrome occurred less often in patients randomly assigned to ERC (94/396; 5.7 per 100 patient-years) compared with patients randomly assigned to usual care (130/402; 7.9 per 100 patient-years; hazard ratio, 0.74 [0.56-0.97]; P =0.03), not altered by heart failure status (interaction P value=0.63). The primary safety outcome (death, stroke, or serious adverse events related to rhythm control therapy) occurred in 71 of 396 (17.9%) patients with heart failure randomly assigned to ERC and in 87 of 402 (21.6%) patients with heart failure randomly assigned to usual care (hazard ratio, 0.85 [0.62-1.17]; P =0.33). LVEF improved in both groups (LVEF change at 2 years: ERC 5.3±11.6%, usual care 4.9±11.6%, P =0.43). ERC also improved the composite outcome of death or hospitalization for worsening of heart failure., Conclusions: Rhythm control therapy conveys clinical benefit when initiated within 1 year of diagnosing atrial fibrillation in patients with signs or symptoms of heart failure. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01288352. URL: http://www.controlled-trials.com; Unique identifier: ISRCTN04708680. URL: https://www.clinicaltrialsregister.eu; Unique identifier: 2010-021258-20.

Non-ischemic cardiomyopathy (NICM) is one of the most important entities for arrhythmias and sudden cardiac death (SCD). Previous studies suggest a lower benefit of implantable cardioverter-defibrillator (ICD) therapy in patients with NICM as compared to ischemic cardiomyopathy (ICM). Nevertheless, current guidelines do not differentiate between the two subgroups in recommending ICD implantation. Hence, risk stratification is required to determine the subgroup of patients with NICM who will likely benefit from ICD therapy. Various predictors have been proposed, among others genetic mutations, left-ventricular ejection fraction (LVEF), left-ventricular end-diastolic volume (LVEDD), and T-wave alternans (TWA). In addition to these parameters, cardiovascular magnetic resonance imaging (CMR) has the potential to further improve risk stratification. CMR allows the comprehensive analysis of cardiac function and myocardial tissue composition. A range of CMR parameters have been associated with SCD. Applicable examples include late gadolinium enhancement (LGE), T1 relaxation times, and myocardial strain. This review evaluates the epidemiological aspects of SCD in NICM, the role of CMR for risk stratification, and resulting indications for ICD implantation.

Aims: Differences between female and male patients in clinical presentation, causes and treatment of cardiogenic shock (CS) are poorly understood. We aimed to investigate sex differences in presentation with and treatment of CS., Methods and Results: We analysed data of 978 patients presenting with CS to a tertiary care hospital between October 2009 and October 2017. Multivariable adjusted logistic/Cox regression models were fitted to investigate the association between sex and clinical presentation, use of treatments and 30 day mortality. Median age was 70 years (interquartile range 58-79 years), and 295 (30.2%) patients were female. After adjustment for multiple relevant confounders, female patients were more likely to be older [odds ratio (OR) 1.21, 95% confidence interval (CI) 1.02-1.42, P = 0.027], but other relevant presentation characteristics did not differ between both sexes. Despite the similar presentation, female patients were less likely to be treated with percutaneous left ventricular assist devices (OR 0.78, 95% CI 0.64-0.94, P = 0.010), but more likely to be treated with catecholamines (OR 1.21, 95% CI 1.02-1.44, P = 0.033) or vasopressors (OR 1.26, 95% CI 1.05-1.50, P = 0.012). A 30 day mortality risk in female patients was as high as in male patients (hazard ratio 1.08, 95% CI 1.00-1.18, P = 0.091)., Conclusions: In this large, contemporary cohort, clinical presentation was comparable in female and male patients, and both sexes were associated with a comparably high mortality risk. Nevertheless, female patients received different treatment for CS and were most importantly less likely to be treated with percutaneous left ventricular assist devices., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Cardiac allograft vasculopathy (CAV) remains a major long-term complication in heart transplant (HT) recipients related to increased mortality. We aimed to identify non-immune recipient- and donor-related risk factors for the development of CAV in HT patients., Methods: 40,647 recipients, prospectively enrolled from April 1995 to January 2019 in the Organ Procurement and Transplantation Network (OPTN), were analyzed after exclusion of pediatric patients, those with missing information on CAV, and re-transplantation. Multivariable-adjusted Cox regression analyses were performed to identify recipient- and donor-related risk factors for CAV. 5-year population attributable risk for classical cardiovascular risk factors was calculated to estimate the recipients' CAV risk. Analyses were based on OPTN data (June 30, 2019)., Results: Of 40,647 post-transplant patients, 14,698 (36.2%) developed CAV with a higher incidence in males (37.3%) than in females (32.6%) (p < 0.001). The mean follow-up time was 68.2 months. In recipients, male sex, African American and Asian ethnicity, ischemic cardiomyopathy, body mass index and smoking were associated with CAV occurrence. In donors, older age, male sex, smoking, diabetes and arterial hypertension were related to CAV. Results remained fairly stable after analysis of different time periods. 5-year attributable CAV risk for classical cardiovascular risk factors was 9.1%., Conclusions: In this large registry with known limitations concerning data completeness, CAV incidence was higher in males than in females. Next to male sex and donor age, the classical cardiovascular risk factors were related to incident CAV. Classical cardiovascular risk factors played only a minor role for the 5-year attributable CAV risk., Competing Interests: Declaration of Competing Interest AMB has received honoraria from Abbott, Abiomed, AstraZeneca, BerlinHeart, Medtronic and Novartis (unrelated to the submitted work). BS has received speakers fee from AstraZeneca and Abiomed (unrelated to the submitted work). CM reports speaker fees from AstraZeneca, Novartis and Loewenstein Medical (unrelated to the current work). RBS has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme under the grant agreement No 648131, from the European Union’s Horizon 2020 research and innovation programme under the grant agreement No 847770 (AFFECT-EU) and German Center for Cardiovascular Research (DZHK e.V.) (81Z1710103); German Ministry of Research and Education (BMBF 01ZX1408A) and ERACoSysMed3 (031L0239)(unrelated to the submitted work). RSP has received honoraria from the Abiomed Advisory Board and the Medtronic Advisory Board (unrelated to the submitted work). SB has received received speaker fees from Medtronic, Pfizer, Roche, Novartis and Siemens Diagnostics (unrelated to the submitted work)., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aims: There is inconsistent evidence on the relation of alcohol intake with incident atrial fibrillation (AF), in particular at lower doses. We assessed the association between alcohol consumption, biomarkers, and incident AF across the spectrum of alcohol intake in European cohorts., Methods and Results: In a community-based pooled cohort, we followed 107 845 individuals for the association between alcohol consumption, including types of alcohol and drinking patterns, and incident AF. We collected information on classical cardiovascular risk factors and incident heart failure (HF) and measured the biomarkers N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin I. The median age of individuals was 47.8 years, 48.3% were men. The median alcohol consumption was 3 g/day. N = 5854 individuals developed AF (median follow-up time: 13.9 years). In a sex- and cohort-stratified Cox regression analysis alcohol consumption was non-linearly and positively associated with incident AF. The hazard ratio for one drink (12 g) per day was 1.16, 95% CI 1.11-1.22, P < 0.001. Associations were similar across types of alcohol. In contrast, alcohol consumption at lower doses was associated with reduced risk of incident HF. The association between alcohol consumption and incident AF was neither fully explained by cardiac biomarker concentrations nor by the occurrence of HF., Conclusions: In contrast to other cardiovascular diseases such as HF, even modest habitual alcohol intake of 1.2 drinks/day was associated with an increased risk of AF, which needs to be considered in AF prevention., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Meal timing may influence food choices, neurobiology and psychological states. Our exploratory study examined if time-of-day eating patterns were associated with mood disorders among adults., Methods: During 2004-2006 (age 26-36 years) and 2009-2011 (follow-up, age 31-41 years), N = 1304 participants reported 24-h food and beverage intake. Time-of-day eating patterns were derived by principal components analysis. At follow-up, the Composite International Diagnostic Interview measured lifetime mood disorder. Log binomial and adjacent categories log-link regression were used to examine bidirectional associations between eating patterns and mood disorder. Covariates included sex, age, marital status, social support, education, work schedule, body mass index and smoking., Results: Three patterns were derived at each time-point: Grazing (intake spread across the day), Traditional (highest intakes reflected breakfast, lunch and dinner), and Late (skipped/delayed breakfast with higher evening intakes). Compared to those in the lowest third of the respective pattern at baseline and follow-up, during the 5-year follow-up, those in the highest third of the Late pattern at both time-points had a higher prevalence of mood disorder [prevalence ratio (PR) = 2.04; 95% confidence interval (CI) 1.20-3.48], and those in the highest third of the Traditional pattern at both time-points had a lower prevalence of first onset mood disorder (PR = 0.31; 95% CI 0.11-0.87). Participants who experienced a mood disorder during follow-up had a 1.07 higher relative risk of being in a higher Late pattern score category at follow-up than those without mood disorder (95% CI 1.00-1.14)., Conclusions: Non-traditional eating patterns, particularly skipped or delayed breakfast, may be associated with mood disorders.

Background: The therapeutic success in patients with congenital heart disease (CHD) leads to a growing number of adults with CHD (adult CHD [ACHD]) who develop end-stage heart failure. We aimed to determine patient characteristics and outcomes of ACHD listed for heart transplantation., Methods: Using data from all the patients with ACHD in 20 transplant centers in the Eurotransplant region from 1999 to 2015, we analyzed patient characteristics, waiting list, and post-transplantation outcomes., Results: A total of 204 patients with ACHD were listed during the study period. The median age was 38 years, and 62.3% of the patients were listed in high urgency (HU), and 37.7% of the patients were in transplantable (T)-listing status. A total of 23.5% of the patients died or were delisted owing to clinical worsening, and 75% of the patients underwent transplantation. Median waiting time for patients with HU-listing status was 4.18 months and with T-listing status 9.07 months. There was no difference in crude mortality or delisting between patients who were HU status listed and T status listed (p = 0.65). In multivariable regression analysis, markers for respiratory failure (mechanical ventilation, hazard ratio [HR]: 1.41, 95% CI: 1.11-1.81, p = 0.006) and arrhythmias (anti-arrhythmic medication, HR: 1.42, 95% CI: 1.01-2.01, p = 0.044) were associated with a higher risk of death or delisting. In the overall cohort, post-transplantation mortality was 26.8% after 1 year and 33.4% after 5 years., Conclusions: Listed patients are at high risk of death without differences in the urgency of listing. Respiratory failure requiring invasive ventilation and possibly arrhythmias requiring anti-arrhythmic medication indicate worse outcomes on waiting list., (Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Aims: There is no gold standard to predict outcome in acute decompensated heart failure (ADHF). Several scores for mortality prediction of patients with ADHF have been developed and mostly consist of complex regression models. None of these models has been widely adopted by clinicians. The quick SOFA score (qSOFA) is a simple score including three parameters (systolic blood pressure ≤ 100 mmHg, respiratory rate ≥22 breathes/min, and GCS <15) and is validated for discrimination of mortality risk in septic patients. Here, we adapted qSOFA score to patients admitted to a Heart Failure Unit (HFU) and assessed the prognostic accuracy. Methods and Results: qSOFA, SOFA score, and SIRS criteria were assessed at admission. Clinical, laboratory, and echocardiographic parameters were recorded. A follow-up was performed 30 days after discharge. Primary outcome was all-cause mortality or readmission to hospital due do worsening of heart failure symptoms. Of 240 patients (73% male, 16-93 years), 25 patients (10%) had a qSOFA ≥2 points and 126 patients (53%) fulfilled none of qSOFA criteria. Within 30 days, the primary endpoint occurred in 46 patients (19%). Seventeen patients (7%) died and 34 patients (14%) were readmitted to hospital due to worsening heart failure. Patients with qSOFA ≥2 reached this endpoint more frequently (48 vs. 19%, p = 0.002), had more often dyspnea NYHA III-IV (OR 2.4, p = 0.005) and a higher risk for multi organ failure during hospital stay (28 vs. 9%, P = 0.005). Conclusions: qSOFA is useful to identify patients with heart failure at high risk for worse outcome and to operationalize severity of decompensation., (Copyright © 2020 Wagner, Sinning, Haumann, Magnussen, Blankenberg, Reichenspurner and Grahn.)

Background and Purpose: Stroke is a common cause of death and a leading cause of disability and morbidity. Stroke risk assessment remains a challenge, but circulating biomarkers may improve risk prediction. Controversial evidence is available on the predictive ability of troponin concentrations and the risk of stroke in the community. Furthermore, reports on the predictive value of troponin concentrations for different stroke subtypes are scarce., Methods: High-sensitivity cardiac troponin I (hsTnI) concentrations were assessed in 82 881 individuals (median age, 50.7 years; 49.7% men) free of stroke or myocardial infarction at baseline from 9 prospective European community cohorts. We used Cox proportional hazards regression to determine relative risks, followed by measures of discrimination and reclassification using 10-fold cross-validation to control for overoptimism. Follow-up was based upon linkage with national hospitalization registries and causes of death registries., Results: Over a median follow-up of 12.7 years, 3033 individuals were diagnosed with incident nonfatal or fatal stroke (n=1654 ischemic strokes, n=612 hemorrhagic strokes, and n=767 indeterminate strokes). In multivariable regression models, hsTnI concentrations were associated with overall stroke (hazard ratio per 1-SD increase, 1.15 [95% CI, 1.10-1.21]), ischemic stroke (hazard ratio, 1.14 [95% CI, 1.09-1.21]), and hemorrhagic stroke (hazard ratio, 1.10 [95% CI, 1.01-1.20]). Adding hsTnI concentrations to classical cardiovascular risk factors (C indices, 0.809, 0.840, and 0.736 for overall, ischemic, and hemorrhagic stroke, respectively) increased the C index significantly but modestly. In individuals with an intermediate 10-year risk (5%-20%), the net reclassification improvement for overall stroke was 0.038 ( P =0.021)., Conclusions: Elevated hsTnI concentrations are associated with an increased risk of incident stroke in the community, irrespective of stroke subtype. Adding hsTnI concentrations to classical risk factors only modestly improved estimation of 10-year risk of stroke in the overall cohort but might be of some value in individuals at an intermediate risk.

Background: We aimed to investigate changes of incidence, outcome and related interventions of patients with acute coronary syndrome (ACS) over the past decade in Germany., Methods: Data on the international statistical classification of diseases and procedural codes from the Federal Bureau of Statistics in Germany was used. This included all ACS cases in Germany in the years 2005-2015. Analyses were performed separately for the diagnoses of overall ACS, ST-elevation myocardial infarction (MI), non-ST-elevation MI and unstable angina pectoris. Procedures including coronary angiography and percutaneous coronary intervention and the endpoint in-hospital mortality were assessed., Results: Between 2005 and 2015 a total of 3797,546 cases of ACS were recorded. The mean age was 69 years and 36% were females. In-hospital mortality was 6.3%, 62% underwent coronary angiography and 42% received percutaneous coronary intervention. In-hospital mortality was highest for patients with ST-elevation MI (12.0%) and lowest for patients with unstable angina pectoris (0.6%). From 2005 to 2015 the incidence rates of ACS, ST-elevation MI and unstable angina pectoris decreased, while the incidence rate of non-ST-elevation MI increased. The percentages of performed coronary angiographies and percutaneous coronary interventions increased from 52 to 70% and 34 to 50%, respectively. The adjusted incidence rate of in-hospital mortality decreased from 64.9 cases per 1000 person-years to 54.8 cases., Conclusion: In a large dataset including more than 3.7 million cases, we report an increase in coronary procedures and a reduction of ACS incidence and related mortality in the past decade in Germany.

Sex differences in patients with acute coronary syndrome (ACS) are a matter of debate. We investigated sex-specific differences in the incidence, outcomes, and related interventions in patients diagnosed with ACS in Germany over the past decade. All ACS cases from 2005 to 2015 were collected. Procedures and inhospital mortality were assessed by sex. Age-adjusted incidence rates were calculated. In total, 1,366,045 females and 2,431,501 males presenting with ACS were recorded. Females were older than males (73.1 vs. 66.4 years of age), had a longer mean hospital stay (7.7 vs. 6.9 days), and less frequently underwent coronary angiographies (55% vs. 66%) and coronary interventions (35% vs. 47%). The age-adjusted incidence rate of ACS was lower in females than in males, and decreased in both sexes from 2005 to 2015. The age-adjusted inhospital mortality rate was substantially higher in females than in males, but decreased in both sexes over time (in females, from 87 to 71 cases per 1000 person years; in males, from 57 to 51 cases per 1000 person years). In conclusion, we reported sex differences in the incidence, treatment, and outcomes of ACS patients in Germany within the past decade. Women had a substantially higher mortality rate and lower rate of coronary interventions.

Background: Right heart failure (RHF) after left ventricular assist device (LVAD) implantation is common and associated with worse outcome. Prediction of RHF remains challenging. Our study aims to assess predictors of RHF focusing on clinical manifestations., Methods: We retrospectively analyzed clinical, echocardiographic and hemodynamic parameters of 112 patients undergoing LVAD implantation. Pre-operative, early (ERHF, day 7 and 14) and late postoperative RHF (LRHF, after 1, 3, 6 and 12 months) were assessed., Results: In the total study population (87.5% men, mean age 55 years), early RHF was frequent (47% on day 7 and 30% on day 14). Prevalence of late RHF and death from RHF was high after 3, 6 and 12 months (23, 24 and 17%). Pre-existing RHF was only associated with early RHF and persistent, but not for new onset late RHF. Early RHF was associated with lower INTERMACS level (p < 0.001), higher pulmonary vascular resistance (p = 0.046) and CVP/PAWP quotient (p = 0.011), higher bilirubin (p = 0.038) and creatinine (p = 0.013). LRHF was associated with creatinine (p = 0.006), urea (p = 0.012) and load adaption index (p = 0.007). Binary logistic regression models identified no single risk factors. Comparing the predictive value of regression models with a model of three clinical findings (INTERMACS level, age and pre-operative RHF) did not reveal differences in RHF., Conclusions: RHF before LVAD implantation enhances the risk of early RHF and persistent late RHF, but not for new onset late RHF, supporting the hypothesis of differences in the etiology. Echocardiographic or hemodynamic parameters did not show a predictive value for new onset late RHF. Similar predictive value of clinical findings and statistic models of risk factors suggest that a clinical evaluation is equally matched to predict RHF.

Background Differences in risk factors for atrial fibrillation (AF) and heart failure (HF) are incompletely understood. Aim of this study was to understand whether risk factors and biomarkers show different associations with incident AF and HF and to investigate predictors of subsequent onset and mortality. Methods and Results In N=58 693 individuals free of AF/HF from 5 population-based European cohorts, Cox regressions were used to find predictors for AF, HF, subsequent onset, and mortality. Differences between associations were estimated using bootstrapping. Median follow-up time was 13.8 years, with a mortality of 15.7%. AF and HF occurred in 5.0% and 5.4% of the participants, respectively, with 1.8% showing subsequent onset. Age, male sex, myocardial infarction, body mass index, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) showed similar associations with both diseases. Antihypertensive medication and smoking were stronger predictors of HF than AF. Cholesterol, diabetes mellitus, and hsCRP (high-sensitivity C-reactive protein) were associated with HF, but not with AF. No variable was exclusively associated with AF. Population-attributable risks were higher for HF (75.6%) than for AF (30.9%). Age, male sex, body mass index, diabetes mellitus, and NT-proBNP were associated with subsequent onset, which was associated with the highest all-cause mortality risk. Conclusions Common risk factors and biomarkers showed different associations with AF and HF, and explained a higher proportion of HF than AF risk. As the subsequent onset of both diseases was strongly associated with mortality, prevention needs to be rigorously addressed and remains challenging, as conventional risk factors explained only 31% of AF risk.

Objectives: The aims of this study were to characterize the association of high-sensitivity cardiac troponin I (hs-cTnI) with heart failure (HF), to determine its predictive value beyond classical cardiovascular risk factors (CVRFs) and N-terminal pro-B-type natriuretic peptide, and to derive a relevant cutoff for potential clinical application., Background: HF is an important contributor to the overall burden of cardiovascular disease. Early identification of individuals at risk could be beneficial for preventive therapies., Methods: Based on the Biomarker for Cardiovascular Risk Assessment in Europe consortium, we analyzed individual-level data from 4 prospective population-based cohort studies including 48,455 individuals. Participants with myocardial infarction, HF, and stroke at baseline were excluded. We investigated the value of adding hs-cTnI to CVRFs and N-terminal pro-B-type natriuretic peptide using Cox proportional hazards survival models and for prediction by calculating C-statistics and Brier score., Results: The median age of the study population was 51 years, and the median follow-up time for occurrence of HF was 6.61 years. Cox regression models adjusted for age, sex, and CVRFs revealed a significant association of hs-cTnI with incident HF (hazard ratio: 1.42 per log [ng/l] unit change [95% confidence interval: 1.31 to 1.53]). The best predictive value was achieved in the model with CVRFs (base model) and both biomarkers (C-index = 0.862; 95% confidence interval: 0.841 to 0.882). Optimal hs-cTnI cutoff values of 2.6 ng/l for women and 4.2 ng/l for men were derived for selecting individuals at risk., Conclusions: In this large dataset from the general population, hs-cTnI could show its independence for the prognosis of HF., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: To determine the interplay between sleep and sedentary behaviours on body mass index (BMI) in children with obesity., Methods: Cross-sectional study of 343 children with obesity aged 4-17 years, from a tertiary care weight management clinic in Melbourne, Victoria, Australia. Multifaceted data relating to activity and sleep from child and parent questionnaires analysed with anthropometric data collected during routine clinical care. Associations between sleep duration and activity measures were examined via regression models with adjustment for potential confounders., Results: Higher BMI was associated with more hours spent watching television (P = 0.04), as well as less reported enjoyment of physical activity (P = 0.005) and less time spent in organised sport activity (P = 0.005). Higher BMI was also associated with higher levels of obstructive sleep apnoea (P = 0.002). Less time in bed was associated with higher levels of BMI (P = 0.03) but analysis by sex revealed this association to only hold for males. In the whole group, a significant television and sleep interaction was seen, such that increasing television watching was associated with higher BMI, but only in those with shortest sleep duration., Conclusions: Both poor sleep and increasing screen time (including television viewing, smart-phone use, internet use or video-gaming) appear to impact BMI in children with obesity, with a particular detrimental effect of television viewing in those who sleep less. Efforts to improve sleep time and quality in children may minimise negative effects of screen time on increasing BMI and should be included in public health strategies to combat obesity in childhood., (© 2019 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Aims: Limited evidence is available on the temporal relationship between atrial fibrillation (AF) and ischaemic stroke and their impact on mortality in the community. We sought to understand the temporal relationship of AF and ischaemic stroke and to determine the sequence of disease onset in relation to mortality., Methods and Results: Across five prospective community cohorts of the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) project we assessed baseline cardiovascular risk factors in 100 132 individuals, median age 46.1 (25th-75th percentile 35.8-57.5) years, 48.4% men. We followed them for incident ischaemic stroke and AF and determined the relation of subsequent disease diagnosis with overall mortality. Over a median follow-up of 16.1 years, N = 4555 individuals were diagnosed solely with AF, N = 2269 had an ischaemic stroke but no AF diagnosed, and N = 898 developed both, ischaemic stroke and AF. Temporal relationships showed a clustering of diagnosis of both diseases within the years around the diagnosis of the other disease. In multivariable-adjusted Cox regression analyses with time-dependent covariates subsequent diagnosis of AF after ischaemic stroke was associated with increased mortality [hazard ratio (HR) 4.05, 95% confidence interval (CI) 2.17-7.54; P < 0.001] which was also apparent when ischaemic stroke followed after the diagnosis of AF (HR 3.08, 95% CI 1.90-5.00; P < 0.001)., Conclusion: The temporal relations of ischaemic stroke and AF appear to be bidirectional. Ischaemic stroke may precede detection of AF by years. The subsequent diagnosis of both diseases significantly increases mortality risk. Future research needs to investigate the common underlying systemic disease processes., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Dilated cardiomyopathy (DCM) is characterized by left ventricular dilatation and, consecutively, contractile dysfunction. The causes of DCM are heterogeneous. DCM often results from myocarditis, exposure to alcohol, drugs or other toxins and metabolic or endocrine disturbances. In about 35% of patients, genetic mutations can be identified that usually involve genes responsible for cytoskeletal, sarcomere and nuclear envelope proteins. Due to its heterogeneity, a detailed diagnostic work-up is necessary to identify the specific underlying cause and exclude other conditions with phenotype overlap. Patients with DCM show typical systolic heart failure symptoms, but, with progress of the disease, diastolic dysfunction is present as well. Depending on the underlying pathology, DCM patients also become apparent through arrhythmias, thromboembolic events or cardiogenic shock. Disease progression and prognosis are mostly driven by disease severity and reverse remodelling within the heart. The worst prognosis is seen in patients with lowest ejection fractions or severe diastolic dysfunction, leading to terminal heart failure with subsequent need for left ventricular assist device implantation or heart transplantation. Guideline-based heart failure medication and device therapy reduces the frequency of heart failure hospitalizations and improves survival., (© 2019 The Association for the Publication of the Journal of Internal Medicine.)

Background: Sex differences in panel-reactive antibody (PRA) levels in heart transplant recipients and their association with transplant-related outcomes are mostly unknown., Methods: In 20 181 (24.7% women) first-time heart transplant recipients included from July 2004 to March 2015 in the prospective Organ Procurement and Transplantation Network (OPTN), we studied sex differences in most recent (mr) and peak (p)PRA and outcomes (graft failure, rejection, cardiac allograft vasculopathy [CAV], retransplantation, and mortality). Median follow-up (all-cause mortality) was 6 years. Analyses are based on OPTN data (March 6, 2017)., Results: MrPRA levels were associated with all-cause mortality (hazard ratio, 95% confidence interval: class I 1.03, 1.01-1.04, P < 0.001) and acute rejection (class II 1.08, 1.03-1.14, P = 0.0044). PPRA levels were associated with all-cause mortality (class I 1.02, 1.00-1.04, P = 0.015) and CAV (class II 1.03, 1.01-1.06, P = 0.020). Sex interactions were seen for the association of pPRA and graft failure with a higher risk in women, and for pPRA and CAV with a higher risk in men., Conclusions: PRA were associated with different transplant-related outcomes in both sexes. However, women with elevated pPRA were shown to be at higher risk for graft failure, whereas higher levels of pPRA were more hazardous for men in developing CAV., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: This study investigates differences between women and men in heart failure (HF) risk and mortality., Background: Sex differences in HF epidemiology are insufficiently understood., Methods: In 78,657 individuals (median 49.5 years of age; age range 24.1 to 98.7 years; 51.7% women) from community-based European studies (FINRISK, DanMONICA, Moli-sani, Northern Sweden) of the BiomarCaRE (Biomarker for Cardiovascular Risk Assessment in Europe) consortium, the association between incident HF and mortality, the relationship of cardiovascular risk factors, prevalent cardiovascular diseases, biomarkers (C-reactive protein [CRP]; N-terminal pro-B-type natriuretic peptide [NT-proBNP]) with incident HF, and their attributable risks were tested in women vs. men., Results: Over a median follow-up of 12.7 years, fewer HF cases were observed in women (n = 2,399 [5.9%]) than in men (n = 2,771 [7.3%]). HF incidence increased markedly after 60 years of age, initially with a more rapid increase in men, whereas incidence in women exceeded that of men after 85 years of age. HF onset substantially increased mortality risk in both sexes. Multivariable-adjusted Cox models showed the following sex differences for the association with incident HF: systolic blood pressure hazard ratio (HR) according to SD in women of 1.09 (95% confidence interval [CI]: 1.05 to 1.14) versus HR of 1.19 (95% CI: 1.14 to 1.24) in men; heart rate HR of 0.98 (95% CI: 0.93 to 1.03) in women versus HR of 1.09 (95% CI: 1.04 to 1.13) in men; CRP HR of 1.10 (95% CI: 1.00 to 1.20) in women versus HR of 1.32 (95% CI: 1.24 to 1.41) in men; and NT-proBNP HR of 1.54 (95% CI: 1.37 to 1.74) in women versus HR of 1.89 (95% CI: 1.75 to 2.05) in men. Population-attributable risk of all risk factors combined was 59.0% in women and 62.9% in men., Conclusions: Women had a lower risk for HF than men. Sex differences were seen for systolic blood pressure, heart rate, CRP, and NT-proBNP, with a lower HF risk in women., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

A single clinic measurement of blood pressure (BP) may be common in low- and middle-income countries because of limited medical resources. This study aimed to examine the potential misclassification error when only one BP measurement is used. Participants (n = 14,706, 53.5% females) aged 25-64 years were selected by multistage stratified cluster sampling from eight provinces, each representing one of the eight geographical regions of Vietnam. Measurements were made using the World Health Organization STEPS protocols. Data were analyzed using complex survey methods. For systolic BP, 62.7% had a higher first reading whereas 30.0% had a lower first reading, and 27.3% had a reduction of at least 5 mmHg whereas 9.6% had an increase of at least 5 mmHg. Irrespective of direction of change, increased variability in BP was associated with greater age, urban living, greater body size and fatness, reduced physical activity levels, elevated glucose, and raised total cholesterol. These measurement variations would lead to substantial misclassification in diagnosis of hypertension based on a single reading because almost 20% of subjects would receive a different diagnosis based on the mean of two readings., (Copyright © 2018 American Heart Association. Published by Elsevier Inc. All rights reserved.)

Sex differences in cardiovascular risk factors, cardiac structure and function, and disease and symptom burden in the common arrhythmia atrial fibrillation (AF) have not been investigated systematically at the population level. Cross-sectional data of 14,796 subjects (age range 35 to 74 years, 50.5% men) from the population-based Gutenberg Health Study were examined to show the distribution of cardiovascular risk factors by AF status and sex, and to determine sex-specific predictors for AF. The prevalence of AF was higher in men (4.3%) than in women (1.9%). Men had a worse cardiovascular risk factor profile, a higher prevalence of cardiovascular disease, but fewer symptoms than women. Age-adjusted Cox regressions showed sex interactions in the association of high-density lipoprotein-cholesterol, triglycerides, diabetes mellitus, coronary artery disease, myocardial infarction, generalized anxiety disorder, and heart rate with AF. After multivariable adjustment, sex interactions were seen for thickness of interventricular end-diastolic septum, odds ratio (OR) per standard deviation (SD), 95% confidence interval women: 0.9 (0.8, 1.1), men: 1.2 (1.1, 1.4), interaction p value = 0.02; left atrial diameter index, OR per SD women: 1.5 (1.3, 1.8), men: 1.9 (1.7, 2.1), interaction p value = 0.03; and myocardial infarction, OR women: 2.7 (1.3, 5.6), men: 0.7 (0.5, 1.1), interaction p value = 0.002. In conclusion, in our large cohort, we observed substantial sex differences in AF distribution and clinical characteristics including comorbidities, symptom burden, and structural cardiac changes., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Heart failure (HF) is a rising epidemic due to the ageing population and progress in all areas of medicine. Thus, research efforts are made to ensure a timely diagnosis, to improve prognosis and treatment of the disease and to facilitate risk prediction at the population level. Because of their noninvasive determination with mostly high sensitivity and accuracy, circulating blood biomarkers are becoming increasingly important for daily clinical practice. Natriuretic peptides, especially B-type natriuretic peptide (BNP), N-terminal pro-B-type natriuretic peptide (Nt-proBNP) and midregional pro-atrial natriuretic peptide (MR-proANP) and cardiac troponins are established blood biomarkers in HF diagnosis and prognosis of HF-related outcomes. Inflammatory molecules as C-reactive protein (CRP) may have added value in anti-inflammatory therapy guidance. Next-generation biomarkers including soluble source of tumorigenicity 2 (sST2), growth differentiation factor-15 (GDF-15), galectin-3 (Gal-3) and diverse microribonucleic acids (miRNAs) may have additional benefit in assessment of cardiac remodeling or differentiation of HF subtypes. Multimarker approaches containing different combinations of established and novel biomarkers might improve HF risk prediction at the population level once they are used on top of clinical variables., (© 2018 The Association for the Publication of the Journal of Internal Medicine.)

Background: Waist circumference (WC) is an indicator of intra-abdominal adipose tissue, high levels of which confer an increased risk of cardiometabolic disease. Population data on WC should be more informative than data on body mass index (BMI), which is a general indicator of body size. This study aimed to evaluate the importance of WC relative to BMI in cross-sectional relationships with blood pressure (BP), glucose, and total cholesterol (TC) in the adult population of Vietnam., Methods: The data were collected in a population-based survey conducted during 2009-10 using the "WHO STEPwise approach to surveillance of risk factors for non-communicable disease" (STEPS) methodology. The survey participants (n = 14 706 aged 25 to 64 years) were selected by multi-stage stratified cluster sampling from eight provinces representative of the eight geographical regions of Vietnam. All measurements were performed in accordance with the STEPS protocols. All analyses were performed using complex survey methods., Results: The measurements of WC and BMI were highly correlated (men r = 0.80, women r = 0.77). For men, the strongest and predominant associations with BP, glucose, and TC were for WC or an index based on WC. For women, this was true for glucose but BMI was more important for BP and TC. WC or an index based on WC provided better discrimination than BMI of hypertension and elevated glucose, and of raised TC for men. Information on four new anthropometric indices did not improve model fit or subject discrimination., Conclusion: For BP/hypertension, glucose/elevated glucose, and TC/raised TC, WC was more informative than BMI for Vietnamese men, but both WC and BMI were important for Vietnamese women. Both WC and BMI need to be assessed for estimation of CVD risk in Vietnam., Competing Interests: The authors have declared that no competing interests exist.

Background: The atypical presentation of women with acute coronary syndrome (ACS) has been related to delayed diagnosis and treatment, which may explain worse outcome compared with men., Methods and Results: We analyzed pooled data of 2520 patients of 2 prospective cohorts in terms of differences in presentation and management of women and men suggestive of ACS. Using logistic regression, we established 2 diagnostic models and tested their diagnostic performance in both sexes separately. Sex-specific differences in management of patients with ACS were ascertained and a 2-year follow-up was performed. Women were older than men (median 67 versus 61 years, P =0.001), had more often dyspnea (22% versus 18%, P =0.024), nausea or vomiting (26% versus 16%, P =0.001) and radiating chest pain (47% versus 40%, P =0.001). Classical risk factors (smoking, diabetes mellitus, dyslipidemia or known coronary artery disease) were less frequent in women. Diagnostic models showed no significant sex-related differences in diagnostic performance in a "first contact" setting (medical history and symptoms) or after "complete triage" (including ECG and biomarkers). Women with ACS underwent coronary angiography (73.8% versus 84.3%, P <0.001) and revascularization (53.8% versus 70.1%, P <0.001) less frequently. Two-year incidence of myocardial infarction and death was similar in both sexes, but revascularization and cardiac rehospitalization were more frequent in men., Conclusions: In a large cohort of patients with suspected ACS, sex differences in clinical presentation did not impair diagnostic accuracy. Two-year outcomes were comparable. Our findings suggest a benefit of chest pain units to minimize sex differences in ACS management and prognosis., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT02355457 (BACC), NCT03227159 (stenoCardia)., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: Right ventricular (RV) dysfunction is a major prognostic predictor in pulmonary arterial hypertension (PAH)., Objectives: The objective of this study was to assess the prognostic impact of a newly developed index merging haemodynamic parameters into 1 variable., Methods: We retrospectively assessed 2 cohorts of 248 patients (164 from Hamburg and 84 from Heidelberg) with invasively diagnosed PAH. During a median follow-up time of 3.6 years (3.1 and 4.0 years for Hamburg and Heidelberg, respectively), the composite endpoint of all-cause mortality and lung transplantation occurred in 57 patients (53 and 4 patients for Hamburg and Heidelberg, respectively). The RV index was developed in the Hamburg cohort and validated in the Heidelberg cohort: (right atrial pressure × pulmonary vascular resistance)/mixed venous oxygen saturation., Results: Patients with a high RV index had a higher incidence of the combined endpoint in Kaplan-Meier analyses in the Hamburg and Heidelberg cohort (p = 0.017 and p = 0.034, respectively). The calculated RV index cut-off value was 91 and identified patients with a worse outcome in the Hamburg cohort and showed a trend in the Heidelberg cohort (p < 0.001 and p = 0.089, respectively). The RV index in Cox regression hazard models was an independent predictor of outcomes after adjustment for sex and age in both cohorts (Hamburg: hazard ratio [HR] 1.26 [95% CI 1.08, 1.47], p = 0.0027; Heidelberg: HR 2.27 [95% CI 1.46, 3.51], p < 0.001). A nomogram based on these results allowed risk stratification., Conclusion: Merging 3 haemodynamic variables into 1 variable, the RV index increased the prognostic power up to an independent risk factor. The RV index is easy to calculate and allows the construction of a nomogram for an individualized risk assessment., (© 2018 S. Karger AG, Basel.)

Background: Despite the increasing use of ventricular assist devices (VADs), gender differences in indications, hemodynamics, and outcome are not well understood. We examined gender differences and gender-specific predictors for perioperative outcome in patients on ventricular support., Methods: Multicenter data of 966 patients (median age 55 years, 151 women) from the European Registry for Patients with Mechanical Circulatory Support (EUROMACS) were analyzed. Median follow-up was 1.26 years., Results: At the time of VAD implantation, women were more often in an unstable condition (Interagency Registry for Mechanically Assisted Circulatory Support [INTERMACS] profile 1 and 2) (51.7% vs 41.6% in men), experiencing significantly more often major bleeding (p = 0.0012), arrhythmias (p = 0.022), and right ventricular (RV) failure (p < 0.001) with need for additional RV support. The survival of women on isolated LVAD support was significantly worse (1-year survival 75.5% vs 83.2% in men). Age-adjusted Cox regression analyses showed significant associations with mortality for preoperative inotropic therapy, percutaneous mechanical support, INTERMACS profile 1 and 2, RV dysfunction, major bleeding, cerebral bleeding, ischemic stroke, and RV failure. In women, pump thrombosis was more strongly related with mortality compared to men, while the direction of the association of renal dysfunction with mortality was different for women and men (p-value interaction 0.028 and 0.023, respectively)., Conclusions: Women and men differ in perioperative hemodynamics, adverse events, and mortality after VAD implantation. A gender-dependent association of pump thrombosis with mortality was seen. The impact on treatment practice needs to be shown., (Copyright © 2018 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Atrial fibrillation (AF) is a common cardiac disease in aging populations with high comorbidity and mortality. Sex differences in AF epidemiology are insufficiently understood., Methods: In N=79 793 individuals without AF diagnosis at baseline (median age, 49.6 years; age range, 24.1-97.6 years; 51.7% women) from 4 community-based European studies (FINRISK, DanMONICA, Moli-sani Northern Sweden) of the BiomarCaRE consortium (Biomarker for Cardiovascular Risk Assessment in Europe), we examined AF incidence, its association with mortality, common risk factors, biomarkers, and prevalent cardiovascular disease, and their attributable risk by sex. Median follow-up time was 12.6 (to a maximum of 28.2) years., Results: Fewer AF cases were observed in women (N=1796; 4.4%), than in men (N=2465; 6.4%). Cardiovascular risk factor distribution and lipid profile at baseline were less beneficial in men than in women, and cardiovascular disease was more prevalent in men. Cumulative incidence increased markedly after the age of 50 years in men and after 60 years in women. The lifetime risk was similar (>30%) for both sexes. Subjects with incident AF had a 3.5-fold risk of death in comparison with those without AF. Multivariable-adjusted models showed sex differences for the association of body mass index and AF (hazard ratio per standard deviation increase, 1.18; 95% confidence interval [CI], 1.12-1.23 in women versus 1.31; 95% CI 1.25-1.38 in men; interaction P value of 0.001). Total cholesterol was inversely associated with incident AF with a greater risk reduction in women (hazard ratio per SD, 0.86; 95% CI, 0.81-0.90 versus 0.92; 95% CI, 0.88-0.97 in men; interaction P value of 0.023). No sex differences were seen for C-reactive protein and N-terminal pro B-type natriuretic peptide. The population-attributable risk of all risk factors combined was 41.9% in women and 46.0% in men. About 20% of the risk was observed for body mass index., Conclusions: Lifetime risk of AF was high, and AF was strongly associated with increased mortality both in women and men. Body mass index explained the largest proportion of AF risk. Observed sex differences in the association of body mass index and total cholesterol with AF need to be evaluated for underlying pathophysiology and relevance to sex-specific prevention strategies., (© 2017 American Heart Association, Inc.)

Background: Lung function has previously been related to increased mortality. Whether pulmonary impairment is associated with an increased mortality independent of cardiac dysfunction remains unclear., Methods: In 15010 individuals from the general population (age range 35-74years, 51% men) in the Gutenberg Health Study we performed spirometry and transthoracic echocardiography. N-terminal pro-B-type natriuretic peptide (Nt-proBNP) and high-sensitive troponin I (hsTnI) were measured in all individuals. 1819 individuals with pulmonary diseases were excluded from further analysis., Results: The median for forced expiratory volume in 1s (FEV1) was 94.2% and for forced vital capacity (FVC) 94.2% as a percentage of their predicted values. The median FEV1/FVC ratio was 79.1%. In 13191 subjects, 335 deaths were verified from death certificate over a median follow-up of 5.5years. Multivariable-adjusted Cox regression analyses for common cardiovascular risk factors and heart failure revealed that an increase of one standard deviation (SD) of percent predicted (%pred.) FEV1 was associated with a 22% risk reduction (hazard ratio [HR] per SD 0.78 [95% confidence interval (CI): 0.70, 0.86]). The association remained statistically significant after additional adjustment for diastolic dysfunction, Nt-proBNP or hsTnI. Comparable results were seen for %pred. FVC. After adjustment, no association of FEV1/FVC ratio with mortality could be shown. No significant interaction by heart failure was observed., Conclusions: The lung function parameters FEV1 and FVC, but not FEV1/FVC ratio, were related to all-cause mortality in individuals from the general population independent of cardiac function., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: The objective of this study was to examine whether childhood cardiorespiratory fitness attenuates or modifies the long-term cardiometabolic risks associated with childhood obesity., Design and Methods: The study consisted of a 20-year follow-up of 1792 adults who participated in the 1985 Australian Schools Health and Fitness Survey when they were 7-15 years of age. Baseline measures included a 1.6-km run to assess cardiorespiratory fitness and waist circumference to assess abdominal adiposity. At follow-up, participants attended study clinics where indicators of Metabolic Syndrome (MetS) (waist circumference, blood pressure, fasting blood glucose and lipids) were measured and cardiorespiratory fitness was reassessed using a submaximal graded exercise test., Results: Both high waist circumference and low cardiorespiratory fitness in childhood were significant independent predictors of MetS in early adulthood. The mutually adjusted relative risk of adult MetS was 3.00 (95% confidence interval: 1.85-4.89) for children in the highest (vs lowest) third of waist circumference and 0.64 (95% confidence interval: 0.43-0.96) for children with high (vs low) cardiorespiratory fitness. No significant interaction between waist circumference and fitness was observed, with higher levels of childhood fitness associated with lower risks of adult MetS among those with either low or high childhood waist circumference values. Participants who had both high waist circumference and low cardiorespiratory fitness in childhood were 8.5 times more likely to have MetS in adulthood than those who had low waist circumference and high cardiorespiratory fitness in childhood. Regardless of childhood obesity status, participants with low childhood fitness who increased their relative fitness by adulthood had a substantially lower prevalence of MetS than those who remained low fit., Conclusions: Childhood waist circumference and cardiorespiratory fitness are both strongly associated with cardiometabolic health in later life. Higher levels of cardiorespiratory fitness substantially reduce the risk of adult MetS, even among those with abdominal obesity in childhood.

Osteogenesis imperfecta (OI) is a congenital disorder caused most often by dominant mutations in the COL1A1 or COL1A2 genes that encode the alpha chains of type I collagen. Severe forms of OI are associated with skeletal deformities and frequent fractures. Skeletal pain can occur acutely after fracture, but also arises chronically without preceding fractures. In this study we assessed OI-associated pain in the Col1a1Jrt/+ mouse, a recently developed model of severe dominant OI. Similar to severe OI in humans, this mouse has significant skeletal abnormalities and develops spontaneous fractures, joint dislocations and vertebral deformities. In this model, we investigated behavioral measures of pain and functional impairment. Significant hypersensitivity to mechanical, heat and cold stimuli, assessed by von Frey filaments, radiant heat paw withdrawal and the acetone tests, respectively, were observed in OI compared to control wildtype littermates. OI mice also displayed reduced motor activity in the running wheel and open field assays. Immunocytochemical analysis revealed no changes between OI and WT mice in innervation of the glabrous skin of the hindpaw or in expression of the pain-related neuropeptide calcitonin gene-related protein in sensory neurons. In contrast, increased sensitivity to mechanical and cold stimulation strongly correlated with the extent of skeletal deformities in OI mice. Thus, we demonstrated that the Col1a1Jrt/+ mouse model of severe OI has hypersensitivity to mechanical and thermal stimuli, consistent with a state of chronic pain., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background/objectives: Adenovirus-36 (Adv-36) infection is associated with exaggerated adipogenesis in cell culture and the development of obesity in animal models and humans, but a causal relationship remains unproven. Our objective was to determine whether serological evidence of Adv-36 infection in childhood and/or adulthood is associated with adult obesity., Subjects/methods: Paired plasma concentrations of Adv-36 antibodies were measured by a novel enzyme-linked immunosorbent assay in a subgroup (n=449) of the Cardiovascular Risk in Young Finns Study in childhood (mean age 11.9 years) and adulthood (mean age 41.3 years). The study group included (1) individuals who had maintained normal-weight status (2) those who became obese adults from a normal-weight status in childhood and (3) those that were overweight/obese as a child and obese as an adult., Results: Mean (s.d.) time between baseline and follow-up was 29.4 (3.2) years (range 21-31 years). A total of 24.4% of individuals who were normal weight throughout life were seropositive for Adv-36 during child and/or adulthood as compared with 32.3% of those who became obese adults (P=0.11). Those who became obese in adulthood were more likely to be Adv-36 seropositive as adults compared with those who maintained normal weight (21.3% vs. 11.6%, P=0.02). This difference was mediated by a decline in Adv-36 seropositivity between child and adulthood in those maintaining normal weight. No differences were observed in body mass index across the life course, nor in waist circumference in adult life, between those who were Adv-36 seronegative or seropositive at any age., Conclusions: Individuals who gained weight across the life course were more likely to be Adv-36 seropositive in adult life than those who did not gain weight. However, analysis of change in weight status in relation to Adv-36 positivity did not support a causal role for Adv-36 in the development of obesity.

Background: Cuff and spared nerve injury (SNI) in the sciatic territory are widely used to model neuropathic pain. Because nociceptive information is first detected in skin, it is important to understand how alterations in peripheral innervation contribute to pain in each model. Over 16 weeks in male rats, changes in sensory and autonomic innervation of the skin were described after cuff and SNI using immunohistochemistry to label myelinated (neurofilament 200 positive-NF200+) and peptidergic (calcitonin gene-related peptide positive-CGRP+) primary afferents and sympathetic fibres (dopamine β-hydroxylase positive-DBH+), Results: Cuff and SNI caused an early loss and later reinnervation of NF200 and CGRP fibres in the plantar hind paw skin. In both models, DBH+ fibres sprouted into the upper dermis of the plantar skin 4 and 6 weeks after injury. Despite these similarities, behavioural pain measures were significantly different in each model. Sympathectomy using guanethidine significantly alleviated mechanical allodynia 6 weeks after cuff, when peak sympathetic sprouting was observed, having no effect at 2 weeks, when fibres were absent. In SNI animals, mechanical allodynia in the lateral paw was significantly improved by guanethidine at 2 and 6 weeks, and the development of cold hyperalgesia, which roughly paralleled the appearance of ectopic sympathetic fibres, was alleviated by guanethidine at 6 weeks. Sympathetic fibres did not sprout into the dorsal root ganglia at 2 or 6 weeks, indicating their unimportance to pain behaviour in these two models., Conclusions: Alterations in sympathetic innervation in the skin represents an important mechanism that contributes to pain in cuff and SNI models of neuropathic pain.

The hyperthermophilic, sulfate-reducing archaeon, Archaeoglobus fulgidus, utilizes CO as an energy source and it is resistant to the toxic effects of high CO concentrations. Herein, transcription profiles were obtained from A. fulgidus during growth with CO and sulfate or thiosulfate, or without an electron acceptor. This provided a basis for a model of the CO metabolism of A. fulgidus. The model suggests proton translocation by "Mitchell-type" loops facilitated by Fqo catalyzing a Fd(red):menaquinone oxidoreductase reaction, as the major mode of energy conservation, rather than formate or H2 cycling during respiratory growth. The bifunctional CODH (cdhAB-2) is predicted to play an ubiquitous role in the metabolism of CO, and a novel nitrate reductase-associated respiratory complex was induced specifically in the presence of sulfate. A potential role of this complex in relation to Fd(red) and APS reduction is discussed. Multiple membrane-bound heterodisulfide reductase (DsrMK) could promote both energy-conserving and non-energy-conserving menaquinol oxidation. Finally, the FqoF subunit may catalyze a Fd(red):F420 oxidoreductase reaction. In the absence of electron acceptor, downregulation of F420H2 dependent steps of the acetyl-CoA pathway is linked to transient formate generation. Overall, carboxidotrophic growth seems as an intrinsic capacity of A. fulgidus with little need for novel resistance or respiratory complexes.

Background: Neuropeptide Y (NPY) has been implicated in the modulation of pain. Under normal conditions, NPY is found in interneurons in the dorsal horn of the spinal cord and in sympathetic postganglionic neurons but is absent from the cell bodies of sensory neurons. Following peripheral nerve injury NPY is dramatically upregulated in the sensory ganglia. How NPY expression is altered in the peripheral nervous system, distal to a site of nerve lesion, remains unknown. To address this question, NPY expression was investigated using immunohistochemistry at the level of the trigeminal ganglion, the mental nerve and in the skin of the lower lip in relation to markers of sensory and sympathetic fibers in a rat model of trigeminal neuropathic pain., Results: At 2 and 6 weeks after chronic constriction injury (CCI) of the mental nerve, de novo expression of NPY was seen in the trigeminal ganglia, in axons in the mental nerve, and in fibers in the upper dermis of the skin. In lesioned animals, NPY immunoreactivity was expressed primarily by large diameter mental nerve sensory neurons retrogradely labelled with Fluorogold. Many axons transported this de novo NPY to the periphery as NPY-immunoreactive (IR) fibers were seen in the mental nerve both proximal and distal to the CCI. Some of these NPY-IR axons co-expressed Neurofilament 200 (NF200), a marker for myelinated sensory fibers, and occasionally colocalization was seen in their terminals in the skin. Peptidergic and non-peptidergic C fibers expressing calcitonin gene-related peptide (CGRP) or binding isolectin B4 (IB4), respectively, never expressed NPY. CCI caused a significant de novo sprouting of sympathetic fibers into the upper dermis of the skin, and most, but not all of these fibers, expressed NPY., Conclusions: This is the first study to provide a comprehensive description of changes in NPY expression in the periphery after nerve injury. Novel expression of NPY in the skin comes mostly from sprouted sympathetic fibers. This information is fundamental in order to understand where endogenous NPY is expressed, and how it might be acting to modulate pain in the periphery.

Inhibitory interneurons are an important component of dorsal horn circuitry where they serve to modulate spinal nociception. There is now considerable evidence indicating that reduced inhibition in the spinal dorsal horn contributes to neuropathic pain. A loss of these inhibitory neurons after nerve injury is one of the mechanisms being proposed to account for reduced inhibition; however, this remains controversial. This is in part because previous studies have focused on global measurements of inhibitory neurons without assessing the number of inhibitory synapses. To address this, we conducted a quantitative analysis of the spatial and temporal changes in the number of inhibitory terminals, as detected by glutamic acid decarboxylase 65 (GAD65) immunoreactivity, in the superficial dorsal horn of the spinal cord following a chronic constriction injury (CCI) to the sciatic nerve in rats. Isolectin B4 (IB4) labelling was used to define the location within the dorsal horn directly affected by the injury to the peripheral nerve. The density of GAD65 inhibitory terminals was reduced in lamina I (LI) and lamina II (LII) of the spinal cord after injury. The loss of GAD65 terminals was greatest in LII with the highest drop occurring around 3-4 weeks and a partial recovery by 56 days. The time course of changes in the number of GAD65 terminals correlated well with both the loss of IB4 labeling and with the altered thresholds to mechanical and thermal stimuli. Our detailed analysis of GAD65+ inhibitory terminals clearly revealed that nerve injury induced a transient loss of GAD65 immunoreactive terminals and suggests a potential involvement for these alterations in the development and amelioration of pain behaviour.

In addition to sensory disturbances, neuropathic pain is associated with an ongoing and persistent negative affective state. This condition may be reflected as altered sensitivity to rewarding stimuli. We examined this hypothesis by testing whether the rewarding properties of morphine are altered in a rat model of neuropathic pain. Neuropathic pain was induced by chronic constriction of the common sciatic nerve. Drug reward was assessed using an unbiased, three-compartment conditioned place preference (CPP) paradigm. The rats underwent two habituation sessions beginning 6 days after surgery. Over the next 8 days, they were injected with drug or vehicle and were confined to one CPP compartment for 30 min. On the following test day, the rats had access to all three compartments for 30 min. Consistent with the literature, systemic administration of morphine dose-dependently increased the CPP in pain-naive animals. In rats with neuropathic pain, however, the dose-dependent effects of morphine were in a bell-shaped curve, with a low dose of morphine (2 mg/kg) producing a greater CPP than a higher dose of morphine (8 mg/kg). In a separate group of animals, acute administration of morphine reversed mechanical allodynia in animals with neuropathic pain at the same doses that produced a CPP. The increased potency of systemic morphine to produce a CPP in animals with neuropathic pain suggests that the motivation for opioid-induced reward is different in the two states., (© 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.)

Objective: Vascular damage is suggested to have origins in childhood adiposity, but it is not clear whether this is a direct consequence of being obese in childhood. We aimed to estimate the associations of childhood body size or adiposity with adult vascular health, and to investigate whether these associations were independent of adult body size or adiposity., Design and Methods: Subjects were 2328 participants aged 7-15 years at baseline in 1985 with follow-up during 2004-2006 when aged 26-36 years. Anthropometric measures were taken at both baseline and follow-up. Carotid intima-media thickness (IMT) and three measures of large artery stiffness (LAS) were measured by ultrasound at follow-up., Results: Childhood body size or adiposity was positively associated with both adult IMT and LAS. Participants who were obese in adulthood had the greatest LAS, particularly those who were normal weight in childhood. Adjustment for adult body size or adiposity eliminated effects of childhood body size or adiposity on LAS. For IMT, adjustment for adult body size or adiposity reduced estimated effects of child height by 44% (male) and 27% (female), of child weight by 46% (male) and 70% (female) and, after adjusting for sex, of child body mass index and body surface area by 60% and 53% respectively., Conclusions: Whereas IMT appeared to be influenced by body size or adiposity during childhood and early adulthood, LAS depended primarily on current adiposity and magnitude of adiposity gain between childhood and adulthood., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)