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Cardiovascular diseases represent a major cause of morbidity and mortality, necessitating research to improve diagnostics, and to discover and test novel preventive and curative therapies. All of which warrant experimental models that recapitulate human disease. The translation of basic science results to clinical practice is a challenging task. In particular for complex conditions such as cardiovascular diseases, which often result from multiple risk factors and co-morbidities. This difficulty might lead some individuals to question the value of animal research, citing the translational 'valley of death', which largely reflects the fact that studies in rodents are difficult to translate to humans. This is also influenced by the fact that new, human-derived in vitro models can recapitulate aspects of disease processes. However, it would be a mistake to think that animal models cannot provide a vital step in the translational pathway as they do provide important pathophysiological insights into disease mechanisms particularly on a organ and systemic level. While stem cell-derived human models have the potential to become key in testing toxicity and effectiveness of new drugs, we need to be realistic, and carefully validate all new human-like disease models. In this position paper, we highlight recent advances in trying to reduce the number of animals for cardiovascular research ranging from stem cell-derived models to in situ modelling of heart properties, bioinformatic models based on large datasets, and improved current animal models, which show clinically relevant characteristics observed in patients with a cardiovascular disease. We aim to provide a guide to help researchers in their experimental design to translate bench findings to clinical routine taking the replacement, reduction and refinement (3R) as a guiding concept. [Abstract copyright: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2022. For permissions please email: journals.permissions@oup.com.]

International audience; BACKGROUND Transthyretin amyloid (ATTR) cardiomyopathy is a progressive and fatal disease caused by misfolded transthyretin. Despite advances in slowing disease progression, there is no available treatment that depletes ATTR from the heart for the amelioration of cardiac dysfunction. NI006 is a recombinant human anti-ATTR antibody that was developed for the removal of ATTR by phagocytic immune cells. METHODS In this phase 1, double-blind trial, we randomly assigned (in a 2:1 ratio) 40 patients with wild-type or variant ATTR cardiomyopathy and chronic heart failure to receive intravenous infusions of either NI006 or placebo every 4 weeks for 4 months. Patients were sequentially enrolled in six cohorts that received ascending doses (ranging from 0.3 to 60 mg per kilogram of body weight). After four infusions, patients were enrolled in an open-label extension phase in which they received eight infusions of NI006 with stepwise increases in the dose. The safety and pharmacokinetic profiles of NI006 were assessed, and cardiac imaging studies were performed. RESULTS The use of NI006 was associated with no apparent drug-related serious adverse events. The pharmacokinetic profile of NI006 was consistent with that of an IgG antibody, and no antidrug antibodies were detected. At doses of at least 10 mg per kilogram, cardiac tracer uptake on scintigraphy and extracellular volume on cardiac magnetic resonance imaging, both of which are imaging-based surrogate markers of cardiac amyloid load, appeared to be reduced over a period of 12 months. The median N-terminal pro-B-type natriuretic peptide and troponin T levels also seemed to be reduced. CONCLUSIONS In this phase 1 trial of the recombinant human antibody NI006 for the treatment of patients with ATTR cardiomyopathy and heart failure, the use of NI006 was associated with no apparent drug-related serious adverse events.

Dit artikel onderzoekt wat werk sociaal nuttig maakt en of er een uitruil plaatsvindt tussen loon en sociaal nuttig werk. Uitgangspunt is dat de mate waarin werk nuttig is vooral afhangt van de functie. De mate waarin het werk als sociaal nuttig wordt ervaren hangt af van de mogelijkheden tot zelfontplooiing en organisatiedoelen. Analyses van EWCS 2015 en ISSP 2015 laten zien dat de oordelen van beroepsbeoefenaren over de nuttigheid van hun werk sterk overeenkomen in deze datasets. Er zijn sterke effecten van aan zelfontplooiing gerelateerde functiekenmerken op sociaal nuttig werk. Ook blijken werkenden in niet-commerciële organisaties hun werk sociaal nuttiger te vinden dan werkenden in commerciële organisaties. Er is een uitruil tussen loon en sociaal nut van het werk als constant wordt gehouden voor aan zelfontplooiing gerelateerde functiekenmerken. We concluderen dat de mate waarin werk sociaal nuttig is sterk afhangt van de mogelijkheden tot zelfontplooiing in de functie, en aanleiding geeft tot uitruil tussen loon en sociaal nut.

Burnout complaints among young workers in The Netherlands are high and increasing. Our research question is whether and how the high burn-out complaints of young workers in the Netherlands are associated with the employment relationships in the flexible labour market. We argue that especially an insecure career perspective contributes to burn-out complaints. Young workers in career jobs feel more insecure and this is a main reason why they have greater burnout complaints. We use the Netherlands Working Conditions Survey 2018 to test this argument. The analyses show that young workers in career jobs feel relatively insecure about their jobs and report a considerable higher level of burn-out complaints than student workers. Especially the workers in flexible career jobs suffer from insecurity and burnout complaints.

A physiological increase in cardiac workload results in adaptive cardiac remodeling, characterized by increased oxidative metabolism and improvements in cardiac performance. Insulin-like growth factor-1 (IGF-1) has been identified as a critical regulator of physiological cardiac growth, but its precise role in cardiometabolic adaptations to physiological stress remains unresolved. Mitochondrial calcium (Ca2+) handling has been proposed to be required for sustaining key mitochondrial dehydrogenase activity and energy production during increased workload conditions, thus ensuring the adaptive cardiac response. We hypothesized that IGF-1 enhances mitochondrial energy production through a Ca2+-dependent mechanism to ensure adaptive cardiomyocyte growth. We found that stimulation with IGF-1 resulted in increased mitochondrial Ca2+ uptake in neonatal rat ventricular myocytes and human embryonic stem cell-derived cardiomyocytes, estimated by fluorescence microscopy and indirectly by a reduction in the pyruvate dehydrogenase phosphorylation. We showed that IGF-1 modulated the expression of mitochondrial Ca2+ uniporter (MCU) complex subunits and increased the mitochondrial membrane potential; consistent with higher MCU-mediated Ca2+ transport. Finally, we showed that IGF-1 improved mitochondrial respiration through a mechanism dependent on MCU-mediated Ca2+ transport. In conclusion, IGF-1-induced mitochondrial Ca2+ uptake is required to boost oxidative metabolism during cardiomyocyte adaptive growth.

Background Serum selenium levels have been associated with the incidence of heart failure (HF) and signs of the metabolic syndrome. In addition, notable differences have been reported between males and females in food intake and micronutrient metabolism, possibly explaining different health outcomes. Objective Our objective was to elucidate sex-specific, cross-sectional phenotypic differences in the association of serum selenium concentrations with parameters of metabolic syndrome and HF. Methods We investigated data from individuals from a community-based cohort (PREVEND; N = 4288) and heart failure cohort (BIOSTAT-CHF; N = 1994). In both populations, cross-sectional analyses were performed for potential interaction (p Results Baseline selenium levels of the total cohort were similar between PREVEND (85.7 μg/L) and BIOSTAT-CHF (89.1 μg/L). Females with lower selenium levels had a higher BMI and increased prevalence of diabetes than females with higher selenium, in both PREVEND (pinteraction interaction = 0.040, resp.) and BIOSTAT-CHF (pinteraction = 0.021; pinteraction = 0.024, resp.), while opposite associations were observed for males. Additionally, in females, but not in males, lower selenium was associated with a higher prevalence of myocardial infarction (MI) in PREVEND (pinteraction = 0.021) and BIOSTAT-CHF (pinteraction = 0.084). Conclusion Lower selenium was associated with a higher BMI and increased prevalence of diabetes in females, opposite to males, and was also associated with more MI in females. Interventional studies are needed to validate this observation.

AimsThe importance of autoantibodies (AABs) against adrenergic/muscarinic receptors in heart failure (HF) is not well-understood. We investigated the prevalence and clinical/prognostic associations of four AABs recognizing the M2-muscarinic receptor or the β1-, β2-, or β3-adrenergic receptor in a large and well-characterized cohort of patients with HF.Methods and resultsSerum samples from 2256 patients with HF from the BIOSTAT-CHF cohort and 299 healthy controls were analysed using newly established chemiluminescence immunoassays. The primary outcome was a composite of all-cause mortality and HF rehospitalization at 2-year follow-up, and each outcome was also separately investigated. Collectively, 382 (16.9%) patients and 37 (12.4%) controls were seropositive for ≥1 AAB (P = 0.045). Seropositivity occurred more frequently only for anti-M2 AABs (P = 0.025). Amongst patients with HF, seropositivity was associated with the presence of comorbidities (renal disease, chronic obstructive pulmonary disease, stroke, and atrial fibrillation) and with medication use. Only anti-β1 AAB seropositivity was associated with the primary outcome [hazard ratio (95% confidence interval): 1.37 (1.04–1.81), P = 0.024] and HF rehospitalization [1.57 (1.13–2.19), P = 0.010] in univariable analyses but remained associated only with HF rehospitalization after multivariable adjustment for the BIOSTAT-CHF risk model [1.47 (1.05–2.07), P = 0.030]. Principal component analyses showed considerable overlap in B-lymphocyte activity between seropositive and seronegative patients, based on 31 circulating biomarkers related to B-lymphocyte function.ConclusionsAAB seropositivity was not strongly associated with adverse outcomes in HF and was mostly related to the presence of comorbidities and medication use. Only anti-β1 AABs were independently associated with HF rehospitalization. The exact clinical value of AABs remains to be elucidated.

BACKGROUND: Despite the widely acknowledged benefit of exercise for patients with cancer, little evidence on the optimal timing of exercise on adverse effects of cancer treatment is available. OBJECTIVES: The aim of this study was to determine whether an exercise intervention initiated during chemotherapy is superior to an intervention initiated after chemotherapy for improving long-term cardiorespiratory fitness (peak oxygen uptake [VO 2peak]). METHODS: In this prospective, randomized clinical trial, patients scheduled to receive curative chemotherapy were randomized to a 24-week exercise intervention, initiated either during chemotherapy (group A) or afterward (group B). The primary endpoint was VO 2peak 1 year postintervention. Secondary endpoints were VO 2peak postintervention, muscle strength, health-related quality of life (HRQoL), fatigue, physical activity, and self-efficacy. Between-group differences were calculated using intention-to-treat linear mixed-models analyses. RESULTS: A total of 266 patients with breast (n = 139), testicular (n = 95), and colon cancer (n = 30) as well as lymphoma (n = 2) were included. VO 2peak immediately postintervention and 1 year postintervention did not differ between the 2 groups. Immediately postchemotherapy, patients in group A exhibited significantly lower decreases in VO 2peak (3.1 mL/kg/min; 95% CI: 2.2-4.0 mL/kg/min), HRQoL, and muscle strength and reported less fatigue and more physical activity than those in group B. CONCLUSIONS: Exercise can be safely performed during chemotherapy and prevents fatigue and decreases in VO 2peak, muscle strength, and HRQoL, in addition to hastening the return of function after chemotherapy. Also, if exercise cannot be performed during chemotherapy, a program afterward can enable patients to regain the same level of function, measured 1 year after completion of the intervention. (Optimal Timing of Physical Activity in Cancer Treatment [ACT]; NCT01642680).

Aims: \ud Several studies have shown that heart failure (HF) drug treatment seems to benefit patients with preserved ejection fraction (HFpEF) and a left ventricular ejection fraction (LVEF) up to 55–60% but not with higher LVEF. Certain HF drugs are now indicated in patients with HFpEF and a LVEF below normal. However, not much is known about patients with a normal LVEF. Therefore, we investigated the prevalence, clinical characteristics and outcome of patients with HF and a normal LVEF.\ud \ud Methods and results: \ud Normal LVEF was defined according to the Recommendations for Cardiac Chamber Quantification from the American Society of Echocardiography as a LVEF ≥62% for men and ≥ 64% for women. Preserved ejection fraction was defined as a LVEF ≥50% and reduced ejection fraction as a LVEF

BACKGROUND:\ud Angiotensin-converting enzyme inhibitors attenuate left ventricular (LV) enlargement after acute myocardial infarction (AMI). Preclinical data suggest similar benefits with combined angiotensin receptor neprilysin inhibition, but human data are conflicting. The PARADISE-MI Echo Study (Prospective ARNI Versus ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After Myocardial Infarction) tested the effect of sacubitril/valsartan compared with ramipril on LV function and adverse remodeling after high risk-AMI.\ud \ud METHODS:\ud In a prespecified substudy, 544 PARADISE-MI participants were enrolled in the Echo Study to undergo protocol echocardiography at randomization and after 8 months. Patients were randomized within 0.5 to 7 days of presentation with their index AMI to receive a target dose of sacubitril/valsartan 200 mg or ramipril 5 mg twice daily. Echocardiographic measures were performed at a core laboratory by investigators blinded to treatment assignment. The effect of treatment on change in echo measures was assessed with ANCOVA with adjustment for baseline value and enrollment region. The primary end points were change in LV ejection fraction (LVEF) and left atrial volume (LAV), and prespecified secondary end points included changes in LV end-diastolic and end-systolic volumes.\ud \ud RESULTS:\ud Mean age was 64±12 years; 26% were women; mean LVEF was 42±12%; and LAV was 49±17 mL. Of 544 enrolled patients, 457 (84%) had a follow-up echo at 8 months (228 taking sacubitril/valsartan, 229 taking ramipril). There was no significant difference in change in LVEF (P=0.79) or LAV (P =0.62) by treatment group. Patients randomized to sacubitril/valsartan demonstrated less increase in LV end-diastolic volume (P=0.025) and greater decline in LV mass index (P=0.037), increase in tissue Doppler e’lat (P=0.005), decrease in E/e’lat (P=0.045), and decrease in tricuspid regurgitation peak velocity (P=0.024) than patients randomized to ramipril. These differences remained significant after adjustment for differences in baseline characteristics. Baseline LVEF, LV end-diastolic volume, LV end-systolic volume, LV mass index, LAV, and Doppler-based diastolic indices were associated with risk of cardiovascular death or incident heart failure.\ud \ud CONCLUSIONS:\ud Treatment with sacubitril/valsartan compared with ramipril after AMI did not result in changes in LVEF or LAV at 8 months. Patients randomized to sacubitril/valsartan had less LV enlargement and greater improvement in filling pressure. Measures of LV size, systolic function, and diastolic properties were predictive of cardiovascular death and incident heart failure after AMI in this contemporary, well-treated cohort.

Although previous empirical research has provided insight into the link between perceived job insecurity and mental health, many questions remained unanswered. These include to what extent job insecurity has a mental health effect when controlling for (unobserved) individual characteristics, and to what extent there is effect heterogeneity. This dissertation therefore focuses on the mental health effect of job insecurity controlling for individual characteristics as well as the moderating effect of various demographic, sociological, and psychological variables. More specifically, it examined, next to a main effect, the role of gender, age, family situation, education, income, type of employment contract, religiousness, personality, and self-efficacy. By using a fixed effects estimator to control for time-invariant unobserved characteristics and data from the Netherlands for 2008-2018 chapter 2 indicates a rather small mean effect of perceived job insecurity on mental health. Some groups, however, have more trouble than others in dealing with perceived job insecurity: men, esp. with intermediate and higher levels of education, and with permanent contracts. Furthermore, negative effects of job insecurity increase with income. The moderating role of religiousness in the mental health effect of job insecurity could go either way: buffer or burden. Chapter 3 finds that religious employees in general, and Protestants among them in particular, despite being at risk due to a higher work ethic, are shielded from the adverse mental health effects of job insecurity. Instrumental are belief beyond doubt in God's existence as well as belief in life after death. The beliefs in God and in afterlife only appear to insulate workers who frequently attend religious gatherings. It is unclear how well people with different personality traits deal with a real-life stressor such as job insecurity. Chapter 4 investigates the interaction between the Big5 traits and job insecurity on mental health in three large, representative household panel data sets from the Netherlands (LISS), Germany (SOEP), and Australia (HILDA). In Dutch and German data we find (almost) no evidence of a moderating effect of Big5 personality traits in the mental health effect of job insecurity. In Australian data we find that extraversion has a mitigating effect on the mental health deterioration following job insecurity, and that openness to experience and neuroticism have an exacerbating effect on the mental health deterioration following job insecurity. There is ambiguity in the literature about the effect of self-efficacy on the stress response. Chapter 5 aims to investigate the role of self-efficacy in the mental health effect of job insecurity. The results indicate that higher baseline self-efficacy statistically significantly exacerbates the detrimental mental health effect of perceived job insecurity. This effect is only found for women; the gender difference is statistically significant. The exacerbating effect of baseline self-efficacy appears furthermore heterogeneous (albeit insignificantly so) across other groups: having completed higher education, being employed in the public sector, having a permanent contract, having a higher income as well as having a partner and having children, all tend to come with a stronger negative influence of self-efficacy in the mental health effect of job insecurity.

Although previous empirical research has provided insight into the link between perceived job insecurity and mental health, many questions remained unanswered. These include to what extent job insecurity has a mental health effect when controlling for (unobserved) individual characteristics, and to what extent there is effect heterogeneity. This dissertation therefore focuses on the mental health effect of job insecurity controlling for individual characteristics as well as the moderating effect of various demographic, sociological, and psychological variables. More specifically, it examined, next to a main effect, the role of gender, age, family situation, education, income, type of employment contract, religiousness, personality, and self-efficacy. By using a fixed effects estimator to control for time-invariant unobserved characteristics and data from the Netherlands for 2008-2018 chapter 2 indicates a rather small mean effect of perceived job insecurity on mental health. Some groups, however, have more trouble than others in dealing with perceived job insecurity: men, esp. with intermediate and higher levels of education, and with permanent contracts. Furthermore, negative effects of job insecurity increase with income. The moderating role of religiousness in the mental health effect of job insecurity could go either way: buffer or burden. Chapter 3 finds that religious employees in general, and Protestants among them in particular, despite being at risk due to a higher work ethic, are shielded from the adverse mental health effects of job insecurity. Instrumental are belief beyond doubt in God's existence as well as belief in life after death. The beliefs in God and in afterlife only appear to insulate workers who frequently attend religious gatherings. It is unclear how well people with different personality traits deal with a real-life stressor such as job insecurity. Chapter 4 investigates the interaction between the Big5 traits and job insecurity on mental health in three large, representative household panel data sets from the Netherlands (LISS), Germany (SOEP), and Australia (HILDA). In Dutch and German data we find (almost) no evidence of a moderating effect of Big5 personality traits in the mental health effect of job insecurity. In Australian data we find that extraversion has a mitigating effect on the mental health deterioration following job insecurity, and that openness to experience and neuroticism have an exacerbating effect on the mental health deterioration following job insecurity. There is ambiguity in the literature about the effect of self-efficacy on the stress response. Chapter 5 aims to investigate the role of self-efficacy in the mental health effect of job insecurity. The results indicate that higher baseline self-efficacy statistically significantly exacerbates the detrimental mental health effect of perceived job insecurity. This effect is only found for women; the gender difference is statistically significant. The exacerbating effect of baseline self-efficacy appears furthermore heterogeneous (albeit insignificantly so) across other groups: having completed higher education, being employed in the public sector, having a permanent contract, having a higher income as well as having a partner and having children, all tend to come with a stronger negative influence of self-efficacy in the mental health effect of job insecurity.

Funding: This work was part of the PhD thesis of the first author, developed at the Graduate Program in Ecology of the National Institute of Amazonian Research (INPA), with a fellowship funded by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES), Finance Code 001, (88887.141433/2017-00). The authors are also grateful for the financial and research support of the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Amazonas State Research Foundation (FAPEAM), the Newton Fund via the Natural Environment Research Council (NE/M022021/1 to O.L.P. and F.R.C.C.), PPBio Manaus, Centro de Estudos Integrados da Biodiversidade Amazônica and RAINFOR. We also thank Karina Melgaço, Aurora Levesley and Gabriela Lopez-Gonzalez for curating and managing ForestPlots.net. This was ForestPlots.net Project 26 led by Thaiane Sousa. This is publication number 832 of the Technical Series of the Biological Dynamics of Forest Fragments Project (BDFFP, INPA/STRI). Aim : Water availability is the major driver of tropical forest structure and dynamics. Most research has focused on the impacts of climatic water availability, whereas remarkably little is known about the influence of water table depth and excess soil water on forest processes. Nevertheless, given that plants take up water from the soil, the impacts of climatic water supply on plants are likely to be modulated by soil water conditions. Location : Lowland Amazonian forests. Time period : 1971–2019. Methods : We used 344 long-term inventory plots distributed across Amazonia to analyse the effects of long-term climatic and edaphic water supply on forest functioning. We modelled forest structure and dynamics as a function of climatic, soil-water and edaphic properties. Results : Water supplied by both precipitation and groundwater affects forest structure and dynamics, but in different ways. Forests with a shallow water table (depth

Background: Higher levels of physical activity are associated with a lower risk of cardiovascular disease in the general population. Whether the same holds for women who underwent treatment for breast cancer is unclear.Objectives: The aim of this study was to evaluate the association between physical activity in a typical week in the past 12 months and cardiac dysfunction in breast cancer survivors.Methods: We used data from a cohort of breast cancer survivors who were treated at ages 40 to 50 years (N = 559). The association between physical activity and global longitudinal strain (GLS) and left ventricular ejection fraction (LVEF) was evaluated using both linear and modified Poisson regression analyses adjusted for relevant confounders.Results: In total, 559 breast cancer survivors were included, with median age of 55.5 years and a median time since treatment of 10.2 years. GLS was less favorable in inactive survivors (-17.1%) than in moderately inactive (-18.4%), moderately active (-18.2%), and active survivors (-18.5%), with an adjusted significant difference for active versus inactive survivors (β = -1.31; 95% CI: -2.55 to -0.06)). Moderately active (n = 57/130) and active survivors (n = 87/124) had significantly lower risks of abnormal GLS (defined as >-18%) compared with inactive survivors (n = 17/26) (RR: 0.65 [95% CI: 0.45-0.94] and RR: 0.61 [95% CI: 0.43-0.87], respectively). LVEF, in normal ranges in all activity categories, was not associated with physical activity.Conclusions: In long-term breast cancer survivors, higher physical activity levels were associated with improved GLS but not LVEF, with the relatively largest benefit for doing any activity versus none. This finding suggests that increasing physical activity may contribute to cardiovascular health benefits, especially in inactive survivors.

Background: Higher levels of physical activity are associated with a lower risk of cardiovascular disease in the general population. Whether the same holds for women who underwent treatment for breast cancer is unclear. Objectives: The aim of this study was to evaluate the association between physical activity in a typical week in the past 12 months and cardiac dysfunction in breast cancer survivors. Methods: We used data from a cohort of breast cancer survivors who were treated at ages 40 to 50 years (N = 559). The association between physical activity and global longitudinal strain (GLS) and left ventricular ejection fraction (LVEF) was evaluated using both linear and modified Poisson regression analyses adjusted for relevant confounders. Results: In total, 559 breast cancer survivors were included, with median age of 55.5 years and a median time since treatment of 10.2 years. GLS was less favorable in inactive survivors (-17.1%) than in moderately inactive (-18.4%), moderately active (-18.2%), and active survivors (-18.5%), with an adjusted significant difference for active versus inactive survivors (β = -1.31; 95% CI: -2.55 to -0.06)). Moderately active (n = 57/130) and active survivors (n = 87/124) had significantly lower risks of abnormal GLS (defined as >-18%) compared with inactive survivors (n = 17/26) (RR: 0.65 [95% CI: 0.45-0.94] and RR: 0.61 [95% CI: 0.43-0.87], respectively). LVEF, in normal ranges in all activity categories, was not associated with physical activity. Conclusions: In long-term breast cancer survivors, higher physical activity levels were associated with improved GLS but not LVEF, with the relatively largest benefit for doing any activity versus none. This finding suggests that increasing physical activity may contribute to cardiovascular health benefits, especially in inactive survivors.

Aim: Water availability is the major driver of tropical forest structure and dynamics. Most research has focused on the impacts of climatic water availability, whereas remarkably little is known about the influence of water table depth and excess soil water on forest processes. Nevertheless, given that plants take up water from the soil, the impacts of climatic water supply on plants are likely to be modulated by soil water conditions. Location: Lowland Amazonian forests. Time period: 1971–2019. Methods: We used 344 long-term inventory plots distributed across Amazonia to analyse the effects of long-term climatic and edaphic water supply on forest functioning. We modelled forest structure and dynamics as a function of climatic, soil-water and edaphic properties. Results Water supplied by both precipitation and groundwater affects forest structure and dynamics, but in different ways. Forests with a shallow water table (depth

RATIONALE: Ischemia and subsequent reperfusion cause myocardial injury in patients presenting with ST-segment elevation myocardial infarction (STEMI). Hydrogen sulfide (H2S) reduces "ischemia-reperfusion injury" in various experimental animal models, but has not been evaluated in humans. This trial will examine the efficacy and safety of the H2S-donor sodium thiosulfate (STS) in patients presenting with a STEMI.STUDY DESIGN: The Groningen Intervention study for the Preservation of cardiac function with STS after STEMI (GIPS-IV) trial (NCT02899364) is a double-blind, randomized, placebo-controlled, multicenter trial, which will enroll 380 patients with a first STEMI. Patients receive STS 12.5 gram intravenously or matching placebo in addition to standard care immediately at arrival at the catheterization laboratory after providing consent. A second dose is administered 6 hours later at the coronary care unit. The primary endpoint is myocardial infarct size as quantified by cardiac magnetic resonance imaging 4 months after randomization. Secondary endpoints include the effect of STS on peak CK-MB during admission and left ventricular ejection fraction and NT-proBNP levels at 4 months follow-up. Patients will be followed-up for 2 years to assess clinical endpoints.CONCLUSIONS: The GIPS-IV trial is the first study to determine the effect of a H2S-donor on myocardial infarct size in patients presenting with STEMI.

Aims:\ud Whereas the combination of anaemia and chronic kidney disease (CKD) has been extensively studied in patients with heart failure (HF), the contribution of iron deficiency (ID) to this dysfunctional interplay is unknown. We aimed to assess clinical associates and pathophysiological pathways related to ID in this multimorbid syndrome.\ud \ud Methods and results:\ud We studied 2151 patients with HF from the BIOSTAT-CHF cohort. Patients were stratified based on ID (transferrin saturation

The co-occurrence of cancer and heart failure (HF) represents a significant clinical drawback as each disease interferes with the treatment of the other. In addition to shared risk factors, a growing body of experimental and clinical evidence reveals numerous commonalities in the biology underlying both pathologies. Inflammation emerges as a common hallmark for both diseases as it contributes to the initiation, and progression of both HF and cancer. Under stress, malignant and cardiac cells change their metabolic preferences to survive, which makes these metabolic derangements a great basis to develop intersection strategies and therapies to combat both diseases. Further, genetic predisposition and clonal hematopoiesis are common drivers for both conditions and they hold great clinical relevance in the context of personalized medicine. Also, altered angiogenesis is a common hallmark for failing hearts and tumors and represents a promising substrate to target in both diseases. Cardiac cells and malignant cells interact with their surrounding environment called stroma. This interaction mediates the progression of the 2 pathologies and understanding the structure and function of each stromal component may pave the way for innovative therapeutic strategies and improved outcomes in patients. The interdisciplinary collaboration between cardiologists and oncologists is essential to establish unified guidelines. Also, preclinical models that mimic the human situation, where both pathologies coexist, are needed to understand all the aspects of the bidirectional relationship between cancer and HF. Finally, adequately powered clinical studies, including all ages, and men and women, with proper adjudication of both cancer and CV end points, are essential to accurately study these two pathologies at the same time.

Aims Patients with heart failure (HF) and iron deficiency experience poor health-related quality of life (HRQoL). We evaluated the impact of intravenous (IV) ferric carboxymaltose (FCM) vs. placebo on HRQoL for the AFFIRM-AHF population. Methods and results The baseline 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12), which was completed for 1058 (535 and 523) patients in the FCM and placebo groups, respectively, was administered prior to randomization and at Weeks 2, 4, 6, 12, 24, 36, and 52. The baseline KCCQ-12 overall summary score (OSS) mean +/- standard error was 38.7 +/- 0.9 (FCM group) and 37.1 +/- 0.8 (placebo group); corresponding values for the clinical summary score (CSS) were 40.9 +/- 0.9 and 40.1 +/- 0.9. At Week 2, changes in OSS and CSS were similar for FCM and placebo. From Week 4 to Week 24, patients assigned to FCM had significantly greater improvements in OSS and CSS scores vs. placebo [adjusted mean difference (95% confidence interval, CI) at Week 4: 2.9 (0.5-5.3, P = 0.018) for OSS and 2.8 (0.3-5.3, P = 0.029) for CSS; adjusted mean difference (95% CI) at Week 24: 3.0 (0.3-5.6, P = 0.028) for OSS and 2.9 (0.2-5.6, P = 0.035) for CSS]. At Week 52, the treatment effect had attenuated but remained in favour of FCM. Conclusion In iron-deficient patients with HF and left ventricular ejection fraction

Supplemental Data to Progressive Diastolic Dysfunction in Survivors of Pediatric DTC

AIMS: Atrial fibrillation (AF) and heart failure (HF) are two growing epidemics that frequently co-exist. We aimed to gain insights into underlying pathophysiological pathways in HF patients with AF by comparing circulating biomarkers using pathway overrepresentation analyses. METHODS AND RESULTS: From a panel of 92 biomarkers from different pathophysiological domains available in 1,620 patients with HF, we first tested which biomarkers were dysregulated in patients with HF and AF (n = 648) compared with patients in sinus rhythm (n = 972). Secondly, pathway overrepresentation analyses were performed to identify biological pathways linked to higher plasma concentrations of biomarkers in patients who had HF and AF. Findings were validated in an independent HF cohort (n = 1,219, 38\% with AF). Patient with AF and HF were older, less often women, and less often had a history of coronary artery disease compared with those in sinus rhythm. In the index cohort, 24 biomarkers were upregulated in patients with AF and HF. In the validation cohort, 8 biomarkers were upregulated, which all overlapped with the 24 biomarkers found in the index cohort. The strongest up-regulated biomarkers in patients with AF were spondin-1 (fold change 1.18, p = 1.33x10-12), insulin-like growth factor-binding protein-1 (fold change 1.32, p = 1.08x10-8), and insulin-like growth factor-binding protein-7 (fold change 1.33, p = 1.35x10-18). Pathway overrepresentation analyses revealed that the presence of AF was associated with activation amyloid-beta metabolic processes, amyloid-beta formation, and amyloid precursor protein catabolic processes with a remarkable consistency observed in the validation cohort. CONCLUSION: In two independent cohorts of patients with HF, the presence of AF was associated with activation of three pathways related to amyloid-beta. These hypothesis-generating results warrant confirmation in future studies. TRANSLATIONAL PERSPECTIVE: Using an unbiased approach, we identified and validated dysregulation of three amyloid-beta related pathways in patients who had heart failure (HF) with concomitant atrial fibrillation (AF). Amyloid-beta depositions are a hallmark of Alzheimer's disease, but might also play a role in pathophysiological processes outside the central nervous system. Biopsy studies are needed to confirm the pathophysiological role of amyloid-beta in patients with AF and HF. Diagnostic and therapeutic implications should be investigated in the light of potential pathophysiological overlap between the three aging-related epidemics: Alzheimer's disease, AF and HF.

The title in the original version of this Article contained a typographical error of ‘unresponsive’. The error has now been corrected in the PDF and HTML versions of the Article.

The carbon sink capacity of tropical forests is substantially affected by tree mortality. However, the main drivers of tropical tree death remain largely unknown. Here we present a pan-Amazonian assessment of how and why trees die, analysing over 120,000 trees representing > 3800 species from 189 long-term RAINFOR forest plots. While tree mortality rates vary greatly Amazon-wide, on average trees are as likely to die standing as they are broken or uprooted—modes of death with different ecological consequences. Species-level growth rate is the single most important predictor of tree death in Amazonia, with faster-growing species being at higher risk. Within species, however, the slowest-growing trees are at greatest risk while the effect of tree size varies across the basin. In the driest Amazonian region species-level bioclimatic distributional patterns also predict the risk of death, suggesting that these forests are experiencing climatic conditions beyond their adaptative limits. These results provide not only a holistic pan-Amazonian picture of tree death but large-scale evidence for the overarching importance of the growth–survival trade-off in driving tropical tree mortality.

Aims Anticancer therapies have extended the lives of millions of patients with malignancies, but for some this benefit is tempered by adverse cardiovascular (CV) effects. Cardiotoxicity may occur early or late after treatment initiation or termination. The extent of this cardiotoxicity is variable, depending on the type of drug used, combination with other drugs, mediastinal radiotherapy, the presence of CV risk factors, and comorbidities. A recent position paper from the European Society of Cardiology addressed the management of CV monitoring and management of patients treated for cancer. Methods and results The current document is focused on the basis of the Cardio-Oncology (C-O) Services, presenting their rationale, organization, and implementation. C-O Services address the spectrum of prevention, detection, monitoring, and treatment of cancer patients at risk of cardiotoxicity and/or with concomitant CV diseases. These services require a multidisciplinary approach, with the aims of promoting CV health and facilitating the most effective cancer therapy. Conclusion The expected growing volume of patients with cancer at risk of developing/worsening CV disease, the advent of new technological opportunities to refine diagnosis, and the necessity of early recognition of cancer therapy-related toxicity mandate an integrative multidisciplinary approach and care in a specialized environment. This document from the ESC Cardio-Oncology council proposes the grounds for creating C-O Services in Europe based on expert opinion.

Aims\ud Heart failure (HF) is frequently caused by an ischaemic event (e.g. myocardial infarction) but might also be caused by a primary disease of the myocardium (cardiomyopathy). In order to identify targeted therapies specific for either ischaemic or non‐ischaemic HF, it is important to better understand differences in underlying molecular mechanisms.\ud \ud Methods and results\ud We performed a biological physical protein–protein interaction network analysis to identify pathophysiological pathways distinguishing ischaemic from non‐ischaemic HF. First, differentially expressed plasma protein biomarkers were identified in 1160 patients enrolled in the BIOSTAT‐CHF study, 715 of whom had ischaemic HF and 445 had non‐ischaemic HF. Second, we constructed an enriched physical protein–protein interaction network, followed by a pathway over‐representation analysis. Finally, we identified key network proteins. Data were validated in an independent HF cohort comprised of 765 ischaemic and 100 non‐ischaemic HF patients. We found 21/92 proteins to be up‐regulated and 2/92 down‐regulated in ischaemic relative to non‐ischaemic HF patients. An enriched network of 18 proteins that were specific for ischaemic heart disease yielded six pathways, which are related to inflammation, endothelial dysfunction superoxide production, coagulation, and atherosclerosis. We identified five key network proteins: acid phosphatase 5, epidermal growth factor receptor, insulin‐like growth factor binding protein‐1, plasminogen activator urokinase receptor, and secreted phosphoprotein 1. Similar results were observed in the independent validation cohort.\ud \ud Conclusions\ud Pathophysiological pathways distinguishing patients with ischaemic HF from those with non‐ischaemic HF were related to inflammation, endothelial dysfunction superoxide production, coagulation, and atherosclerosis. The five key pathway proteins identified are potential treatment targets specifically for patients with ischaemic HF.

Aims We sought to describe the clinical presentation, management, and 6-month outcomes in women with peripartum cardiomyopathy (PPCM) globally. Methods and results In 2011, >100 national and affiliated member cardiac societies of the European Society of Cardiology (ESC) were contacted to contribute to a global registry on PPCM, under the auspices of the ESC EURObservational Research Programme. These societies were tasked with identifying centres who could participate in this registry. In low-income countries, e.g. Mozambique or Burkina Faso, where there are no national societies due to a shortage of cardiologists, we identified potential participants through abstracts and publications and encouraged participation into the study. Seven hundred and thirty-nine women were enrolled in 49 countries in Europe (33%), Africa (29%), Asia-Pacific (15%), and the Middle East (22%). Mean age was 31 ± 6 years, mean left ventricular ejection fraction (LVEF) was 31 ± 10%, and 10% had a previous pregnancy complicated by PPCM. Symptom-onset occurred most often within 1 month of delivery (44%). At diagnosis, 67% of patients had severe (NYHA III/IV) symptoms and 67% had a LVEF ≤35%. Fifteen percent received bromocriptine with significant regional variation (Europe 15%, Africa 26%, Asia-Pacific 8%, the Middle East 4%, P 50%) occurred only in 46%, most commonly in Asia-Pacific (62%), and least commonly in the Middle East (25%). Neonatal death occurred in 5% with marked regional variation (Europe 2%, the Middle East 9%). Conclusion Peripartum cardiomyopathy is a global disease, but clinical presentation and outcomes vary by region. Just under half of women experience myocardial recovery. Peripartum cardiomyopathy is a disease with substantial maternal and neonatal morbidity and mortality.

Aims Recent international heart failure (HF) guidelines recognize anaemia as an important comorbidity contributing to poor outcomes in HF, based on data mainly from Western populations. We sought to determine the prevalence, clinical correlates, and prognostic impact of anaemia in patients with HF with reduced ejection fraction across Asia. Methods and results We prospectively studied 3886 Asian patients (60 ± 13 years, 21% women) with HF (ejection fraction ≤40%) from 11 regions in the Asian Sudden Cardiac Death in Heart Failure study. Anaemia was defined as haemoglobin

BackgroundGenome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear.ResultsHere, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction.ConclusionsOur approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.

BACKGROUND: Obese subjects have lower natriuretic peptide levels, but males and females have different anthropometric characteristics and fat distribution. Whether obesity-associated lowering of natriuretic peptides differs among males and females is unknown. Therefore, we investigated sex-specific associations of obesity and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels among adults in the general population. METHODS AND RESULTS: Using 8260 participants (50.1% females) from the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) cohort, we evaluated the relationship of NT-proBNP levels with obesity-associated parameters, i.e. waist circumference (WC), body mass index (BMI) and body weight in the overall population, and in males and females separately. NT-proBNP levels were higher in females (median, interquartile range: 50.5, 28.2-87.0 ng/L) than in males (24.3, 10.1-54.6 ng/L; P

Peripartum cardiomyopathy is an idiopathic cardiomyopathy presenting with heart failure secondary to left ventricular systolic dysfunction towards the end of pregnancy or in the months following delivery, where no other cause for heart failure is identified. Outcome varies from full recovery to residual left ventricular systolic dysfunction and even death. Many women return to their physician to acquire information on their long‐term prognosis, to seek medical advice regarding contraception, or when planning a subsequent pregnancy. This position paper summarizes current evidence for long‐term outcome, risk stratification of further pregnancies and overall management. Based on the best available evidence, as well as the clinical experience of the European Society of Cardiology Study Group on Peripartum Cardiomyopathy members, a consensus on pre‐ and postpartum management algorithms for women undergoing a subsequent pregnancy is presented.

AIMS: Iron deficiency is common in patients with heart failure and associated with a poor cardiac function and higher mortality. How iron deficiency impairs cardiac function on a cellular level in the human setting is unknown. This study aims to determine the direct effects of iron deficiency and iron repletion on human cardiomyocytes. METHODS AND RESULTS: Human embryonic stem cell-derived cardiomyocytes were depleted of iron by incubation with the iron chelator deferoxamine (DFO). Mitochondrial respiration was determined by Seahorse Mito Stress test, and contractility was directly quantified using video analyses according to the BASiC method. The activity of the mitochondrial respiratory chain complexes was examined using spectrophotometric enzyme assays. Four days of iron depletion resulted in an 84% decrease in ferritin (P < 0.0001) and significantly increased gene expression of transferrin receptor 1 and divalent metal transporter 1 (both P < 0.001). Mitochondrial function was reduced in iron-deficient cardiomyocytes, in particular ATP-linked respiration and respiratory reserve were impaired (both P < 0.0001). Iron depletion affected mitochondrial function through reduced activity of the iron-sulfur cluster containing complexes I, II and III, but not complexes IV and V. Iron deficiency reduced cellular ATP levels by 74% (P < 0.0001) and reduced contractile force by 43% (P < 0.05). The maximum velocities during both systole and diastole were reduced by 64% and 85%, respectively (both P < 0.001). Supplementation of transferrin-bound iron recovered functional and morphological abnormalities within 3 days. CONCLUSION: Iron deficiency directly affects human cardiomyocyte function, impairing mitochondrial respiration, and reducing contractility and relaxation. Restoration of intracellular iron levels can reverse these effects.

Background:\ud Hyperkalaemia is a common co-morbidity in patients with heart failure with reduced ejection fraction (HFrEF). Whether it affects the use of renin–angiotensin–aldosterone system inhibitors and thereby negatively impacts outcome is unknown. Therefore, we investigated the association between potassium and uptitration of angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB) and its association with outcome.\ud \ud Methods and results:\ud Out of 2516 patients from the BIOSTAT-CHF study, potassium levels were available in 1666 patients with HFrEF. These patients were sub-optimally treated with ACEi/ARB or beta-blockers and were anticipated and encouraged to be uptitrated. Potassium levels were available at inclusion and at 9 months. Outcome was a composite of all-cause mortality and heart failure hospitalization at 2 years. Patients' mean age was 67 ± 12 years and 77% were male. At baseline, median serum potassium was 4.3 (interquartile range 3.9–4.6) mEq/L. After 9 months, 401 (24.1%) patients were successfully uptitrated with ACEi/ARB. During this period, mean serum potassium increased by 0.16 ± 0.66 mEq/L (P 0.5 for all).\ud \ud Conclusion:\ud Higher potassium levels are an independent predictor of enduring lower dosages of ACEi/ARB. Higher potassium levels do not attenuate the beneficial effects of ACEi/ARB uptitration.

Background Serial measurement of natriuretic peptides may guide management in heart failure (HF) patients. In previous trials, natriuretic peptides were infrequently monitored, which may undervalue the benefit of this approach. Methods and results HOME was an adaptive three-arm randomized clinical study to test whether home monitoring of BNP could reduce HF-related death, hospitalization due to acute decompensated HF (ADHF), and ADHF treated with intravenous diuretics in the emergency department or outpatient setting. Enrolment was terminated early because of slow enrolment, low event rates, and the belief that an algorithm for assessing BNP trends was needed. Justification for pooling data from all study arms was made and analysis as a single observational study was performed. The analysis resulted in 107 patients who were monitored for a median of 172 days with BNP measures on a median of 74% of days. BNP values were highly variable within a patient. Dispersion between serial BNPs was calculated to be 39.3%, 57.7%, and 73.6% for 1, 60, and 120 days between measures, respectively. A moving average filter (fBNP) was calculated to reduce day-to-day fluctuations and track changes from week to week. There were 27 primary events in 17 362 patient days of monitoring; the hazard ratio for time-varying fBNP was 2.22 (95% confidence interval 1.48-3.34) per unit natural log (corresponding to a 2.72-fold change in fBNP level). Conclusion The HOME HF study demonstrates the feasibility of home BNP measurement and shows the potential value of fBNP as an index of emerging clinical deterioration. Assessment of the clinical value of this is required.

Aims N-terminal pro-B-type natriuretic peptide (NT-proBNP) is the most frequently used biomarker in heart failure (HF), but its prognostic utility across ethnicities is unclear. Methods and results This study included 546 Caucasians with HF from the Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure and 578 Asians with HF from the Singapore Heart Failure Outcomes and Phenotypes study. NT-proBNP was measured at discharge after HF hospitalization. The studied outcome was a composite of all-cause mortality and HF hospitalization at 18 months. Compared with Caucasian patients, Asian patients were younger (63 +/- 12 vs. 71 +/- 11 years); less often female (26% vs. 39%); and had lower body mass index (26 vs. 27 kg/m(2)), better renal function (61 +/- 37 vs. 54 +/- 20 mL/min/1.73 m(2)), lower rates of atrial fibrillation (25% vs. 46%), strikingly higher rates of diabetes (59% vs. 30%), and higher rates of hypertension (76% vs. 44%). Despite these clear inter-group differences in individual drivers of NT-proBNP, average levels were similar in Asians [2709 (1350, 6302) pg/mL] and Caucasians [2545 (1308, 5484) pg/mL] (P = 0.514). NT-proBNP was strongly associated with outcome [hazard ratio 1.28 (per doubling), 95% confidence interval 1.18-1.39, P

Aims To investigate the prevalence of iron deficiency (ID) in heart failure (HF) patients with normal vs. abnormal red cell indices (RCI), the associations between iron parameters and RCI, and prognostic consequences of ID independently of RCI. Methods and results We analysed clinical data of 1821 patients with HF [mean age 66 13 years; 71% men; New York Heart Association class I/II/III/IV (11%/39%/44%/6%); left ventricular ejection fraction >45%: 19%]. Iron deficiency (ferritin Conclusions Patients with HF should be routinely screened for ID irrespective of the presence of anaemia or abnormal RCI. The detrimental impact of ID on long-term survival in HF is partially independent of RCI.

Background Hyperkalaemia is a common co-morbidity in patients with heart failure with reduced ejection fraction (HFrEF). Whether it affects the use of renin-angiotensin-aldosterone system inhibitors and thereby negatively impacts outcome is unknown. Therefore, we investigated the association between potassium and uptitration of angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB) and its association with outcome. Methods and results Out of 2516 patients from the BIOSTAT-CHF study, potassium levels were available in 1666 patients with HFrEF. These patients were sub-optimally treated with ACEi/ARB or beta-blockers and were anticipated and encouraged to be uptitrated. Potassium levels were available at inclusion and at 9 months. Outcome was a composite of all-cause mortality and heart failure hospitalization at 2 years. Patients' mean age was 67 +/- 12 years and 77% were male. At baseline, median serum potassium was 4.3 (interquartile range 3.9-4.6) mEq/L. After 9 months, 401 (24.1%) patients were successfully uptitrated with ACEi/ARB. During this period, mean serum potassium increased by 0.16 +/- 0.66 mEq/L (P 0.5 for all). Conclusion Higher potassium levels are an independent predictor of enduring lower dosages of ACEi/ARB. Higher potassium levels do not attenuate the beneficial effects of ACEi/ARB uptitration.

Aims: \ud A higher body mass index (BMI) is associated with better survival in heart failure (HF) patients, also known as the obesity paradox. However, BMI does not account for body composition. We therefore analysed the association between abdominal fat, measured via waist‐to‐hip ratio (WHR), BMI and all‐cause mortality in patients with HF.\ud \ud Methods and results: \ud For this analysis, 1738 patients from the Scottish BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT‐CHF) validation study were included. Patients without waist and hip measurements were excluded. WHR was defined as waist circumference/hip circumference, divided into tertiles and split for sex. A linear regression of principal components from an extensive panel of biomarkers was performed to provide insight in the pathophysiology behind a higher WHR. In total, 1479 patients were included, of which 33% were female and mean age was 75 ±11 years. A higher WHR was independently associated with a higher BMI, a higher prevalence of diabetes and higher New York Heart Association functional class. There was a significant interaction between sex and WHR on its association with mortality (P

AIMS: Although echocardiography is generally used for the diagnosis of heart failure with preserved ejection fraction (HFpEF), invasive measurements of filling pressures are the gold standard. Studies simultaneously performing echocardiography and invasive measurements in HFpEF are sparse. METHODS AND RESULTS: Invasive haemodynamic and echocardiographic measurements were simultaneously performed in 98 patients with heart failure New York Heart Association class ≥II, left ventricular ejection fraction (LVEF) ≥45%, and suspected pulmonary hypertension on a previous echocardiogram. Multivariable linear regression analyses were used to establish echocardiographic predictors of pulmonary artery wedge pressure (PAWP), left ventricular end-diastolic pressure (LVEDP), and mean pulmonary arterial pressure (mPAP). Mean age of the study patients was 74 ± 9 years, 68% were female, mean LVEF was 57 ± 5%, and 30% had atrial fibrillation at the time of measurement. Mean PAWP, LVEDP and mPAP were 17.2 ± 6.2, 16.7 ± 5.8 and 30.9 ± 10.2 mmHg, respectively. Isovolumetric relaxation time (IVRT) and left atrial reservoir strain could moderately estimate PAWP (r = 0.656; P

Background—Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association.\ud \ud Methods and Results—Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (P