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Abstract The cardiac conduction system in large carnivores, such as the African lion (Panthera leo), represents a significant knowledge gap in both veterinary science and in cardiac electrophysiology. Short QT intervals have been reported from zoo‐kept, anaesthetized lions, and our goal was to record the first ECGs from wild, conscious lions roaming freely, and compare them to zoo‐kept lions under the hypothesis that short QT is unique to zoo‐kept lions. Macroscopic and histological examinations were performed on heart tissue removed from nine healthy zoo lions. ECGs were recorded from the nine anaesthetized zoo‐kept lions, and from 15 anaesthetized and conscious wild lions in Africa. Our histological and topographical description of the lion's heart matched what has previously been published. In conscious lions, the ECG recordings revealed a mean heart rate of 70 ± 4 beats/min, with faster heart rates during the night. PQ and QT intervals were heart rate dependent in the conscious lions. Interestingly, QT intervals recorded in wild lions were markedly longer than QT intervals from zoo lions (398 ± 40 vs. 297 ± 9 ms, respectively; P

Cancer of unknown primary (CUP) tumors are biologically very heterogeneous, which complicates stratification of patients for treatment. Consequently, these patients face limited treatment options and a poor prognosis. With this study, we aim to expand on the current knowledge of CUP biology by analyzing two cohorts: a well‐characterized cohort of 44 CUP patients, and 213 metastatic patients with known primary. These cohorts were treated at the same institution and characterized by identical molecular assessments. Through comparative analysis of genomic and transcriptomic data, we found that CUP tumors were characterized by high expression of immune‐related genes and pathways compared to other metastatic tumors. Moreover, CUP tumors uniformly demonstrated high levels of tumor‐infiltrating leukocytes and circulating T cells, indicating a strong immune response. Finally, the genetic landscape of CUP tumors resembled that of other metastatic cancers and demonstrated mutations in established cancer genes. In conclusion, CUP tumors possess a distinct immunophenotype that distinguishes them from other metastatic cancers. These results may suggest an immune response in CUP that facilitates metastatic tumor growth while limiting growth of the primary tumor.

ABSTRACT Purpose Carbonic anhydrase IX (CAIX) is a well‐established prognostic marker in breast cancer (BC). Nevertheless, this prognostic value is yet to be confirmed in BC subtypes. This study aims to investigate the prognostic effects of CAIX in oestrogen receptor (ER)‐negative (ER−) BCs and to establish pathways related to cytoplasmic CAIX expression in ER− and lymph node‐negative BCs. Methods Immunohistochemistry was performed to identify the prognostic role of CAIX protein expression in ER− tissue microarrays (TMAs) (n = 191). CAIX‐positive samples (n = 37) were transcriptionally profiled by TempO‐Seq and analysed by STRING. Real‐time quantitative PCR (RT‐qPCR) analysis was used to validate differentially expressed genes. Results Overexpression of cytoplasmic CAIX was an independent predictor of recurrence free survival, disease‐free survival and overall survival in ER− cohort. RNA transcriptomic analysis identified 10 significant genes in ER− cohort and 3 genes in the node‐negative group. The STRING database demonstrated a significant interaction between MUCL1 and GALNT6, which were linked with extracellular matrix organisation, degradation of the extracellular matrix and disease of glycosylation pathways. In the node‐negative group, SPNS2 is mainly involved in the sphingolipid de novo biosynthesis pathway. A significant correlation between cytoplasmic SphK1 and cytoplasmic hypoxia‐inducible factor‐1α was observed. Among the 10 genes, 7 genes (SERHL2, GALNT6, MUCL1, MMP7, PITX2, CEACAM6 and SPNS2) were selected, and their expression was quantitatively assessed by RT‐qPCR. The PCR data of these genes showed that SERHL2, GALNT6, MUCL1, PITX2, and SPNS2 mRNA levels were expressed in MDA‐MB‐231 BC cell lines at variable levels of hypoxic exposure. Conclusion Cytoplasmic CAIX was independently associated with poor prognosis in ER− BC. Gene expression profiles shed light on the pathways and genes associated with hypoxia in ER− BC. In node‐negative patients, SPNS2 was of particular interest.

Abstract Background Patients suffering from chronic spontaneous urticaria (CSU) are typically classified as type I or type IIb autoimmune CSU, but further patient stratification is hindered by the lack of biomarkers. Objectives We investigated whether the histamine content of individual basophils differ between patient subtypes in CSU to evaluate its potential as a biomarker. Methods A total of 101 patients diagnosed with CSU were included in the study. The histamine content per circulating basophil was derived from the basophil count in peripheral blood and levels of total cellular blood histamine. These measures, together with results from the serum‐induced basophil histamine release assay (s‐BHRA), were correlated to information on demographics, clinical characteristics, patient reported outcomes and laboratory analyses. Results The histamine content per basophil was significantly different between s‐BHRA positive and ‐negative patients (0.175 vs. 1.40 pg/cell, p

Abstract Background Heart failure due to myocardial infarction (MI) involves fibrosis driven by epicardium‐derived cells (EPDCs) and cardiac fibroblasts, but strategies to inhibit and provide cardio‐protection remains poor. The imprinted gene, non‐canonical NOTCH ligand 1 (Dlk1), has previously been shown to mediate fibrosis in the skin, lung and liver, but very little is known on its effect in the heart. Methods Herein, human pericardial fluid/plasma and tissue biopsies were assessed for DLK1, whereas the spatiotemporal expression of Dlk1 was determined in mouse hearts. The Dlk1 heart phenotype in normal and MI hearts was assessed in transgenic mice either lacking or overexpressing Dlk1. Finally, in/ex vivo cell studies provided knowledge on the molecular mechanism. Results Dlk1 was demonstrated in non‐myocytes of the developing human myocardium but exhibited a restricted pericardial expression in adulthood. Soluble DLK1 was twofold higher in pericardial fluid (median 45.7 [34.7 (IQR)) μg/L] from cardiovascular patients (n = 127) than in plasma (median 26.1 μg/L [11.1 (IQR)]. The spatial and temporal expression pattern of Dlk1 was recapitulated in mouse and rat hearts. Similar to humans lacking Dlk1, adult Dlk1−/− mice exhibited a relatively mild developmental, although consistent cardiac phenotype with some abnormalities in heart size, shape, thorax orientation and non‐myocyte number, but were functionally normal. However, after MI, scar size was substantially reduced in Dlk1−/− hearts as compared with Dlk1+/+ littermates. In line, high levels of Dlk1 in transgenic mice Dlk1fl/flxWT1GFPCre and Dlk1fl/flxαMHCCre/+Tam increased scar size following MI. Further mechanistic and cellular insight demonstrated that pericardial Dlk1 mediates cardiac fibrosis through epithelial to mesenchymal transition (EMT) of the EPDC lineage by maintaining Integrin β8 (Itgb8), a major activator of transforming growth factor β and EMT. Conclusions Our results suggest that pericardial Dlk1 embraces a, so far, unnoticed role in the heart augmenting cardiac fibrosis through EMT. Monitoring DLK1 levels as well as targeting pericardial DLK1 may thus offer new venues for cardio‐protection.

Abstract Colorectal cancer (CRC) is a heterogenous malignancy and research is focused on identifying novel ways to subtype patients. In this study, a novel classification system, tumour microenvironment score (TMS), was devised based on Klintrup–Mäkinen grade (KMG), tumour stroma percentage (TSP), and tumour budding. TMS was performed using a haematoxylin and eosin (H&E)‐stained section from retrospective CRC discovery and validation cohorts (n = 1,030, n = 787). TMS0 patients had high KMG, TMS1 were low for KMG, TSP, and budding, TMS2 were high for budding, or TSP and TMS3 were high for TSP and budding. Scores were assessed for association with survival and clinicopathological characteristics. Mutational landscaping and Templated Oligo‐Sequencing (TempO‐Seq) profiling were performed to establish differences in the underlying biology of TMS. TMS was independently prognostic in both cohorts (p

Abstract Introduction Triple‐negative breast cancer (TNBC) patients have the poorest clinical outcomes compared to other molecular subtypes of breast cancer. IL6/JAK/STAT3 signalling is upregulated in breast cancer; however, there is limited evidence for its role in TNBC. This study aimed to assess the expression of IL6/JAK/STAT3 in TNBC as a prognostic biomarker. Methods Tissue microarrays consisting of breast cancer specimens from a retrospective cohort (n = 850) were stained for IL6R, JAK1, JAK2 and STAT3 via immunohistochemistry. Staining intensity was assessed by weighted histoscore and analysed for association with survival/clinical characteristics. In a subset of patients (n = 14) bulk transcriptional profiling was performed using TempO‐Seq. Nanostring GeoMx® digital spatial profiling was utilised to establish the differential spatial gene expression in high STAT3 tumours. Results In TNBC patients, high expression of stromal STAT3 was associated with reduced cancer‐specific survival (HR = 2.202, 95% CI: 1.148–4.224, log rank p = 0.018). TNBC patients with high stromal STAT3 had reduced CD4+ T‐cell infiltrates within the tumour (p = 0.001) and higher tumour budding (p = 0.003). Gene set enrichment analysis (GSEA) of bulk RNA sequencing showed high stromal STAT3 tumours were characterised by enrichment of IFNγ, upregulation of KRAS signalling and inflammatory signalling Hallmark pathways. GeoMx™ spatial profiling showed high stromal STAT3 samples. Pan cytokeratin (panCK)‐negative regions were enriched for CD27 (p

Abstract Background Studies report an elevated risk of maltreatment in children with attention deficit/hyperactivity disorder (ADHD), and elevated levels of ADHD in people who suffered childhood maltreatment (CM). However, the direction(s) of causality between CM and ADHD remain unclear—does ADHD create a context for CM, does CM cause ADHD, or both? Objective This study systematically reviews and qualitatively synthesizes the research evidence relating to this question using Bradford‐Hill criteria for establishing causality—strength, temporality, dose‐response and plausibility. Methods We conducted a systematic review, following PRISMA guidelines, of prospective longitudinal studies examining both CM and ADHD. We then used Bradford‐Hill criteria to assess the quality of evidence for a causal link between CM and ADHD. Results All 11 included studies demonstrated an association between CM and ADHD. Seven included evidence for temporality: five suggesting that CM precedes ADHD in the lifespan; two suggesting ADHD precedes CM. Four studies demonstrated a dose response relationship in which greater CM exposure was associated with elevated risk of ADHD. Studies presented a range of plausible mechanisms, including CM causing ADHD through biological programming, versus ADHD causing CM through parental stress. Conclusions The high quality prospective longitudinal studies reviewed confirm the association between ADHD and CM, but present conflicting evidence about the direction of causality and mechanisms underpinning this association. To better understand the complex interplay between CM and ADHD, more studies using new research designs will be required that can partition effects by type of CM and account for bidirectional effects and other complexities.

Abstract Background Hidradenitis suppurativa (HS) is a chronic inflammatory disease of recurrent painful nodules and sinus tracts mainly located in intertriginous skin areas. HS can cause physical and psychosocial impairments, and patients have a need for information and social support. Objectives An educational event was established to accommodate the aforementioned patient needs. The event presents updated information concerning HS and debates the lived experience of HS. This article outlines our approach to patient education. Methods The educational HS‐event has yearly welcomed patients and relatives at Roskilde hospital since 2010—except in year 2020 due to corona‐legislation. The educational content includes information on HS aetiology, epidemiology, treatment, psychosocial aspects of HS and current research. The team of educators is multidisciplinary and includes patients. Results Twelve thematic patient reported questions and concerns reoccur at the events. They include: The aetiology of HS and lifestyle, daily life, employment and economy, emotions, locations of lesions, heredity, comorbidities, self‐care to alleviate symptoms, treatment, the healthcare system, prognosis and new research. The participants are satisfied with the arrangement. Conclusion Educational activities such as the one outlined in this manuscript provides requested information, coping strategies social support. Studies are needed to investigate if systematic education of HS patients improves subjective and objectives measures. Plain abstract Patient education is an important part of disease management. It is essential to share different experiences and practices of patient education to optimize and inspire future educational programs. This study presents a decade of experiences from an annual event that has educated patients with the skin disease Hidradenitis suppurativa (HS). HS is a chronic inflammatory disease that causes skin abscess, nodules, and substantial scarring. The abscesses are extremely painful and located in areas of the body with skin‐to‐skin contact. Due to the painful condition the disease can cause both physical as well as psychological and social difficulties, and the patient group have a need for medical information and social support. In 2010 Roskilde hospital established an annual educational event for patients with HS and their relatives. The educational content includes general information regarding the disease, medical and surgical therapy options, psychosocial aspects of HS, and the latest scientific research concerning HS. The team of educators includes dermatologists, medical and PhD students, experts in psychology, representatives from the HS Patient Association and patients. In this study we outline our approach to patient education for those with HS and their relatives and present the participants' questions and comments as raised at these events. Arrangements such as this can be used to support the patients with the information needed to better understand their disease, but also to facilitate coping strategies and provide a framework for social support. Other studies are needed to investigate if education of patients with HS can improve subjective or objective measures.

Abstract Pharmacokinetics is the cornerstone of understanding drug absorption, distribution, metabolism, and elimination. It is also the key to describing variability in drug response caused by drug‐drug interactions (DDIs), pharmacogenetics, impaired kidney and liver function, etc. This tutorial aims to provide a guideline and step‐by‐step tutorial on essential considerations when designing clinical pharmacokinetic studies and reporting results. This includes a comprehensive guide on how to conduct the statistical analysis and a complete code for the statistical software R. As an example, we created a mock dataset simulating a clinical pharmacokinetic DDI study with 12 subjects who were administered 2 mg oral midazolam with and without an inducer of cytochrome P450 3A. We provide a step‐by‐step guide to the statistical analysis of this clinical pharmacokinetic study, including sample size/power calculation, descriptive statistics, noncompartmental analyses, and hypothesis testing. The different analyses and parameters are described in detail, and we provide a complete R code ready to use in supplementary files. Finally, we discuss important considerations when designing and reporting clinical pharmacokinetic studies. The scope of this tutorial is not limited to DDI studies, and with minor adjustments, it applies to all types of clinical pharmacokinetic studies. This work was done by early career researchers for early career researchers. We hope this tutorial may help early career researchers when getting started on their own pharmacokinetic studies. We encourage you to use this as an inspiration and starting point and continuously evolve your statistical skills.

Abstract The choroid plexus secrets cerebrospinal fluid (CSF) composed of electrolytes, cytokines, growth factors, metabolites and extracellular vesicles (EVs) that flow through the interconnected brain ventricles. On their course, CSF components can act as signals that affect, for example, neural stem cells (NSCs) residing in niches of the ventricular wall. We studied EV‐born CSF signals in an in vitro culture system. We purified EVs from the secretome of a choroid plexus cell line (Z310 cells), and from primary choroid plexus cultures and co‐cultured those EVs with NSCs isolated from the niche of the lateral and the third ventricle. EVsZ310 and EVsCHP were purified by differential centrifugation. This yielded fractions of EVs of 50–150‐nm diameter that induced a complex multicellular network formation and NSC differentiation. Both types of EV converted the round NSCs to cells that extended long processes that contacted nearby, alike‐shaped cells. Mass spectrometry showed that the differentiation‐inducing EVZ310 were enriched for membrane and membrane‐associated proteins involved in cell differentiation, membrane trafficking, and membrane organization. We hypothesize that this type of EV Z310 cargo causes changes of stem cell morphology that leads to multicellular networks in the niches. This cell‐shape transition may represent an initial step in NSC differentiation.

Summary The fluorinase enzyme represents the only biological mechanism capable of forming stable C–F bonds characterized in nature thus far, offering a biotechnological route to the biosynthesis of value‐added organofluorines. The fluorinase is known to operate in a hexameric form, but the consequence(s) of the oligomerization status on the enzyme activity and its catalytic properties remain largely unknown. In this work, this aspect was explored by rationally engineering trimeric fluorinase variants that retained the same catalytic rate as the wild‐type enzyme. These results ruled out hexamerization as a requisite for the fluorination activity. The Michaelis constant (KM) for S‐adenosyl‐l‐methionine, one of the substrates of the fluorinase, increased by two orders of magnitude upon hexamer disruption. Such a shift in S‐adenosyl‐l‐methionine affinity points to a long‐range effect of hexamerization on substrate binding – likely decreasing substrate dissociation and release from the active site. A practical application of trimeric fluorinase is illustrated by establishing in vitro fluorometabolite synthesis in a bacterial cell‐free system.

Abstract Diagnosis and management of chronic kidney disease (CKD) requires accurate assessment of glomerular filtration rate (GFR). In practice, GFR is typically estimated by equations based on creatinine concentration in blood, but creatinine is affected by non‐GFR factors such as age and sex. Alternative filtration markers such as cystatin C, beta‐trace protein (BTP), and beta‐2 microglobulin (B2M) may be less dependent on age and sex, but equations combining these markers have not been investigated in patients with chronic kidney disease (CKD). In this cross‐sectional study of 50 patients with CKD stage 3–4, we compared kidney function estimates based on creatinine, cystatin C, BTP, B2M, or a combination of markers. Compared to the creatinine/cystatin C combination equation, the panel equation yielded a mean difference of only 2.8 ml/min/1.73 m2, indicating that switching to the panel equation would be unlikely to affect management.

Background Left atrial (LA) volumes and emptying fraction in the general population may address structural and functional aspects of atrial cardiomyopathy associated with long‐term risk of ischemic stroke in the absence of atrial fibrillation or prior stroke. We investigated the association between LA volumes and function and ischemic stroke. Methods and Results In a community‐based cohort, we measured LA minimal volume, LA maximal volume, and LA emptying fraction by transthoracic echocardiography. The primary end point was ischemic stroke. Participants with known atrial fibrillation or prior ischemic stroke were excluded, which resulted in 1866 participants. The mean age was 58±16 years, and 57% were women. During a median follow‐up of 16.5 years (interquartile range: 11.4–16.8 years), 176 (9.4%) ischemic strokes occurred. In multivariable cause‐specific regression models and competing risk models with death as a competing risk, LA emptying fraction was associated with ischemic stroke (hazard ratio [HR], 1.14 per 10% decrease [95% CI, 1.02–1.28]) and (subdistribution HR, 1.14 [95% CI, 1.01–1.29]). This association remained when adjusting for participants who developed atrial fibrillation during follow‐up (HR, 1.12 per 10% decrease [95% CI, 1.00–1.26]). Indexed LA volumes were not associated with ischemic stroke in the same models. LA emptying fraction and indexed LA volumes were not associated with all‐cause mortality. Conclusions Lower LA emptying fraction measured by transthoracic echocardiography was associated with future ischemic stroke independently of incident atrial fibrillation. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02993172.

Abstract Arteriovenous fistulas (AVFs) are iatrogenic vascular connections established to allow high‐flow intravascular access for patients with chronic kidney disease requiring hemodialysis. The left‐right flow shunt results in changes in extracellular fluid volume and blood pressure‐controlling hormones that could affect the residual kidney function. We present a case where a female patient with a brachiocephalic AVF had a fistula flow of >4 L/min. To reduce the flow, a banding procedure was performed. The patient was examined prior to banding and 1 and 2 weeks thereafter. Banding resulted in a marked decrease in AVF flow from >4 to 1 L/min and was associated with reductions in N‐terminal pro‐brain natriuretic peptide of 51% and 67% at 1‐ and 2‐weeks post‐banding, respectively. Mid‐regional pro‐atrial natriuretic peptide concentrations were reduced post‐banding by 17% after 1 week and 25% after 2 weeks. After 1 week, renin, angiotensin II, and aldosterone levels in plasma decreased transiently by 44%, 47%, and >86%, respectively, and returned to pre‐banding levels after 2 weeks. Creatinine clearance tended to decrease while blood pressure and total body water increased 2 weeks after banding. This indicates that high‐flow AVF is associated with increased natriuretic peptides and hormones of the renin–angiotensin–aldosterone system, that may balance each other regarding fluid retention and hypertension and support remaining kidney function.

Abstract China is one of the most species‐rich countries in the world, harboring many rare gymnosperms. Following recent human‐led loss of forests, China is now experiencing increases in forest cover resulting from efforts of reforestation schemes. As anthropogenic activities have previously been found to interact with topography in shaping forest cover in China and considering the large human population and the ongoing population increase of the country, it is important to understand the role of anthropogenic pressures relative to environmental drivers for shaping species distributions here. Based on the well‐established relationship between human population density and topography, we propose a hypothesis for explaining species distributions in a country dominated by human activities, predicting that species are more likely to occur in areas of steep topography under medium human population densities compared to low and high human population densities. Using species occurrence data from the Chinese Vascular Plant Distribution Database along with a common SDM method (maximum entropy modeling), we tested this hypothesis. Our results show that steep topography has the highest importance for predicting Chinese gymnosperm species occurrences in general, and threatened species specifically, in areas of medium human population densities. Consequently, these species are more often found in areas of steep terrain, supporting the proposed hypothesis. Results from this study highlight the need to include topographically heterogeneous habitats when planning new protected areas for species conservation.

Abstract Background Associations between body mass index (BMI), outcome, and leukemia‐related factors in children with acute myeloid leukemia (AML) remain unclear. We investigated associations between pretherapeutic BMI, cytogenetic abnormalities, and outcome in a large multinational cohort of children with AML. Methods We included patients, age 2‐17 years, diagnosed with de novo AML from the five Nordic countries (2004‐2016), Hong Kong (2007‐2016), the Netherlands and Belgium (2010‐2016), and Canada and USA (1995‐2012). BMI standard deviations score for age and sex was calculated and categorized according to the World Health Organization. Cumulative incidence functions, Kaplan‐Meier estimator, Cox regression, and logistic regression were used to investigate associations. Results In total, 867 patients were included. The median age was 10 years (range 2‐17 years). At diagnosis, 32 (4%) were underweight, 632 (73%) were healthy weight, 127 (15%) were overweight, and 76 (9%) were obese. There was no difference in relapse risk, treatment‐related mortality or overall mortality across BMI groups. The frequency of t(8;21) and inv(16) increased with increasing BMI. For obese patients, the sex, age, and country adjusted odds ratio of having t(8;21) or inv(16) were 1.9 (95% confidence interval (CI) 1.1‐3.4) and 2.8 (95% CI 1.3‐5.8), respectively, compared to healthy weight patients. Conclusions This study did not confirm previous reports of associations between overweight and increased treatment‐related or overall mortality in children. Obesity was associated with a higher frequency of t(8;21) and inv(16). AML cytogenetics appear to differ by BMI status.

Background. The enteroendocrine hormone glucagon-like peptide- (GLP-) 2 is a potent trophic factor in the gastrointestinal tract. The GLP-2 receptor (GLP-2R) is expressed in the stroma of the large bowel wall, which is the major therapeutic target area to prevent anastomotic leakage. We investigated the efficacy of the long-acting GLP-2 analogue ZP1849 on colonic anastomotic wound healing. Methods. Eighty-seven male Wistar rats were stratified into four groups and received daily treatment with vehicle or ZP1849 starting one day before (day -1) end-to-end anastomosis was constructed in the left colon on day 0, and on days 0 (resected colon segment), 3, and 5, gene expressions of GLP-2R, Ki67, insulin-like growth factor- (IGF-) 1, type I (COL1A1) and type III (COL3A1) procollagens, cyclooxygenase- (COX-) 1, COX-2, and matrix metalloproteinase- (MMP-) 7 were quantified by RT-qPCR. Breaking strength, myeloperoxidase (MPO), transforming growth factor- (TGF-) β1, and soluble collagen proteins were measured on days 3 and 5. Results. ZP1849 treatment increased Ki67 (P

Abstract Aging decreases skeletal muscle mass and strength, but aerobic and resistance exercise training maintains skeletal muscle function. NAD+ is a coenzyme for ATP production and a required substrate for enzymes regulating cellular homeostasis. In skeletal muscle, NAD+ is mainly generated by the NAD+ salvage pathway in which nicotinamide phosphoribosyltransferase (NAMPT) is rate‐limiting. NAMPT decreases with age in human skeletal muscle, and aerobic exercise training increases NAMPT levels in young men. However, whether distinct modes of exercise training increase NAMPT levels in both young and old people is unknown. We assessed the effects of 12 weeks of aerobic and resistance exercise training on skeletal muscle abundance of NAMPT, nicotinamide riboside kinase 2 (NRK2), and nicotinamide mononucleotide adenylyltransferase (NMNAT) 1 and 3 in young (≤35 years) and older (≥55 years) individuals. NAMPT in skeletal muscle correlated negatively with age (r2 = 0.297, P

Background Cardiovascular disease remains a leading cause of death. Right ventricular (RV) function is a strong predictor of outcome in many cardiovascular diseases, but its significance is often neglected. Little is known about the prognostic value of RV systolic function in the general population. Therefore, we aimed to determine the prognostic value of RV systolic function, evaluated by tricuspid annular plane systolic excursion (TAPSE), in predicting cardiovascular death (CVD) in the general population. Methods and Results A total of 1039 participants from the general population without heart failure or atrial fibrillation had an echocardiogram performed and TAPSE measured. The end point was CVD. During a median follow‐up of 12.7 years (interquartile range, 12.0–12.9 years), 69 participants (6.6%) experienced CVD, whereas 162 participants (15.6%) experienced non‐CVD. Decreasing RV systolic function, assessed as TAPSE, was a univariable predictor of CVD (hazard ratio, 1.13; 95% CI, 1.07–1.20; P