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Importance: Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19., Objective: To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19., Design, Setting, and Participants: In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non-critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022)., Interventions: Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days., Main Outcomes and Measures: The primary outcome was organ support-free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes., Results: On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support-free days among critically ill patients was 10 (-1 to 16) in the ACE inhibitor group (n = 231), 8 (-1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support-free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively)., Conclusions and Relevance: In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes., Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.

Background: Bicuspid aortic valve (BAV) is associated with ascending aorta aneurysms and dissections. Presently, genetic factors and pathological flow patterns are considered responsible for aneurysm formation in BAV while the exact role of inflammatory processes remains unknown., Methods: In order to objectify inflammation, we employ a highly sensitive, quantitative immunohistochemistry approach. Whole slides of dissected, dilated and non-dilated ascending aortas from BAV patients were quantitatively analyzed., Results: Dilated aortas show a 4-fold increase of lymphocytes and a 25-fold increase in B lymphocytes in the adventitia compared to non-dilated aortas. Tertiary lymphoid structures with B cell follicles and helper T cell expansion were identified in dilated and dissected aortas. Dilated aortas were associated with an increase in M1-like macrophages in the aorta media, in contrast the number of M2-like macrophages did not change significantly., Conclusion: This study finds unexpected large numbers of immune cells in dilating aortas of BAV patients. These findings raise the question whether immune cells in BAV aortopathy are innocent bystanders or contribute to the deterioration of the aortic wall., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Staal, Cortenbach, Gorris, van der Woude, Srinivas, Heijmen, Geuzebroek, Grewal, Hebeda, de Vries, DeRuiter and van Kimmenade.)

Background: No clear guidelines exist for performing preventive surgery for ascending aortic (AA) aneurysm in elderly patients. This study aims to provide insights by: (1) evaluating patient and procedural characteristics and (2) comparing early outcomes and long-term mortality after surgery between elderly and non-elderly patients., Methods: A multicenter retrospective observational cohort-study was performed. Data was collected on patients who underwent elective AA surgery in three institutions (2006-2017). Clinical presentation, outcomes, and mortality were compared between elderly (≥70 years) and non-elderly patients., Results: In total, 724 non-elderly and 231 elderly patients were operated upon. Elderly patients had larger aortic diameters (57.0 mm (IQR 53-63) vs. 53.0 mm (IQR 49-58), p < 0.001) and more cardiovascular risk factors at the time of surgery than non-elderly patients. Elderly females had significantly larger aortic diameters than elderly males (59.5 mm (55-65) vs. 56.0 mm (51-60), p < 0.001). Short-term mortality was comparable between elderly and non-elderly patients (3.0% vs. 1.5%, p = 0.16). Five-year survival was 93.9% in non-elderly patients and 81.4% in elderly patients ( p < 0.001), which are both lower than that of the age-matched general Dutch population., Conclusion: This study showed that in elderly patients, a higher threshold exists to undergo surgery, especially in elderly females. Despite these differences, short-term outcomes were comparable between 'relatively healthy' elderly and non-elderly patients.

Background: Patients receiving thoracic aortic repair suffer from long-term impairment in daily functioning and quality of life following intervention due to a combination of their life-threatening condition (i.e. aortic aneurysm or dissection), undergoing major surgery, as well as long-term exercise restrictions thereafter. Despite the known risks of exercise, it is vital that patients regain physical activity in order to recover their daily functioning and quality of life. Cardiac rehabilitation could be a safe and effective treatment to support patients to become physically active by providing exercise training, comprehensive rehabilitation services, and safety recommendations. Despite new insights in recent literature and clinical practice, international guidelines do not recommend cardiac rehabilitation due to limited evidence. We aim to fill this knowledge gap by performing a systematic review and meta-analysis on the effectiveness of cardiac rehabilitation in patients following thoracic aortic repair., Methods: This protocol has been developed following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). MEDLINE, Embase, and CINAHL will be searched for eligible observational and interventional studies from inception up to April 2022. Screening (title/abstract and full text), data extraction, risk of bias assessment, and therapeutic validity rating will be conducted by two independent reviewers. A random-effects model will be used to meta-analyse performance-based outcomes, patient-reported outcomes, clinician-reported outcomes, and researcher-reported outcomes. Subsequently, meta-bias and confidence in evidence will be analysed by two independent reviewers., Discussion: To exercise or not to exercise in patients following thoracic aortic repair has been a topic of discussion for years. The intended systematic review and meta-analysis will provide comprehensive evidence on the effectiveness of phase III outpatient exercise-based cardiac rehabilitation in patients following thoracic aortic repair. Findings from this review may inform future guidelines for the management of patients with thoracic aortic disease., Systematic Review Registration: PROSPERO CRD42022301204., (© 2023. The Author(s).)

Background: Patients with chronic kidney disease (CKD) undergoing coronary catheterization are at increased risk of cardiovascular events (CVE). Measuring biomarkers before the procedure may guide clinicians in identifying patients at higher risk of future cardiovascular events., Methods: In this sub-study the Catheter Sampled Blood Archive in Cardiovascular Diseases (CASABLANCA), 927 patients underwent coronary catheterization and were followed up for two years. Using machine learning algorithm and targeted proteomics from samples of patients with CKD, 4 biomarkers (kidney injury molecule-1, N-terminal pro B-type natriuretic peptide, osteopontin, and tissue inhibitor of metalloproteinase-1) were integrated into a prognostic algorithm to predict CVE. Results from the panel are expressed in a graded fashion (CVE higher risk and lower risk) using a data-driven cutoff optimized for balanced sensitivity and specificity., Results: During the 2-year follow-up, 74 CVE were ascertained. 51 (rate: 51/378 = 13.5%) events occurred in stage 1-2 CKD and 23 (rate: 23/68 = 33.8%) events occurred in stage 3-5 CKD. The C-statistic for predicting 2-years cardiovascular events in all 446 patients was 0.77 (0.72, 0.82). The model was well-calibrated (Hosmer-Lemeshow test p-value >0.40). Considering patients at CVE lower-risk within each CKD staging group as a reference, the hazard ratio (95% confidence interval) of cardiovascular events was 2.82 (1.53, 5.22) for CKD stage 1-2/CVE higher-risk, and 8.32 (1.12, 61.76) for CKD stage 3-5/CVE higher-risk., Conclusion: Measuring biomarker panel prior to coronary catheterization may be useful to individualize CVE risk assessment among patients with CKD., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: Midaortic syndrome (MAS) is narrowing of the distal thoracic and or abdominal aorta with congenital, inflammatory, or idiopathic aetiology. If left untreated, the prognosis is poor due to hypertensive complications. Follow up data after treatment are sparse, contrary to aortic coarctation. This study aimed to investigate hypertension during follow up after medical, endovascular, and surgical therapy in juveniles and adults., Data Sources: A meta-analysis of case series and reports was performed, focusing on the incidence of hypertension during the follow up of juvenile (i.e., age 0-17 years) and adult MAS patients after medical, endovascular, or surgical therapy., Review Methods: Search queries were performed in PubMed, Embase, and Web of Science, and eligible articles underwent quality control. Descriptive statistics were reported based on available data, and individual patient data meta-analyses were performed using a one stage approach, accounting for clustering by case series or decades of reporting for case reports. For the meta-analysis, missing outcome and aetiology data were multiply imputed., Results: The number of juveniles and adults who underwent endovascular therapy (33.7% vs. 27.3%; p = .42) and surgery (52.2% vs. 58.0%; p = .46) was similar. At baseline, 92.4% of juveniles and 87.5% of adults were hypertensive, decreasing to 23.2% and 24.1% during a follow up of 23 months (juveniles) and 18 months (adults), respectively. More hypertension was found compared with surgery in juveniles after endovascular therapy (38.1% vs. 10.8%; p = .020). Meta-analysis also demonstrated a trend for hypertension after endovascular therapy in juveniles, whereas hypertension was more prevalent following surgery in adults compared with endovascular therapy or medication., Conclusion: This review and meta-analysis investigated therapeutic options for MAS in juveniles and adults. It found that complications and hypertension during follow up were more common in juveniles after endovascular treatment, whereas surgery in adults was associated with more hypertension., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Heritable thoracic aortic diseases (HTAD) are rare pathologies associated with thoracic aortic aneurysms and dissection, which can be syndromic or non-syndromic. They may result from genetic defects. Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFβ pathway and (c) smooth muscle contractile mechanism. Timely diagnosis allows for prompt aortic surveillance and prophylactic surgery, hence improving life expectancy and reducing maternal complications as well as providing reassurance to family members when a diagnosis is ruled out. This document is an expert opinion reflecting strategies put forward by medical experts and patient representatives involved in the HTAD Rare Disease Working Group of VASCERN. It aims to provide a patient pathway that improves patient care by diminishing time to diagnosis, facilitating the establishment of a correct diagnosis using molecular genetics when possible, excluding the diagnosis in unaffected persons through appropriate family screening and avoiding overuse of resources. It is being recommended that patients are referred to an expert centre for further evaluation if they meet at least one of the following criteria: (1) thoracic aortic dissection (<70 years if hypertensive; all ages if non-hypertensive), (2) thoracic aortic aneurysm (all adults with Z score >3.5 or 2.5-3.5 if non-hypertensive or hypertensive and <60 years; all children with Z score >3), (3) family history of HTAD with/without a pathogenic variant in a gene linked to HTAD, (4) ectopia lentis without other obvious explanation and (5) a systemic score of >5 in adults and >3 in children. Aortic imaging primarily relies on transthoracic echocardiography with magnetic resonance imaging or computed tomography as needed. Genetic testing should be considered in those with a high suspicion of underlying genetic aortopathy. Though panels vary among centers, for patients with thoracic aortic aneurysm or dissection or systemic features these should include genes with a definitive or strong association to HTAD. Genetic cascade screening and serial aortic imaging should be considered for family screening and follow-up. In conclusion, the implementation of these strategies should help standardise the diagnostic work-up and follow-up of patients with suspected HTAD and the screening of their relatives., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Marfan syndrome (MFS) is a connective tissue disorder affecting the cardiovascular, ocular, and skeletal system, which may be accompanied by psychological features. This study aimed to determine the prevalence of fatigue, anxiety, and symptoms of depression in MFS patients, and to assess the degree to which sociodemographic and clinical variables are associated with fatigue and psychological aspects. The prevalence of fatigue, anxiety, and symptoms of depression were assessed in two cohorts of MFS patients and compared with healthy controls. The checklist individual strength (CIS), and hospital anxiety and depression scale (HADS) questionnaires were utilized. Medical status was assessed (family history of MFS, aortic root dilatation >40 mm, previous aortic surgery, aortic dissection, chronic pain, skeletal involvement, and scoliosis). Severe fatigue was experienced by 37% of the total MFS cohort (n = 155). MFS patients scored significantly higher on the CIS questionnaire, concerning severe fatigue, as compared with the general Dutch population (p < 0.0001). There were no differences in HADS anxiety or depression scores. In older MFS patients, with a more severe cardiovascular phenotype, chronic pain, and a higher unemployment rate, significantly more symptoms of depression were observed, when compared with the general population (p = 0.027) or compared with younger MFS patients (p = 0.026). Multivariate analysis, showed that anxiety was associated with chronic pain (p = 0.022) and symptoms of depression with unemployment (p = 0.024). MFS patients report significantly more severe fatigue as compared with the general population. Since the cause of fatigue is unclear, more research may be needed. Psychological intervention, for example, cognitive behavioral therapy, may contribute to a reduction in psychological symptoms., (© 2022 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Background: It is difficult to assess the risk for aortic dissection beyond the aortic root in patients with Marfan syndrome (MFS). To aid risk assessment in these patients, we investigated aortic flow and wall shear stress (WSS) by 4D flow magnetic resonance imaging (MRI) in patients with MFS and compared the results with healthy volunteers. We hypothesized that MFS patients with a high-risk profile for aortic dissection would show abnormal hemodynamics in aortic regions associated with aortic dissection., Methods: MFS patients (n = 55) and healthy subjects (n = 25), matched for age and sex, prospectively underwent 4D flow MRI. 4D flow maps were constructed to detect elevated (defined as higher than the three-dimensional 95 % confidence interval) and deviant directed (defined as vector angle differences higher than 120°) WSS in MFS patients as compared to the controls. Univariate and multivariate associations with risk factors for aortic dissection in MFS patients were assessed., Results: The maximum incidence for elevated WSS was 20 % (CI 9 %-31 %) and found in the ascending aorta. The maximum for deviant directed WSS was 39 % (CI 26 %-52 %) and found in the inner descending aorta. Significantly more male patients had deviant directed WSS in the inner proximal descending aorta (63 % vs 24 %, p = 0.014). Multivariate analysis showed that deviant directed WSS was associated with male sex (p = 0.019), and a haplo-insufficient FBN1 mutation type (p = 0.040). In 60 % of MFS patients with a previous aortic root replacement surgery, abnormal hemodynamics were found in the ascending aorta. No significant differences between hemodynamics were found in the descending aorta between operated and non-operated patients., Conclusion: Deviant directed WSS in the proximal descending aorta is associated with known risk factors for aortic dissection in MFS patients, namely male sex and a haploinsufficient FBN1 mutation type., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Background: Inflammation, measured by traditional biomarkers such as C-reactive protein, has been linked to cardiovascular (CV) events. Recent technological advancement has allowed for measuring larger numbers of inflammatory biomarkers. A contemporary evaluation with established and novel biomarkers of inflammation is needed., Methods: 1,090 individuals who underwent coronary angiography were enrolled. Twenty-four inflammatory biomarkers were collected prior to angiography. Unsupervised machine learning cluster analyses determined unique patterns of inflammatory biomarkers. Cox proportional hazard regression assessed both association of inflammatory biomarker clusters and individual biomarker associations with major adverse cardiovascular events (MACE; non-fatal myocardial infarction or stroke, and CV death) during a median follow-up of 3.67 years., Results: Four distinct clusters were recognized. Incremental increases in inflammatory biomarkers were observed from cluster 1 to cluster 4. During follow-up, 263 MACE were ascertained. Considering cluster 1 as a reference, study participants with inflammatory cluster 2 (Hazard ratio [HR] 1.55, 95% confidence interval [CI]: 1.01-2.37), cluster 3 (HR 1.89, CI: 1.25-2.85), and cluster 4 (HR 2.93, CI: 1.95-4.42) were at increased risk of MACE. Interleukin (IL)-1α IL-6, IL-8, IL-10, IL-12, Adhesion molecule-1 high-sensitivity C-reactive protein, ferritin, myeloperoxidase, macrophage inflammatory protein (MIP)-1a, MIP 3, and macrophage colony-stimulating factor-1 were independently associated with MACE., Conclusions: Among persons undergoing coronary angiography procedures, distinct clusters of inflammatory biomarker distributions with significant prognostic meaning may be identified. These results may identify unique targets for anti-inflammatory treatments aimed at CV disease., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aims: It is common practice for clinicians to advise fluid restriction in patients with heart failure (HF), but data from clinical trials are lacking. Moreover, fluid restriction is associated with thirst distress and may adversely impact quality of life (QoL). To address this gap in evidence, the Fluid REStriction in Heart failure vs liberal fluid UPtake (FRESH-UP) study was initiated., Methods: The FRESH-UP study is a randomized, controlled, open-label, multicenter trial to investigate the effects of a 3-month period of liberal fluid intake vs fluid restriction (1500 mL/day) on QoL in outpatients with chronic HF (New York Heart Association Classes II--III). The primary aim is to assess the effect on QoL after 3 months using the Overall Summary Score of the Kansas City Cardiomyopathy Questionnaire (KCCQ). Thirst distress, as assessed by the Thirst Distress Scale for patients with HF, KCCQ Clinical Summary Score, each of the KCCQ domains and clinically meaningful changes in these scores, the EQ-5D-5L, patient-reported fluid intake and safety (ie, death, HF hospitalizations) are secondary outcomes. The FRESH-UP study is registered at ClinicalTrials.gov (NCT04551729)., Conclusion: The results of the FRESH-UP study will add substantially to the level of evidence concerning fluid management in chronic HF and may impact the QoL of these patients., Competing Interests: Conflicts of Interest None declared., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background Published randomized controlled trials are underpowered for binary clinical end points to assess the safety and efficacy of renin-angiotensin system inhibitors (RASi) in adults with COVID-19. We therefore performed a meta-analysis to assess the safety and efficacy of RASi in adults with COVID-19. Methods and Results MEDLINE, EMBASE, ClinicalTrials.gov, and the Cochrane Controlled Trial Register were searched for randomized controlled trials that randomly assigned patients with COVID-19 to RASi continuation/commencement versus no RASi therapy. The primary outcome was all-cause mortality at ≤30 days. A total of 14 randomized controlled trials met the inclusion criteria and enrolled 1838 participants (aged 59 years, 58% men, mean follow-up 26 days). Of the trials, 11 contributed data. We found no effect of RASi versus control on all-cause mortality (7.2% versus 7.5%; relative risk [RR], 0.95; [95% CI, 0.69-1.30]) either overall or in subgroups defined by COVID-19 severity or trial type. Network meta-analysis identified no difference between angiotensin-converting enzyme inhibitors versus angiotensin II receptor blockers. RASi users had a nonsignificant reduction in acute myocardial infarction (2.1% versus 3.6%; RR, 0.59; [95% CI, 0.33-1.06]), but increased risk of acute kidney injury (7.0% versus 3.6%; RR, 1.82; [95% CI, 1.05-3.16]), in trials that initiated and continued RASi. There was no increase in need for dialysis or differences in congestive cardiac failure, cerebrovascular events, venous thromboembolism, hospitalization, intensive care admission, inotropes, or mechanical ventilation. Conclusions This meta-analysis of randomized controlled trials evaluating angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers versus control in patients with COVID-19 found no difference in all-cause mortality, a borderline decrease in myocardial infarction, and an increased risk of acute kidney injury with RASi. Our findings provide strong evidence that RASi can be used safely in patients with COVID-19.

Background: Aim of this study was to investigate immune cells and subsets in different stages of human coronary artery disease with a novel multiplex immunohistochemistry (mIHC) technique., Methods: Human left anterior descending coronary artery specimens were analyzed: eccentric intimal thickening (N = 11), pathological intimal thickening (N = 10), fibroatheroma (N = 9), and fibrous plaque (N = 9). Eccentric intimal thickening was considered normal, and pathological intimal thickening, fibroatheroma, and fibrous plaque were considered diseased coronary arteries. Two mIHC panels, consisting of six and five primary antibodies, autofluoresence, and DAPI, were used to detect adaptive and innate immune cells. Via semi-automated analysis, (sub)types of immune cells in whole plaques and specific plaque regions were quantified., Results: Increased numbers of CD3 + T cells (P < 0.001), CD20 + B cells (P = 0.013), CD68 + macrophages (P = 0.003), CD15 + neutrophils (P = 0.017), and CD31 + endothelial cells (P = 0.024) were identified in intimas of diseased coronary arteries compared to normal. Subset analyses of T cells and macrophages showed that diseased coronary arteries contained an abundance of CD3 + CD8 - non-cytotoxic T cells and CD68 + CD206 - non-M2-like macrophages. Proportions of CD3 + CD45RO + memory T cells were similar to normal coronary arteries. Among pathological intimal thickening, fibroatheroma, and fibrous plaque, all immune cell numbers and subsets were similar., Conclusions: The type of immune response does not differ substantially between different stages of plaque development and may provide context for mechanistic research into immune cell function in atherosclerosis. We provide the first comprehensive map of immune cell subtypes across plaque types in coronary arteries demonstrating the potential of mIHC for vascular research., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Aims: To investigate the association between the timing of cardiac surgery during pregnancy and both maternal and foetal outcomes., Methods and Results: Studies published up to 6 February 2021 on maternal and/or foetal mortality after cardiac surgery during pregnancy that included individual patient data were identified. Maternal and foetal mortality was analysed per trimester for the total population and stratified for patients who underwent caesarean section (CS) prior to cardiac surgery (Caesarean section (CaeSe) group) vs. patients who did not (Cardiac surgery (CarSu) group). Multivariable logistic regression analysis was performed to evaluate predictors of both maternal and foetal mortality. In total, 179 studies were identified including 386 patients of which 120 underwent CS prior to cardiac surgery. Maternal mortality was 7.3% and did not differ significantly among trimesters of pregnancy (P = 0.292) nor between subgroup CaeSe and CarSu (P = 0.671). Overall foetal mortality was 26.5% and was lowest when cardiac surgery was performed during the third trimester (10.3%, P < 0.01). CS prior to surgery was significantly associated with a reduced risk of foetal mortality in a multivariable model [odds ratio 0.19, 95% confidence interval [0.06-0.56)]. Trimester was not identified as an independent predictor for foetal nor maternal mortality., Conclusion: Maternal mortality after cardiac surgery during pregnancy is not associated with the trimester of pregnancy. Cardiac surgery is associated with high foetal mortality but is significantly lower in women where CS is performed prior to cardiac surgery. When the foetus is viable, CS prior to cardiac surgery might be safe. When CS is not feasible, trimester stage does not seem to influence foetal mortality., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To evaluate the diagnostic performance of N-terminal pro-B-type natriuretic peptide (NT-proBNP) thresholds for acute heart failure and to develop and validate a decision support tool that combines NT-proBNP concentrations with clinical characteristics., Design: Individual patient level data meta-analysis and modelling study., Setting: Fourteen studies from 13 countries, including randomised controlled trials and prospective observational studies., Participants: Individual patient level data for 10 369 patients with suspected acute heart failure were pooled for the meta-analysis to evaluate NT-proBNP thresholds. A decision support tool (Collaboration for the Diagnosis and Evaluation of Heart Failure (CoDE-HF)) that combines NT-proBNP with clinical variables to report the probability of acute heart failure for an individual patient was developed and validated., Main Outcome Measure: Adjudicated diagnosis of acute heart failure., Results: Overall, 43.9% (4549/10 369) of patients had an adjudicated diagnosis of acute heart failure (73.3% (2286/3119) and 29.0% (1802/6208) in those with and without previous heart failure, respectively). The negative predictive value of the guideline recommended rule-out threshold of 300 pg/mL was 94.6% (95% confidence interval 91.9% to 96.4%); despite use of age specific rule-in thresholds, the positive predictive value varied at 61.0% (55.3% to 66.4%), 73.5% (62.3% to 82.3%), and 80.2% (70.9% to 87.1%), in patients aged <50 years, 50-75 years, and >75 years, respectively. Performance varied in most subgroups, particularly patients with obesity, renal impairment, or previous heart failure. CoDE-HF was well calibrated, with excellent discrimination in patients with and without previous heart failure (area under the receiver operator curve 0.846 (0.830 to 0.862) and 0.925 (0.919 to 0.932) and Brier scores of 0.130 and 0.099, respectively). In patients without previous heart failure, the diagnostic performance was consistent across all subgroups, with 40.3% (2502/6208) identified at low probability (negative predictive value of 98.6%, 97.8% to 99.1%) and 28.0% (1737/6208) at high probability (positive predictive value of 75.0%, 65.7% to 82.5%) of having acute heart failure., Conclusions: In an international, collaborative evaluation of the diagnostic performance of NT-proBNP, guideline recommended thresholds to diagnose acute heart failure varied substantially in important patient subgroups. The CoDE-HF decision support tool incorporating NT-proBNP as a continuous measure and other clinical variables provides a more consistent, accurate, and individualised approach., Study Registration: PROSPERO CRD42019159407., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the British Heart Foundation, Medical Research Council, and Chief Scientist Office; Y-EC has received honorariums for lectures and presentations from Biomérieux, Roche Diagnostics, and Thermo Fisher; CdF has received consulting fees from Fuji Rebio, Ortho Diagnostics, Quidel, and Roche Diagnostics and a patent entitled “Methods for assessing differential risk for developing heart failure” (patent number: PCT/US2015/029838); SS has received a grant from Roche Diagnostics and a patent entitled “Methods for assessing differential risk for developing heart failure” (patent number: PCT/US2015/029838); ABG has received personal fees and non-financial support from Roche Diagnostics during the conduct of the study and personal fees from Abbott and AstraZeneca, grants, personal fees, and non-financial support from Boehringer-Ingelheim, and personal fees and non-financial support from Novartis and Vifor outside the submitted work. YP has received consulting fees from Roche Diagnostics, Pfizer, and Forbion and honorariums from CVOI and Daiichi Sankyo; HKG has received grants from Roche Diagnostics, Jana Care, Ortho Clinical, Novartis, Pfizer, Alnylam, and Akcea (IONIS), consulting fees from Amgen, Eko, Merck, and Pfizer, and stock in Eko; JCW works as a biostatistician at the biotech company BRAHMS GmbH, part of Thermo Fisher Scientific; MM has received grants from Health Care Research Projects and Biomarker Research and personal fees from Consulting outside the submitted work; ASVS has received speaker fees from Abbott Diagnostics outside the submitted work; AMR has received grants, personal fees, and non-financial support from Roche Diagnostics outside the submitted work; JJVM has received consulting fees from Alnylam, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardurion, Dal-Cor, GSK, Ionis, KBP Biosciences, Novartis, Pfizer, and Theracos, payments for advisory boards, symposiums, or lectures from Abbott, Alkem Metabolics, Canadian Medical and Surgical Knowledge Translation Research Group, Eris Lifesciences, Hikma, Lupin, Sun Pharmaceuticals, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Servier, and the Corpus, has participated on a data safety monitoring board or advisory board for Cardialysis (MONITOR study) and Merck (VICTORIA trial), and works as company director for Global Clinical Trial Partners Ltd (GCTP) outside the submitted work; CM has received grants and non-financial support from several diagnostic companies during the conduct of the study and grants, personal fees, and non-financial support from several diagnostic companies outside the submitted work; JJ has received grants from Abbott Diagnostics, Innolife, and Novartis and consulting fees from Abbott, Jana Care, Novartis, Roche Diagnostics, Bristol-Myers Squibb, Janssen, and Prevencio; NLM has received grants from Siemens Healthineers, consulting fees from Roche Diagnostics and LumiraDx, and speaker fees from Abbott Diagnostics and Siemens Healthineers outside the submitted work; KKL, DD, and NLM are employed by the University of Edinburgh, which has filed a patent on the CoDE-HF score (patent reference: PCT/GB2021/051470); no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.)

Background The 2020 Acute Disease Quality Initiative Consensus provided recommendations on novel acute kidney injury biomarkers. In this study, we sought to assess the added value of novel kidney biomarkers to a clinical score in the CASABLANCA (Catheter Sampled Blood Archive in Cardiovascular Diseases) study. Methods and Results We evaluated individuals undergoing coronary and/or peripheral angiography and added 4 candidate biomarkers for acute kidney injury (kidney injury molecule-1, interleukin-18, osteopontin, and cystatin C) to a previously described contrast-associated acute kidney injury (CA-AKI) risk score. Participants were categorized into integer score groups based on the risk assigned by the biomarker-enhanced CA-AKI model. Risk for incident cardiorenal outcomes during a median 3.7 years of follow-up was assessed. Of 1114 participants studied, 55 (4.94%) developed CA-AKI. In adjusted models, neither kidney injury molecule-1 nor interleukin-18 improved discrimination for CA-AKI; addition of osteopontin and cystatin C to the CA-AKI clinical model significantly increased the c-statistic from 0.69 to 0.73 ( P for change <0.001) and resulted in a Net Reclassification Index of 59.4. Considering those with the lowest CA-AKI integer score as a reference, the intermediate, high-risk, and very-high-risk groups were associated with adverse cardiorenal outcomes. The corresponding hazard ratios of the very-high-risk group were 3.39 (95% CI, 2.14-5.38) for nonprocedural acute kidney injury, 5.58 (95% CI, 3.23-9.63) for incident chronic kidney disease, 6.21 (95% CI, 3.67-10.47) for myocardial infarction, and 8.94 (95% CI, 4.83-16.53) for all-cause mortality. Conclusions A biomarker-enhanced risk model significantly improves the prediction of CA-AKI beyond clinical variables alone and may stratify the risk of future cardiorenal outcomes. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00842868.

Objective: Longitudinal data on age-related changes in the diameters of the thoracic aorta are scarce. To better understand normal variation and to identify factors influencing this process, we aimed to report male-female-specific and age-specific aortic growth rate in the ageing general population and identify factors associated with growth rate., Methods: From the prospective population-based Rotterdam Study, 943 participants (52.0% females, median age at baseline 65 years (62-68)) underwent serial non-enhanced cardiac CT. We measured the diameters of the ascending (AA) and descending aorta (DA) at two time points and expressed absolute and relative differences. Linear mixed effects analysis was performed to identify determinants associated with change in aortic diameters., Results: Mean AA diameter at baseline was 37.3±3.6 mm in male population and 34.7±3.2 mm in female population, mean DA diameter was 29.6±2.3 in male population and 26.9±2.2 mm in female population. The median absolute change in diameters during follow-up (mean scan interval 14.1±0.3 years) was 1 mm (0-2) for both the AA and DA. Absolute change per decade in AA diameter was significantly larger in males than in females (0.72 mm/decade (0.00-1.43) vs 0.70 mm/decade (0.00-1.41), p=0.006), as well as absolute change in AD diameter (0.71 mm/decade (0.00-1.42) vs 0.69 mm/decade (0.00-1.36), p=0.008). There was no significant difference between male and female population in relative change of their aortic diameters during follow-up. Age, male sex, higher body mass index (BMI) and higher diastolic blood pressure (DBP) showed a statistically significant independent association with increase in AA and DA diameters over time., Conclusions: Some degree of increase in thoracic aortic diameters is typical in both men and women of an aging population. Factors associated with this change in thoracic aortic diameters were sex, age, BMI and DBP., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: This study aims to systematically review published literature on male-female differences in presentation, management and outcomes in patients diagnosed with acute thoracic aortic dissection (AD)., Methods: A systematic literature search was conducted for studies published between 1 January 1999 and 19 October 2020 investigating mortality and morbidity in adult patients diagnosed with AD. Patient and treatment characteristics were compared with odds ratios (ORs) and standardized mean differences and a meta-analysis using a random-effects model was performed for early mortality. Overall survival and reoperation were visualized by pooled Kaplan-Meier curves., Results: Nine studies investigating type A dissections (AD-A), 1 investigating type B dissections (AD-B) and 3 investigating both AD-A and AD-B were included encompassing 18 659 patients. Males were younger in both AD-A (P < 0.001) and AD-B (P < 0.001), and in AD-A patients males had more distally extended dissections [OR 0.57, 95% confidence interval (CI) 0.46-0.70; P < 0.001]. Longer operation times were observed for males in AD-A (standardized mean difference 0.29, 95% CI 0.17-0.41; P < 0.001) while male patients were less often treated conservatively in AD-B (OR 0.65, 95% CI 0.58-0.72; P < 0.001). The pooled early mortality risk ratio for males versus females was 0.94 (95% CI 0.84-1.06, P = 0.308) in AD-A and 0.92 (95% CI 0.83-1.03, P = 0.143) in AD-B. Pooled overall mortality in AD-A showed no male-female difference, whereas male patients had more reinterventions during follow-up., Conclusions: This systematic review shows male-female differences in AD patient and treatment characteristics, comparable early and overall mortality and inconsistent outcome reporting. As published literature is scarce and heterogeneous, large prospective studies with standardized reporting of male-female characteristics and outcomes are clearly warranted. Improved knowledge of male-female differences in AD will help shape optimal individualized care for both males and females., Clinical Registration Number: PROSPERO, ID number: CRD42020155926., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Background: The European Society of Cardiology (ESC) 0 h/1h algorithm is the preferred diagnostic strategy for chest pain patients in the emergency department (ED). It is suggested that adding clinical information to the algorithm improves its diagnostic performance. This study evaluates implementation of the ESC 0 h/1h algorithm in the ED and investigates the potential advantages of combining it with a clinical decision rule, which might be especially relevant in the heterogenous observation category., Methods: In this prospective cohort study, chest pain patients in whom the ESC 0 h/1h algorithm was applied were enrolled. HEART score components were collected. Diagnostic characteristics were determined for the algorithm with and without addition of the HEART score. Primary endpoint was a composite endpoint at 30-day follow-up, consisting of myocardial infarction and death., Results: A total of 668 patients were enrolled. The rule-in and rule-out categories consisted of 8.2% and 54.9% of the patients, respectively. Positive predictive value and specificity of the rule-in category were 67.3% and 97.1%, respectively. Negative predictive value (NPV) and sensitivity of the rule-out category were both 100%. In the observation category, a HEART score ≤ 3 yielded a NPV and sensitivity of 97.1% and 93.8%, respectively., Conclusion: The ESC 0 h/1h algorithm yielded a NPV and sensitivity of 100% for myocardial infarction and death at 30-day follow-up. Addition of the HEART score did not provide clinically relevant advantages. Although the HEART score can be used to guide diagnostic testing in the observation category, a low HEART score did not yield an NPV of > 99%., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 Published by Elsevier B.V.)

Rationale: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored., Objective: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA., Methods and Results: We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10 -10 , OR=0.69 per C allele). SNP-based heritability analysis showed that 25% of variance in susceptibility to D-TGA may be explained by common variants. A genome-wide polygenic risk score derived from the discovery set was significantly associated to D-TGA in the replication set (P=4x10 -5 ). The genome-wide significant locus (3p14.3) co-localizes with a putative regulatory element that interacts with the promoter of WNT5A , which encodes the Wnt Family Member 5A protein known for its role in cardiac development in mice. We show that this element drives reporter gene activity in the developing heart of mice and zebrafish and is bound by the developmental transcription factor TBX20. We further demonstrate that TBX20 attenuates Wnt5a expression levels in the developing mouse heart., Conclusions: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 near WNT5A . Genomic and functional data support a causal role of WNT5A at the locus.

Objectives: This study investigated whether patients with chronic heart failure (HF) can be stratified according to the combination of soluble neprilysin and corin concentrations and whether this is related to clinical outcome., Background: Natriuretic peptide processing by the enzymes corin and neprilysin plays a pivotal role in conversion of pro-natriuretic peptides to active natriuretic peptides, as well as their degradation, respectively., Methods: A prospective cohort of patients with chronic HF (n = 1,009) was stratified into 4 equal groups based on high or low neprilysin/corin concentration relative to the median: 1) low neprilysin/low corin; 2) low neprilysin/high corin; 3) high neprilysin/low corin; and 4) high neprilysin/high corin. Cox regression survival analysis was performed for the composite primary endpoint of cardiovascular death and HF hospitalization., Results: Median neprilysin and corin concentrations were not correlated (rho: -0.04; p = 0.21). Although in univariate analysis there was no association with outcome, after correction for baseline differences in age and sex, a significant association with survival was demonstrated: with highest survival in group 1 (low neprilysin/low corin) and lowest in group 4 (high neprilysin/high corin) (adjusted hazard ratio: 1.56; p = 0.003), which remained statistically significant after comprehensive multivariable analysis (adjusted hazard ratio: 1.41; p = 0.03)., Conclusions: Stratification of patients with chronic HF based on circulating neprilysin and corin concentrations is associated with clinical outcomes. These results suggest that regulation of these enzymes is of importance in chronic HF and may offer an interesting approach for classification of patients with HF in a step toward individualized HF patient management., Competing Interests: Funding Support and Author Disclosures Drs. Bayes-Genis and Lupón share holding from Critical Diagnostics, outside the submitted work; and have a patent EP14182846.7 licensed to Critical Diagnostics. Drs. Gommans, Vart, van Royen, and van Kimmenade have received grants from Novartis Pharma B.V., during the conduct of the study. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Women with Turner syndrome (TS) have high prevalence of cardiovascular anomalies. Literature suggests pregnancy is associated with a higher dissection risk, presumably preceded by aortic dilatation. Whether the aortic diameter truly changes during pregnancy in TS is not well investigated. This study aims to evaluate ascending aortic diameter change during pregnancy and reports on cardiac events during and directly after pregnancy. This tertiary hospital retrospective study investigated all TS women pregnancies (2009 to 2018). Outcome parameters included aortic diameter growth and aortic complications, specifically dissection. Thirty-five pregnancies in 30 TS women, 57% assisted by oocyte donation. Mean age at delivery 32 ± 5 years. In 27 pregnancies of 22 women imaging was available. From over 350 childless TS women a comparison group of 27 was individually matched. The median ascending aortic diameter growth between pre- and postpregnancy imaging was 1.0 mm (IQR -1.0; 2.0), no significant change (p = 0.077). Whether the patient had a bicuspid aortic valve (p = 0.571), monosomy X or mosaic karyotype (p = 0.071) or spontaneous pregnancy or resulting from oocyte donation (p = 0.686) had no significant influence on diameter change. Aortic growth between pregnancy and matched childless group (0.23 vs 0.32 mm/year, p = 0.788) was not significant over 3.3 ± 2 versus 4.4 ± 1 years. During pregnancy or the first 6 months after delivery no aortic complications were observed. In conclusion, this study suggests pregnancy in TS women does not induce faster ascending aortic diameter increase. Also not in presence of a bicuspid aortic valve, monosomy X karyotype, and oocyte donation. No aortic complications occurred. Based on current study pregnancy in TS women seems safe., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Progressive ascending aortic dilatation has been observed after mechanical aortic valve replacement (mAVR), possibly due to altered blood flow and wall shear stress (WSS) patterns induced by their bileaflet design. We examined the effect of mAVR on WSS in the ascending aorta using time-resolved 4D flow MRI. Fifteen patients with mechanical aortic valve prostheses, 10 patients with bicuspid aortic valve disease and 10 healthy individuals underwent thoracic 4D flow MRI. Peak systolic hemodynamic parameters (velocity and WSS) and vessel diameters were assessed in the ascending aorta. In addition, three-dimensional per-voxel analysis was used to compare velocity and WSS between patient groups and healthy controls. Peak aortic diameters were significantly higher in mAVR and BAV patients compared to healthy controls (p = 0.011). Mean aortic diameters were comparable between mAVR and BAV patients. No differences in 4D flow MRI-derived mean blood flow velocity and peak WSS were found between the three groups. Compared to healthy controls, mean WSS was significantly lower in mAVR patients (p = 0.031). Per-voxel analysis revealed no increased WSS in the ascending aortic wall and significantly lower velocity and WSS values in mAVR patients compared to healthy controls. In contrast, regions of significantly increased outer lumen velocities and WSS in BAV patients compared to healthy controls were found. This study shows that there is no increased ascending aortic WSS after mAVR. Our results suggest that, in contrast to BAV patients, there is no indication for intensified follow-up of the ascending aorta after mAVR.

Purpose: Previous studies have suggested that extreme endurance exercise may induce cardiac microdamage that could lead to subsequent myocardial fibrosis. Soluble suppression of tumorigenicity 2 (sST2) is a cardiac biomarker for assessment of myocardial fibrosis, inflammation, and strain. We evaluated baseline and exercise-induced sST2 concentrations in a heterogeneous cohort of marathon runners to identify predictors for sST2 concentrations., Methods: Ninety-two runners supplied demographic data, health status, physical activity levels, and marathon experience. Before (baseline) and immediately after (finish) the marathon, blood was collected for analysis of sST2 and cardiac troponin I (cTnI)., Results: Eighty-two participants (45 ± 8 yr, 79% male) finished the race in 227 ± 28 min at 92% (88%-94%) of their predicted maximum heart rate (exercise intensity). sST2 concentrations increased in all runners, from 34 (25-46) ng·mL to 70 (53-87) ng·mL (P < 0.001), and cTnI increased from 9 (5-21) ng·L to 60 (34-102) ng·L (P < 0.001). sST2 concentrations were higher in the fastest marathon runners. Sex and marathon personal best time were associated with baseline sST2 (R = 0.27); baseline sST2, weight loss, and exercise intensity during marathon were associated with finish sST2 (R = 0.54); baseline sST2, height, sex, and weekly training hours were associated with the exercise-induced increase in sST2 (R = 0.47). We observed no association between sST2 and cTnI concentrations., Conclusion: An exercise-induced increase in sST2 was observed in all marathon runners with sST2 concentrations exceeding cutoff values both at baseline (48%) and finish (94%). Faster runners had higher sST2 concentrations. Our data suggest complex variables determine sST2 concentrations in marathon runners.

Objective: Severe aortic valve stenosis (AS) develops via insidious processes and can be challenging to correctly diagnose. We sought to develop a circulating biomarker panel to identify patients with severe AS., Methods: We enrolled study participants undergoing coronary or peripheral angiography for a variety of cardiovascular diseases at a single academic medical centre. A panel of 109 proteins were measured in blood obtained at the time of the procedure. Statistical learning methods were used to identify biomarkers and clinical parameters that associate with severe AS. A diagnostic model incorporating clinical and biomarker results was developed and evaluated using Monte Carlo cross-validation., Results: Of 1244 subjects (age 66.4±11.5  years, 28.7% female), 80 (6.4%) had severe AS (defined as aortic valve area (AVA) <1.0  cm 2 ). A final model included age, N-terminal pro-B-type natriuretic peptide, von Willebrand factor and fetuin-A. The model had good discrimination for severe AS (OR=5.9, 95% CI 3.5 to 10.1, p<0.001) with an area under the curve of 0.76 insample and 0.74 with cross-validation. A diagnostic score was generated. Higher prevalence of severe AS was noted in those with higher scores, such that 1.6% of those with a score of 1 had severe AS compared with 15.3% with a score of 5 (p<0.001), and score values were inversely correlated with AVA (r=-0.35; p<0.001). At optimal model cut-off, we found 76% sensitivity, 65% specificity, 13% positive predictive value and 98% negative predictive value., Conclusions: We describe a novel, multiple biomarker approach for diagnostic evaluation of severe AS., Trial Registration Number: NCT00842868., Competing Interests: Competing interests: SE receives institutional research support from Siemens and Boehringer Ingelheim Pharmaceuticals and consulting fees from Medtronic and Edwards Lifesciences. The remaining authors have no relationships to disclose. JLJ has received grant support from Abbott Diagnostics, Roche Diagnostics, Singulex and Prevencio; consulting income from Roche Diagnostics, Critical Diagnostics, Philips and Novartis; and participates in clinical endpoint committees/data safety monitoring boards for Novartis, Amgen, AbbVie, Pfizer, Janssen and Boehringer Ingelheim. CM is a consultant to Prevencio. RR and GB are employees of Prevencio. Siemens Diagnostics had no involvement in the present study design, collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. All other authors have reported that they have no relationships relevant to the content of this paper to disclose.

Aims: Methods to identify patients at risk for incident HF would be welcome as such patients might benefit from earlier interventions., Methods and Results: From a registry of 1251 patients referred for coronary and/or peripheral angiography, we sought to identify independent predictors of incident HF during follow-up and develop a clinical and biomarker strategy to predict this outcome. There were 991 patients free of prevalent HF at baseline. Cox proportional hazard models were developed to predict adjudicated diagnosis of incident HF. Model discrimination and reclassification were evaluated. At follow-up, 177 (18%) developed new-onset HF. Independent predictors of new-onset HF included five clinical variables (age, male sex, heart rate, history of atrial fibrillation/flutter, and history of hypertension) and two biomarkers (amino-terminal pro-B type natriuretic peptide and ST2). The c-statistic for the model without biomarkers was 0.69; including biomarkers increased the c-statistic to 0.76 (P < 0.001). A score was developed from the model. Patients in the highest score quintile had shortest time to incident HF compared with lower quintiles (log-rank P < 0.001). Following 100 bootstrap iterations, internal validation was confirmed with Harrell's c-statistic of 0.77. Use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and beta-blockers at enrollment was associated with substantial attenuation of predictive value of the risk score., Conclusions: Patients undergoing coronary/peripheral angiographic procedures are a population at high risk for incident HF. We describe an accurate clinical and biomarker strategy for predicting incident HF and possibly intervening in such patients (NCT00842868)., (© 2018 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Background: Red cell distribution width (RDW) is a standard component of the automated blood count, and is of prognostic value in heart failure and coronary heart disease. We investigated the association between RDW and cardiovascular events in patients with adult congenital heart disease (ACHD)., Methods and Results: In this prospective cohort study, 602 consecutive patients with ACHD who routinely visited the outpatient clinic were enrolled between 2011 and 2013. RDW was measured in fresh venous blood samples at inclusion in 592 patients (median age 33 [IQR 25-41] years, 58% male, 90% NYHA I) and at four annual follow-up visits. During 4.3 [IQR 3.8-4.7] years of follow-up, the primary endpoint (death, heart failure, hospitalization, arrhythmia, thromboembolic events, cardiac intervention) occurred in 196 patients (33%). Median RDW was 13.4 (12.8-14.1)% versus 12.9 (12.5-13.4)% in patients with and without the primary endpoint (P < 0.001). RDW was significantly associated with the endpoint when adjusted for age, sex, clinical risk factors, CRP, and NT-proBNP (HR 1.20; 95% CI 1.06-1.35; P = 0.003). The C-index of the model including RDW was slightly, but significantly (P = 0.005) higher than the model without (0.74, 95% CI 0.70-0.78 versus 0.73, 95% CI 0.69-0.78). Analysis of repeated RDW measurements (n = 2449) did not show an increase in RDW prior to the occurrence of the endpoint., Conclusions: RDW is associated with cardiovascular events in patients with ACHD, independently of age, sex, clinical risk factors, CRP, and NT-proBNP. This readily available biomarker could therefore be considered as an additive biomarker for risk stratification in these patients., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

We sought to develop a multiple biomarker approach for prediction of incident major adverse cardiac events (MACE; composite of cardiovascular death, myocardial infarction, and stroke) in patients referred for coronary angiography. In a 649-participant training cohort, predictors of MACE within 1 year were identified using least-angle regression; over 50 clinical variables and 109 biomarkers were analyzed. Predictive models were generated using least absolute shrinkage and selection operator with logistic regression. A score derived from the final model was developed and evaluated with a 278-patient validation set during a median of 3.6 years follow-up. The scoring system consisted of N-terminal pro B-type natriuretic peptide (NT-proBNP), kidney injury molecule-1, osteopontin, and tissue inhibitor of metalloproteinase-1; no clinical variables were retained in the predictive model. In the validation cohort, each biomarker improved model discrimination or calibration for MACE; the final model had an area under the curve (AUC) of 0.79 (p <0.001), higher than AUC for clinical variables alone (0.75). In net reclassification improvement analyses, addition of other markers to NT-proBNP resulted in significant improvement (net reclassification improvement 0.45; p = 0.008). At the optimal score cutoff, we found 64% sensitivity, 76% specificity, 28% positive predictive value, and 93% negative predictive value for 1-year MACE. Time-to-first MACE was shorter in those with an elevated score (p <0.001); such risk extended to at least to 4 years. In conclusion, in a cohort of patients who underwent coronary angiography, we describe a novel multiple biomarker score for incident MACE within 1 year (NCT00842868)., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: The aim of this work was to assess the prognostic value of absolute N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentration in combination with changes during admission because of acute heart failure (AHF) and early after hospital discharge., Background: In AHF, readmission and mortality rates are high. Identifying those at highest risk for events early after hospital discharge might help to select patients in need of intensive outpatient monitoring., Methods and Results: We evaluated the prognostic value of NT-proBNP concentration on admission, at discharge, 1 month after hospital discharge and change over time in 309 patients included in the PRIMA (Can PRo-brain-natriuretic peptide guided therapy of chronic heart failure IMprove heart fAilure morbidity and mortality?) study. Primary outcome measures were mortality and the combined end point of heart failure (HF) readmission or mortality. In a multivariate Cox regression analysis, change in NT-proBNP concentration during admission, change from discharge to 1 month after discharge, and the absolute NT-proBNP concentration at 1 month after discharge were of independent prognostic value for both end points (hazard ratios for HF readmission or mortality: 1.71, 95% confidence interval [CI] 1.13-2.60, Wald 6.4 [P = .011] versus 2.71, 95% CI 1.76-4.17, Wald 20.5 [P < .001] versus 1.81, 95% CI 1.13-2.89, Wald 6.1 [P = .014], respectively., Conclusions: Knowledge of change in NT-proBNP concentration during admission because of AHF in combination with change early after discharge and the absolute NT-proBNP concentration at 1 month after discharge allows accurate risk stratification., (Copyright © 2014 Elsevier Inc. All rights reserved.)