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Objective: Diabetes and depression are both linked to an increased mortality risk after myocardial infarction (MI). Population-based studies suggest that having both diabetes and depression results in an increased mortality risk, beyond that of having diabetes or depression alone. The purpose of this study was to examine the joint association of diabetes and depression with mortality in MI patients.Research Design and Methods: Data were derived from two multicenter cohort studies in the Netherlands, comprising 2,704 patients who were hospitalized for MI. Depression, defined as a Beck Depression Inventory score ≥10, and diabetes were assessed during hospitalization. Mortality data were retrieved for 2,525 patients (93%).Results: During an average follow-up of 6.2 years, 439 patients died. The mortality rate was 14% (226 of 1,673) in patients without diabetes and depression, 23% (49 of 210) in patients with diabetes only, 22% (118 of 544) in patients with depression only, and 47% (46 of 98) in patients with both diabetes and depression. After adjustment for age, sex, smoking, hypertension, left ventricular ejection fraction, prior MI, and Killip class, hazard ratios for all-cause mortality were 1.38 (95% CI 1.00-1.90) for patients with diabetes only, 1.39 (1.10-1.76) for patients with depression only, and as much as 2.90 (2.07-4.07) for patients with both diabetes and depression.Conclusions: We observed an increased mortality risk in post-MI patients with both diabetes and depression, beyond the association with mortality of diabetes and depression alone. [ABSTRACT FROM AUTHOR]

Objective: Diabetes is a predictor of both coronary artery disease (CAD) and heart failure. It is unknown to what extent the association between diabetes and heart failure is influenced by other risk factors for heart failure.Research Design and Methods: We evaluated the association of diabetes and A1C with incident heart failure in outpatients with stable CAD and no history of heart failure (average follow-up 4.1 years).Results: Of 839 participants, 200 had diabetes (23.8%). Compared with patients who did not have diabetes, those with diabetes had an increased risk of heart failure (hazard ratio [HR] 2.17 [95% CI 1.37-3.44]). Adjustment for risk factors for CAD (age, sex, race, smoking, physical inactivity, obesity, blood pressure, and LDL cholesterol), interim myocardial infarction, and myocardial ischemia did not alter the strength of the association between diabetes and heart failure. After inclusion also of other risk factors for heart failure (left ventricular ejection fraction, diastolic dysfunction, and C-reactive protein) and medication use, diabetes remained an independent predictor of heart failure (HR 3.34 [95% CI 1.65-6.76]; P = 0.001). Each 1% increase in A1C concentration was associated with a 36% increased HR of heart failure hospitalization (HR 1.36 [95% CI 1.17-1.58]).Conclusions: In patients with stable CAD who are free from heart failure at baseline, diabetes and glycemic control are independent risk factors for new-onset heart failure. The mechanisms by which diabetes and hyperglycemia lead to heart failure deserve further study, as the association is independent of baseline functional assessment of ischemia, systolic and diastolic function, and interim myocardial infarction. [ABSTRACT FROM AUTHOR]

BACKGROUND: We investigated whether depressive disorder and Type D personality refer to different forms of distress in the Myocardial INfarction and Depression - Intervention Trial (MIND-IT).MethodA total of 1205 myocardial infarction (MI) patients were screened at 3, 6, 9 and 12 months post-MI; those with a Beck Depression Inventory (BDI) score 10 underwent the World Health Organization (WHO) Composite International Diagnostic Interview (CIDI). Patients completed the DS14 measure of Type D personality at 12 months and were stratified to one of four subgroups: depressed/Type D, depressed/non-Type D, non-depressed/Type D, or non-distressed. RESULTS: Two hundred and six (17%) patients were diagnosed with depression and 224 (19%) with Type D. Only 7% (n=90) had both forms of distress, and 60% of Type D patients were free of depression in the first year post-MI. Type D moderated the relationship between depressive and cardiac disorder. Depressed patients without Type D had the worst clinical status (left ventricular dysfunction, heart failure, Killip class 2) as compared to other patients, whereas depressed patients with a Type D personality did not differ in clinical status from non-distressed patients. Contrasting 'pure' Type D and depression subgroups showed that Type D patients without depression were less likely to have left ventricular dysfunction [odds ratio (OR) 0.47, 95% confidence interval (CI) 0.35-0.65, p<0.0001] than depressed patients without Type D. CONCLUSIONS: Depression and Type D refer to different forms of distress in post-MI patients; most Type D patients display non-psychiatric levels of distress and Type D moderates the relationship between depressive and cardiac disorder. Different depression/Type D subgroups may be involved in the prediction of cardiac prognosis. [ABSTRACT FROM AUTHOR]

Background: Renal dysfunction is a well-established risk factor in cardiovascular disease, but little is known about the prevalence and factors associated with deterioration in renal function in patients with a Fontan circulation., Objectives: The purpose of the study was to investigate the course and factors associated with deterioration in renal function in patients with a Fontan circulation and its association with mortality., Methods: This is a longitudinal study of patients with a Fontan circulation (n = 82), in which creatinine-based estimated glomerular filtration rate (eGFR cr ) was measured over an 11-year time period. Cystatin C and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels were measured at baseline. Renal dysfunction was defined as an eGFR <90 ml/min/1.73 m 2 . Factors associated with annual change in eGFR cr were investigated with linear mixed-effect models and compared with data from a healthy Dutch cohort. The primary endpoint for the survival analyses was all-cause mortality. Associations between repeated eGFR cr levels and the primary endpoint were assessed using a joint model., Results: The median age at baseline was 20 years (IQR: 14-27 years). Twelve percent of the cohort had renal dysfunction based on eGFR cr and 24% based on cystatin C-based eGFR cys . During follow-up, eGFR cr deteriorated on average by 1.36 ml/min/1.73 m 2 /year, which is faster than the healthy cohort. Higher baseline NT-proBNP z-scores were associated with a more rapid decline in eGFR cr . A larger decline in eGFR cr was associated with all-cause mortality., Conclusions: Declines in eGFR cr in patients with Fontan circulation are more rapid than in healthy individuals. Higher baseline NT-proBNP z-scores are associated with a more rapid deterioration of eGFR cr , and eGFR cr deterioration is associated with mortality., Competing Interests: Dr Berger has UMCG contracts with Johnson & Johnson, MSD, Ferrer, and GSK for steering committee and advisory board activities of RMFB, outside the scope of this manuscript. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Purpose: The aim of this study was to test the hypothesis that the levels of High Sensitive Troponin T (HS-TNT) and N-terminal Brain Natriuretic Peptide (NT-ProBNP) increase after radiation therapy in a dose dependent way and are predictive for clinical cardiac events., Materials and Methods: Blood samples during and after radiotherapy of 87 esophageal cancer patients were analysed regarding the course of HS-TNT and NT-ProBNP levels and their relationship with clinical toxicity endpoints and radiation dose volume parameters., Results: HS-TNT values at the end of treatment correlated with the mean heart dose (p = 0.02), whereas the rise of NT-ProBNP correlated with the mean lung dose (p = 0.01). Furthermore, the course of both HS-TNT (p < 0.001) and NT-ProBNP (p < 0.01) levels were significantly different for patients who developed new cardiac events as opposed to those without new cardiac events., Conclusion: Significant correlations were found for both biomarkers with radiation dose and clinical toxicity endpoints after treatment. Therefore, these markers might be of additional value in NTCP models for cardiac events and might help us unravelling the mechanisms behind these toxicity endpoints., Competing Interests: Declaration of competing interest 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., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Adults with a systemic right ventricle (sRV) are at a high risk for heart failure (HF) hospitalization and mortality. Bioactive adrenomedullin (bio-ADM) has been proposed as a marker of congestion and prognosis in patients with cardiovascular disease. We aimed to evaluate the association between bio-ADM and mortality and HF events in sRV patients., Methods: Plasma bio-ADM was measured by a novel immunoassay in plasma of 85 sRV patients. A composite endpoint of all-cause mortality and HF events was used as outcome. HF events were defined as onset or progression of HF signs or symptoms requiring hospitalization, initiation or intensification of therapy. Multivariable Cox regression analyses were performed to evaluate the association between bio-ADM and outcome., Results: The mean age of the patients was 37 ± 9 years and 65% were male. Patients with higher plasma bio-ADM concentrations were more often treated with diuretics (p = 0.007), possibly because of signs and/or symptoms of congestion. During a median follow-up of 10.2 years, 33.7% of the patients reached the endpoint. After adjustment for age and N-terminal pro B-type natriuretic peptide (NT-pro BNP), higher bio-ADM levels were associated with a higher risk of the composite endpoint (hazard ratio: 2.09 [95%-confidence interval: 1.15-3.78]). Bio-ADM improved risk prediction when added to NT-proBNP and age (C-statistic improved from 0.748 to 0.776 [p = 0.03])., Conclusions: Bio-ADM can be considered as a marker of congestion and independent predictor of death and HF events in adult patients with a sRV. Moreover, in terms of risk prediction, it has added value to NT-proBNP., Competing Interests: Declaration of competing interest The authors report no relationships that could be construed as a conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Iron deficiency (ID) has been reported in patients with congenital heart disease. There is, however, a scarcity of data on its prevalence in patients with a Fontan circulation. The aim of this study is to investigate the prevalence of ID in Fontan patients and to investigate the association between ID and exercise capacity in this population., Methods and Results: Blood count and haematological parameters were determined in plasma of 61 Fontan patients (51% female, mean age 29±9 years). ID was defined as transferrin saturation (TSAT) ≤19.8%. The prevalence of ID was 36% (22/61 patients). Especially among women, the diagnosis of ID was highly prevalent (52%) despite normal haemoglobin levels (153.7±18.4 g/L). Mean ferritin levels were 98±80 µg/L and mean TSAT levels were 22%±12%. Cardiopulmonary exercise testing was performed in 46 patients (75%). Patients with ID had a lower peak oxygen uptake (V̇O 2 peak) (1397±477 vs 1692±530 mL/min; p=0.039), although this relationship was confounded by sex. The presence of ID increased the likelihood of not achieving a respiratory exchange ratio (RER) ≥1.1 by 5-fold (p=0.035)., Conclusion: ID is highly prevalent among patients with a Fontan circulation. V̇O 2 peak is lower in patients with ID. Fontan patients with ID are less likely to achieve an RER≥1.1 during cardiopulmonary exercise testing., Competing Interests: Competing interests: RMFB: The University Medical Center Groningen contracts with Janssen, MSD and GSK for steering committee and advisory board committee activities of RMFB, outside the scope of this manuscript., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The number of patients with an arterial switch operation (ASO) for transposition of the great arteries (TGA) is steadily growing; limited information is available regarding the clinical course in the current era., Objectives: The purpose was to describe clinical outcome late after ASO in a national cohort, including survival, rates of (re-)interventions, and clinical events., Methods: A total of 1,061 TGA-ASO patients (median age 10.7 years [IQR: 2.0-18.2 years]) from a nationwide prospective registry with a median follow-up of 8.0 years (IQR: 5.4-8.8 years) were included. Using an analysis with age as the primary time scale, cumulative incidence of survival, (re)interventions, and clinical events were determined., Results: At the age of 35 years, late survival was 93% (95% CI: 88%-98%). The cumulative re-intervention rate at the right ventricular outflow tract and pulmonary branches was 36% (95% CI: 31%-41%). Other cumulative re-intervention rates at 35 years were on the left ventricular outflow tract (neo-aortic root and valve) 16% (95% CI: 10%-22%), aortic arch 9% (95% CI: 5%-13%), and coronary arteries 3% (95% CI: 1%-6%). Furthermore, 11% (95% CI: 6%-16%) of the patients required electrophysiological interventions. Clinical events, including heart failure, endocarditis, and myocardial infarction occurred in 8% (95% CI: 5%-11%). Independent risk factors for any (re-)intervention were TGA morphological subtype (Taussig-Bing double outlet right ventricle [HR: 4.9, 95% CI: 2.9-8.1]) and previous pulmonary artery banding (HR: 1.6, 95% CI: 1.0-2.2)., Conclusions: TGA-ASO patients have an excellent survival. However, their clinical course is characterized by an ongoing need for (re-)interventions, especially on the right ventricular outflow tract and the left ventricular outflow tract indicating a strict lifelong surveillance, also in adulthood., Competing Interests: Support was received from the Netherlands Cardiovascular Research lnitiative: An initiative with support of the Dutch Heart Foundation and Hartekind, CVON2019-002 OUTREACH. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Aims: Cardiac magnetic resonance (CMR) imaging is a main diagnostic tool in the follow-up of Fontan patients. However, the value of serial CMR for the evaluation of Fontan attrition is unknown. The aim of this prospective study of serial CMR is to describe the analysis of time-dependent evolution of blood flow distribution, ventricular volumes, and function in patients after Fontan completion., Methods and Results: In this prospective single-centre study, between 2012 and 2022, 281 CMR examinations were performed in 88 Fontan patients with distribution of blood flows, measurements of ventricular volumes, and ejection fraction. Linear mixed model regression for repeated measurements was used to analyse changes of measurements across serial CMR examinations. During a time interval of 10 years, the median number of CMR per patient was 3 (range 1-5). Indexed flow of ascending aorta, caval veins, and pulmonary arteries decreased significantly across serial CMR examinations. Although a decrease of mean indexed aortic flow (3.03 ± 0.10 L/min/m 2 at first CMR vs. 2.36 ± 0.14 L/min/m 2 at fourth CMR, P < 0.001) was observed, ejection fraction did not decline (50 ± 1% at first CMR vs. 54 ± 2% at fourth CMR, P = 0.070). Indexed ventricular volumes did not differ significantly across serial CMR examinations., Conclusion: The decrease of indexed aortic and cavopulmonary flows reflects the attrition of univentricular circulation and can be detected by means of serial CMR. Ventricular systolic dysfunction does not contribute significantly to this attrition. In order to detect significant change of indexed aortic flow, we recommend performing serial CMR as routine practice in the Fontan population., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Patients with a transposition of the great arteries (TGA) and a systemic right ventricle are at risk of heart failure (HF) development, arrhythmia and early mortality. Prognostic evaluations in clinical studies are hampered by small sample sizes and single-centred approaches. We aimed to investigate yearly rate of outcome and factors affecting it., Methods: A systematic literature search of four electronic databases (PubMed, EMBASE, Web of Science and Scopus) was conducted from inception to June 2022. Studies reporting the association of a systemic right ventricle with mortality with a minimal follow-up of 2 years during adulthood were selected. Incidence of HF hospitalization and/or arrhythmia were captured as additional endpoints. For each outcome, a summary effect estimate was calculated., Results: From a total of 3891 identified records, 56 studies met the selection criteria. These studies described the follow-up (on average 7.27 years) of 5358 systemic right ventricle patients. The mortality incidence was 1.3 (1-1.7) per 100 patients/year. The incidence of HF hospitalization was 2.6 (1.9-3.7) per 100 patients/year. Predictors of poor outcome were a lower left ventricular (LV) and right ventricular ejection fraction (RVEF) (standardized mean differences (SMD) of -0.43 (-0.77 to -0.09) and - 0.85 (-1.35 to -0.35), respectively), higher plasma concentrations of NT-proBNP (SMD of 1.24 (0.49-1.99)), and NYHA class ≥2 (risk ratio of 2.17 (1.40-3.35))., Conclusions: TGA patients with a systemic right ventricle have increased incidence of mortality and HF hospitalization. A lower LVEF and RVEF, higher levels of NT-proBNP and NYHA class ≥2 are associated with poor outcome., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Systemic-to-pulmonary collateral flow is a well-recognised phenomenon in patients with single ventricle physiology, but remains difficult to quantify. The aim was to compare the reported formula's that have been used for calculation of systemic-to-pulmonary-collateral flow to assess their consistency and to quantify systemic-to-pulmonary collateral flow in patients with a Glenn and/or Fontan circulation using four-dimensional flow MRI (4D flow MR)., Methods: Retrospective case-control study of Glenn and Fontan patients who had a 4D flow MR study. Flows were measured at the ascending aorta, left and right pulmonary arteries, left and right pulmonary veins, and both caval veins. Systemic-to-pulmonary collateral flow was calculated using two formulas: 1) pulmonary veins - pulmonary arteries and 2) ascending aorta - caval veins. Anatomical identification of collaterals was performed using the 4D MR image set., Results: Fourteen patients (n = 11 Fontan, n = 3 Glenn) were included (age 26 [22-30] years). Systemic-to-pulmonary collateral flow was significantly higher in the patients than the controls (n = 10, age 31.2 [15.1-38.4] years) with both formulas: 0.28 [0.09-0.5] versus 0.04 [-0.66-0.21] l/min/m 2 (p = 0.036, formula 1) and 0.67 [0.24-0.88] versus -0.07 [-0.16-0.08] l/min/m 2 (p < 0.001, formula 2). In patients, systemic-to-pulmonary collateral flow differed significantly between formulas 1 and 2 (13% versus 26% of aortic flow, p = 0.038). In seven patients, veno-venous collaterals were detected and no aortopulmonary collaterals were visualised., Conclusion: 4D flow MR is able to detect increased systemic-to-pulmonary collateral flow and visualise collaterals vessels in Glenn and Fontan patients. However, the amount of systemic-to-pulmonary collateral flow varies with the formula employed. Therefore, further research is necessary before it could be applied in clinical care.

Background: Clinical factors are used to estimate late complication risk in adults after atrial switch operation (AtrSO) for transposition of the great arteries (TGA), but heterogeneity in clinical course remains. We studied whether common genetic variants are associated with outcome and add value to a clinical risk score in TGA-AtrSO patients., Methods and Results: This multicenter study followed 133 TGA-AtrSO patients (aged 28 [IQR 24-35] years) for 13 (IQR 9-16) years and examined the association of genome-wide single-nucleotide polymorphisms (SNPs) with a composite endpoint of symptomatic ventricular arrhythmia, heart failure hospitalization, ventricular assist device implantation, heart transplantation, or mortality. Thirty-two patients (24%) reached the endpoint. The genome-wide association study yielded one genome-wide significant (p < 1 × 10 -8 ) locus and 18 suggestive loci (p < 1 × 10 -5 ). A genetic risk score constructed on the basis of independent SNPs with p < 1 × 10 -5 was associated with outcome after correction for the clinical risk score (HR = 1.26/point increase [95%CI 1.17-1.35]). Risk stratification improved with a combined risk score (clinical score + genetic score) compared to the clinical score alone (p = 2 × 10 -16 , C-statistic 0.95 vs 0.85). In 51 patients with a clinical intermediate (5-20%) 5-year risk of events, the combined score reclassified 32 patients to low (<5%) and 5 to high (>20%) risk. Stratified by the combined score, observed 5-year event-free survival was 100%, 79% and 31% for low, intermediate, and high-risk patients, respectively., Conclusions: Common genetic variants may explain some variation in the clinical course in TGA-AtrSO and improve risk stratification over clinical factors alone, especially in patients at intermediate clinical risk. These findings support the hypothesis that including genetic variants in risk assessment may be beneficial., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Congenital Heart Disease (CHD) predisposes to Infective Endocarditis (IE), but data about characterization and prognosis of IE in CHD patients is scarce., Methods: The ESC-EORP-EURO-ENDO study is a prospective international study in IE patients (n = 3111). In this pre-specified analysis, adult CHD patients (n = 365, 11.7%) are described and compared with patients without CHD (n = 2746) in terms of baseline characteristics and mortality., Results: CHD patients (73% men, age 44.8 ± 16.6 years) were younger and had fewer comorbidities. Of the CHD patients, 14% had a dental procedure before hospitalization versus 7% in non-CHD patients (p < 0.001) and more often had positive blood cultures for Streptococcus viridans (16.4% vs 8.8%, p < 0.001). As in non-CHD patients, IE most often affected the left-sided valves. For CHD patients, in-hospital mortality was 9.0% vs 18.1% in non-CHD patients (p < 0.001), and also, during the entire follow-up of 700 days, survival was more favorable (log-rank p < 0.0001), even after adjustment for age, gender and major comorbidities (Hazard Ratio (HR) 0.68; 95%CI 0.50-0.92). Within the CHD population, multivariable Cox regression revealed the following effects (HR and [95% CI]) on mortality: fistula (HR 6.97 [3.36-14.47]), cerebral embolus (HR 4.64 [2.08-10.35]), renal insufficiency (HR 3.44 [1.48-8.02]), Staphylococcus aureus as causative agent (HR 2.06 [1.11-3.81]) and failure to undertake surgery when indicated (HR 5.93 [3.15-11.18])., Conclusions: CHD patients with IE have a better outcome in terms of all-cause mortality. The observed high incidence of dental procedures prior to IE warrants further studies about the current use, need and efficacy of antibiotic prophylaxis in CHD patients., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aims: Improvement in left ventricular ejection fraction (LVEF) after up-titration of guideline-directed medical therapy (GDMT) has been well described in heart failure (HF) patients. Less is known about the prevalence and clinical course of right ventricular dysfunction (RVD) in patients with new-onset HF., Methods and Results: From 2012 to 2018, 625 patients with a recent (<3 months) diagnosis of HF were referred to a specialized nurse-led HF clinic for protocolized up-titration of GDMT. RVD, defined as tricuspid annular plane systolic excursion (TAPSE) <17 mm, was assessed at baseline and at the follow-up visit. Patients were followed for the combined endpoint of all-cause mortality and HF hospitalization for a mean of 3.3 ± 1.9 years. Of the 625 patients, 241 (38.6%) patients had RVD at baseline. Patients with RVD were older, more symptomatic, had a lower LVEF, and more often had a history of cardiothoracic surgery and atrial fibrillation. After a median follow-up of 9 months, right ventricular function normalized in 49% of the patients with baseline RVD. RVD at baseline was associated with a higher risk of the combined endpoint (hazard ratio [HR] 1.62, 95% confidence interval [CI] 1.21-2.18). Right ventricular function normalization was associated with a lower risk for the combined endpoint (HR 0.56, 95% CI 0.31-0.99), independent of baseline TAPSE, age, sex, and LVEF., Conclusion: More than one-third of patients with new-onset HF have RVD. RVD is associated with a higher risk of all-cause mortality and HF hospitalization. Recovery of RVD regularly occurs during up-titration of GDMT and is associated with improved clinical outcomes., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

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)., Competing Interests: This work was supported by the Dutch Cancer Society, Alpe d’HuZes (grant DCS 2011-5265). The funder had no role in the design, data collection, management, analysis, interpretation, report writing, and decision to submit the manuscript. Dr Hummel has patents, royalties, and other intellectual properties with Us2.ai (institutional). Dr van der Meer has received research funding from Vifor Pharma (institutional), AstraZeneca (institutional), Ionis (institutional), and Pfizer (institutional); and has received payments or honoraria from Vifor Pharma (institutional), Novartis (institutional), and Pharmacosmos (institutional). Dr Nijland has received research funding from Takeda (institutional) and Roche (institutional); and has performed consulting in an advisory role for Genmab (institutional). Dr de Vries has received research funding from Amgen (institutional), AstraZeneca (institutional), Bayer (institutional), Chugai Pharma (institutional), Crescendo (institutional), CytomX (institutional), Therapeutics (institutional), G1 Therapeutics (institutional), Genentech (institutional), Nordic Nanovector (institutional), Radius Health (institutional), Regeneron, Roche (institutional), Servier (institutional), and Synthon (institutional); and has performed consulting in an advisory role for Daiichi Sankyo (institutional), the National Surgical Adjuvant Breast and Bowel Project (institutional), and Sanofi (institutional). Dr Gietema has received research funding from Abbvie (institutional), Roche (institutional), and Siemens (institutional). Dr Walenkamp has received a grant from the Dutch Cancer Society (institutional); has received research funding from Abbvie (institutional), Bristol Myers Squibb (institutional), Genzyme (institutional), Karyopharm Therapeutics (institutional), and Roche (institutional); and has performed consulting in an advisory role for Polyphor (institutional), Ipsen (institutional), Karyopharm (institutional), and Novartis (institutional). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Rationale: Pulmonary hyperinflation in patients with chronic obstructive pulmonary disease has been related to smaller cardiac chamber sizes and impaired cardiac function. Currently, bronchoscopic lung volume reduction (BLVR) with endobronchial valves is a treatment option to reduce pulmonary hyperinflation in patients with severe emphysema. Objectives: We hypothesized that reduction of hyperinflation would improve cardiac preload in this patient group. In addition, we investigated whether the treatment would result in elevated pulmonary artery pressures because of pulmonary vascular bed reduction. Methods: We included patients with emphysema and severe hyperinflation (defined by a baseline residual volume >175% of predicted) who were eligible for BLVR with endobronchial valves. Cardiac magnetic resonance imaging was obtained one day before treatment and at 8-week follow-up. Primary endpoint was cardiac preload, as measured by the right ventricle end-diastolic volume index. As secondary endpoints, we measured indexed end-diastolic and end-systolic volumes of the right ventricle, left atrium, and left ventricle; pulmonary artery pressures; cardiac output; ejection fraction; and strain. Measurements and Main Results: Twenty-four patients were included. At 8-week follow-up, right ventricle end-diastolic volume index was significantly improved (+7.9 ml/m 2 ; SD, 10.0; P  = 0.001). In addition to increased stroke volumes, we found significantly higher ejection fractions and strain measurements. Although cardiac output was significantly increased (+0.9 L/min; SD, 1.5; P  = 0.007), there were no changes in pulmonary artery pressures. Conclusions: We found that reduction of hyperinflation using BLVR with endobronchial valves significantly improved cardiac preload, myocardial contractility, and cardiac output, without changes in pulmonary artery pressures. Clinical trial registered with www.clinicaltrials.gov (NCT03474471).

Left atrial (LA) structure and function in heart failure with reduced (HFrEF) versus preserved ejection fraction (HFpEF) is only established in small studies. Therefore, we conducted a systematic review of LA structure and function in order to find differences between patients with HFrEF and HFpEF. English literature on LA structure and function using echocardiography was reviewed to calculate pooled prevalence and weighted mean differences (WMD). A total of 61 studies, comprising 8806 patients with HFrEF and 9928 patients with HFpEF, were included. The pooled prevalence of atrial fibrillation (AF) was 34.4% versus 42.8% in the acute inpatient setting, and 20.1% versus 33.1% in the chronic outpatient setting when comparing between HFrEF and HFpEF. LA volume index (LAVi), LA reservoir global longitudinal strain (LAGLS R ), and E/e' was 59.7 versus 52.7 ml/m 2 , 9.0% versus 18.9%, and 18.5 versus 14.0 in the acute inpatient setting, and 48.3 versus 38.2 ml/m 2 , 12.8% versus 23.4%, and 16.9 versus 13.5 in the chronic outpatient setting when comparing HFrEF versus HFpEF, respectively. The relationship between LAVi and LAGLS R was significant in HFpEF, but not in HFrEF. Also, in those studies that directly compared patients with HFrEF versus HFpEF, those with HFrEF had worse LAGLS R [WMD = 16.3% (22.05,8.61); p < 0.001], and higher E/e' [WMD = -0.40 (-0.56, -0.24); p < 0.05], while LAVi was comparable. When focusing on acute hospitalized patients, E/e' was comparable between patients with HFrEF and HFpEF. Despite the higher burden of AF in HFpEF, patients with HFrEF had worse LA global function. Left atrial myopathy is not specifically related to HFpEF., (© 2022. The Author(s).)

Aim: Different associations between epicardial adipose tissue (EAT) and cardiac function have been suggested in patients with heart failure with preserved (HFpEF) versus reduced and mildly reduced ejection fraction (HFrEF/HFmrEF). However, few studies have directly compared the association between EAT and left atrial (LA) and left ventricular (LV) function in patients with HFpEF and HFrEF/HFmrEF., Methods and Results: We studied EAT thickness using transthoracic echocardiography in a multicentre cohort of 149 community-dwelling controls without heart failure, 99 patients with HFpEF, and 366 patients with HFrEF/HFmrEF. EAT thickness was averaged from parasternal long-axis and short-axis views, respectively, and off-line speckle tracking analysis was performed to quantify LA and LV function. Data were validated in an independent cohort of 626 controls, 243 patients with HFpEF, and 180 patients with HFrEF/HFmrEF. For LV function, LV global longitudinal strain (GLS) was measured in both derivation and validation cohorts. For LA function, LAGLS at reservoir, contractile and conduit phase were measured in the derivation cohort, and only LAGLS at reservoir phase was measured in the validation cohort. In the derivation cohort, EAT thickness was lower in HFrEF/HFmrEF (7.3 ± 2.5 mm) compared to HFpEF (8.3 ± 2.6 mm, p < 0.05) and controls (7.9 ± 1.8 mm, p < 0.05). Greater EAT thickness was associated with better LV and contractile LA function in HFrEF/HFmrEF, but not in HFpEF (p for interaction <0.05). These findings were confirmed in the validation cohort, where EAT thickness was lower in HFrEF/HFmrEF (6.7 ± 1.4 mm) compared to HFpEF (9.6 ± 2.8 mm; p < 0.05) and controls (7.7 ± 2.3 mm; p < 0.05). Greater EAT thickness was associated with better LV and reservoir LA function in patients with HFrEF/HFmrEF but worse LV and reservoir LA function in patients with HFpEF (p for interaction <0.05). Thickened EAT (EAT thickness >10 mm) was associated with LA dysfunction (LAGLS at reservoir phase <23%) in HFpEF, but not in HFrEF/HFmrEF., Conclusion: Epicardial adipose tissue thickness is greater in patients with HFpEF than HFrEF/HFmrEF. Increased EAT thickness is associated with worse LA and LV function in HFpEF but the opposite in HFrEF/HFmrEF., (© 2022 European Society of Cardiology.)

Background: To identify the association between comorbidities and left atrial (LA) and right atrial (RA) function in patients with paroxysmal atrial fibrillation (AF)., Methods: This is a cross-sectional study. Speckle-tracking echocardiography was performed in 344 patients with paroxysmal AF at baseline, and available in 298 patients after 1-year follow-up. The number of comorbidities (hypertension, diabetes mellitus, coronary artery disease, body mass index > 25 kg/m 2 , age > 65 years, moderate to severe mitral valve regurgitation and kidney dysfunction (estimated glomerular filtration rate < 60 ml/min/1.73 m 2 )) was determined and the association with atrial strain was tested., Results: Mean age of the patients was 58 (SD 12) years and 137 patients were women (40%). Patients with a higher number of comorbidities had larger LA volumes (p for trend <0.001), and had a decrease in all strain phases from the LA and RA, except for the RA contraction phase (p for trend 0.47). A higher number of comorbidities was associated with LA reservoir and conduit strain decrease independently of LA volume (p < 0.001, p < 0.001 respectively). Patients with 1-2 comorbidities, but not patients with 3 or more comorbidities, showed a further progression of impaired LA and RA function in almost all atrial strain phases at 14 [13-17] months follow-up., Conclusions: In patients with paroxysmal AF, individual and combined comorbidities are related to lower LA and RA strain. In patients with few comorbidities, impairment in atrial function progresses during one year of follow-up. Whether comorbidity management prevents or reverses decrease in atrial function warrants further study., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: The clinical and prognostic implications of a hypertensive response to exercise after repair of coarctation of the aorta (CoA) remain controversial. We aimed to determine the prevalence of a hypertensive response to exercise, identify factors associated with peak exercise systolic blood pressure (SBP) and explore the association of peak exercise SBP with resting blood pressure and cardiovascular events during follow-up., Methods: From the Dutch national CONgenital CORvitia (CONCOR) registry, adults with repaired CoA who underwent exercise stress testing were included. A hypertensive response to exercise was defined as a peak exercise SBP ≥210 mm Hg in men and ≥190 mm Hg in women. Cardiovascular events consisted of coronary artery disease, stroke, aortic complications and cardiovascular death., Results: Of the original cohort of 920 adults with repaired CoA, 675 patients (median age 24 years (range 16-72 years)) underwent exercise stress testing. Of these, 299 patients (44%) had a hypertensive response to exercise. Mean follow-up duration was 10.1 years. Male sex, absence of a bicuspid aortic valve and elevated resting SBP were independently associated with increased peak exercise SBP. Peak exercise SBP was positively predictive of office SBP (β=0.11, p<0.001) and 24-hour SBP (β=0.05, p=0.03) at follow-up, despite correction for baseline SBP. During follow-up, 100 patients (15%) developed at least 1 cardiovascular event. Peak exercise SBP was not significantly associated with the occurrence of cardiovascular events (HR 0.994 (95% CI 0.987 to 1.001), p=0.11)., Conclusions: A hypertensive response to exercise was present in nearly half of the patients in this large, prospective cohort of adults with repaired CoA. Risk factors for increased peak exercise SBP were male sex, absence of a bicuspid aortic valve and elevated resting SBP. Increased peak exercise SBP independently predicted hypertension at follow-up. These results support close follow-up of patients with a hypertensive response to exercise to ensure timely diagnosis and treatment of future hypertension., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Type D personality has been previously shown to increase the risk for mortality in patients with acquired heart disease., Objective: We aimed to compare mortality in adult patients with congenital heart disease (CHD) with and without type D., Methods: Survival was assessed using prospective data from the Dutch national Congenital Corvitia registry for adults with CHD. Patients were randomly selected from the registry and characterized at inclusion in 2009 for the presence of type D using the DS14 questionnaire., Results: One thousand fifty-five patients, with 484 (46%) males, a mean (SD) age of 41 (14) years, 613 (58%) having mild CHD, 348 (33%) having moderate CHD, and 94 (9%) having severe CHD, were included. Type D personality was present in 225 patients (21%). Type D was associated with an increased risk for all-cause mortality independent of age, sex, New York Heart Association class, number of prescribed medications, depression, employment status, and marital status (hazard ratio, 1.94; 95% confidence interval, 1.05-3.57; P = .033)., Conclusion: Type D personality was associated with an increased risk for all-cause mortality in adult patients with CHD., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: Although cure rates in esophageal cancer (EC) have improved since the introduction of neoadjuvant chemoradiation (nCRT), evidence for treatment-related cardiac toxicity is growing, of which the exact mechanisms remain unknown. The primary objective of this study was to identify (subclinical) cardiac dysfunction in EC patients after nCRT followed by surgical resection as compared to surgery alone., Materials and Methods: EC survivors followed for 5-15 years after curative resection with (n = 20) or without (n = 20) nCRT were enrolled in this prospective cross-sectional pilot study. All patients underwent several clinical and diagnostic tests in order to objectify (sub)clinical cardiac toxicity including cardiac CT and MRI, echocardiography, ECG, 6-minutes walking test, physical examination and EORTC questionnaires., Results: We found an increased rate of myocardial fibrosis (Linear late gadolinium enhancement (LGE) 4 vs. 1; p = 0.13; mean extracellular volume (ECV) 28.4 vs. 24.0; p < 0.01), atrial fibrillation (AF) (6 vs. 2; p = 0.07) and conduction changes in ECG among patients treated with nCRT as compared to those treated with surgery alone. The results suggested an impact on quality of life in terms of worse role functioning for this patient group (95.0 vs. 88.8; p = 0.03)., Conclusion: Based on our analyses we hypothesize that in EC patients, radiation-induced myocardial fibrosis plays a central role in cardiac toxicity leading to AF, conduction changes and ultimately to decreased role functioning. The results emphasize the need to verify these findings in larger cohorts of patients., Competing Interests: Declaration of Competing Interest 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., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background The long-term burden of cardiovascular disease after repair of coarctation of the aorta (CoA) has not been elucidated. We aimed to determine the incidence of and risk factors for cardiovascular events in adult patients with repaired CoA. Additionally, mortality rates were compared between adults with repaired CoA and the general population. Methods and Results Using the Dutch Congenital Corvitia (CONCOR) registry, patients aged ≥16 years with previous surgical or transcatheter CoA repair from 5 tertiary referral centers were included. Cardiovascular events were recorded, comprising coronary artery disease, stroke/transient ischemic attack, aortic complications, arrhythmias, heart failure hospitalizations, endocarditis, and cardiovascular death. In total, 920 patients (median age, 24 years [range 16-74 years]) were included. After a mean follow-up of 9.3±5.1 years, 191 patients (21%) experienced at least 1 cardiovascular event. A total of 270 cardiovascular events occurred, of which aortic complications and arrhythmias were most frequent. Older age at initial CoA repair (hazard ratio [HR], 1.017; 95% CI, 1.000-1.033 [ P =0.048]) and elevated left ventricular mass index (HR, 1.009; 95% CI, 1.005-1.013 [ P <0.001]) were independently associated with an increased risk of cardiovascular events. The mortality rate was 3.3 times higher than expected based on an age- and sex-matched cohort from the Dutch general population (standardized mortality ratio, 3.3; 95% CI, 2.3-4.4 [ P <0.001]). Conclusions This large, prospective cohort of adults with repaired CoA showed a high burden of cardiovascular events, particularly aortic complications and arrhythmias, during long-term follow-up. Older age at initial CoA repair and elevated left ventricular mass index were independent risk factors for the occurrence of cardiovascular events. Mortality was 3.3-fold higher compared with the general population. These results advocate stringent follow-up after CoA repair and emphasize the need for improved preventive strategies.

Purpose: Radiation-induced cardiac toxicity is a potential lethal complication. The aim of this study was to assess whether there is a dose-dependent relationship between radiation dose and myocardial fibrosis in patients who received neoadjuvant chemoradiation (nCRT) for esophageal cancer (EC)., Methods and Materials: Forty patients with EC treated with a transthoracic esophagectomy with (n = 20) or without (n = 20) nCRT (CROSS study regimen) were included. Cardiovascular magnetic resonance imaging (1.5 Tesla) for left ventricular (LV) function, late gadolinium enhancement, and T1 mapping were performed. Extracellular volume (ECV), as a surrogate for collagen burden, was measured for all LV segments separately. The dose-response relationship between ECV and mean radiation dose per LV myocardial segment was evaluated using a mixed-model analysis., Results: Seventeen nCRT and 16 control patients were suitable for analysis. The mean time after treatment was 67.6 ± 8.1 (nCRT) and 122 ± 35 (controls) months (P = .02). In nCRT patients, we found a significantly higher mean global ECV of 28.2% compared with 24.0% in the controls (P < .001). After nCRT, LV myocardial segments with elevated ECV had received significantly higher radiation doses. In addition, a linear dose-effect relation was found with a 0.136% point increase of ECV for each Gy (P < .001). There were no differences in LV function measures and late gadolinium enhancement between both groups., Conclusions: Myocardial ECV was significantly higher in long-term EC survivors after nCRT compared with surgery only. Moreover, this ECV increase was linear with the radiation dose per LV segment, indicating radiation-induced myocardial fibrosis., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Transcatheter atrial septal defect (ASD) and patent foramen ovale (PFO) closure might have opposite short- and long-term haemodynamic consequences compared with restricted interatrial shunt creation, which recently emerged as a potential treatment modality for patients with heart failure with preserved ejection fraction (HFpEF). Given the opposing approaches of ASD and PFO closure versus shunt creation, we investigated the early and sustained cardiac structural and functional changes following transcatheter ASD or PFO closure., Methods: In this retrospective study, adult secundum-type ASD and PFO patients with complete echocardiography examinations at baseline and at 1‑day and 1‑year follow-up who also underwent transcatheter closure between 2013 and 2017 at the University Medical Centre Groningen, the Netherlands were included., Results: Thirty-nine patients (mean age 48 ± standard deviation 16 years, 61.5% women) were included. Transcatheter ASD/PFO closure resulted in an early and persistent decrease in right ventricular systolic and diastolic function. Additionally, transcatheter ASD/PFO closure resulted in an early and sustained favourable response of left ventricular (LV) systolic function, but also in deterioration of LV diastolic function with an increase in LV filling pressure (LVFP), as assessed by echocardiography. Age (β = 0.31, p = 0.009) and atrial fibrillation (AF; β = 0.24, p = 0.03) were associated with a sustained increase in LVFP after transcatheter ASD/PFO closure estimated by mean E/e' ratio (i.e. ratio of mitral peak velocity of early filling to diastolic mitral annular velocity). In subgroup analysis, this was similar for ASD and PFO closure., Conclusion: Older patients and patients with AF were predisposed to sustained increases in left-sided filling pressures resembling HFpEF following ASD or PFO closure. Consequently, these findings support the current concept that creating a restricted interatrial shunt might be beneficial, particularly in elderly HFpEF patients with AF., (© 2021. The Author(s).)

Background: Aortic root dilatation is common in adults with repaired tetralogy of Fallot (rTOF) and might lead to aortic dissection. However, little is known on progression of aortic dilatation and the effect of pharmaceutical treatment. This study aims to determine factors associated with aortic growth and investigate effects of losartan., Methods and Results: We performed a prespecified analysis from the 1:1 randomized, double-blind REDEFINE trial. Aortic root diameters were measured at baseline and after 2.0 ± 0.3 years of follow-up using cardiovascular magnetic resonance (CMR) imaging. A total of 66 patients were included (68% men, age 40 ± 12 years, baseline aortic root 37 ± 6 mm, 32% aortic dilatation (>40 mm)). There was a trend towards slow aortic root growth (+0.6 ± 2.3 mm after two years, p = 0.06) (n = 60). LV stroke volume was the only factor associated with both a larger baseline aortic root (β: 0.09 mm/ml (95% C.I.:0.02, 0.15), p = 0.010) and with aortic growth during follow-up (β: 0.04 mm/ml (95% C.I.:0.005, 0.066), p = 0.024), after correction for age, sex, and body surface area using linear regression analysis. No treatment effect of losartan was found (p = 0.17)., Conclusions: Aortic root dilatation was present in about one-third of rTOF patients. A larger LV stroke volume was associated with both a larger baseline aortic root and ongoing growth. Our findings provide no arguments for lower aortic diameter thresholds for prophylactic surgery compared to the general population., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose Substantial differences between sexes exist with respect to cardiovascular diseases, including congenital heart disease. Nevertheless, clinical decisions in the long-term follow-up of patients with repaired tetralogy of Fallot (rTOF) are currently based on unisex thresholds for cardiac magnetic resonance (CMR) measurements. This study aimed to assess whether sex differences exist in cardiac adaptation to hemodynamic loading conditions in patients with rTOF. Methods and Results This cross-sectional, two-center, combined pediatric and adult cohort included 320 rTOF patients (163 males, 51%) who underwent routine CMR. Despite similar age (median and interquartile range [m + IQR] 23.4 [15.2-34.4] years), surgical history, and hemodynamic loading, males with rTOF demonstrated higher biventricular CMR-derived volumes and masses, indexed for body surface area, compared to females (e.g. m + IQR right ventricular (RV) end-diastolic volume: males 123 [100-151] mL/m 2 , females 114 [94-131] mL/m 2 , P = 0.007). Sex-specific Z-scores of biventricular volumes and masses were similar for males and females. RV volumes and masses correlated with hemodynamic loading, but these relations did not differ between sexes. Biventricular ejection fraction (EF) appeared to be lower in male patients, compared to female patients (e.g. m + IQR RVEF: males 48 [43-54]%, females 52 [46-57]%, P < 0.001). Conclusion Indexed ventricular volumes and masses are higher in males with rTOF, compared to females, similar to the healthy population. RV hypertrophy and dilatation correlated to loading conditions similarly for both sexes. However, under comparable loading conditions, males demonstrated more severe functional impairment. These results indicate that sex-differences should no longer be ignored in treatment strategies, including timing of pulmonary valve replacement.

Introduction: Infective endocarditis (IE) is associated with a high in-hospital and long term mortality. Although progress has been made in diagnostic approach and management of IE, morbidity and mortality of IE remain high. In the latest European guidelines, the importance of the multi-modality imaging in diagnosis and follow up of IE is emphasized., Aim: The aim was to provide information regarding mortality and adverse events of IE, to determine IE characteristics and to assess current use of imaging in the diagnostic workup of IE., Methods: This is a prospective observational cohort study. We used data from the EURO-ENDO registry. Seven hospitals in the Netherlands have participated and included patients with IE between April 2016 and April 2018., Results: A total of 139 IE patients were included. Prosthetic valve endocarditis constituted 32.4% of the cases, cardiac device related IE 7.2% and aortic root prosthesis IE 3.6%. In-hospital mortality was 14.4% (20 patients) and one-year mortality was 21.6% (30 patients). The incidence of embolic events under treatment was 16.5%, while congestive heart failure or cardiogenic shock occurred in 15.1% of the patients. Transthoracic and transoesophageal echocardiography were performed most frequently (97.8%; 81.3%) and within 3 days after IE suspicion, followed by 18 F‑fluorodeoxyglucose positron emission tomography/computed tomography (45.3%) within 6 days and multi-slice computed tomography (42.4%) within 7 days., Conclusion: We observed a high percentage of prosthetic valve endocarditis, rapid and extensive use of imaging and a relatively low in-hospital and one-year mortality of IE in the Netherlands. Limitations include possible selection bias.

Background: Predicting heart failure events in patients with a systemic right ventricle (sRV) due to transposition of the great arteries (TGA) is important for timely intensification of follow-up. This study assessed the value of strain compared with currently used parameters as predictor for heart failure-free survival in patients with sRV., Methods: In participants of a multicentre trial, speckle-tracking echocardiography (STE) was performed to assess global longitudinal strain (GLS), mechanical dispersion (MD), and postsystolic shortening (PSS). Cox regression was used to determine the association of STE parameters with the combined end point of progression of heart failure and death, compared with cardiovascular magnetic resonance (CMR) and computed tomography (CT) derived parameters., Results: Echocardiograms of 60 patients were analyzed (mean age 34 ± 11 years, 65% male, 35% congenitally corrected TGA). Mean GLS was -13.5 ± 2.9%, median MD was 49 (interquartile range [IQR] 30-76) ms, and 14 patients (23%) had PSS. During a median 8 (IQR 7-9) years, 15 patients (25%) met the end point. GLS, MD, and PSS were all associated with heart failure-free survival in univariable analysis. After correction for age, only GLS (optimal cutoff > -10.5%) and CMR/CT-derived sRV ejection fraction (optimal cutoff < 30%) remained associated with heart failure-free survival: hazard ratio (HR) 8.27, 95% confidence interval (CI) 2.50-27.41 (P < 0.001), and HR 4.34, 95% CI 1.48-12.74 (P = 0.007), respectively). Combining GLS and ejection fraction improved prediction, with patients with both GLS > -10.5% and sRV ejection fraction < 30% at highest risk (HR 19.69, 95% CI 4.90-79.13; P < 0.001)., Conclusions: The predictive value of GLS was similar to that of CMR/CT-derived ejection fraction. The combination of GLS and ejection fraction identified patients at highest risk of heart failure and death. Easily available STE parameters can be used to guide follow-up intensity and can be integrated into future risk prediction scores., (Copyright © 2020 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Aims: Heart failure is traditionally classified by left ventricular ejection fraction (LVEF), rather than by left ventricular (LV) geometry, with guideline-recommended therapies in heart failure with reduced ejection fraction (HFrEF) but not heart failure with preserved ejection fraction (HFpEF). Most patients with HFrEF have eccentric LV hypertrophy, but some have concentric LV hypertrophy. We aimed to compare clinical characteristics, biomarker patterns, and response to treatment of patients with HFrEF and eccentric vs. concentric LV hypertrophy., Methods and Results: We performed a retrospective post-hoc analysis including 1015 patients with HFrEF (LVEF <40%) from the multinational observational BIOSTAT-CHF study. LV geometry was classified using two-dimensional echocardiography. Network analysis of 92 biomarkers was used to investigate pathophysiologic pathways. Concentric LV hypertrophy was present in 142 (14%) patients, who were on average older and more likely hypertensive compared to those with eccentric LV hypertrophy. Network analysis revealed that N-terminal pro-B-type natriuretic peptide was an important hub in eccentric hypertrophy, whereas in concentric hypertrophy, tumour necrosis factor receptor 1, urokinase plasminogen activator surface receptor, paraoxonase and P-selectin were central hubs. Up-titration of beta-blockers was associated with a mortality benefit in HFrEF with eccentric but not concentric LV hypertrophy (P-value for interaction ≤0.001). For angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, the hazard ratio for mortality was higher in concentric hypertrophy, but the interaction was not significant., Conclusion: Patients with HFrEF with concentric hypertrophy have a clinical and biomarker phenotype that is distinctly different from those with eccentric hypertrophy. Patients with concentric hypertrophy may not experience similar benefit from up.-titration of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and beta-blockers compared to patients with eccentric hypertrophy., (© 2019 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Objective: N-terminal pro-brain natriuretic peptide has an established role in the diagnosis and prognosis of heart failure. In Fontan patients, this peptide is often increased, but its diagnostic value in this particular non-physiologic, univentricular circulation is unclear. We investigated whether N-terminal pro-brain natriuretic peptide represents ventricular function or other key variables in Fontan patients., Methods and Results: Ninety-five consecutive Fontan patients ≥10 years old who attended the outpatient clinic of the Center for Congenital Heart Diseases in 2012-2013 were included. Time since Fontan completion was 16 ± 9 years. Median N-terminal pro-brain natriuretic peptide was 114 (61-264) ng/l and was higher than gender-and age-dependent normal values in 54% of the patients. Peptide Z-scores were higher in patients in NYHA class III/IV compared to those in class I/II, but did not correlate with ventricular function assessed by MRI and echocardiography, nor with peak exercise capacity. Instead, peptide Z-scores significantly correlated with follow-up duration after Fontan completion (p < 0.001), right ventricular morphology (p = 0.004), indexed ventricular mass (p = 0.001), and inferior caval vein diameter (p < 0.001) (adjusted R2 = 0.615)., Conclusions: N-terminal pro-brain natriuretic peptide levels in Fontan patients correlate with functional class, but do not necessarily indicate ventricular dysfunction. Increased peptide levels were associated with a longer existence of the Fontan circulation, morphologic ventricular characteristics, and signs of increased systemic venous congestion. Since the latter are known to be key determinants of the performance of the Fontan circulation, these findings suggest increase in N-terminal pro-brain natriuretic peptide levels to indicate attrition of the Fontan circulation, independent of ventricular function.

Background We investigated serial serum levels of GDF-15 (growth differentiation factor 15) in Fontan patients and their relation to outcome. Methods and Results In this single-center prospective study of consecutive Fontan patients, serial serum GDF-15 measurement and clinical assessment was done at baseline (n=81) and after 2 years (n=51). The association between GDF-15 and the combined end point of all-cause mortality, heart transplant listing, and Fontan-related hospitalization was investigated. Median age at baseline was 21 years (interquartile range: 15-28 years). Median GDF-15 serum levels at baseline were 552 pg/mL (interquartile range: 453-729 pg/mL). GDF-15 serum levels correlated positively with age, age at Fontan initiation, New York Heart Association class, and serum levels of NT-proBNP (N-terminal pro-B-type natriuretic peptide) and ɣGT (γ-glutamyltransferase) and negatively with exercise capacity. During a median follow-up of 4.8 years (interquartile range: 3.3-5.5 years), the combined end point occurred in 30 patients (37%). Multivariate Cox regression showed that patients with the highest baseline GDF-15 (n=20, defined as the upper quartile) had a higher risk of hospitalization or death than the lowest 3 quartiles (hazard ratio [HR], 2.76; 95% CI, 1.27-6.00; P =0.011). After 2 years of follow-up, patients in whom serum level of GDF-15 increased to >70 pg/mL (n=13) had a higher risk of hospitalization or death than the lowest 3 quartiles (HR, 2.69; 95% CI, 1.03-6.99; P =0.043). Conclusions In Fontan patients, elevated serum levels of GDF-15 are associated with worse functional status and predict Fontan-related events. Furthermore, serial measurements showed that an increase in GDF-15 serum level was associated with increased risk for adverse outcome.

Background: Coronary artery disease (CAD) will increasingly determine outcome in the aging adult congenital heart disease (CHD) population. We aimed to determine sex-specific incidence of CAD in adult CHD patients throughout adulthood, compared to the general population., Methods and Results: We followed 11,723 adult CHD patients (median age 33 years; 49% male; 57% mild, 34% moderate, 9% severe CHD) from the Dutch CONCOR registry, and two age-sex-matched persons per patient from the general population for first CAD event in national registers (period 2002-2012). Incidence rates were estimated using smoothed hazard functions. CAD risk during follow-up, stratified by CHD severity, was compared using proportional subdistribution hazards regression. In ACHD patients, 103 CAD events (43 women) occurred over 60,456 person-years. Rates per 1000person-years increased from 0.3(95% confidence interval: 0.1-0.6) at age 20 to 5.8(3.7-8.9) at 70 years in female, and from 0.5(0.3-1.0) to 7.8(5.1-11.8) in male patients. Compared to the general population, relative risk was 12.0(2.5-56.3) in women and 4.6(1.7-12.1) in men aged 20 years. Relative risk declined with age, remaining significant up to age ~65 years in women and ~50 years in men. In patients with mild, moderate and severe CHD, CAD risk was 1.3(0.9-1.9), 1.6(1.0-2.5) and 2.9(1.3-6.9) times increased compared to the general population, respectively., Conclusions: We found increased CAD risk in adult CHD patients, with greater relative risk at younger age, in women and those with more severe CHD. These results underline the importance of screening for and treatment of CAD risk factors in these patients., Competing Interests: Declaration of competing interest The authors report no relationships that could be construed as a conflict of interest., (Copyright © 2019. Published by Elsevier B.V.)

Background: In Fontan patients, attrition of ventricular function is well recognized, but early detection of ventricular dysfunction is difficult. The aim of this study is to longitudinally assess ventricular strain in Fontan patients using a new method for cardiac magnetic resonance (CMR) feature tracking, and to investigate the relationship between ventricular strain and cardiac systolic function., Methods and Results: In this prospective, standardized follow-up study in 51 Fontan patients, age ≥ 10 years, CMR and concomitant clinical assessment was done at the start of the study and after 2 years. CMR feature tracking was done combining the dominant and hypoplastic ventricles. Global longitudinal strain (GLS) (-17.3% versus -15.9%, P = 0.041) and global circumferential strain (GCS) (-17.7 versus -16.1, P = 0.047) decreased over 2 years' time. Ejection fraction (EF) (57%), cardiac index (CI) (2.7 l/min/m 2 ) and NYHA functional class (97% in class I/II) were preserved. The strain values of the combined dominant and hypoplastic ventricles were significantly worse compared to those of the dominant ventricle only (GLS -16.8 (-19.5 to -14.0) versus -18.8 (-21.3 to -15.3) respectively, P = 0.001, GCS -18.3 (-22.1 to -14.8) versus -22.5 (-26.3 to -19.4) respectively, P < 0.001)., Conclusions: This study showed a decrease in cardiac strain over 2 years in Fontan patients without clinical signs of Fontan failure, where EF, CI and clinical status were still preserved. Cardiac strain might be a sensitive early indicator of systolic ventricular decline. Furthermore, combined strain of the hypoplastic and dominant ventricles seems a more accurate representation of cardiac strain in functionally univentricular hearts., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Chronic non-invasive ventilation (NIV) has become evidence-based care for stable hypercapnic COPD patients. While the number of patients increases, home initiation of NIV would greatly alleviate the healthcare burden. We hypothesise that home initiation of NIV with the use of telemedicine in stable hypercapnic COPD is non-inferior to in-hospital NIV initiation., Methods: Sixty-seven stable hypercapnic COPD patients were randomised to initiation of NIV in the hospital or at home using telemedicine. Primary outcome was daytime arterial carbon dioxide pressure (PaCO 2 ) reduction after 6 months NIV, with a non-inferiority margin of 0.4 kPa. Secondary outcomes were health-related quality of life (HRQoL) and costs., Results: Home NIV initiation was non-inferior to in-hospital initiation (adjusted mean difference in PaCO 2 change home vs in-hospital: 0.04 kPa (95% CI -0.31 to 0.38 kPa), with both groups showing a PaCO 2 reduction at 6 months compared with baseline (home: from 7.3±0.9 to 6.4±0.8 kPa (p<0.001) and in-hospital: from 7.4±1.0 to 6.4±0.6 kPa (p<0.001)). In both groups, HRQoL improved without a difference in change between groups (Clinical COPD Questionnaire total score-adjusted mean difference 0.0 (95% CI -0.4 to 0.5)). Furthermore, home NIV initiation was significantly cheaper (home: median €3768 (IQR €3546-€4163) vs in-hospital: median €8537 (IQR €7540-€9175); p<0.001)., Discussion: This is the first study showing that home initiation of chronic NIV in stable hypercapnic COPD patients, with the use of telemedicine, is non-inferior to in-hospital initiation, safe and reduces costs by over 50%., Trial Registration Number: NCT02652559., Competing Interests: Competing interests: MLD reports a grant from the Dutch Lung Foundation (junior investigator grant number 5.2.15.057JO) and the Philips Respironics, Murrysville, Pennsylvania, USA, provided for the conduct of the present study. Furthermore, MLD received grants and personal fees from Vivisol B.V., grants from Fisher and Paykel Ltd, and personal fees from Philips, outside the submitted work. JMV, GB, AH, JN, JPvM and JFMvB have no competing interests. HAMK reports an unrestricted research grant and fees for participation in advisory boards from Boehringer Ingelheim, Novartis and GlaxoSmithKline, and fees for advisory board participation from AstraZeneca and Chiesi, all above paid to his institution and outside the submitted work. PJW reports grants and personal fees from Philips and RESMED, grants from Vital Air, VIVISOL and Goedegebuure, and personal fees from Synapse and Bresotec, all outside the submitted work., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: The Carpentier Edwards Perimount Magna Ease aortic valvular prosthesis (Edwards Lifesciences, Irvine, Calif) has been among the most frequently and successfully used tissue prosthetic cardiac valves. Furthermore, this prosthesis has been used off-label in the pulmonary position. Until now, there has been a paucity of data regarding the functioning of tissue prosthetic valves under pulmonary conditions., Methods: Using a pulse duplicator, hydrodynamic characteristics of a 21-mm and 25-mm Magna Ease valve were evaluated. Among parameters evaluated were leakage orifice area, closing time (ie, time required to close), and leakage duration. This procedure was performed under different pulmonic pressure conditions (15/5 mm Hg, 28/11 mm Hg, 73/32 mm Hg) and normal aortic pressure (120/80 mm Hg) as a reference. Moving images were obtained using a Phantom MIRO M320S high-speed camera (Vision Research Inc, Wayne, NJ) at 600 frames per second and used to analyze valve area in closed position., Results: Under normal pulmonic conditions (28/11 mm Hg) the leakage orifice area was 0.020 ± 0.012 mm 2 for the 21-mm valve and 0.054 ± 0.041 mm 2 for the 25-mm valve (P = .03). Hydrodynamic characteristics of the valves differed between pulmonary and aortic testing condition. Valve closing volumes were significantly lower under pulmonary hypotension and normal pulmonary conditions than under normal aortic conditions (P < .05)., Conclusions: Under normal pulmonary pressure conditions, the hydrodynamic characteristics of Magna Ease valves are significantly different compared with aortic conditions. Further research is needed to determine whether these results are associated with prosthetic valve failure., (Copyright © 2019 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)