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Background: The adult congenital heart disease (ACHD) population is growing and risk prediction is important to predict adverse outcome and consult patients during their lifecourse. Objectives: This study aims to describe the long-term prognostic value of blood biomarkers in ACHD. Methods: In this prospective observational cohort study, 602 patients with moderate or complex ACHD were included (median age 32.5 years [IQR: 24.7-41.2], 42% female, 90% New York Heart Association I). N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitive-troponin T, growth differentiation factor 15, high-sensitive-C-reactive protein, suppression of tumorigenicity-2 and galectin-3, as well as full blood count, renal function, LDL, and HDL were measured. Cox models were applied to relate the selected biomarkers with the primary end point of all-cause mortality and secondary end point of mortality or heart failure. Standardized HRs adjusted for relevant prognostic factors, including age, sex, and complexity of diagnosis, were reported. Results: Abnormal biomarker levels were present in 424 (70.4%) patients. During a median follow-up of 10.1 years, 41 (6.8%) patients died and 81 (13.5%) developed heart failure. Associations were observed between the primary and secondary end point and red cell distribution width, NT-proBNP, and growth differentiation factor 15. In a multibiomarker model, only NT-proBNP remained associated with mortality (HR: 2.74; 95% CI: 2.01-3.74). NT-proBNP significantly improved the C-statistic of the clinical prediction model (0.85-0.92). Based on NT-proBNP alone, low-risk patients could be identified. Patients with NT-proBNP

Introduction: Patients after surgical correction of Tetralogy of Fallot (ToF) often show adverse cardiac remodeling. To better understand the underlying biological processes, we studied the relation between changes in blood biomarkers and changes in biventricular size and function as assessed by cardiac magnetic resonance imaging (CMR). Methods: This study included 50 ToF patients, who underwent blood biomarker and CMR analysis at least twice between 2002 and 2018.34 (68 %) of these patients were male. Patients had an average age of 16.1 at first visit. Biomarkers were chosen based on earlier research by our group and included: NT-proBNP, ST2, GDF-15, DLK-1, IGFBP-1/7, and FABP-4. Pearson correlations coefficients (rpearson) were determined to quantify the relationship between changes in biomarkers and CMR measurements. Results: For changes in parameters of right ventricular (RV) size significant correlations were observed with changes in NT-proBNP, ST-2, GDF-15, IGFBP7 and FABP-4 (rpearson between 0.28 and 0.51). Correlations with NT-proBNP were driven by changes in RV size induced by pulmonary valve replacement (n = 9). For LV serial size changes, significant correlations were noted with changes in NT-pro-BNP, ST-2, GDF-15 and FABP-4 (rpearson between 0.32 and 0.52). Conclusion: In clinically stable ToF patients changes in right and left ventricular size and function correlated with alterations in blood biomarkers of inflammation and immune response to stress.

Background: Bicuspid aortic valve (BAV) is a common congenital heart defect. Patients with BAV are at risk for long-term complications such as valve stenosis and regurgitation. This study aimed to investigate sex differences in blood and imaging biomarkers and to describe the long-term prognostic value of blood and echocardiographic biomarkers. Methods: Patients were included from 2 prospective observational cohort studies; they underwent venous blood sampling and transthoracic echocardiography including speckle tracking. Analyzed blood biomarkers were red-cell distribution width (RDW), creatinine, C-reactive protein (CRP), troponin T, N-terminal pro B-type natriuretic peptide (NT-proBNP), and transforming growth factor-beta (TGF-β). Sex differences were analyzed at baseline. Associations between biomarkers and arrhythmia-free and intervention-free survival were determined by Cox regression, adjusted for age and sex. Results: A total of 182 patients with BAV were included: median age 34; interquartile range [IQR]: 23-46 years; 55.5% male. CRP, NT-proBNP, and RDW were higher in women, whereas creatinine, troponin T and TGF-β were higher among men. After a median follow-up time of 6.9 (IQR: 6.5-9.9) years, arrhythmia-free and intervention-free survival was, 81.0% and 73.1%, respectively. NT-proBNP was associated with both arrhythmia-free and intervention-free survival (hazard ratio [HR], 1.94, P = 0.005 and HR, 2.06, P = 0.002, respectively). On echocardiography higher left atrial (LA) size, left ventricular end-diastolic diameter (LVEDD), left ventricular (LV) mass index and E/e’ ratio were associated with lower arrhythmia-free survival, whereas higher LA size, LV mass index, aortic valve peak velocity, and aortic regurgitation were associated with lower intervention-free survival. Conclusions: Differences were observed in blood biomarkers between men and women with BAV. Besides LV systolic parameters, diastolic LV function and NT-proBNP should have a more prominent role as prognostic markers in clinical care. Résumé: Contexte: La bicuspide valvulaire aortique (BVA) est une anomalie cardiaque congénitale fréquente. Les patients atteints d’une BVA présentent des risques de complications à long terme, comme la sténose valvulaire ou la régurgitation valvulaire. Cette étude visait 1) à évaluer les différences entre les sexes en ce qui concerne les biomarqueurs sanguins et les biomarqueurs à l’imagerie; et 2) à décrire la valeur pronostique à long terme des biomarqueurs sanguins et échocardiographiques. Méthodologie: Des patients de 2 études de cohortes observationnelles prospectives ont été inclus dans l’analyse. Des échantillons de sang veineux ont été prélevés, et des échocardiographies transthoraciques, y compris le suivi des marqueurs acoustiques, ont été effectuées. Les biomarqueurs sanguins analysés étaient les suivants : indice de distribution des globules rouges (IDR), créatinine, protéine C-réactive (CRP), troponine T, propeptide natriurétique de type B N-terminal (NT-proBNP) et facteur de croissance transformant β (TGF-β). Les différences entre les sexes ont été analysées au départ. Les liens entre les biomarqueurs et la survie sans arythmie et sans intervention ont été déterminés par la régression de Cox, avec correction en fonction de l’âge et du sexe. Résultats: Cent quatre-vingt-deux patients présentant une BVA étaient inclus (âge médian de 34 [écart interquartile : 23-46] ans, 55,5 % hommes). La CRP, la NT-proBNP et l’IDR étaient plus élevées chez les femmes, alors que la créatinine, la troponine T et le TGF-β étaient plus élevés chez les hommes. Après une période de suivi médiane de 6,9 (écart interquartile : 6,5-9,9) ans, les taux de survie sans arythmie et sans intervention étaient respectivement de 81,0 % et de 73,1 %. La NT-proBNP a été associée à la survie sans arythmie (rapport des risques instantanés [RRI] : 1,94, p = 0,005) et à la survie sans intervention (RRI : 2,06, p = 0,002). À l’échocardiographie, des valeurs élevées pour la taille de l’oreillette gauche, le diamètre télédiastolique du ventricule gauche (VG), l’indice de masse du VG et le rapport E/e’ étaient associées à un faible taux de survie sans arythmie, alors que des valeurs élevées pour la taille de l’oreillette gauche, l’indice de masse du VG, la vitesse maximale aortique et la régurgitation aortique étaient associées à un faible taux de survie sans intervention. Conclusions: Les biomarqueurs sanguins variaient en fonction du sexe des personnes présentant une BVA. Outre les paramètres systoliques du VG, la fonction VG diastolique et la NT-proBNP devraient être davantage utilisées comme marqueurs pronostiques en soins cliniques.

Objectives: To evaluate the ongoing debate concerning the choice of valve prosthesis for women requiring mitral valve replacement (MVR) and who wish to conceive. Bioprostheses are associated with risk of early structural valve deterioration. Mechanical prostheses require lifelong anticoagulation and carry maternal and fetal risks. Also, the optimal anticoagulation regimen during pregnancy after MVR remains unclear. Methods: A systematic review and meta-analysis was conducted of studies reporting on pregnancy after MVR. Valve- and anticoagulation-related maternal and fetal risks during pregnancy and 30 days’ postpartum were analyzed. Results: Fifteen studies reporting 722 pregnancies were included. In total, 87.2% of pregnant women had a mechanical prosthesis and 12.5% a bioprosthesis. Maternal mortality risk was 1.33% (95% confidence interval [CI], 0.69-2.56), any hemorrhage risk 6.90% (95% CI, 3.70-12.88). Valve thrombosis risk was 4.71% (95% CI, 3.06-7.26) in patients with mechanical prostheses. 3.23% (95% CI, 1.34-7.75) of the patients with bioprostheses experienced early structural valve deterioration. Of these, the mortality was 40%. Pregnancy loss risk was 29.29% (95% CI, 19.74-43.47) with mechanical prostheses versus 13.50% (95% CI, 4.31-42.30) for bioprostheses. Switching to heparin during the first trimester demonstrated a bleeding risk of 7.78% (95% CI, 3.71-16.31) versus 4.08% (95% CI, 1.17-14.28) for women on oral anticoagulants throughout pregnancy and a valve thrombosis risk of 6.99% (95% CI, 2.08-23.51) versus 2.89% (95% CI, 1.40-5.94). Administration of anticoagulant dosages greater than 5 mg resulted in a risk of fetal adverse events of 74.24% (95% CI, 56.11-98.23) versus 8.85% (95% CI, 2.70-28.99) in ≤5 mg. Conclusions: A bioprosthesis seems the best option for women of childbearing age who are interested in future pregnancy after MVR. If mechanical valve replacement is preferred, the favorable anticoagulation regimen is continuous low-dose oral anticoagulants. Shared decision-making remains priority when choosing a prosthetic valve for young women.

ABSTRACT: Background: Aortic wall shear stress (WSS) is a known predictor of ascending aortic growth in patients with a bicuspid aortic valve (BAV). The aim of this study was to study regional WSS and changes over time in BAV patients. Methods: BAV patients and age-matched healthy controls underwent four-dimensional (4D) flow cardiovascular magnetic resonance (CMR). Regional, peak systolic ascending aortic WSS, aortic valve function, aortic stiffness measures, and aortic dimensions were assessed. In BAV patients, 4D flow CMR was repeated after 3 years of follow-up and both at baseline and follow-up computed tomography angiography (CTA) were acquired. Aortic growth (volume increase of ≥5%) was measured on CTA. Regional WSS differences within patients’ aorta and WSS changes over time were analyzed using linear mixed-effect models and were associated with clinical parameters. Results: Thirty BAV patients (aged 34 years [interquartile range (IQR) 25–41]) were included in the follow-up analysis. Additionally, another 16 BAV patients and 32 healthy controls (aged 33 years [IQR 28–48]) were included for other regional analyses. Magnitude, axial, and circumferential WSS increased over time (all p 95th percentile of healthy controls increased from 21% (baseline 506/2400 regions) to 31% (follow-up 734/2400 regions) (p

Background Acute type B aortic dissection is a cardiovascular emergency with considerable mortality and morbidity risk. Male–female differences have been observed in cardiovascular disease; however, literature on type B aortic dissection is scarce. Methods and Results A retrospective cohort study was conducted including all consecutive patients with acute type B aortic dissection between 2007 and 2017 in 4 tertiary hospitals using patient files and questionnaires for late morbidity. In total, 384 patients were included with a follow‐up of 6.1 (range, 0.02–14.8) years, of which 41% (n=156) were female. Women presented at an older age than men (67 [interquartile range (IQR), 57–73] versus 62 [IQR, 52–71]; P=0.015). Prior abdominal aortic aneurysm (6% versus 15%; P=0.009), distally extending dissections (71 versus 85%; P=0.001), and clinical malperfusion (18% versus 32%; P=0.002) were less frequently observed in women. Absolute maximal descending aortic diameters were smaller in women (36 [IQR: 33–40] mm versus 39 [IQR, 36–43] mm; P

Abstract Background Mothers requiring the antiarrhythmic agent flecainide are often advised not to breastfeed, because of the lack of data concercing neonatal effects and flecainide plasma concentrations following maternal exposure as well as via lactation. This is the first report on combined maternal, fetal, neonatal and breastmilk flecainide concentrations in a breastfed infant of a mother requiring flecainide treatment. Case presentation A 35-year old Gravida 2 Para 1, known with ventricular arrhythmia, was referred to our tertiary center at 35 + 4 weeks of gestation. Because of an increase of ventricular ectopy, oral metoprolol 11.9 milligrams once daily was switched to oral flecainide 87.3 milligrams twice daily. Weekly collected maternal flecainide plasma trough concentrations fell within the therapeutic range of 0.2 to 1.0 mg/L and no further clinically significant arrhythmias occurred during the study period. A healthy son was born at 39 weeks of gestation and had a normal electrocardiogram. The fetal to maternal flecainide ratio was 0.72 and at three different timepoints, the flecainide concentration was higher in breastmilk than in maternal plasma. The relative infant dose received via breastmilk compared to maternal dose was 5.6%. Neonatal plasma concentrations were not detectable, despite the flecainide passage into breastmilk. All electrocardiograms to assess the neonatal antiarrhytmic effect were normal. Conclusions Our results assume that flecainide can be prescribed safely to lactating mothers. Quantification of drug concentrations in neonatal blood in addition to measurements in maternal and fetal blood, and breastmilk, are helpful to evaluate the effects and safety of maternal medication use during pregnancy and lactation.

BackgroundOptimal timing of pulmonary valve replacement (PVR) in Tetralogy of Fallot (TOF) patients remains challenging. Ventricular wall stress is considered to be an early marker of right ventricular (RV) dysfunction.ObjectivesTo investigate the association of RV wall stresses and their change over time with functional parameters in TOF patients.MethodsTen TOF patients after surgical repair with moderate/severe pulmonary regurgitation were included. At two timepoints (median follow-up time 7.2 years), patient-specific computational biventricular models for wall stress assessment were created using CMR short-axis cine images and echocardiography-based RV pressures. RV ejection fraction (RVEF), NT-proBNP and cardiopulmonary exercise tests were used as outcome measures reflecting RV function. Associations between regional RV diastolic wall stress and RV function were investigated using linear mixed models.ResultsIncreased wall stress correlated with lower RV mass (rrm = −0.70, p = 0.017) and lower RV mass-to-volume (rrm = −0.80, p = 0.003) using repeated measures. Wall stress decreased significantly over time, especially in patients with a stable RVEF (p

Abstract Background The aim of this systematic review was to evaluate current inter-modality agreement of noninvasive clinical intraventricular flow (IVF) assessment with 3 emerging imaging modalities: echocardiographic particle image velocimetry (EPIV), vector flow mapping (VFM), and 4-dimensional flow cardiovascular magnetic resonance imaging (4D flow CMR). Methods We performed a systematic literature review in the databases EMBASE, Medline OVID and Cochrane Central for identification of studies evaluating left ventricular (LV) flow patterns using one of these flow visualization modalities. Of the 2224 initially retrieved records, 10 EPIV, 23 VFM, and 25 4D flow CMR studies were included in the final analysis. Results Vortex parameters were more extensively studied with EPIV, while LV energetics and LV transport mechanics were mainly studied with 4D flow CMR, and LV energy loss and vortex circulation were implemented by VFM studies. Pooled normative values are provided for these parameters. The meta- analysis for the values of two vortex morphology parameters, vortex length and vortex depth, failed to reveal a significant change between heart failure patients and healthy controls. Conclusion Agreement between the different modalities studying intraventricular flow is low and different methods of measurement and reporting were used among studies. A multimodality framework with a standardized set of flow parameters is necessary for implementation of noninvasive flow visualization in daily clinical practice. The full potential of noninvasive flow visualization in addition to diagnostics could also include guiding medical or interventional treatment.

IntroductionThis study aims to provide an overview of outcomes after right ventricular outflow tract (RVOT) reconstruction using different valve substitutes in different age groups for different indications.MethodsThe literature was systematically searched for articles published between January 2000 and June 2021 reporting on clinical and/or echocardiographic outcomes after RVOT reconstruction with valve substitutes. A random-effects meta-analysis was conducted for outcomes, and time-related outcomes were visualized by pooled Kaplan–Meier curves. Subgroup analyses were performed according to etiology, implanted valve substitute and patient age.ResultsTwo hundred and seventeen articles were included, comprising 37,078 patients (age: 22.86 ± 11.29 years; 31.6% female) and 240,581 patient-years of follow-up. Aortic valve disease (Ross procedure, 46.6%) and Tetralogy of Fallot (TOF, 27.0%) were the two main underlying etiologies. Homograft and xenograft accounted for 83.7 and 32.6% of the overall valve substitutes, respectively. The early mortality, late mortality, reintervention and endocarditis rates were 3.36% (2.91–3.88), 0.72%/y (95% CI: 0.62–0.82), 2.62%/y (95% CI: 2.28–3.00), and 0.38%/y (95%CI: 0.31–0.47) for all patients. The early mortality for TOF and truncus arteriosus (TA) were 1.95% (1.31–2.90) and 10.67% (7.79–14.61). Pooled late mortality and reintervention rate were 0.59%/y (0.39–0.89), 1.41%/y (0.87–2.27), and 1.20%/y (0.74–1.94), 10.15%/y (7.42–13.90) for TOF and TA, respectively. Endocarditis rate was 0.21%/y (95% CI: 0.16–0.27) for a homograft substitute and 0.80%/y (95%CI: 0.60–1.09) for a xenograft substitute. Reintervention rate for infants, children and adults was 8.80%/y (95% CI: 6.49–11.95), 4.75%/y (95% CI: 3.67–6.14), and 0.72%/y (95% CI: 0.36–1.42), respectively.ConclusionThis study shows RVOT reconstruction with valve substitutes can be performed with acceptable mortality and morbidity rates for most patients. Reinterventions after RVOT reconstruction with valve substitutes are inevitable for most patients in their life-time, emphasizing the necessity of life-long follow-up and multidisciplinary care. Follow-up protocols should be tailored to individual patients because patients with different etiologies, ages, and implanted valve substitutes have different rates of mortality and morbidity.Systematic review registration[www.crd.york.ac.uk/prospero], identifier [CRD42021271622].

Abstract Background To evaluate the indications for admission and mortality rates of women of reproductive age admitted to a tertiary Intensive Care Unit (ICU) and to compare the outcomes of obstetric and non-obstetric admissions. Methods A retrospective cohort study was performed, including all women aged 17–41 years admitted to a level 3 ICU in the Netherlands, between January 1, 2000 and January 1, 2016. Primary outcome was indication for admission and mortality. Mortality, length of stay (LOS), need for mechanical ventilation and APACHE II score were compared between obstetric and non-obstetric admissions. The obstetric group was further analyzed for maternal and perinatal outcomes. Results 3461 women (median age 32 years) were included, with an overall mortality rate of 13.3%. The obstetric group consisted of 265 women (7.7%). The non-obstetric group (n = 3196) was admitted most often for cardiovascular disease (19.6%), followed by oncologic disease (15%). Mortality was the highest in women with oncologic disease (23.9%). The obstetric group had lower mortality compared to the non-obstetric group (4.9% vs. 14%, p

Abstract Background Cardiovascular magnetic resonance (CMR) phase contrast (PC) flow measurements suffer from phase offset errors. Background subtraction based on stationary phantom measurements can most reliably be used to overcome this inaccuracy. Stationary tissue correction is an alternative and does not require additional phantom scanning. The aim of this study was 1) to compare measurements with and without stationary tissue correction to phantom corrected measurements on different GE Healthcare CMR scanners using different software packages and 2) to evaluate the clinical implications of these methods. Methods CMR PC imaging of both the aortic and pulmonary artery flow was performed in patients on three different 1.5 T CMR scanners (GE Healthcare) using identical scan parameters. Uncorrected, first, second and third order stationary tissue corrected flow measurement were compared to phantom corrected flow measurements, our reference method, using Medis QFlow, Circle cvi42 and MASS software. The optimal (optimized) stationary tissue order was determined per scanner and software program. Velocity offsets, net flow, clinically significant difference (deviation > 10% net flow), and regurgitation severity were assessed. Results Data from 175 patients (28 (17–38) years) were included, of which 84% had congenital heart disease. First, second and third order and optimized stationary tissue correction did not improve the velocity offsets and net flow measurements. Uncorrected measurements resulted in the least clinically significant differences in net flow compared to phantom corrected data. Optimized stationary tissue correction per scanner and software program resulted in net flow differences (> 10%) in 19% (MASS) and 30% (Circle cvi42) of all measurements compared to 18% (MASS) and 23% (Circle cvi42) with no correction. Compared to phantom correction, regurgitation reclassification was the least common using uncorrected data. One CMR scanner performed worse and significant net flow differences of > 10% were present both with and without stationary tissue correction in more than 30% of all measurements. Conclusion Phase offset errors had a significant impact on net flow quantification, regurgitation assessment and varied greatly between CMR scanners. Background phase correction using stationary tissue correction worsened accuracy compared to no correction on three GE Healthcare CMR scanners. Therefore, careful assessment of phase offset errors at each individual scanner is essential to determine whether routine use of phantom correction is necessary. Trial registration Observational Study

Abstract Background Maternal right ventricular (RV) dysfunction (measured by echocardiography) is associated with impaired uteroplacental circulation, however echocardiography has important limitations in the assessment of RV function. We therefore aimed to investigate the association of pre-pregnancy RV and left ventricular (LV) function measured by cardiovascular magnetic resonance with uteroplacental Doppler flow parameters in pregnant women with repaired Tetralogy of Fallot (ToF). Methods Women with repaired ToF were examined, who had been enrolled in a prospective multicenter study of pregnant women with congenital heart disease. Clinical data and CMR evaluation before pregnancy were compared with uteroplacental Doppler parameters at 20 and 32 weeks gestation. In particular, pulsatility index (PI) of uterine and umbilical artery were studied. Results We studied 31 women; mean age 30 years, operated at early age. Univariable analyses showed that reduced RV ejection fraction (RVEF; P = 0.037 and P = 0.001), higher RV end-systolic volume (P = 0.004) and higher LV end-diastolic and end-systolic volume (P = 0.001 and P = 0.003, respectively) were associated with higher uterine or umbilical artery PI. With multivariable analyses (corrected for maternal age and body mass index), reduced RVEF before pregnancy remained associated with higher umbilical artery PI at 32 weeks (P = 0.002). RVEF was lower in women with high PI compared to women with normal PI during pregnancy (44% vs. 53%, p = 0.022). LV ejection fraction was not associated with uterine or umbilical artery PI. Conclusions Reduced RV function before pregnancy is associated with abnormal uteroplacental Doppler flow parameters. It could be postulated that reduced RV function on pre-pregnancy CMR (≤2 years) is a predisposing factor for impaired placental function in women with repaired ToF.

Conventionally, scuba diving has been discouraged for adult patients with congenital heart disease (ACHD). This restrictive sports advice is based on expert opinion in the absence of high-quality diving-specific studies. However, as survival and quality of life in congenital heart disease (CHD) patients have dramatically improved in the last decades, a critical appraisal whether such restrictive sports advice is still applicable is warranted. In this review, the cardiovascular effects of diving are described and a framework for the work-up for ACHD patients wishing to engage in scuba diving is provided. In addition, diving recommendations for specific CHD diagnostic groups are proposed.

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

The risk of developing new-onset arrhythmia or exacerbation of a pre-existing arrhythmia is increased during pregnancy because of profound physiological and hormonal changes. The incidence of arrhythmias in pregnancy is not well-reported and especially data on ventricular arrhythmia are scarce. Arrhythmia during pregnancy is associated with adverse maternal and fetal outcomes and the optimization of clinical management is hindered by a paucity of evidence, as guidelines are either based on studies in the general population or on case series in pregnancy. In any case, optimal care for these patients includes a multidisciplinary approach, integrating the different considerations in maternal cardiac, obstetric and fetal health. In this manuscript we present three cases of ventricular arrhythmia during pregnancy and describe our considerations in clinical decision-making with regard to diagnostic challenges and treatment choices.

Background Patients who have undergone the Fontan procedure are at high risk of circulatory failure. In an exploratory analysis we aimed to determine the prognostic value of blood biomarkers in a young cohort who have undergone the Fontan procedure. Methods and Results In multicenter prospective studies patients who have undergone the Fontan procedure underwent blood sampling, cardiopulmonary exercise testing, and stress cardiac magnetic resonance imaging. Several biomarkers including NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), GDF‐15 (growth differentiation factor 15), Gal‐3 (galectin‐3), ST2 (suppression of tumorigenicity 2), DLK‐1 (protein delta homolog 1), FABP‐4 (fatty acid‐binding protein 4), IGFBP‐1 (insulin‐like growth factor‐binding protein 1), IGFBP‐7, MMP‐2 (matrix metalloproteinase 2), and vWF (von Willebrand factor) were assessed in blood at 9.6 (7.1–12.1) years after Fontan completion. After this baseline study measurement, follow‐up information was collected on the incidence of adverse cardiac events, including cardiac death, out of hospital cardiac arrest, heart transplantation (listing), cardiac reintervention (severe events), hospitalization, and cardioversion/ablation for arrhythmias was collected and the relation with blood biomarkers was assessed by Cox proportional hazard analyses. The correlation between biomarkers and other clinical parameters was evaluated. We included 133 patients who have undergone the Fontan procedure, median age 13.2 (25th, 75th percentile 10.4–15.9) years, median age at Fontan 3.2 (2.5–3.9) years. After a median follow‐up of 6.2 (4.9–6.9) years, 36 (27.1%) patients experienced an event of whom 13 (9.8%) had a severe event. NT‐proBNP was associated with (all) events during follow‐up and remained predictive after correction for age, sex, and dominant ventricle (hazard ratio, 1.89; CI, 1.32–2.68). The severe event‐free survival was better in patients with low levels of GDF‐15 (P=0.005) and vWF (P=0.008) and high levels of DLK‐1 (P=0.041). There was a positive correlation (β=0.33, P=0.003) between DLK‐1 and stress cardiac magnetic resonance imaging functional reserve. Conclusions NT‐proBNP, GDF‐15, vWF, DLK‐1, ST‐2 FABP‐4, and IGFBP‐7 levels relate to long‐term outcome in young patients who have undergone the Fontan procedure.

Background: Tetralogy of Fallot (TOF) is the commonest cyanotic congenital heart defect. When surgically repaired at young age over 90% of patients reach adult age and most women have a desire to become pregnant However, pregnancy is associated with up to 50% increase in cardiac output and also associated with an elevated risk of arrhythmias and thrombosis. The aim of this study was to describe the outcomes in women with TOF for both mother and baby and to assess the influence of pregnancy on right ventricular (RV) dimensions. Methods: Within the prospective, international ESC EORP Registry Of Pregnancy And Cardiac disease (ROPAC), we describe the outcomes in 421 women with repaired TOF. Primary outcome was the occurrence of maternal cardiovascular events. Secondary outcomes were obstetric and fetal events and RV dilatation and pulmonary valve deterioration. Results: The mean age was 28.8 years and 52.3% were nulliparous. There were no maternal deaths, and heart failure and ventricular tachyarrhythmias complicated respectively 5% and 2% of pregnancies. Almost half of women underwent a Caesarean section (48%). Fetal mortality was 1%, while no neonatal mortality occurred. Pregnancy induced hypertension and HELLP/(pre)eclampsia were found in 3% and 1% respectively. Preterm delivery was observed in 14% and 10% had low birth weight. RV dilatation occurred in 49% and was significantly associated with moderate and severe pulmonary regurgitation (PR). Conclusion: Women with repaired TOF tolerate pregnancy relatively well, with no maternal mortality, and low complication rate. Pulmonary regurgitation predicts RV dilatation. Fetal and neonatal outcomes were also favorable and women should be counselled as low to moderate risk. However, nearly half of women underwent Caesarean section, while probably more women should have a vaginal delivery.

Background In the past 3 decades, the arterial switch procedure has replaced the atrial switch procedure as treatment of choice for transposition of the great arteries. Although survival is superior after the arterial switch procedure, data on pregnancy outcomes are scarce and transposition of the great arteries after arterial switch is not yet included in the modified World Health Organization classification of maternal cardiovascular risk. Methods and Results The ROPAC (Registry of Pregnancy and Cardiac disease) is an international prospective registry of pregnant women with cardiac disease, part of the European Society of Cardiology EURObservational Research Programme. Pregnancy outcomes in all women after an arterial switch procedure for transposition of the great arteries are described. The primary end point was a major adverse cardiovascular event, defined as combined end point of maternal death, supraventricular or ventricular arrhythmias requiring treatment, heart failure, aortic dissection, endocarditis, ischemic coronary events, and thromboembolic events. Altogether, 41 pregnant women (mean age, 26.7±3.9 years) were included, and there was no maternal mortality. A major adverse cardiovascular event occurred in 2 women (4.9%): heart failure in one (2.4%) and ventricular tachycardia in another (2.4%). One woman experienced fetal loss, whereas no neonatal mortality was observed. Conclusions Women after an arterial switch procedure for transposition of the great arteries tolerate pregnancy well, with a favorable maternal and fetal outcome. During counseling, most women should be reassured that the risk of pregnancy is low. Classification as modified World Health Organization risk class II seems appropriate.

Background: We sought to assess the effects of percutaneous atrial septal defect (ASD) closure on blood biomarker levels that possibly reflect reverse cardiac remodeling. Therefore, this study investigated temporal changes in six blood biomarkers following percutaneous ASD closure in adults. Methods: In this prospective observational cohort study, adults with ASD type II scheduled for percutaneous closure were included (2012–2016). NT-proBNP, high-sensitive troponin-T (hs-TnT), high-sensitive C-reactive protein (hs-CRP), red blood cell distribution width (RDW), growth differentiation factor-15 (GDF-15) and galectin-3 were measured one day prior to ASD closure and one day, three months and one year post ASD closure and changes were evaluated using paired T-tests. Echocardiographic measurements were obtained. Results: Fifty patients were included (median age 50 years, 62% women, 32% NYHA II). At baseline, biomarker levels were elevated in a substantial number of patients; NT-proBNP n = 22 (45%), hs-TnT n = 6 (13%) hs-CRP n = 19 (40%), galectin-3n = 5 (11%) and GDF n = 10 (23%). One day after ASD closure, significant increases of hs-TnT (median change (Δ) = 12 ng/L), hs-CRP (Δ = 1.9 mg/L), GDF-15(Δ = 129 pg/mL) and RDW (Δ = 0.1%) were observed, and a decrease in galectin-3 (Δ = −1.0 ng/mL). Consequently, 92% had at least one abnormal biomarker directly after closure. At three months biomarker levels returned to baseline, and while echocardiographic measures 1 year post closure were indicative of reverse cardiac remodeling, biomarker levels did not further decrease. Conclusion: Percutaneous ASD closure in adults leads to a direct increase in most blood biomarkers, in particular hs-CRP and hs-TnT. After three months, biomarkers returned to baseline levels and remained stable up to one year.

Background The prevalence of ischemic heart disease (IHD) in women of child‐bearing age is rising. Data on pregnancies however are scarce. The objective is to describe the pregnancy outcomes in these women. Methods and Results The European Society of Cardiology‐EURObservational Research Programme ROPAC (Registry of Pregnancy and Cardiac Disease) is a prospective registry in which data on pregnancies in women with heart disease were collected from 138 centers in 53 countries. Pregnant women with preexistent and pregnancy‐onset IHD were included. Primary end point were maternal cardiac events. Secondary end points were obstetric and fetal complications. There were 117 women with IHD, of which 104 had preexisting IHD. Median age was 35.5 years and 17.1% of women were smoking. There was no maternal mortality, heart failure occurred in 5 pregnancies (4.8%). Of the 104 women with preexisting IHD, 11 women suffered from acute coronary syndrome during pregnancy. ST‐segment‒elevation myocardial infarction were more common than non‒ST‐segment‒elevation myocardial infarction, and atherosclerosis was the most common etiology. Women who had undergone revascularization before pregnancy did not have less events than women who had not. There were 13 women with pregnancy‐onset IHD, in whom non‒ST‐segment‒elevation myocardial infarction was the most common. Smoking during pregnancy was associated with acute coronary syndrome. Caesarean section was the primary mode of delivery (55.8% in preexisting IHD, 84.6% in pregnancy‐onset IHD) and there were high rates of preterm births (20.2% and 38.5%, respectively). Conclusions Women with IHD tolerate pregnancy relatively well, however there is a high rate of ischemic events and these women should therefore be considered moderate‐ to high‐risk. Ongoing cigarette smoking is associated with acute coronary syndrome during pregnancy.

With the growth of the adult congenital heart disease (CHD) population, so do the considerations of reproduction, contraception and maternal health become more pressing. Fertility issues and concerns about hereditability may impact both male and female CHD patients. CHD can also influence the choice between contraceptive options, as some involve cardiovascular risks that make them less well-suited to the cardiac patient. For women with CHD, pregnancy acts as a haemodynamic stress test for the maternal cardiovascular system and often precipitates cardiac complications including heart failure, arrhythmias and thromboembolic events. For those with CHD, preconception counselling on the cardiac, obstetric and fetal risks involved in pregnancy is crucial for shared decision making and to optimize pregnancy outcomes. Risk stratification should be individualized, multidisciplinary and includes consideration of the complexity of the original CHD lesion, any residual or recurrent lesions, functional class, ventricular and valvular function, cyanosis, previous cardiac events and comorbidities, as well as the use of diagnostic modalities.In this review, we examine reproductive concerns in CHD patients, including preconception counselling, fertility issues and hereditability of CHD. We describe the advantages and disadvantages of the currently available contraceptive options in the context of cardiac disease. We discuss general considerations in the management of pregnancy in CHD, as well as the current knowledge on the most common CHD lesions.

Thoracic aortic aneurysm is a potentially life-threatening disease with a strong genetic contribution. Despite identification of multiple genes involved in aneurysm formation, little is known about the specific underlying mechanisms that drive the pathological changes in the aortic wall. The aim of our study was to unravel the molecular mechanisms underlying aneurysm formation in Marfan syndrome (MFS). We collected aortic wall samples from FBN1 variant-positive MFS patients (n = 6) and healthy donor hearts (n = 5). Messenger RNA (mRNA) expression levels were measured by RNA sequencing and compared between MFS patients and controls, and between haploinsufficient (HI) and dominant negative (DN) FBN1 variants. Immunohistochemical staining, proteomics and cellular respiration experiments were used to confirm our findings. FBN1 mRNA expression levels were highly variable in MFS patients and did not significantly differ from controls. Moreover, we did not identify a distinctive TGF-β gene expression signature in MFS patients. On the contrary, differential gene and protein expression analysis, as well as vascular smooth muscle cell respiration measurements, pointed toward inflammation and mitochondrial dysfunction. Our findings confirm that inflammatory and mitochondrial pathways play important roles in the pathophysiological processes underlying MFS-related aortic disease, providing new therapeutic options.

Abstract Background Reproductive disorders, such as polycystic ovary syndrome (PCOS), primary ovarian insufficiency (POI) and hypertensive pregnancy disorders (HPD) like pre-eclampsia (PE), are associated with an increased risk of cardiovascular disease (CVD). Detection of early signs of cardiovascular disease (CVD), as well as identification of risk factors among women of reproductive age which improve cardiovascular risk prediction, is a challenge and current models might underestimate long-term health risks. The aim of this study is to assess cardiovascular disease in patients with a history of a reproductive disorder by low-dose computed tomography (CT). Methods Women of 45 - 55 years, who experienced a reproductive disorder (PCOS, POI, HPD), are invited to participate in this multicenter, prospective, cohort study. Women will be recruited after regular cardiovascular screening, including assessment of classical cardiovascular risk factors. CT of the coronary arteries (both coronary artery calcium scoring (CACS), and contrast-enhanced coronary CT angiography (CCTA)) and carotid siphon calcium scoring (CSC) is planned in 300 women with HPD and 300 women with PCOS or POI. In addition, arterial stiffness (non-invasive pulse wave velocity (PWV)) measurement and cell-based biomarkers (inflammatory circulating cells) will be obtained. Discussion Initial inclusion is focused on women of 45 - 55 years. However, the age range (40 - 45 years and/or ≥ 55 years) and group composition may be adjusted based on the findings of the interim analysis. Participants can potentially benefit from information obtained in this study concerning their current cardiovascular health and expected future risk of cardiovascular events. The results of this study will provide insights in the development of CVD in women with a history of reproductive disorders. Ultimately, this study may lead to improved cardiovascular prediction models and will provide an opportunity for timely adjustment of preventive strategies. Limitations of this study include the possibility of overdiagnosis and the average radiation dose of 3.5 mSv during coronary and carotid siphon CT, although the increased lifetime malignancy risk is negligible. Trial registration Netherlands Trial Register, NTR5531 . Date registered: October 21st, 2015.

Aims Assessment of feasibility, accuracy and applicability in clinical practice of real-time three-dimensional echocardiography (RT-3DE) in children with congenital heart defects. Methods and results From September 2004 to June 2005, 100 consecutive children (57 infants, 43 children > 1 year of age), who were scheduled for corrective intracardiac surgery, were enrolled in this study. RT-3DE was performed with Philips Sonos 7500 echo-system and off-line analysis with TomTec Echoview© software. Quantitative and qualitative assessments of the region of interest were performed on the 3D reconstruction, comparing these results with the anatomic findings and measurements performed during intracardiac surgery. Acquisition of RT-3DE datasets was feasible in 92 of the 100 (92%) patients and acquisition time was 6 ± 3 minutes. The overall quantitative analyses showed an excellent correlation (r < 0.90) between RT-3De and surgery. Also the qualitative analyses were accurate compared with surgical findings, in all patients in which RT-3DE was feasible. Conclusion This study shows that RT-3DE can be used in the clinical practice for the assessment of intracardiac anatomy in children with congenital heart disease. The information derived from the 3D reconstructions can be taken into consideration in the preoperative planning and management regarding interventional or surgical therapy.

Introduction: Turner syndrome (TS) is associated with subfertility and infertility. Nevertheless, an increasing number of women become pregnant through oocyte donation. The wish to conceive may be negatively influenced by the fear of cardiovascular complications. The aim was to investigate the wish to conceive and the concerns about cardiovascular complications during pregnancy in women with TS. Methods: The patient association for TS invited all members of ≥18 years old (n = 344) to complete a specifically developed, disease-specific questionnaire, including questions about fertility, wish to conceive, attempts and concerns. Results were compared with previously published results of this questionnaire in women with congenital heart disease. Results: The questionnaire was completed by 89 women (median age 30.1 years, Q1–Q3 = 22.9–39.4). Of them, 51% had 45, X0-monosomy and 38% had ≥1 cardiac abnormality. Seventeen women (19%) had attempted to become pregnant and 12 of them succeeded to become pregnant. Women who had not undertaken attempts to conceive (81%), considered themselves mainly too young or had no partner. Of the total sample, 58% were concerned about the influence of pregnancy on their cardiovascular status. This was higher (75%) in the sample of women with TS and cardiac abnormalities, than in women with congenital heart disease from a previously published cohort (21%), (p

Background Adults with a systemic right ventricle (sRV) have a high risk of cardiac complications. This study aimed to identify prognostic markers in adults with sRV based on clinical evaluation, echocardiography, and blood biomarkers. Methods and Results In this prospective cohort study, consecutive clinically stable adults with sRV caused by Mustard‐ or congenitally corrected transposition of the great arteries were included (2011–2013). Eighty‐six patients were included (age 37±9 years, 65% male, 83% New York Heart Association functional class I, 76% Mustard transposition of the great arteries, 24% congenitally corrected transposition of the great arteries). Venous blood sampling was performed including N‐terminal pro B‐type natriuretic peptide, high‐sensitive‐troponin‐T, high‐sensitivity C‐reactive protein, growth differentiation factor‐15, galectin‐3, red cell distribution width, estimated glomerular filtration rate, and hemoglobin. Besides conventional echocardiographic measurements, longitudinal, circumferential, and radial strain were assessed using strain analysis. During a median follow‐up of 5.9 (interquartile range 5.3–6.3) years, 19 (22%) patients died or had heart failure (primary end point) and 29 (34%) patients died or had arrhythmia (secondary end point). Univariable Cox regression analysis was performed using dichotomous or standardized continuous variables. New York Heart Association functional class >I, systolic blood pressure, and most blood biomarkers were associated with the primary and secondary end point (galectin‐3 not for primary, N‐terminal pro B‐type natriuretic peptide and high‐sensitivity C‐reactive protein not for secondary end point). Growth differentiation factor‐15 showed the strongest association with both end points (hazard ratios; 2.44 [95% CI 1.67–3.57, P

BackgroundA single NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) measurement is a strong prognostic factor in adult congenital heart disease. This study investigates NT‐proBNP profiles within patients with adult congenital heart disease and relates these to cardiovascular events. Methods and ResultsIn this prospective cohort, 602 patients with adult congenital heart disease were enrolled at the outpatient clinic (years 2011–2013). NT‐proBNP was measured at study inclusion in 595 patients (median age 33 [IQR 25–41] years, 58% male, 90% NYHA I) and at subsequent annual visits. The primary end point was defined as death, heart failure, hospitalization, arrhythmia, thromboembolic event, or cardiac intervention; the secondary end point as death or heart failure. Repeated measurements were analyzed using linear mixed models and joint models. During a median follow‐up of 4.4 [IQR 3.8–4.8] years, a total of 2424 repeated measurements were collected. Average NT‐proBNP increase was 2.9 pmol/L the year before the primary end point (n=199, 34%) and 18.2 pmol/L before the secondary end point (n=58, 10%), compared with 0.3 pmol/L in patients who remained end point‐free (P‐value for difference in slope 0.006 and 14 pmol/L, n=315, 53%), repeated measurements were associated with the primary end point (HR per 2‐fold higher value 2.08; 95% CI 1.31–3.87; P

Bicuspid aortic valve (BAV), the most common congenital heart defect, is associated with an increased prevalence of aortic dilation, aortic rupture and aortic valve calcification. Endothelial cells (ECs) play a major role in vessel wall integrity. Little is known regarding EC function in BAV patients due to lack of patient derived primary ECs. Endothelial colony forming cells (ECFCs) have been reported to be a valid surrogate model for several cardiovascular pathologies, thereby facilitating an in vitro system to assess patient-specific endothelial dysfunction. Therefore, the aim of this study was to investigate cellular functions in ECFCs isolated from BAV patients. Outgrowth and proliferation of ECFCs from patients with BAV (n = 34) and controls with a tricuspid aortic valve (TAV, n = 10) were determined and related to patient characteristics. Interestingly, we were only able to generate ECFCs from TAV and BAV patients without aortic dilation, and failed to isolate ECFC colonies from patients with a dilated aorta. Analyzing EC function showed that while proliferation, cell size and endothelial-to-mesenchymal transition were similar in TAV and BAV ECFCs, migration and the wound healing capacity of BAV ECFCs is significantly higher compared to TAV ECFCs. Furthermore, calcification is blunted in BAV compared to TAV ECFCs. Our results reveal ECs dysfunction in BAV patients and future research is required to unravel the underlying mechanisms and to further validate ECFCs as a patient-specific in vitro model for BAV.

Abstract Background: Three-dimensional (3D) echocardiography coupled with speckle-tracking echocardiographic (STE) capability is a novel methodology which has been demontrated to be useful for the assessment of left atrial (LA) volumes and functional properties. There is increased scientific interest on myocardial deformation analysis in adult patients with corrected tetralogy of Fallot (cTOF). Objectives: To compare LA volumes, volume-based functional properties and strain parameters between cTOF patients and age- and gender-matched healthy controls. Methods: The study population consisted of 19 consecutive adult patients with cTOF in sinus rhythm nursing at the University of Szeged, Hungary (mean age: 37.9 ± 11.3 years, 8 men, who had repair at the age of 4.1 ± 2.5 years). They all had undergone standard transthoracic two-dimensional Doppler echocardiographic study extended with 3DSTE. Their results were compared to 23 age- and gender-matched healthy controls (mean age: 39.2 ± 10.6 years, 14 men). Results: Increased LA volumes and reduced LA emptying fractions respecting cardiac cycle could be demonstrated in cTOF patients compared to controls. LA stroke volumes featuring all LA functions showed no differences between the 2 groups examined. LA global and mean segmental uni- and multidirectional peak strains featuring LA reservoir function were found to be diminished in adult patients with cTOF as compared to controls. Similarly to peak strains reduced global and mean segmental LA strains at atrial contraction characterizing atrial booster pump function could be demonstrated in cTOF patients as compared to controls. Conclusions: Significant deterioration of all LA functions could be demonstrated in adult patients with cTOF late after repair.