Blood and Imaging Biomarkers in the Long-term Follow-up of Bicuspid Aortic Valve Patients.

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-ß). 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-ß 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.

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 ß (TGF-ß). 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-ß 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.

Heart rate: an accessible risk indicator in adult congenital heart disease.

BACKGROUND: Higher resting heart rate has been described as a risk factor for adverse outcome in healthy individuals and cardiovascular patients. The aim of this study was to evaluate resting heart rate as risk factor in adult congenital heart disease (ACHD). METHODS: In this prospective observational cohort study, patients with moderate or complex ACHD were included at routine outpatient visit. Standard 12-lead ECGs were obtained in rest. Heart rate was obtained from the ECG automatically by the Modular ECG Analysis System (MEANS). The primary endpoint was all-cause mortality and the secondary endpoint was a composite of all-cause mortality and heart failure. Survival was derived using the Kaplan-Meier estimator. Subgroups based on heart rate tertiles were compared by the log-rank test. Cox proportional hazards models were adjusted for clinical factors including age, sex and diagnosis (moderate vs complex ACHD). RESULTS: A total of 556 patients were included (median age 32 years (IQR 24-41), 57.6% male). Mean heart rate was 69±13 bpm. Negative chronotropic medication was used by 74 (13.3%) patients. During a median follow-up of 10.1 (IQR 9.6-10.5) years, 36 patients (6.5%) died and 83 (14.9%) reached the secondary endpoint. Patients with higher heart rates had significantly lower survival and heart failure-free survival. After adjusting for clinical factors, heart rate remained associated with mortality (HR 1.57 per 10 bpm, 95% CI 1.26 to 1.96) and mortality or heart failure (HR 1.33 per 10 bpm, 95% CI 1.13 to 1.57). CONCLUSION: Higher heart rate is associated with lower survival and heart failure-free survival in ACHD.

Long term outcome after surgical ASD-closure at young age: Longitudinal follow-up up to 50 years after surgery.

OBJECTIVES: To describe the clinical outcome and quality of life up to 50 years after surgical atrial septal defect (ASD) closure at young age. Primary outcome is defined as MACE (all-cause mortality, cardiac re-interventions, ischemic stroke, endocarditis, heart failure and symptomatic arrhythmia). METHODS: Single-center, longitudinal cohort-study evaluating 135 consecutive patients who underwent ASD-closure before the age of 15 years between 1968 and 1980. Participants were invited for extensive cardiac evaluation and assessment of quality-of-life every 10 years. RESULTS: Eighty patients (86%) of 93 eligible survivors were included in this study (mean age 52 ± 5 years (range 41-63), 40% male). Median follow-up since surgery was 45 years (range 40-51). Cumulative survival after 50 years was 86% and comparable to the normal Dutch population. Cumulative event-free survival after 45 and 50-years was 59% and 46% respectively (re-intervention in 6, symptomatic arrhythmia in 25, and pacemaker implantation in 10 patients). Right ventricular ejection fraction on CMR was diminished in 6%. Exercise capacity was normal in 77%. There was no pulmonary hypertension. NT-proBNP was elevated in 61%. Quality of life was comparable with the general population. No predictors for late events were identified. CONCLUSION: Long-term survival after surgical ASD-closure in childhood is good and not statistically different at 50 years compared to the normal Dutch population. Re-intervention rate is low, there is no pulmonary hypertension. Right ventricular function was diminished in 6%, exercise capacity was good and stable over time with quality of life comparable to the general population. However, supraventricular tachycardia is common.

Life expectancy and end-of-life communication in adult patients with congenital heart disease, 40-53 years after surgery.

Aims: Although survival of patients with congenital heart disease (CHD) improved significantly over time, life expectancy is still not normal. We aimed to investigate how adult patients, their partners, and treating cardiologists estimated the individual life expectancy of CHD patients. Furthermore, preferences regarding end-of-life (EOL) communication were investigated. Methods and results: In this study, we included 202 patients (age: 50 ± 5) who were operated in childhood (<15 years old) between 1968 and 1980 for one of the following diagnoses: atrial septal defect, ventricular septal defect, pulmonary stenosis, tetralogy of Fallot, or transposition of the great arteries. A specific questionnaire was administered to both the patients and their partners, exploring their perceived life expectancy and EOL wishes. Two cardiologists independently assessed the life expectancy of each patient. Most adults with CHD believed their life expectancy to be normal. However, significant differences were found between estimated life expectancy by the cardiologist and patients (female: P = 0.001, male: P = 0.002) with moderate/severe defects, as well as for males with mild defects (P = 0.011). Regarding EOL communication, 85.1% of the patients reported that they never discussed EOL with a healthcare professional. Compared with patients with mild CHD, significantly more patients with moderate/severe defect discussed EOL with a physician (P = 0.011). The wish to discuss EOL with the cardiologist was reported by 49.3% of the patients and 41.7% of their partners. Conclusion: Adult patients, especially with moderate/severe CHD, perceived their life expectancy as normal, whereas cardiologists had a more pessimistic view than their patients. Increased attention is warranted for discussions on life expectancy and EOL to improve patient-tailored care.

What endocrinologists can do to prevent cardiovascular complications in adults with Prader-Willi syndrome: Lessons from a case series.

Context: Prader-Willi syndrome (PWS) is a complex rare genetic syndrome. Mortality in patients with PWS is 3% per year. In nearly half of the patients, the cause of death is of cardiopulmonary origin. Prevention, diagnosis and treatment of cardiovascular (CV) disease in PWS adults is complicated by the behavioral phenotype, reduced ability to express physical complaints, high pain threshold and obesity. Objective: To describe the challenges in prevention, diagnosis and treatment of CV disease in PWS adults, in order to increase awareness and improve medical care. Methods: Retrospective study of medical records of adults visiting the Dutch PWS reference center. Results: We describe the challenges encountered during diagnosis and treatment of four PWS adults with heart failure. All had pre-existent peripheral edema. CV risk factors in these patients were obesity (n=4), type 2 diabetes mellitus (n=2), hypertension (n=2), hypogonadism (n=3) and sleep apnea (n=2). Remarkably, all patients were younger than 40 years during their first cardiac decompensation. All patients presented with progressive shortness of breath and/or orthopnea and progressive pitting edema. In 117 controls with PWS without CV problems, 31% had leg edema. Conclusion: Diagnosing CV problems in PWS adults is challenging. Peripheral edema is common in PWS adults without CV morbidity, which makes edema in general a poor marker for heart failure. However, when edema is of the pitting kind and progressive, this is a strong predictor of cardiac decompensation. We provide practical recommendations for diagnosing and treating CV problems in this vulnerable patient population.

SCUBA Diving in Adult Congenital Heart Disease.

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.

Clinical outcome of anomalous coronary artery with interarterial course in adults: Single-center experience combined with a systematic review.

BACKGROUND: Anomalous coronary artery originating from the opposite sinus of Vasalva with interarterial course (ACAOS-IAC) is associated with sudden cardiac death (SCD) in young athletes. If identified in adulthood prognosis is usually more benign, resulting in a dilemma regarding revascularization. METHODS: This is a retrospective observational single-center study, including adults with ACAOS-IAC. Medical records between 2012 and 2019 were reviewed for management approach, mortality, cardiac death and coronary related adverse events. Coronary computed tomographic angiography (CCTA) were reviewed. We provide a literature review in regard to clinical outcome. RESULTS: We identified 40 patients with ACAOS-IAC (mean age 51). Presentation was acute in 7/40 (18%). Ischemia detection with single photon emission tomography (SPECT), cardiac magnetic resonance (CMR) or dobutamine stress echocardiography were performed in 25/40 (63%) patients. Ischemia in the vascular territory of the anomaly was present in 2/25 (8%). In 39/40 (98%) patients were treated expectative. During median follow-up of 2.7 years (IQR 1.5-5.3) no cardiovascular death was observed. Mortality occurred in 1/40 (3%) and coronary related adverse events in 2/40 (5%). We identified 20 studies describing 1194 patients. Revascularization was performed in 376/1154 (32.6%) patients. Mortality stratified for clinical management was 23/431 (5.3%) in the non-revascularization versus 16/253 (6.3%) in the revascularization group during 4.0 years follow-up (weighted median). Cause of death was cardiovascular in 10/596 (1.7%) in 4.2 years (weighted median) follow up. CONCLUSIONS: Both revascularization and non-invasive management have good prognosis in adults with ACAOS-IAC during early follow up. There is need for guidelines and long-term surveillance.

Prognostic value of C-reactive protein in adults with congenital heart disease.

BACKGROUND: High-sensitivity C reactive protein (hs-CRP) has been associated with outcomes in adult congenital heart disease (ACHD). However, its prognostic value beyond N-terminal pro B type natriuretic peptide (NT-proBNP) or troponin T remains unknown. We studied the temporal evolution of hs-CRP, as well as the relation between hs-CRP and adverse clinical outcomes independent of NT-proBNP and troponin T in patients with ACHD. METHODS: In this prospective cohort study, we enrolled 602 patients with ACHD (2011-2013) who underwent baseline and thereafter annual blood sampling during 4 years. Hs-CRP, hs-troponin T and NT-proBNP were measured. The primary endpoint was composed of death or heart failure (HF). Cox regression and Joint Modelling was used to relate 2log hs-CRP levels with the endpoint, with adjustment for baseline characteristics and (repeated) hs-troponin T and NT-proBNP measurements. RESULTS: Hs-CRP was measured at baseline in 591 patients, median age 33 years, 58% men, 90% New York Heart Association I with an average of 4.3 measurements per patient. Median follow-up was 5.9 (IQR 5.3-6.3) years (99.2% complete) and 69 patients met the endpoint. Higher baseline hs-CRP was independently associated with higher risk of death or HF (HR 1.36, 95% CI 1.19 to 1.55). Hs-CRP increased over time prior to death or HF, and repeated hs-CRP measurements were associated with the endpoint, independent of repeated NT-proBNP and hs-troponin T (HR 1.54, 95% CI 1.24 to 1.98). CONCLUSIONS: Hs-CRP carries incremental prognostic value for the risk of death or HF, beyond NT-proBNP and hs-troponin T. Hs-CRP increased prior to the occurrence of HF or death, supporting the role of inflammation in the clinical deterioration of patients with ACHD.

Evolution of blood biomarker levels following percutaneous atrial septal defect closure in adults.

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-3 n = 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.

Prognostic Value of Serial High-Sensitivity Troponin T Measurements in Adults With Congenital Heart Disease.

BACKGROUND: Single high-sensitivity troponin T (hs-TnT) measurement is predictive of cardiac events in adults with congenital heart disease (ACHD). We aimed to study the prognostic value of serial hs-TnT measurements in stable patients with ACHD. METHODS: In total, 602 consecutive patients with ACHD were enrolled in this prospective study (2011-2013). Blood sampling was performed at enrollment and thereafter yearly during scheduled visits, up to 4 years. Hs-TnT, N-terminal pro B-type natriuretic peptide (NT-proBNP), and estimated glomerular filtration rate (eGFR) were measured. The composite primary endpoint was defined as all-cause mortality, heart failure, arrhythmia, hospitalization, cardiac (re)interventions, or thromboembolic events. The relationship between changes in serial hs-TnT and the primary endpoint was studied by joint models with adjustment for repeated NT-proBNP and eGFR. RESULTS: In 601 patients (median age, 33 [interquartile range, 25-41] years, 42% women, 90% NYHA I), at least 1 hs-TnT measurement was performed; a mean of 4.3 hs-TnT measurements per patient were collected. After a median follow-up of 5.8 [interquartile range, 5.3-6.3] years, 229 (38.1%) patients reached the primary endpoint. On average, hs-TnT levels increased over time, and more in patients who reached the primary endpoint (P < 0.001). A 2-fold higher hs-TnT was associated with the primary endpoint (unadjusted hazard ratio, 1.62; 95% confidence interval, 1.44-1.82; P < 0.001). The association remained after adjustment for repeated eGFR but not when adjusted for repeated NT-proBNP; repeated NT-proBNP remained associated with the primary endpoint. CONCLUSION: In stable patients with ACHD, hs-TnT levels increased before the occurrence of an event and repeated hs-TnT was associated with the risk of adverse cardiac events. However, repeated hs-TnT was not superior to repeated NT-proBNP.

Timing of pulmonary valve replacement in patients with corrected Fallot to prevent QRS prolongation.

OBJECTIVES: Timing of pulmonary valve replacement (PVR) remains one of the most heavily debated topics in congenital cardiac surgery. We aimed to analyse the temporal evolution of QRS duration before and after PVR. METHODS: We included 158 consecutive patients who underwent PVR after previous correction with transannular patch. All 3549 available serial standard 12-lead surface QRS measurements of 158 (100%) patients were analysed with linear mixed-effect modelling. RESULTS: PVR was performed at a mean age of 28.0 ± 10.7 years, 23.4 ± 8.4 years after correction. Hospital survival was 98.1%. A longer time interval between ToF correction and PVR (P < 0.001), and an older age at correction (P = 0.015) were predictive of progressive QRS prolongation after PVR. Women on average had a shorter QRS duration (P = 0.005) after PVR. The model predicted that in patients corrected early (model age 0.5 years), PVR within 17 years after correction leads to narrowing or stabilization of QRS width. PVR beyond 17 years was associated with prolongation of QRS duration. In a patient corrected late (model age 5 years), PVR has to be performed within 15 years after correction to prevent prolongation. Finally, a longer time period between correction and PVR was associated with an increased hazard of cardiac death (hazard ratio 1.097, 95% confidence interval 1.002-1.200). CONCLUSIONS: Prolongation of QRS duration after PVR was associated with a longer time between correction and PVR, older age at correction and male sex. Prevention of progressive QRS prolongation by earlier PVR can potentially reduce the hazard of adverse events after PVR.

Early detection of ventricular arrhythmias in adults with congenital heart disease using an insertable cardiac monitor (EDVA-CHD study).

BACKGROUND: Sudden cardiac death (SCD) due to ventricular arrhythmias (VA) is an important mode of death in adults with congenital heart disease (CHD). Risk stratification is difficult in this heterogeneous population. Insertable cardiac monitors (ICM) may be useful for risk stratification. The purpose of the present study was to evaluate the use of ICM for the detection of VA in adults with CHD. METHODS: In this prospective single-center observational study we included consecutive adults with CHD deemed at risk of VA who received an ICM between March 2013 and February 2019. The decision to implant an ICM was made in a Heart Team consisting of a cardiac electrophysiologist and a cardiologist specialized in CHD. RESULTS: A total of 30 patients (mean age, 38 ± 15 years; 50% male) received an ICM. During a median follow-up of 16 months, 8 patients (27%) had documented nonsustained VA. Of these 8 patients, 3 (10%) received a prophylactic ICD. Furthermore, ICM-detected arrhythmias were present in 22 patients (73%) leading to a change in clinical management in 16 patients (53%). Besides the patients receiving an ICD, 10 patients (33%) had a change in their antiarrhythmic drugs, 6 patients (20%) underwent an electrophysiology study, and 1 patient (3%) received a pacemaker. CONCLUSIONS: The detection of VA by the ICM contributed to the clinical decision to implant a prophylactic ICD. Furthermore, ICM-detected arrhythmias led to important changes in the clinical management. Therefore, long-term arrhythmia monitoring by an ICM seems valuable for risk stratification in adults with CHD.

Ventricular response to dobutamine stress cardiac magnetic resonance imaging is associated with adverse outcome during 8-year follow-up in patients with repaired Tetralogy of Fallot.

AIMS: The aim of this study was to evaluate the possible value of dobutamine stress cardiac magnetic resonance imaging (CMR) to predict adverse outcome in Tetralogy of Fallot (TOF) patients. METHODS AND RESULTS: In previous prospective multicentre studies, TOF patients underwent low-dose dobutamine stress CMR (7.5 µg/kg/min). Subsequently, during regular-care patient follow-up, patients were assessed for reaching the composite endpoint (cardiac death, arrhythmia-related hospitalization, or cardioversion/ablation, VO2 max ≤65% of predicted). A normal stress response was defined as a decrease in end-systolic volume (ESV) and increase in ejection fraction. The relative parameter change during stress was calculated as relative parameter change = [(parameterstress - parameterrest)/parameterrest] * 100. The predictive value of dobutamine stress CMR for the composite endpoint was determined using time-to-event analyses (Kaplan-Meier) and Cox proportional hazard analysis. We studied 100 patients [67 (67%) male, median age at baseline CMR 17.8 years (interquartile range 13.5-34.0), age at TOF repair 0.9 years (0.6-2.1)]. After a median follow-up of 8.6 years (6.7-14.1), 10 patients reached the composite endpoint. An abnormal stress response (30% vs. 4.4%, P = 0.021) was more frequently observed in composite endpoint patients. Also in endpoint patients, the relative decrease in right ventricular ESV decreased less during stress compared with the patients without an endpoint (-17 ± 15 vs. -26 ± 13 %, P = 0.045). Multivariable analyses identified an abnormal stress response (hazard ratio 10.4; 95% confidence interval 2.5-43.7; P = 0.001) as predictor for the composite endpoint. CONCLUSION: An abnormal ventricular response to dobutamine stress is associated with adverse outcome in patients with repaired TOF.

Exploring the Prognostic Value of Novel Markers in Adults With a Systemic Right Ventricle.

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<0.001], 2.00 [95% CI 1.46-2.73, P<0.001], respectively). End-diastolic basal dimension of the subpulmonary ventricle was associated with both end points (hazard ratio: 1.95 [95% CI 1.34-2.85], P<0.001, 1.70 [95% CI 1.21-2.38, P=0.002], respectively). Concerning strain analysis, only sRV septal strain was associated with the secondary end point (hazard ratio 0.58 [95% CI 0.39-0.86], P=0.006). Conclusions Clinical, conventional echocardiographic, and blood measurements are important markers for risk stratification in adults with a sRV. The value of novel echocardiographic strain analysis seems limited.

The Prognostic Value of Myocardial Deformation in Adult Patients With Corrected Tetralogy of Fallot.

BACKGROUND: Adult patients with repaired tetralogy of Fallot (ToF) are at risk for complications such as heart failure and sudden cardiac death, and identifying high-risk patients is important. Reduced left ventricular (LV) and right ventricular (RV) function has been identified as a predictor of outcomes. However, LV ejection fraction is often preserved, and RV function is difficult to assess. With the introduction of strain analysis, an easy and more sensitive parameter became available. The aim of this study was to investigate the association between strain variables and cardiovascular events in patients with ToF. METHODS: Stable adult patients with repaired ToF were consecutively included in a prospective observational study between 2011 and 2013 (N = 151; median age, 33.2 years [interquartile range, 25.5-42.0 years]; 61.6% men). For the left ventricle, global longitudinal strain and apical and basal rotation were measured, and longitudinal strain was measured for the right ventricle. The primary endpoint was a composite of death or heart failure. The secondary endpoint was a composite of death, heart failure, arrhythmia, reintervention, or hospitalization for cardiac reasons. RESULTS: During a median follow-up period of 71.5 months (interquartile range, 64.0-75.3 months), the primary and secondary endpoints occurred in 14 (9%) and 62 (41%) patients, respectively. After adjusting for LV ejection fraction and LV global longitudinal strain, RV longitudinal strain remained independently associated with the primary endpoint in a ridge regression analysis. LV apical rotation remained independently associated with the secondary end point (adjusted hazard ratio, 0.72; 95% CI, 0.52-0.98; P = .035) after adjusting for age, New York Heart Association functional class, QRS duration, LV ejection fraction, RV longitudinal strain, and LV global longitudinal strain. CONCLUSIONS: Myocardial deformation variables of both the left and right ventricles were associated with cardiovascular events in patients with ToF. LV and RV longitudinal strain and LV rotation should become part of the routine assessment of patients with ToF.

Echocardiographic parameters of severe pulmonary regurgitation after surgical repair of tetralogy of Fallot.

AIMS: Reliable evaluation of the severity and consequences of pulmonary regurgitation (PR) in patients with repaired tetralogy of Fallot (TOF) is crucial to timely identify the need for pulmonary valve intervention. We aimed to identify the accuracy of echocardiographic parameters to differentiate between moderate and severe PR, using phase contrast cardiac magnetic resonance imaging (CMR) as gold standard. METHODS AND RESULTS: In this cross-sectional study, 45 TOF patients with both echocardiographic and CMR measurements of PR were enrolled. All quantitative and semiquantitative echocardiographic measurements such as pressure half time (PHT), Color flow jet width (CFJW), ratio CFJW/right ventricle outflow tract (RVOT) diameter, PR index and the presence of early termination of the PR jet, end-diastolic antegrade flow and diastolic backflow in main pulmonary artery (MPA), and PA branches correlated significantly with PR fraction on CMR. Qualitative assessment with color flow on echocardiography overestimated PR Multivariate linear regression analysis identified the ratio of CFJW/RVOT diameter and PHT as independent predictors of PR fraction. Accuracy of echo parameters was tested to differentiate between mild-to-moderate and severe PR Combining different echocardiographic parameters increased sensitivity and specificity. The addition of diastolic flow reversal in the PA branches to PHT below 167 milliseconds increased the NPV from 87% to 89% and PPV from 62% to 76%. CONCLUSIONS: Comparison with CMR confirms that echocardiographic parameters are reliable in predicting PR severity. Combined measurement of diastolic flow reversal in the pulmonary artery branches and PHT is reliable in the detection of severe PR in the follow-up of TOF patients.

Prognostic value of soluble ST2 in adults with congenital heart disease.

OBJECTIVE: Soluble suppression of tumourigenicity-2 (sST2) is upregulated as response to myocardial stress and may be a potential biomarker for risk stratification in patients with adult congenital heart disease (ACHD). This study aimed to investigate the release of sST2 and its association with cardiovascular events in ACHD. METHODS: In this prospective cohort study, 602 consecutive patients with ACHD visiting the outpatient clinic were included (2011-2013). The association between sST2 and a primary composite endpoint of all-cause mortality, heart failure, hospitalisation, arrhythmia, thromboembolic events or cardiac interventions was investigated using multivariable Cox regression. RESULTS: sST2 was measured in 590 (98%) patients (median age 33 [25-41] years, 42% women). After a median follow-up of 5.8 [IQR 5.1-6.2) years, 225 (38.5%) reached the primary endpoint. sST2 was significantly associated with the primary endpoint when adjusted for age, sex, creatinine and N terminal pro-B type brain natriuretic peptide (NT-proBNP) (HR per twofold higher sST2: 1.28, 95% CI 1.03 to 1.58, p=0.025). This association negated when adjusted for clinical variables and NT-proBNP (HR per twofold higher sST2: 1.19, 95% CI 0.96 to 1.48, p=0.106). Stratified analysis in complex ACHD did show a significant association between sST2 and the primary endpoint when adjusted for clinical variables and NT-proBNP (HR per twofold higher sST2: 1.31, 95% CI 1.01 to 1.69, p=0.043). Sex-specific analysis showed an association between sST2 and the primary endpoint in women (HR per twofold higher sST2 1.80, 95% CI 1.30 to 2.49, p<0.001) but not in men (HR per twofold higher sST2 1.19, 95% CI 0.90 to 1.56, p=0.223). CONCLUSIONS: sST2 is a promising novel biomarker in patients with ACHD, specifically in complex ACHD and women. Future research is warranted to elucidate sex-specific and diagnosis-specific differences.

Development and validation of a risk prediction model in patients with adult congenital heart disease.

AIMS: To develop and validate a clinically useful risk prediction tool for patients with adult congenital heart disease (ACHD). METHODS AND RESULTS: A risk model was developed in a prospective cohort of 602 patients with moderate/complex ACHD who routinely visited the outpatient clinic of a tertiary care centre in the Netherlands (2011-2013). This model was externally validated in a retrospective cohort of 402 ACHD patients (Czech Republic, 2004-2013). The primary endpoint was the 4-year risk of death, heart failure, or arrhythmia, which occurred in 135 of 602 patients (22%). Model development was performed using multivariable logistic regression. Model performance was assessed with C-statistics and calibration plots. Of the 14 variables that were selected by an expert panel, the final prediction model included age (OR 1.02, 95%CI 1.00-1.03, p = 0.031), congenital diagnosis (OR 1.52, 95%CI 1.03-2.23, p = 0.034), NYHA class (OR 1.74, 95%CI 1.07-2.84, p = 0.026), cardiac medication (OR 2.27, 95%CI 1.56-3.31, p < 0.001), re-intervention (OR 1.41, 95%CI 0.99-2.01, p = 0.060), BMI (OR 1.03, 95%CI 0.99-1.07, p = 0.123), and NT-proBNP (OR 1.63, 95%CI 1.45-1.84, p < 0.001). Calibration-in-the-large was suboptimal, reflected by a lower observed event rate in the validation cohort (17%) than predicted (36%), likely explained by heterogeneity and different treatment strategies. The externally validated C-statistic was 0.78 (95%CI 0.72-0.83), indicating good discriminative ability. CONCLUSION: The proposed ACHD risk score combines six readily available clinical characteristics and NT-proBNP. This tool is easy to use and can aid in distinguishing high- and low-risk patients, which could further streamline counselling, location of care, and treatment in ACHD.

Screening for thoracic aortic pathology: Clinical practice in a single tertiary center.

OBJECTIVE: The aim is to present current clinical practice of thoracic aorta screening in a tertiary referral center. We identified how often imaging techniques were used for screening and established the value of transthoracic echocardiography (TTE) in comparison with computed tomography (CT) to detect aortic dilation. We also investigated which additional abnormalities of the heart, aorta or smaller arteries were discovered. DESIGN: All patients ≥15 years who visited our tertiary center in 2012-2016 for first thoracic aortic screening were retrospectively included. Diameters of the sinus of Valsalva (SoV) and maximum ascending aorta (AA) were compared between TTE and CT. The sensitivity and specificity of TTE to detect aortic dilation (≥40 mm) was assessed with CT as reference standard. Intracardiac abnormalities found with TTE and arterial abnormalities found with CT were identified. RESULTS: In total 349 patients (155 men, age 41 ± 15 years, 10% genetic mutation) were included. Screening was performed with TTE only in 35% and with TTE and CT in 65%. Patients who underwent TTE only were younger, had less often hypertension and less often a family history of aortic pathology. Although there was a good correlation between TTE and CT, the diameters measured with TTE were typically lower (SoV -1.0, 95%CI -6.6 to 4.7 and AA -0.4, 95%CI -6.5 to 5.8). Sensitivity of TTE for detecting aortic dilation was 61% (SoV) and 57% (AA) and specificity was 96% (SoV) and 100% (AA). Valve abnormalities, ventricular dilation or reduced ventricular function was found with TTE in 26 patients (7%). In 47 patients (13%) ascending aortic dilation was diagnosed and in 10 patients (4%) relevant peripheral arterial abnormalities were identified using CT. CONCLUSIONS: Most often patients received both TTE and CT (65%). Since TTE showed a low sensitivity to detect aortic dilation, CT imaging is advised at least once in patients referred for thoracic aortic screening.