Hypertensive response to exercise in adult patients with repaired aortic coarctation.

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 (ß=0.11, p<0.001) and 24-hour SBP (ß=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.

Cardiovascular Morbidity and Mortality in Adult Patients With Repaired Aortic Coarctation.

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.

Homograft durability after correction of pulmonary atresia and ventricular septal defect with or without systemic pulmonary collateral arteries.

Background: Pulmonary atresia and ventricular septal defect (PA-VSD), with or without systemic pulmonary collateral arteries (SPCAs), represents a complex anatomic and surgical spectrum of congenital heart disease. Currently, there is limited evidence on homograft durability after complete correction, which potentially could be affected by anatomic differences in pulmonary vasculature. Methods: This retrospective single-center study included all 69 consecutive PA-VSD patients (46 with SPCAs, 23 without SPCAs) operated on between 1978 and 2018. The primary interest was in homograft durability after complete repair. Longitudinal echocardiographic homograft function and right ventricular systolic pressure were analyzed with linear mixed-effects models. Results: The median duration of follow-up was 20 years. Of the 46 patients with SPCAs, 37 (80.4%) underwent biventricular correction at a median age of 2.7 years (interquartile range [IQR], 1.8-6.3 years). Two patients are currently awaiting unifocalization and correction. All 23 patients without SPCAs underwent successful complete correction at a median age of 1.6 years (IQR, 1.1-3.6 years). Freedom from any reintervention after 20 years was 15%. When a homograft was used during correction, freedom from homograft replacement after 20 years was comparable in the 2 groups (P = .925), at 32 ± 11% in the SPCA group and 32 ± 13% in the non-SPCA group. Indications for homograft replacement were isolated stenosis (n = 7; 46.7%), isolated regurgitation (n = 3; 20.0%), and mixed stenosis and regurgitation (n = 5; 33.3%) in the SPCA group and isolated stenosis (n = 8; 88.9%) and stenosis and regurgitation (n = 1; 11.1%) in the non-SPCA group. Peak homograft gradient was significantly (P = .0003) higher in patients without SPCA, with a comparable rate of progression in the 2 groups. However, the prevalence of severe pulmonary regurgitation (PR) was higher in patients with SPCAs, estimated at 35% at 10 years, compared with 15% in patients without SPCAs. Conclusions: Homografts used for right ventricular outflow tract reconstruction in patients with PA-VSD, either with or without SPCAs, have similar limited durability. Repeated reintervention is common, and careful follow-up with attention to severe PR is warranted.

Surgical repair of aortic coarctation in adults: half a century of a single centre clinical experience.

OBJECTIVES: Coarctation of the aorta (CoA) is rarely diagnosed and treated in adults and nowadays mostly treated with percutaneous techniques. The objective of this study is to report the long-term outcomes and health-related quality of life in a unique cohort of patients treated with an open surgical repair for their primary adult CoA. METHODS: Ninety adult patients underwent primary surgical repair of CoA at our tertiary referral centre between 1961 and 2008 when the treatment strategy for adult CoA was exclusively surgical. RESULTS: The median age at surgery was 24 years (interquartile range 20-36 years), and 39 patients (43%) were asymptomatic at presentation. CoA was located paraductally in most patients (64%), and bicuspid aortic valve was present in 39 (43%) patients. Surgical reconstruction of CoA with an end-to-end anastomosis was performed in majority of the patients (57%). Overall, in-hospital mortality occurred in 1 patient (1%). There was no in-hospital stroke, spinal cord ischaemia, renal replacement therapy or respiratory failure. The cumulative survival was 97.7%, 89.5%, 82.6%, 70.9% and 61.4% at 10, 20, 30, 40 and 50 years, respectively. Thirty-one patients (34%) required an additional cardiac surgery during follow-up. The majority of patients (77%) suffered from refractory hypertension even after decades of surgery. Compared with the matched Dutch population, patients reported a lower social functioning, mental health, vitality and general health with a higher body pain. CONCLUSIONS: Patients with native adult CoA have low in-hospital morbidity and mortality when treated with an open surgical reconstruction. However, refractory hypertension and impaired quality of life remain important challenges during follow-up.

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.

Acute and midterm outcomes of the post-approval MELODY Registry: a multicentre registry of transcatheter pulmonary valve implantation.

AIMS: The post-approval MELODY Registry aimed to obtain multicentre registry data after transcatheter pulmonary valve implantation (TPVI) with the Melody™ valve (Medtronic plc.) in a large-scale cohort of patients with congenital heart disease (CHD). METHODS AND RESULTS: Retrospective analysis of multicentre registry data after TPVI with the Melody™ valve. Eight hundred and forty-five patients (mean age: 21.0 ± 11.1 years) underwent TPVI in 42 centres between December 2006 and September 2013 and were followed-up for a median of 5.9 years (range: 0-11.0 years). The composite endpoint of TPVI-related events during follow-up (i.e. death, reoperation, or reintervention >48 h after TPVI) showed an incidence rate of 4.2% per person per year [95% confidence interval (CI) 3.7-4.9]. Transcatheter pulmonary valve implantation infective endocarditis (I.E.) showed an incidence rate of 2.3% per person per year (95% CI 1.9-2.8) and resulted in significant morbidity and in nine deaths. In multivariable Cox proportional hazard models, the invasively measured residual right ventricle (RV)-to-pulmonary artery (PA) pressure gradient (per 5 mmHg) was associated with the risk of the composite endpoint (adjusted hazard ratio: 1.21, 95% CI 1.12-1.30; P < 0.0001) and the risk of TPVI I.E. (adjusted hazard ratio: 1.19, 95% CI 1.07-1.32; P = 0.002). Major procedural complications (death, surgical, or interventional treatment requirement) occurred in 0.5%, 1.2%, and 2.0%, respectively. Acutely, the RV-to-PA pressure gradient and the percentage of patients with pulmonary regurgitation grade >2 improved significantly from 36 [interquartile range (IQR) 24-47] to 12 (IQR 7-17) mmHg and 47 to 1%, respectively (P < 0.001 for each). CONCLUSION: The post-approval MELODY Registry confirms the efficacy of TPVI with the Melody™ valve in a large-scale cohort of CHD patients. The residual invasively measured RV-to-PA pressure gradient may serve as a target for further improvement in the composite endpoint and TPVI I.E. However, TPVI I.E. remains a significant concern causing significant morbidity and mortality.

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.

Risk Factors for Pulmonary Hypertension in Adults After Atrial Septal Defect Closure.

Atrial septal defect (ASD) closure is performed to prevent pulmonary hypertension (PH), which is associated with poor outcome. This study investigated the prevalence of PH in adults before and after ASD closure and explored associations between patient characteristics and PH after ASD closure. Consecutive adult patients who underwent surgical or percutaneous ASD closure in the Erasmus MC, the Netherlands, were included (2000 to 2014). Echocardiograms before and after ASD closure were retrospectively assessed. Patients were categorized into 3 groups (no PH, possible PH, and PH) based on tricuspid regurgitation velocity (<2.9, 2.9 to 3.4, and ≥3.4 m/s) or mean pulmonary arterial pressure (<20, 20 to 24, and ≥25 mm Hg). Cox regression was performed to identify associations between patient characteristics and PH after ASD closure. Of the 244 eligible patients who underwent ASD closure, 198 (81%) had echocardiograms both before and median 15 (interquartile range 12 to 35) months after ASD closure (median age at closure 45 [interquartile range 30 to 57] years, 75% woman). The prevalence of PH was 13.1% (n = 26) before ASD closure and 5.0% (n = 10) after closure. New York Heart Association III to IV (hazard ratio [HR] 11.07, 95% confidence interval [CI] 3.12 to 39.29, p <0.001), pulmonary disease (HR 10.43, 95% CI 2.12 to 51.21, p = 0.004), cardiac medication use (HR 3.96, 95% CI 1.02 to 15.34, p = 0.047), right ventricular fractional area change (HR 0.87, 95% CI 0.81 to 0.93, p <0.001), and tricuspid annular plane systolic excursion (HR 0.75, 95% CI 0.59 to 0.95, p = 0.018) were significantly associated with PH. In conclusion, adult patients with low pulmonary pressures before ASD closure are not at risk of PH after closure. Nevertheless, PH remained prevalent in approximately 5% of patients. Especially those patients with high New York Heart Association functional class, presence of pulmonary disease, cardiac medication use and impaired RV function at baseline are at risk.

Cardiac CT to assess the risk of coronary compression in patients evaluated for percutaneous pulmonary valve implantation.

BACKGROUND: Coronary compression (CC) is a life threatening complication that can occur during percutaneous pulmonary valve implantation (PPVI). We describe our experience using cardiac CT prior to PPVI to identify patients at high CC-risk due to a close relationship between the coronary arteries and pulmonary trunk (PT). METHODS: A retrospective evaluation of candidates for PPVI who underwent CT prior to the procedure was done. Measurements of PT were performed using double oblique reconstructed images, with special attention to the stenotic tract of the PT. The analysis of coronary arteries included detection of anomalies of origin and course and assessment of their relationship with the PT, measuring the minimum distance between the coronary artery and the intended site of the future percutaneous valve implantation. RESULTS: CT analysis was performed for 52 patients. Thirty patients underwent PPVI after CT and 22 didn't. In 6/22 cases the reason not to receive a PPVI was high CC-risk detected at CT. In 6 other patients CT detected an intermediate CC-risk but the test balloon performed during angiography prior to valve placement was safe and the patients successfully underwent the procedure. None of the patients deemed as no CC-risk at CT had CC during PPVI. CONCLUSION: CT can detect patients with high and intermediate CC-risk and therefore may identify which patients are unlikely to undergo successful PPVI and those who need a careful analysis with balloon testing. CT can also rule out CC-risk identifying those patients in which balloon inflation testing could be omitted.

Multicenter experience with endovascular treatment of aortic coarctation in adults.

OBJECTIVE: The objective of this study was to evaluate outcomes of endovascular treatment of aortic coarctation in adults. METHODS: Clinical data and imaging studies of 93 consecutive patients treated at nine institutions from 1999 to 2015 were reviewed. We included newly diagnosed aortic coarctation (NCO), recurrent coarctation, and aneurysmal/pseudoaneurysmal degeneration (ANE) after prior open surgical repair (OSR) of coarctation. Primary end points were morbidity and mortality. Secondary end points were stent patency and freedom from reintervention. RESULTS: There were 54 (58%) male and 39 (42%) female patients with a mean age of 44 ± 17 years. Thirty-two patients had NCO (mean age, 48 ± 16 years) and 61 had endovascular reinterventions after prior OSR during childhood (mean, 30 ± 17 years after initial repair), including 50 patients (54%) with recurrent coarctation and 11 (12%) with ANE. Clinical presentation included asymptomatic in 31 patients (33%), difficult to control hypertension in 42 (45%), and lower extremity claudication in 20 (22%). Endovascular treatment was performed using balloon-expandable covered stents in 47 (51%) patients, stent grafts in 36 (39%) patients, balloon-expandable uncovered stents in 9 (10%) patients, and primary angioplasty in 1 (1%) patient. Mean lesion length and diameter were 64.5 ± 50.6 mm and 19.5 ± 6.7 mm, respectively. Mean systolic pressure gradient decreased from 24.0 ± 17.5 mm Hg to 4.4 ± 7.4 mm Hg after treatment (P < .001). Complications occurred in nine (10%) patients, including aortic dissections in three (3%) patients and intraoperative ruptures in two patients; type IA endoleak, renal embolus, spinal headache, and access site hemorrhage occurred in one patient each. The aortic dissections and ruptures were treated successfully by deploying an additional covered stent proximal to the site of dissection or rupture. Two patients died within 30 days of the index procedure. After a mean follow-up of 3.2 ± 3.1 years, nearly all patients (98%) were clinically improved and all stents were patent. Reintervention was needed in 10 (11%) patients. Freedom from reintervention at 5 years was 85%. Two additional patients died during follow-up of coarctation-related causes, including rupture of an infected graft and visceral ischemia. Patient survival at 5 years was 89%. CONCLUSIONS: Endovascular repair is effective with an acceptable safety profile in the treatment of NCO and postsurgical complications of coarctation after initial OSR. Aortic rupture is an infrequent (2%) but devastating complication with high mortality. Balloon-expandable covered stents are preferred for NCO, whereas stent grafts are used for ANE. The rate of reinterventions is acceptable, with high procedural and long-term clinical success.

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.

Late complications of an atrial septal occluder provoked by anticoagulant therapy.

Late complications of an atrial septal occluder device (ASO) are rare but may be serious. We report a case with extensive hemopericardium five years after ASO implantation most likely triggered by anticoagulant therapy. Although not surgically confirmed, indirect clues for erosion of the atrial wall by the device were the exclusion of other etiologies, lack of recurrence after pericardial drainage and withdrawal of anticoagulants. In addition, multimodality imaging using echocardiography, computed tomography, and cardiac magnetic resonance imaging were helpful to elucidate this unusual cause. Initiation of anticoagulant treatment in patients with an ASO should be carefully balanced and may warrant more frequent echocardiographic follow-up. .

Soporte circulatorio mediante asistencia ventricular percutánea durante la ablación de taquicardias auriculares en pacientes con circulación de Fontan / Percutaneous ventricular assist device for circulatory support during ablation of atrial tachycardias in patients with Fontan Circulation

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Prognostic Value of Serial N-Terminal Pro-B-Type Natriuretic Peptide Measurements in Adults With Congenital Heart Disease.

BACKGROUND: A 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 RESULTS: In 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 <0.001, respectively). In patients with elevated baseline NT-proBNP (>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<0.001) and secondary end point (HR 2.47; 95% CI 1.13-5.70; P=0.017), when adjusted for the baseline measurement. CONCLUSIONS: NT-proBNP increased before the occurrence of events, especially in patients who died or developed heart failure. Serial NT-proBNP measurements could be of additional prognostic value in the annual follow-up of patients with adult congenitive heart disease with an elevated NT-proBNP.

Red cell distribution width in adults with congenital heart disease: A worldwide available and low-cost predictor of cardiovascular events.

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

Prognostic value of galectin-3 in adults with congenital heart disease.

OBJECTIVE: Galectin-3 is an emerging biomarker for risk stratification in patients with heart failure. This study aims to investigate the release of galectin-3 and its association with cardiovascular events in patients with adult congenital heart disease (ACHD). METHODS: In this prospective cohort study, 602 consecutive patients with ACHD who routinely visited the outpatient clinic were enrolled between 2011 and 2013. Galectin-3 was measured in thaw serum by batch analysis. The association between galectin-3 and a primary endpoint of all-cause mortality, heart failure, hospitalisation, arrhythmia, thromboembolic events and cardiac interventions was investigated using multivariable Cox models. Reference values and reproducibility were established by duplicate galectin-3 measurements in 143 healthy controls. RESULTS: Galectin-3 was measured in 591 (98%) patients (median age 33 (25-41) years, 58% male, 90% New York Heart Association (NYHA) class I). Median galectin-3 was 12.7 (range 4.2-45.7) ng/mL and was elevated in 7% of patients. Galectin-3 positively correlated with age, cardiac medication use, NYHA class, loss of sinus rhythm, cardiac dysfunction and N-terminal pro-B-type natriuretic peptide (NT-proBNP). During a median follow-up of 4.4 (IQR 3.9-4.8) years, the primary endpoint occurred in 195 patients (33%). Galectin-3 was significantly associated with the primary endpoint in the univariable analysis (HR per twofold higher value 2.05; 95% CI 1.44 to 2.93, p<0.001). This association was negated after adjustment for NT-proBNP (HR 1.04; 95% CI 0.72 to 1.49, p=0.848). CONCLUSIONS: Galectin-3 is significantly associated with functional capacity, cardiac function and adverse cardiovascular events in patients with ACHD. Nevertheless, the additive value of galectin-3 to a more conventional risk marker such as NT-proBNP seems to be limited.

Pulmonary arterial stiffness indices assessed by intravascular ultrasound in children with early pulmonary vascular disease: prediction of advanced disease and mortality during 20-year follow-up.

Aims: Prognosis in children with pulmonary vascular disease (PVD) is closely linked to right ventricular (RV) failure due to increased RV-afterload. Pulmonary arterial (PA) stiffening is known to occur early in the course of PVD and constitutes a main component of RV-afterload. This study aimed to evaluate the clinical value of PA-stiffness in children with PVD by determining its association with advanced pulmonary arterial hypertension (PAH) and mortality at long-term follow-up. Methods and results: Forty-one children with various stages of arterial PVD, defined as mean PA-pressure ≥20 mmHg and/or pulmonary-to-systemic flow-ratio ≥1.2, and mean pulmonary capillary wedge pressure <15 mmHg, underwent cardiac catheterization with intravascular ultrasound (IVUS) imaging between 1994 and 1997 with follow-up until 2015. PA-stiffness indices evaluated were PA-area-compliance (PA-compliance) and PA-area-distensibility (PA-distensibility). During follow-up, advanced PAH was determined by echocardiography and cardiac catheterization. During a median follow-up of 19 years, in 31 (76%) patients PVD had reversed and 10 (24%) had advanced PAH. Six (15%) died due to PVD. In addition to conventional haemodynamics, PA-compliance and PA-distensibility were associated with advanced PAH at long-term follow-up (adjusted OR [95% CI] 0.56 [0.37-0.85] and 0.52 [0.31-0.86]), and mortality (adjusted HR [95% CI] 0.60 [0.41-0.87] and 0.67 [0.49-0.90]). Also in a subgroup of patients with favourable haemodynamics, baseline PA-compliance and PA-distensibility were lower in patients with advanced PAH at follow-up (P = 0.002 /P = 0.030). Conclusion: In children with PVD, PA-stiffness indices assessed by IVUS predict advanced PAH and mortality at long term follow-up. Especially in patients with favourable haemodynamics, assessment of intrinsic PA-stiffness may enhance the prognostication of disease progression and survival.