Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries.

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

Type D Personality Associated With Increased Risk for Mortality in Adults With Congenital Heart Disease.

BACKGROUND: Type D personality has been previously shown to increase the risk for mortality in patients with acquired heart disease. OBJECTIVE: We aimed to compare mortality in adult patients with congenital heart disease (CHD) with and without type D. METHODS: Survival was assessed using prospective data from the Dutch national Congenital Corvitia registry for adults with CHD. Patients were randomly selected from the registry and characterized at inclusion in 2009 for the presence of type D using the DS14 questionnaire. RESULTS: One thousand fifty-five patients, with 484 (46%) males, a mean (SD) age of 41 (14) years, 613 (58%) having mild CHD, 348 (33%) having moderate CHD, and 94 (9%) having severe CHD, were included. Type D personality was present in 225 patients (21%). Type D was associated with an increased risk for all-cause mortality independent of age, sex, New York Heart Association class, number of prescribed medications, depression, employment status, and marital status (hazard ratio, 1.94; 95% confidence interval, 1.05-3.57; P = .033). CONCLUSION: Type D personality was associated with an increased risk for all-cause mortality in adult patients with CHD.

Pulmonary hypertension in connective tissue diseases, new evidence and challenges.

Pulmonary arterial hypertension is a lethal complication of different connective tissue diseases such as systemic sclerosis, mixed connective tissue disease and systemic lupus erythematosus. Although the treatment possibilities for patients with pulmonary arterial hypertension have increased in the last two decades and survival of patients with idiopathic pulmonary arterial hypertension has improved, the latter is not the case for patients with pulmonary arterial hypertension associated with connective tissue disease. In this narrative review, we review recent literature and describe the improvement of early diagnostic possibilities, screening modalities and treatment options. We also point out the pitfalls in diagnosis in this patient category and describe the unmet needs and what the focus of future research should be.

Acute impact of changes to hemodynamic load on the left ventricular strain-volume relationship in young and older men.

Chronic changes in left ventricular (LV) hemodynamics, such as those induced by increased afterload (i.e., hypertension), mediate changes in LV function. This study examined the proof of concept that 1) the LV longitudinal strain (ε)-volume loop is sensitive to detecting an acute increase in afterload, and 2) these effects differ between healthy young versus older men. Thirty-five healthy male volunteers were recruited, including 19 young (24 ± 2 yr) and 16 older participants (67 ± 5 yr). Tests were performed before, during, and after 10-min recovery from acute manipulation of afterload. Real-time hemodynamic data were obtained and LV longitudinal ε-volume loops were calculated from four-chamber images using two-dimensional echocardiography. Inflation of the anti-gravity (anti-G) suit resulted in an immediate increase in heart rate, blood pressure, and systemic vascular resistance and a decrease in stroke volume (all P < 0.05). This was accompanied by a decrease in LV peak ε, slower slope of the ε-volume relationship during early diastole, and an increase in uncoupling (i.e., compared with systole; little change in ε per volume decline during early diastole and large changes in ε per volume decline during late diastole) (all P < 0.05). All values returned to baseline levels after recovery (all P > 0.05). Manipulation of cardiac hemodynamics caused comparable effects in young versus older men (all P > 0.05). Acute increases in afterload immediately change the diastolic phase of the LV longitudinal ε-volume loop in young and older men. This supports the potency of the LV longitudinal ε-volume loop to provide novel insights into dynamic cardiac function in humans in vivo.

Reduced right ventricular function on cardiovascular magnetic resonance imaging is associated with uteroplacental impairment in tetralogy of Fallot.

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.

The clinical spectrum of Fontan-associated liver disease: results from a prospective multimodality screening cohort.

AIMS: Liver fibrosis and cirrhosis are a consequence of a Fontan physiology, and determine prognosis. It is unclear whether non-invasive assessment of liver pathology is helpful to provide clinically relevant information. The aims of this study were to assess the spectrum of Fontan-associated liver disease (FALD) and usefulness of non-invasive methods to assess biopsy confirmed liver fibrosis. METHODS AND RESULTS: Hepatic screening of consecutive patients consisted of a blood panel, ultrasonography, elastography, contrast-enhanced magnetic resonance imaging (MRI)/computed tomography (CT) scan, and liver biopsy (scored with Fontan specific fibrosis scores and collagen proportionate area; CPA). Fibrosis parameters, varices, ascites, and splenomegaly were measured on imaging. Thirty-eight of 49 referred patients (27 ± 6.6 years, 73.7% male) underwent the complete screening protocol. Liver fibrosis on biopsy was present in all patients, and classified as severe (Stages 3-4) in 68%. Median CPA was 22.5% (16.9-29.5) and correlated with individual fibrosis scores. ELF® and liver stiffness were elevated, but MELD-XI scores were low in all patients. Fibrosis severity neither correlated to ELF® and liver stiffness, nor to (semi-) quantitative fibrosis parameters on MRI/CT. Varices were present in 50% and hyperenhancing nodules in 25% of patients, both independent of fibrosis stage, but varices were associated with higher CPA values. CONCLUSION: The FALD spectrum includes both hepatic congestion and severe fibrosis, with signs of portal hypertension and hyperenhancing nodules as significant manifestations. Routine imaging, transient elastography, and serum biomarkers are unable to accurately assess severity of liver fibrosis in this cohort. Future research should focus on validating new diagnostic tools with biopsy as the reference standard.

Effect of Losartan on Right Ventricular Dysfunction: Results From the Double-Blind, Randomized REDEFINE Trial (Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-Angiotensin-Aldosterone System) in Adults With Repaired Tetralogy of Fallot.

BACKGROUND: The effect of angiotensin II receptor blockers on right ventricular (RV) function is still unknown. Angiotensin II receptor blockers are beneficial in patients with acquired left ventricular dysfunction, and recent findings have suggested a favorable effect in symptomatic patients with systemic RV dysfunction. The current study aimed to determine the effect of losartan, an angiotensin II receptor blocker, on subpulmonary RV dysfunction in adults after repaired tetralogy of Fallot. METHODS: The REDEFINE trial (Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-Angiotensin-Aldosterone System) is an investigator-initiated, multicenter, prospective, 1:1 randomized, double-blind, placebo-controlled study. Adults with repaired tetralogy of Fallot and RV dysfunction (RV ejection fraction [EF] <50%) but without severe valvular dysfunction were eligible. Patients were randomly assigned between losartan (150 mg daily) and placebo with target treatment duration between 18 and 24 months. The primary outcome was RV EF change, determined by cardiovascular MRI in intention-to-treat analysis. RESULTS: Of 95 included patients, 47 patients received 150 mg losartan daily (age, 38.0±12.4 years; 74% male), and 48 patients received placebo (age, 40.6±11.4 years; 63% male). Overall, RV EF did not change in patients allocated to losartan (n=42) (44.4±5.1% to 45.2±5.0%) and placebo (n=46) (43.2±6.3% to 43.6±6.9%). Losartan did not significantly improve RV EF in comparison with placebo (+0.51%; 95% confidence interval, -1.0 to +2.0; P=0.50). No significant treatment effects were found on secondary outcomes: left ventricular EF, peak aerobic exercise capacity, and N-terminal pro-brain natriuretic peptide (P>0.30 for all). In predefined subgroup analyses, losartan did not have a statistically significant impact on RV EF in subgroups with symptoms, restrictive RV, RV EF<40%, pulmonary valve replacement, or QRS fragmentation. However, in a post hoc analysis, losartan was associated with improved RV EF in a subgroup (n=30) with nonrestrictive RV and incomplete remodeling (QRS fragmentation and previous pulmonary valve replacement) (+2.7%; 95% confidence interval, +0.1 to +5.4; P=0.045). CONCLUSIONS: Losartan had no significant effect on RV dysfunction or secondary outcome parameters in repaired tetralogy of Fallot. Future larger studies may determine whether there might be a role for losartan in specific vulnerable subgroups. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02010905.

Anomalous coronary artery originating from the opposite sinus of Valsalva (ACAOS), fractional flow reserve- and intravascular ultrasound-guided management in adult patients.

OBJECTIVES: To describe the use of fractional flow reserve (FFR) and intravascular ultrasound (IVUS) in the evaluation of patients with anomalous coronary arteries originating from the opposite sinus of Valsalva (ACAOS). BACKGROUND: ACAOS of the right and left coronary are rare, but may lead to symptoms and impose a risk for sudden cardiac death, depending on several anatomical features. Assessment and risk estimation is challenging in (nonathlete) adults, especially if they present without symptoms or with atypical complaints. METHODS: The team retrospectively studied 30 consecutive patients with ACAOS with interarterial course, who received IVUS- and FFR-guided treatment at our institution between October 2010 and September 2017. RESULTS: FFR was abnormal in only seven patients. IVUS showed the typical slit-like anatomy of the orifice in 23 patients. Based on FFR and/or IVUS results, in conjunction with the clinical presentation, clinical decision was made. A decision for intervention was made if at least two out of three entities were abnormal. Intervention implied unroofing of the coronary artery (n = 10) or coronary artery bypass grafting (n = 1). In all other patients a conservative strategy was followed. No adverse events occurred in the total population after a median of 37 (0-62) months of follow-up. CONCLUSIONS: Conservative treatment may be justifiable in adult patients with ACAOS in the presence of normal FFR and nonsuspicious symptoms, despite the presence of an interarterial course and/or slitlike orifice on IVUS. We recommend the use of FFR and IVUS in the standard work-up for adult patients with ACAOS and propose the use of a flowchart to aid in decision-making.

Tricuspid flow and regurgitation in congenital heart disease and pulmonary hypertension: comparison of 4D flow cardiovascular magnetic resonance and echocardiography.

BACKGROUND: Tricuspid valve (TV) regurgitation (TR) is a common complication of pulmonary hypertension and right-sided congenital heart disease, associated with increased morbidity and mortality. Estimation of TR severity by echocardiography and conventional cardiovasvular magnetic resonance (CMR) is not well validated and has high variability. 4D velocity-encoded (4D-flow) CMR was used to measure tricuspid flow in patients with complex right ventricular (RV) geometry and varying degrees of TR. The aims of the present study were: 1) to assess accuracy of 4D-flow CMR across the TV by comparing 4D-flow CMR derived TV effective flow to 2D-flow derived effective flow across the pulmonary valve (PV); 2) to assess TV 4D-flow CMR reproducibility, and 3) to compare TR grade by 4D-flow CMR to TR grade by echocardiography. METHODS: TR was assessed by both 4D-flow CMR and echocardiography in 21 healthy subjects (41.2 ± 10.5 yrs., female 7 (33%)) and 67 RV pressure-load patients (42.7 ± 17.0 yrs., female 32 (48%)). The CMR protocol included 4D-flow CMR measurement across the TV, 2D-flow measurement across the PV and conventional planimetric measurements. TR grading on echocardiographic images was performed based on the international recommendations. Bland-Altman analysis and intra-class correlation coefficients (ICC) were used to asses correlations and agreement. RESULTS: TV effective flow measured by 4D-flow CMR showed good correlation and agreement with PV effective flow measured by 2D-flow CMR with ICC = 0.899 (p < 0.001) and mean difference of -1.79 ml [limits of agreement -20.39 to 16.81] (p = 0.084). Intra-observer agreement for effective flow (ICC = 0.981; mean difference - 1.51 ml [-12.88 to 9.86]) and regurgitant fraction (ICC = 0.910; mean difference 1.08% [-7.90; 10.06]) was good. Inter-observer agreement for effective flow (ICC = 0.935; mean difference 2.12 ml [-15.24 to 19.48]) and regurgitant fraction (ICC = 0.968; mean difference 1.10% [-7.96 to 5.76]) were comparable. In 25/65 (38.5%) TR grade differed by at least 1 grade using 4D-flow CMR compared to echocardiography. CONCLUSION: TV effective flow derived from 4D-flow CMR showed excellent correlation to PV effective flow derived from 2D-flow CMR, and was reproducible to measure TV flow and regurgitation. Twenty-five out of 65 patients (38.5%) were classified differently by at least one TR grade using 4D-flow CMR compared to echocardiography.

Exploratory assessment of left ventricular strain-volume loops in severe aortic valve diseases.

KEY POINTS: Severe aortic valve diseases are common cardiac abnormalities that are associated with poor long-term survival. Before any reduction in left ventricular (LV) function, the left ventricle undergoes structural remodelling under the influence of changing haemodynamic conditions. In this study, we combined temporal changes in LV structure (volume) with alterations in LV functional characteristics (strain, ԑ) into a ԑ-volume loop, in order to provide novel insight into the haemodynamic cardiac consequences of aortic valve diseases in those with preserved LV ejection fraction. We showed that our novel ԑ-volume loop and the specific loop characteristics provide additional insight into the functional and mechanical haemodynamic consequences of severe aortic valve diseases (with preserved LV ejection fraction). Finally, we showed that the ԑ-volume loop characteristics provide discriminative capacity compared with conventional measures of LV function. ABSTRACT: The purpose of this study was to examine left ventricular (LV) strain (ԑ)-volume loops to provide novel insight into the haemodynamic cardiac consequences of aortic valve stenosis (AS) and aortic valve regurgitation (AR). Twenty-seven participants were retrospectively recruited: AR (n = 7), AS (n = 10) and control subjects (n = 10). Standard transthoracic echocardiography was used to obtain apical four-chamber images to construct ԑ-volume relationships, which were assessed using the following parameters: early systolic ԑ (ԑ_ES); slope of ԑ-volume relationship during systole (Sslope); end-systolic peak ԑ (peak ԑ); and diastolic uncoupling (systolic ԑ-diastolic ԑ at same volume) during early diastole (UNCOUP_ED) and late diastole (UNCOUP_LD). Receiver operating characteristic curves were used to determine the ability to detect impaired LV function. Although LV ejection fraction was comparable between groups, longitudinal peak ԑ was reduced compared with control subjects. In contrast, ԑ_ES and Sslope were lower in both pathologies compared with control subejcts (P < 0.01), but also different between AS and AR (P < 0.05). UNCOUP_ED and UNCOUP_LD were significantly higher in both patient groups compared with control subjects (P < 0.05). Receiver operating characteristic curves revealed that loop characteristics (AUC = 0.99, 1.00 and 1.00; all P < 0.01) were better able then peak ԑ (AUC = 0.75, 0.89 and 0.76; P = 0.06, <0.01 and 0.08, respectively) and LV ejection fraction (AUC = 0.56, 0.69 and 0.69; all P > 0.05) to distinguish AS vs control, AR vs control and AS vs AR groups, respectively. Temporal changes in ԑ-volume characteristics provide novel insight into the haemodynamic cardiac impact of AS and AR. Contrary to traditional measures (i.e. ejection fraction, peak ԑ), these novel measures successfully distinguish between the haemodynamic cardiac impact of AS and AR.

Right vEntricular Dysfunction in tEtralogy of Fallot: INhibition of the rEnin-angiotensin-aldosterone system (REDEFINE) trial: Rationale and design of a randomized, double-blind, placebo-controlled clinical trial.

Renin-angiotensin-aldosterone system (RAAS) inhibition with angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors is beneficial in patients with acquired left ventricular dysfunction. Adult patients with tetralogy of Fallot (TOF) with right ventricular (RV) dysfunction are at high risk for heart failure, arrhythmias, and sudden cardiac death. However, the efficacy of RAAS inhibition has not been established in these patients. METHODS: The REDEFINE is an investigator-initiated, multicenter, prospective, randomized, double-blind, placebo-controlled trial to study the effects of the angiotensin II receptor blocker losartan (target dosage of 150 mg once daily) in adult patients with TOF. Patients with RV dysfunction in the absence of severe valvular dysfunction are eligible for inclusion. The primary end point is the change in RV ejection fraction after 18 to 24 months, as measured by cardiovascular magnetic resonance imaging. In addition, laboratory measurements, echocardiography, and cardiopulmonary exercise testing are performed. CONCLUSION: The REDEFINE trial will study the effects of RAAS inhibition with losartan in TOF patients with RV dysfunction.

Preoperative thresholds for mid-to-late haemodynamic and clinical outcomes after pulmonary valve replacement in tetralogy of Fallot.

AIMS: The right ventricle (RV) remodels early after pulmonary valve replacement (PVR) in tetralogy of Fallot (TOF) patients. Previously reported preoperative thresholds to achieve early postoperative RV normalization were consistently close to 80 mL/m(2) for end-systolic volume (ESV) and 160 mL/m(2) for end-diastolic volume (EDV). Our objective was to determine whether these thresholds were also associated with mid-to-late RV normalization and clinical events. METHODS AND RESULTS: Out of a multicentre cohort of 157 TOF patients who had undergone PVR, in 65 patients (62% male, age 29 ± 8 years, homograft in 98%) cardiovascular magnetic resonance (CMR) imaging was performed preoperatively and >3 years (6.3 years, interquartile range: 4.9-9.5) postoperatively. Mid-to-late haemodynamic outcome was classified as: 'RV normalization' [RV ejection fraction (EF) > 48% and RV EDV < 108 mL/m(2)] in 14 of 65 (22%) patients, 'intermediate' in 34 of 65 (52%) patients, and 'suboptimal' (RV EF < 45% and RV EDV > 120 mL/m(2)) in 17 of 65 (26%) patients. Preoperative RV ESV < 80 mL/m(2) was strongly associated with favourable mid-to-late haemodynamic outcome in a proportional odds model [common odds ratio (OR): 0.04 for worse class, 95% confidence interval (CI): 0.01-0.17]. During 7.8 ± 4.0 years follow-up after PVR, adverse clinical events (death, sustained ventricular tachycardia, or heart failure) occurred in 18 of 106 (17%) patients with preoperative CMR available. Patients with preoperative RV ESV > 95 mL/m(2) were at increased risk for unfavourable mid-to-late haemodynamic outcome (common OR: 25.5, 95% CI: 5.35-122) and events (hazard ratio: 2.89, 95% CI: 1.03-8.11). CONCLUSION: In TOF patients who had undergone PVR, the best preoperative threshold to achieve mid-to-late RV normalization was RV ESV < 80 mL/m(2). Patients with preoperative RV ESV > 95 mL/m(2) were at increased risk for suboptimal haemodynamic outcome and adverse clinical events. Our findings may assist in timing of PVR.

Cardiac magnetic resonance findings predicting mortality in patients with pulmonary arterial hypertension: a systematic review and meta-analysis.

OBJECTIVES: To provide a comprehensive overview of all reported cardiac magnetic resonance (CMR) findings that predict clinical deterioration in pulmonary arterial hypertension (PAH). METHODS: MEDLINE and EMBASE electronic databases were systematically searched for longitudinal studies published by April 2015 that reported associations between CMR findings and adverse clinical outcome in PAH. Studies were appraised using previously developed criteria for prognostic studies. Meta-analysis using random effect models was performed for CMR findings investigated by three or more studies. RESULTS: Eight papers (539 patients) investigating 21 different CMR findings were included. Meta-analysis showed that right ventricular (RV) ejection fraction was the strongest predictor of mortality in PAH (pooled HR 1.23 [95 % CI 1.07-1.41], p = 0.003) per 5 % decrease. In addition, RV end-diastolic volume index (pooled HR 1.06 [95 % CI 1.00-1.12], p = 0.049), RV end-systolic volume index (pooled HR 1.05 [95 % CI 1.01-1.09], p = 0.013) and left ventricular end-diastolic volume index (pooled HR 1.16 [95 % CI 1.00-1.34], p = 0.045) were of prognostic importance. RV and LV mass did not provide prognostic information (p = 0.852 and p = 0.983, respectively). CONCLUSION: This meta-analysis substantiates the clinical yield of specific CMR findings in the prognostication of PAH patients. Decreased RV ejection is the strongest and most well established predictor of mortality. KEY POINTS: • Cardiac magnetic resonance imaging is useful for prognostication in pulmonary arterial hypertension. • Right ventricular ejection fraction is the strongest predictor of mortality. • Serial CMR evaluation seems to be of additional prognostic importance. • Accurate prognostication can aid in adequate and timely intensification of PAH-specific therapy.

Secundum atrial septal defect is associated with reduced survival in adult men.

AIMS: The identification of sex differences in the prognosis of adults with a secundum atrial septal defect (ASD2) could help tailor their clinical management, as it has in other cardiovascular diseases. We investigated whether disparity between the sexes exists in long-term outcome of adult ASD2 patients. METHODS AND RESULTS: Patients with ASD2 classified as the primary defect were selected from the Dutch national registry of adult congenital heart disease. Survival stratified by sex was compared with a sex-matched general population. In a total of 2207 adult patients (mean age at inclusion 44.8 years, 33.0% male), 102 deaths occurred during a cumulative follow-up of 13 584 patient-years. Median survival was 79.7 years for men and 85.6 years for women with ASD2. Compared with the age- and sex-matched general population, survival was lower for male, but equal for female patients (P = 0.015 and 0.766, respectively). Logistic regression analyses showed that men had a higher risk of conduction disturbances (OR = 1.63; 95% CI, 1.22-2.17) supraventricular dysrhythmias (OR = 1.41; 1.12-1.77), cerebrovascular thromboembolic events (OR = 1.53; 1.10-2.12), and heart failure (OR = 1.91; 1.06-3.43). CONCLUSION: In contrast to women, adult men with an ASD2 have worse survival than a sex-matched general population. Male patients also have a greater risk of morbidity during adult life. Sex disparity in survival and morbidity suggests the need for a sex-specific clinical approach towards these patients.

Cardiac function and cardiac events 1-year postpartum in women with congenital heart disease.

BACKGROUND: Pregnancy is increasingly common in women with congenital heart disease (CHD), but little is known about long-term cardiovascular outcome after pregnancy in these patients. We studied the incidence of cardiovascular events 1-year postpartum and compared cardiac function prepregnancy and 1-year postpartum in women with CHD. METHODS: From our national, prospective multicenter cohort study, 172 women were studied. Follow-up with clinical evaluation and echocardiography and NT-proBNP measurement were performed during pregnancy and 12 months postpartum. Cardiovascular events were defined as need for an urgent invasive cardiovascular procedure, heart failure, arrhythmia, thromboembolic events, myocardial infarction, cardiac arrest, cardiac death, endocarditis, and aortic dissection. RESULTS: Cardiovascular events were observed after 11 pregnancies (6.4%). Women with cardiovascular events postpartum had significant higher NT-proBNP values at 20-week gestation (191 [137-288] vs 102.5 [57-167]; P = .049) and 1-year postpartum compared with women without cardiovascular events postpartum (306 [129-592] vs 105 [54-187] pg/mL; P = .014). Women with cardiovascular events during pregnancy were at higher risk for late cardiovascular events (HR 7.1; 95% CI 2.0-25.3; P = .003). In women with cardiovascular events during pregnancy, subpulmonary end-diastolic diameter had significantly increased 1-year postpartum (39.0 [36.0-48.0] to 44.0 [40.0-50.0]; P = .028). No other significant differences were found in cardiac function or size 1-year postpartum compared with preconception values. CONCLUSIONS: Cardiovascular events are relatively rare 1 year after pregnancy in women with CHD. Women with cardiovascular events during pregnancy are prone to develop cardiovascular events 1-year postpartum and have increased subpulmonary ventricular diameter compared with preconception values.

Heart failure patients demonstrate impaired changes in brachial artery blood flow and shear rate pattern during moderate-intensity cycle exercise.

NEW FINDINGS: What is the central question of this study? We explored whether heart failure (HF) patients demonstrate different exercise-induced brachial artery shear rate patterns compared with control subjects. What is the main finding and its importance? Moderate-intensity cycle exercise in HF patients is associated with an attenuated increase in brachial artery anterograde and mean shear rate and skin temperature. Differences between HF patients and control subjects cannot be explained fully by differences in workload. HF patients demonstrate a less favourable shear rate pattern during cycle exercise compared with control subjects. Repeated elevations in shear rate (SR) in conduit arteries, which occur during exercise, represent a key stimulus to improve vascular function. We explored whether heart failure (HF) patients demonstrate distinct changes in SR in response to moderate-intensity cycle exercise compared with healthy control subjects. We examined brachial artery SR during 40 min of cycle exercise at a work rate equivalent to 65% peak oxygen uptake in 14 HF patients (65 ± 7 years old, 13 men and one woman) and 14 control subjects (61 ± 5 years old, 12 men and two women). Brachial artery diameter, SR and oscillatory shear index (OSI) were assessed using ultrasound at baseline and during exercise. The HF patients demonstrated an attenuated increase in mean and anterograde brachial artery SR during exercise compared with control subjects (time × group interaction, P = 0.003 and P < 0.001, respectively). Retrograde SR increased at the onset of exercise and remained increased throughout the exercise period in both groups (time × group interaction, P = 0.11). In control subjects, the immediate increase in OSI during exercise (time, P < 0.001) was normalized after 35 min of cycling. In contrast, the increase in OSI after the onset of exercise did not normalize in HF patients (time × group interaction, P = 0.029). Subgroup analysis of five HF patients and five control subjects with comparable workload (97 ± 13 versus 90 ± 22 W, P = 0.59) confirmed the presence of distinct changes in mean SR during exercise (time × group interaction, P = 0.030). Between-group differences in anterograde/retrograde SR or OSI did not reach statistical significance (time × group interactions, P > 0.05). In conclusion, HF patients demonstrate a less favourable SR pattern during cycle exercise than control subjects, characterized by an attenuated mean and anterograde SR and by increased OSI.

Parental mental health moderates the efficacy of exercise training on health-related quality of life in adolescents with congenital heart disease.

To evaluate the moderating influence of parental variables on changes in health-related quality of life (HRQoL) in adolescents with Tetralogy of Fallot (ToF) or a Fontan circulation after participation in standardized exercise training. A multicenter randomized controlled trail in which 56 patients, aged 10-15, were randomly allocated (stratified by age, gender, and congenital heart disease) to a 12-week period with either: (a) 3 times per week standardized exercise training or (b) care-as-usual (randomization ratio 2:1). Adolescents and their parents filled in online questionnaires at baseline and at 12-week follow-up. In this randomized controlled trail, primary analyses involved influence of parental mental health and parental social support for exercise on changes in the TNO/AZL Child Quality of Life Questionnaire Child Form at follow-up. Secondary analyses concerned comparing levels of parental characteristics with normative data. Compared with controls, adolescents in the exercise group reported a decrease in social functioning when their parents had more anxiety/insomnia or severe depression themselves. Adolescents also reported a decrease in social functioning when their parents showed poorer overall mental health themselves. Parents reported comparable or even better mental health compared with normative data. The effect of a standardized exercise program on HRQoL changes in adolescents with ToF or a Fontan circulation is moderated by parental mental health, more specifically by parental anxiety/insomnia and severe depression. The trial registration number of this article is NTR2731 ( www.trialregister.nl ).

N-terminal pro-B-type natriuretic peptide predicts cardiovascular complications in pregnant women with congenital heart disease.

AIMS: In women with congenital heart disease (CHD), cardiovascular complications during pregnancy are common, but the risk assessment of these patients remains difficult. This study sought to determine the independent role of N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in addition to other parameters in predicting adverse cardiovascular events during pregnancy in women with CHD. METHODS AND RESULTS: We conducted a national, prospective multicentre cohort study. Follow-up with clinical evaluation and echocardiography and NT-proBNP measurement was performed at 20-week gestation. Adverse cardiovascular events occurred in 10.3% of 213 pregnancies. N-terminal pro-B-type natriuretic peptide levels >128 pg/mL at 20-week gestation, the presence of a mechanical valve, and subpulmonary ventricular dysfunction before conception were independently associated with events [odds ratio (OR) 10.6 (P = 0.039), OR 12.0 (P = 0.016), and OR 4.2 (P = 0.041), respectively]. The negative predictive value of NT-proBNP levels <128 pg/mL was 96.9%. N-terminal pro-B-type natriuretic peptide levels >128 pg/mL at 20 weeks of gestation had an additional value in predicting the occurrence of adverse cardiovascular events on the top of the other identified predictors (area under the curve 0.90 vs. 0.78, P = 0.035). CONCLUSION: Increased NT-proBNP levels at 20 weeks of gestation are an independent risk predictor of cardiovascular events during pregnancy in women with CHD.

Association of Fitness Level With Cardiovascular Risk and Vascular Function in Older Nonexercising Individuals.

It is currently unknown whether differences in physical fitness in older, nonexercising individuals affect cardiovascular risk profile and vascular function. To examine this, 40 healthy older individuals (age 69 ± 4 years) who were classified as nonexercising for the past 5-10 years were allocated to a lower physical fitness (LF; VO2max 20.7 ± 2.4 mlO2/min/kg) or higher physical fitness group (HF; VO2max 29.1 ± 2.8 mlO2/ min/kg, p < .001). Cardiovascular risk profile was calculated using the Lifetime Risk Score (LRS). Vascular function was examined using the gold standard venous occlusion plethysmography to assess blood flow changes in response to intra-arterial infusion of acetylcholine, sodium nitroprusside, and L-NNMA. Daily life activity level of the HF group was higher compared with the LF group (p = .04). LRS was higher (p < .001) and blood flow ratio response to acetylcholine was lower (p = .04) in the LF group. This study shows that a higher physical fitness level is associated with better cardiovascular health and vascular function in nonexercising older individuals.

Effect of valsartan on systemic right ventricular function: a double-blind, randomized, placebo-controlled pilot trial.

BACKGROUND: The role of angiotensin II receptor blockers in patients with a systemic right ventricle has not been elucidated. METHODS AND RESULTS: We conducted a multicenter, double-blind, parallel, randomized controlled trial of angiotensin II receptor blocker valsartan 160 mg twice daily compared with placebo in patients with a systemic right ventricle caused by congenitally or surgically corrected transposition of the great arteries. The primary end point was change in right ventricular ejection fraction during 3-year follow-up, determined by cardiovascular magnetic resonance imaging or, in patients with contraindication for magnetic resonance imaging, multirow detector computed tomography. Secondary end points were change in right ventricular volumes and mass, Vo(2)peak, and quality of life. Primary analyses were performed on an intention-to-treat basis. A total of 88 patients (valsartan, n=44; placebo, n=44) were enrolled in the trial. No serious adverse effects occurred in either group. There was no significant effect of 3-year valsartan therapy on systemic right ventricular ejection fraction (treatment effect, 1.3%; 95% confidence interval, -1.3% to 3.9%; P=0.34), maximum exercise capacity, or quality of life. There was a larger increase in right ventricular end-diastolic volume (15 mL; 95% confidence interval, 3-28 mL; P<0.01) and mass (8 g; 95% confidence interval, 2-14 g; P=0.01) in the placebo group than in the valsartan group. CONCLUSIONS: There was no significant treatment effect of valsartan on right ventricular ejection fraction, exercise capacity, or quality of life. Valsartan was associated with a similar frequency of significant clinical events as placebo. Small but significant differences between valsartan and placebo were present for change in right ventricular volumes and mass. CLINICAL TRIAL REGISTRATION: URL: http://www.controlled-trials.com. Unique identifier: ISRCTN52352170.