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ObjectiveThe 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.MethodsFrom 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.ResultsOf the original cohort of 920 adults with repaired CoA, 675 patients (median age 24 years (range 16–72 years)) underwent exercise stress testing. Of these, 299 patients (44%) had a hypertensive response to exercise. Mean follow-up duration was 10.1 years. Male sex, absence of a bicuspid aortic valve and elevated resting SBP were independently associated with increased peak exercise SBP. Peak exercise SBP was positively predictive of office SBP (β=0.11, p<0.001) and 24-hour SBP (β=0.05, p=0.03) at follow-up, despite correction for baseline SBP. During follow-up, 100 patients (15%) developed at least 1 cardiovascular event. Peak exercise SBP was not significantly associated with the occurrence of cardiovascular events (HR 0.994 (95% CI 0.987 to 1.001), p=0.11).ConclusionsA 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.

Background/objectivesPregnancy may potentiate the inherent hypercoagulability of the Fontan circulation, thereby amplifying adverse events. This study sought to evaluate thrombosis and bleeding risk in pregnant women with a Fontan.MethodsWe performed a retrospective observational cohort study across 13 international centres and recorded data on thrombotic and bleeding events, antithrombotic therapies and pre-pregnancy thrombotic risk factors.ResultsWe analysed 84 women with Fontan physiology undergoing 108 pregnancies, average gestation 33±5 weeks. The most common antithrombotic therapy in pregnancy was aspirin (ASA, 47 pregnancies (43.5%)). Heparin (unfractionated (UFH) or low molecular weight (LMWH)) was prescribed in 32 pregnancies (30%) and vitamin K antagonist (VKA) in 10 pregnancies (9%). Three pregnancies were complicated by thrombotic events (2.8%). Thirty-eight pregnancies (35%) were complicated by bleeding, of which 5 (13%) were severe. Most bleeds were obstetric, occurring antepartum (45%) and postpartum (42%). The use of therapeutic heparin (OR 15.6, 95% CI 1.88 to 129, p=0.006), VKA (OR 11.7, 95% CI 1.06 to 130, p=0.032) or any combination of anticoagulation medication (OR 13.0, 95% CI 1.13 to 150, p=0.032) were significantly associated with bleeding events, while ASA (OR 5.41, 95% CI 0.73 to 40.4, p=0.067) and prophylactic heparin were not (OR 4.68, 95% CI 0.488 to 44.9, p=0.096).ConclusionsCurrent antithrombotic strategies appear effective at attenuating thrombotic risk in pregnant women with a Fontan. However, this comes with high (>30%) bleeding risk, of which 13% are life threatening. Achieving haemostatic balance is challenging in pregnant women with a Fontan, necessitating individualised risk-adjusted counselling and therapeutic approaches that are monitored during the course of pregnancy.

BackgroundMobile health (mHealth) can improve quality of care and empower cardiac patients. However, large-scale adoption is still lacking, as several challenges continue to be encountered in daily practice. We aimed to explore the mHealth experiences and challenges in cardiac patients, healthcare professionals, healthcare managers and information and communications technology (ICT) developers.MethodsA qualitative research was employed where semistructured interviews were conducted in patients, healthcare professionals, managers and ICT developers. We aimed to enrol participants of every stakeholder group, with diversity in sex, age group and occupation. Thematic analysis was used to identify themes reflecting experiences and challenges in mHealth in cardiac patients.ResultsIn total, 24 interviews were conducted in six patients, eight healthcare professionals, five managers and five ICT developers. Monitoring/care at home was reported as important advantage of mHealth (n=20, 83%). Patients valued increase of self-care (n=6, 100%) and remote reassurance (n=6, 100%), but reported medicalisation as important concern (n=4, 67%). Healthcare professionals warned for increased data burden (n=4, 50%). Managers agreed on the importance of device reliability (n=5, 100%) and ICT developers emphasised that the goal of mHealth is to replace care, rather than being supplementary (n=4, 80%). The majority of all participants (n=22, 92%) considered future use of mHealth as promising.ConclusionsAll stakeholders foresee benefit of mHealth in cardiac patients, especially for remote care and reassurance. Frequently mentioned challenges included the need to replace care with mHealth, rather than adding more workload, and employing reliable devices and applications. If collaboration can be improved and group-specific challenges overcome, success of mHealth in cardiac patients can improve significantly.

To assess medication use in adult congenital heart disease (ACHD) patients compared to the age- and sex-matched general population, identify patterns of pharmacotherapy, and analyse associations between pharmacotherapy and adverse outcomes in ACHD.

ObjectiveTo study neo-aortic growth and the evolution of neo-aortic valve regurgitation (AR) in patients with transposition of the great arteries (TGA) after arterial switch operation (ASO) from newborn to adulthood and to identify patients at risk.MethodsNeo-aortic dimensions (annulus/root/sinotubular junction) and neo-aortic valve regurgitation were assessed serially in 345 patients with TGA who underwent ASO between 1977 and 2015. Linear mixed-effect models were used to assess increase of neo-aortic dimensions over time and to identify risk factors for dilatation. Risk factor analysis for AR by using time-dependent Cox regression models.ResultsAfter a rapid increase in the first year after ASO and proportional growth in childhood, neo-aortic dimensions continue to increase in adulthood without stabilisation. Annual diameter increase in adulthood was 0.39±0.06, 0.63±0.09 and 0.54±0.11 mm for, respectively, neo-aortic annulus, root and sinotubular junction, all significantly exceeding normal growth. AR continues to develop over time: freedom from AR ≥moderate during the first 25 years post-ASO was 69%. Risk factors for root dilatation were complex TGA anatomy (TGA-ventricular septal defect (VSD), double outlet right ventricle with subpulmonary VSD) and male gender. Risk factors for AR ≥moderate were: complex TGA anatomy and neo-aortic growth. Per millimetre increase in aortic root dimension, there was a 9% increase in the hazard of AR ≥moderate. Bicuspid pulmonary valve did not relate to the presence of root dilatation or AR.ConclusionAfter ASO, neo-aortic dilatation proceeds beyond childhood and is associated with an increase in AR incidence over time. Careful follow-up of the neo-aortic valve and root function is mandatory, especially in males and in patients with complex TGA anatomy.

IntroductionStudies on pregnancy risk in women with ischaemic heart disease (IHD) have mainly excluded pregnancies in women with pre-existent IHD. There is a need for better information about the pregnancy risks in these women and their offspring.MethodsWe performed a systematic review searching the PubMed/MEDLINE public database for pregnancy in women with pre-existent IHD analysing the cardiac, obstetric and fetal/neonatal outcome of pregnancy in women with pre-existing IHD. Individual patient data were requested from large series. The primary outcome endpoints was a composite of ischaemic complications including maternal death, acute coronary syndrome and ventricular tachycardia.Results116 women with pre-existent IHD had 124 pregnancies including one twin pregnancy. They had a 21% chance of having an uncomplicated pregnancy (completed pregnancy without cardiovascular, obstetric or fetal/neonatal complications, n=26). Primary (ischaemic) endpoints occurred in 9% (n=11). Women with atherosclerosis had more cardiovascular complications compared with pregnancies in women with other underlying pathology for IHD (50%vs23%, P=0.02) but no significant difference in occurrence of primary endpoints (13% vs 9%, P=0.53). There were two maternal cardiac deaths (2%), one of which occurred in the 18th week of pregnancy and the other postpartum. Obstetric complications occurred in 58% (n=65) of pregnancies and fetal/neonatal complications in 42% (n=47).ConclusionPregnancies in women with pre-existing IHD are high-risk pregnancies. These women have a high risk of ischaemic cardiovascular complications including 2% maternal mortality. The risk of ischaemic complications is especially high among women with atherosclerotic coronary artery disease.

ObjectiveLong-term prognosis of patients with coarctation of the aorta (CoA) is impaired due to the high prevalence of hypertension and consequent cardiovascular complications. Although stent implantation results in acute anatomical and haemodynamic benefit, limited evidence exists regarding the late clinical outcome. In this meta-analysis, we aimed to evaluate the medium-term effect of stent placement for CoA on systemic blood pressure (BP).MethodsPubMed, EMBASE and Cochrane databases were searched for non-randomised cohort studies addressing systemic BP ≥12 months following CoA stenting. Meta-analysis was performed on the change in BP from baseline to last follow-up using a random-effects model. Subgroup analyses and meta-regression were conducted to identify sources of heterogeneity between studies.ResultsTwenty-six studies with a total of 1157 patients and a median follow-up of 26 months were included for final analysis. Meta-analysis showed a 20.3 mm Hg (95% CI 16.4 to 24.1 mm Hg; p<0.00001) reduction in systolic BP and an 8.2 mm Hg (12 studies; 95% CI 5.2 to 11.3 mm Hg; p<0.00001) reduction in diastolic BP. A concomitant decrease in the use of antihypertensive medication was observed. High systolic BP and peak systolic gradient at baseline and stenting of native CoA were associated with a greater reduction in systolic BP at follow-up.ConclusionsStent implantation for CoA is associated with a significant decline in systolic and diastolic BP during medium-term follow-up. The degree of BP reduction appears to be dependent on baseline systolic BP, baseline peak systolic gradient, and whether stenting is performed for native or recurrent CoA.

ObjectiveTo determine factors associated with coronary artery disease (CAD) and ischaemic stroke in ageing adult congenital heart disease (ACHD) patients.MethodsWe performed a multicentre case–control study, using data from the national CONgenital CORvitia (CONCOR) registry to identify ACHD patients within five participating centres. Patients with CAD were matched (1:2 ratio) with ACHD patients without CAD on age, CHD defect group and gender. Patients with ischaemic stroke (or transient ischaemic attack) were matched similarly. Medical charts were reviewed and a standardised questionnaire was used to determine presence of risk factors.ResultsOf 6904 ACHD patients, a total of 55 cases with CAD (80% male, mean age 55.1±12.4 years) and 56 cases with stroke (46% male, mean age 46.9±15.2) were included and matched with control patients. In multivariable logistic regression analysis, traditional atherosclerotic risk factors (hypertension (OR 2.45; 95% CI 1.15 to 5.23), hypercholesterolaemia (OR 3.99; 95% CI 1.62 to 9.83) and smoking (OR 2.25; 95% CI 1.09 to 4.66)) were associated with CAD. In contrast, these risk factors were not associated with ischaemic stroke. In multivariable analysis, stroke was associated with previous shunt operations (OR 4.20; 95% CI 1.36 to 12.9), residual/unclosed septal defects (OR 2.38; 95% CI 1.03 to 5.51) and left-sided mechanical valves (OR 2.67; 95% CI 1.09 to 6.50).ConclusionsTraditional atherosclerotic risk factors were associated with CAD in ACHD patients. In contrast, ischaemic stroke was related to factors (previous shunts, septal defects, mechanical valves) suggesting a cardioembolic aetiology. These findings may inform surveillance and prevention strategies.

IMPORTANCE: Adults late after total correction of tetralogy of Fallot (TOF) are at risk for major complications. Cardiovascular magnetic resonance (CMR) imaging is recommended to quantify right ventricular (RV) and left ventricular (LV) function. However, a commonly used risk model by Khairy et al requires invasive investigations and lacks CMR imaging to identify high-risk patients. OBJECTIVE: To implement CMR imaging in noninvasive risk stratification to predict major adverse clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS: This multicenter study included 575 adult patients with TOF (4.083 patient-years at risk) from a prospective nationwide registry in whom CMR was performed. This study involved 5 tertiary referral centers with a specialized adult congenital heart disease unit. Multivariable Cox hazards regression analysis was performed to determine factors associated with the primary end point. The CMR variables were combined with the noninvasive components of the Khairy et al risk model, and the C statistic of the final noninvasive risk model was determined using bootstrap sampling. The data analysis was conducted from January to December 2016. MAIN OUTCOMES AND MEASURES: The composite primary outcome was defined as all-cause mortality or ventricular arrhythmia, defined as aborted cardiac arrest or documented ventricular fibrillation and ventricular tachycardia (lasting ≥30 seconds or recurrent symptomatic). RESULTS: Of the 575 patients with TOF, 57% were male, and the mean (SD) age was 31 (11) years. During a mean (SD) follow-up of 7.1 (3.5) years, the primary composite end point occurred in 35 patients, including all-cause mortality in 13 patients. Mean (SD) RV ejection fraction (EF) was 44% (10%), and mean (SD) LV EF was 53% (8%). There was a correlation between RV EF and LV EF (R, 0.36; 95% CI, 0.29-0.44; P &lt; .001). Optimal thresholds for ventricular function (RV EF &lt;30%: hazard ratio, 3.90; 95% CI, 1.84-8.26; P &lt; .001 and LV EF &lt;45%: hazard ratio, 3.23; 95% CI, 1.57-6.65; P = .001) were independently predictive in multivariable analysis. Both thresholds were included in a point-based noninvasive risk model (C statistic, 0.75; 95% CI, 0.63-0.85) and combined with the noninvasive components of the Khairy et al risk model. CONCLUSIONS AND RELEVANCE: In patients with repaired TOF, biventricular dysfunction on CMR imaging was associated with major adverse clinical outcomes. The quantified thresholds (RV EF &lt;30% and LV EF &lt;45%) may be implemented in noninvasive risk stratification.

BackgroundAlthough QRS duration >180 ms has prognostic value in adults with tetralogy of Fallot (TOF), its sensitivity to predict mortality is low. Fragmented QRS complexes, a simple measurement on ECG, are related to myocardial fibrosis and dysfunction in patients with TOF. Our objective was to determine whether QRS fragmentation predicts major outcomes in TOF.MethodsThis multicentre study included adult patients with TOF from a prospective registry. Notches in the QRS complex in ≥2 contiguous leads on a 12-lead ECG, not related to bundle branch block, were defined as QRS fragmentation, which was classified as none, moderate (≤4 leads) or severe (≥5 leads). The primary and secondary outcomes were all-cause mortality and clinical ventricular arrhythmia, respectively.ResultsA total of 794 adult patients with TOF (median age 27 years, 55% male; 52% no QRS fragmentation, 32% moderate, 16% severe) were included. During long-term (median 10.4 years) follow-up, 46 (6%) patients died and 35 (4%) patients had ventricular arrhythmias. Overall, 10-year survival was 98% in patients without fragmented QRS complexes, 93% in patients with moderate QRS fragmentation and 81% in patients with severe QRS fragmentation. In multivariable Cox hazards regression analysis, extent of QRS fragmentation (HR: 2.24/class, 95% CI 1.48 to 3.40, p<0.001) remained independently predictive for mortality, whereas QRS duration was not predictive (p=0.85). The extent of QRS fragmentation was also independently predictive for ventricular arrhythmia (HR: 2.00/class, 95% CI 1.26 to 3.16, p=0.003).ConclusionsThe extent of QRS fragmentation is superior to QRS duration in predicting mortality in adult patients with TOF and may be used in risk stratification.

Purpose:The genetic etiology of atrioventricular septal defect (AVSD) is unknown in 40% cases. Conventional sequencing and arrays have identified the etiology in only a minority of nonsyndromic individuals with AVSD.Methods:Whole-exome sequencing was performed in 81 unrelated probands with AVSD to identify potentially causal variants in a comprehensive set of 112 genes with strong biological relevance to AVSD.Results:A significant enrichment of rare and rare damaging variants was identified in the gene set, compared with controls (odds ratio (OR): 1.52; 95% confidence interval (CI): 1.35–1.71; P = 4.8?×?10-11). The enrichment was specific to AVSD probands, compared with a cohort without AVSD with tetralogy of Fallot (OR: 2.25; 95% CI: 1.84–2.76; P = 2.2?×?10-16). Six genes (NIPBL, CHD7, CEP152, BMPR1a, ZFPM2, and MDM4) were enriched for rare variants in AVSD compared with controls, including three syndrome-associated genes (NIPBL, CHD7, and CEP152). The findings were confirmed in a replication cohort of 81 AVSD probands.Conclusion:Mutations in genes with strong biological relevance to AVSD, including syndrome-associated genes, can contribute to AVSD, even in those with isolated heart disease. The identification of a gene set associated with AVSD will facilitate targeted genetic screening in this cohort.Genet Med 18 2, 189–198.

AbstractBackgroundPatient satisfaction with care has received little attention within the field of congenital heart disease. Our objective was to examine patient satisfaction with the care received when undergoing open-heart surgery in order to identify the best and worst aspects of peri-operative care. Moreover, we examined whether having contact with a specialised nurse in addition to usual care is associated with higher patient satisfaction levels.MethodsPatient satisfaction was measured by the Satisfaction with Hospital Care Questionnaire, evaluating nine aspects of care by answering individual items and giving overall grades. A top 10 of the best and worst items was selected. Linear regression analyses were used to examine the relationship between having contact with a specialised nurse and patient satisfaction (9 grades), independent of patient characteristics – sex, age, educational level, and health status.ResultsData were available for 75 patients. Grades ranged from 6.74 for “discharge and after care” to 8.18 for “medical care”. In all, 21% of patients were dissatisfied with the clarity of the information about lifestyle adjustments given by the surgeon. However, patients who had contact with a specialised nurse were more satisfied with the provided information (B-coefficient is 0.497, p-value is 0.038), independent of patient characteristics.ConclusionsPatients were satisfied with the received care, although there is room for improvement, especially in discharge and after care and the clarity of the information provided by the surgeon. This gap in care can be compensated for by specialised nurses, as patients who were counselled by a specialised nurse were more satisfied with the provided information.

Congenital heart disease is the most frequent of congenital disorders in newborns. Reliable epidemiological data for congenital heart disease, however, have been difficult to obtain owing to divergences in definitions, classifications, and methodologies of different studies. The authors of this Review discuss the latest changes in the epidemiology of congenital heart disease and its complications.

The aim of the study was to evaluate segmental and global right ventricular function at rest and during stress in patients having a systemic morphologically right ventricle. We studied 17 patients after atrial correction for transposition, 13 with congenitally corrected transposition, and 11 age-matched controls using cardiovascular magnetic resonance at rest and during stress with dobutamine given at 15 micrograms per kilogram per minute. Blood was drawn to obtain levels of brain natriuretic peptide. Right ventricular ejection fraction was calculated, and wall-motion and wall-thickening were assessed, in 4 segments of a midventricular slice. The findings for the systemic right ventricle were compared to the left ventricle in controls. Patients with transposition showed a decreased ejection fraction at rest (57 percent versus 69 percent, p equal to 0.005), decreased wall motion of the anterior, lateral and septal wall (p less than 0.01, p less than 0.01, and p less than 0.01) and decreased thickening of the lateral wall (p less than 0.01). Patients with congenitally corrected transposition showed normal ejection fraction, wall thickening, and wall motion at rest. During dobutamine stress, we found no significant differences in wall motion and thickening between the two groups. Ejection fraction, also increased to comparable values during stress, at 67 percent versus 66 percent, p not being significant. In both groups, we observed similarly increased levels of brain natriuretic peptide (p equal to 0.02 and 0.03, respectively). We conclude that only patients with transposition showed segmental wall motion and wall thickening abnormalities at rest. After dobutamine stress, however, segmental and global right ventricular dysfunction was similar in both groups.

Patients with congenitally corrected transposition are at risk of right ventricular dysfunction and failure. With this in mind, we examined 13 patients with congenitally corrected transposition, 7 not having undergone surgery, and 6 after physiological repair, comparing them with 6 healthy subjects matched for age and sex, using cardiac magnetic resonance imaging, at rest and during dobutamine stress, in order to determine regional and global right ventricular response to stress.At rest, the patients had significantly decreased overall wall motion compared to their healthy peers (7.2 ± 0.5, versus 9.8 ± 0.4 mm). During infusion of dobutamine, overall wall motion increased to 12.8 ± 0.4 mm in the healthy subjects, versus 8.8 ± 1.0 mm in patients. At the regional level, significant differences in mural motion were found between patients and controls in the anterior (9.5 ± 1.1, versus 13.2 ± 0.6 mm), posterior (10.2 ± 1.6, versus 13.2 ± 0.8 mm), and septal segments (5.0 ± 0.8, versus 11.2 ± 0.6 mm).At rest, overall mural thickening in patients was similar to that of controls, but significantly less in patients during stress. During dobutamine stress, patients showed significantly less regional wall thickening than controls, particularly in the septal (2.7 ± 0.6, versus 6.0 ± 0.4 mm, respectively) and in the anterior segments (4.2 ± 0.6, versus 7.8 ± 0.6 mm, respectively). Right ventricular ejection fraction strongly correlated with mural motion and thickening, both at rest and during stress.Abnormal regional function in the systemic morphologically right ventricle may occur in patients with congenitally corrected transposition, which strongly correlates with right ventricular ejection fraction. Our findings support the hypothesis that, in patients with congenitally corrected transposition, ischemia of the right ventricular myocardium contributes to the development of right ventricular dysfunction.

Right ventricular function is of great importance in patients with both acute and chronic ventricular overload. The early detection of right ventricular dysfunction may have an impact on therapeutic decision making, helping to prevent or further delay functional deterioration of the right ventricle.In patients with right ventricular overload due to congenital cardiac diseases, dobutamine stress testing combined with magnetic resonance imaging, electrocardiographic changes, and monitoring of concentrations of plasma brain natriuretic peptide are very suitable parameters for the early detection of ventricular dysfunction, and should therefore be used in the follow-up of these patients.It is apparent that no single measurement of anatomy or function can ever adequately describe the form or performance of the right ventricle. Rather, we should be looking more towards an integrated approach of different parameters for right ventricular function. The quantitative parameters described in this study can serve this purpose. The strong correlation found between these non-invasive and independent parameters encourages their clinical implementation.

Uncertainty surrounds the benefit of preventive pharmacological therapies in reducing aortic disease in patients with Marfan syndrome. The Marfan Sartan trial now suggests that losartan is not beneficial in reducing the rate of aortic dilatation—the precursor of dissections and premature death in Marfan syndrome.