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Patients with a Fontan circulation for single-ventricle physiology are at increased risk of developing thromboembolic events. Thromboembolic events can lead to failure of the Fontan circulation, chronic sequelae in case of stroke, and early mortality. Controversies exist regarding the substrates, risk factors, and optimal detection methods for thromboembolic events. Despite the major clinical implications, there is currently no consensus regarding the optimal antithrombotic therapy to prevent or treat thromboembolic events after the Fontan procedure. In this review we aimed to untangle the available literature regarding antithrombotic prophylaxis and treatment for pediatric and adult Fontan patients. A decision-tree algorithm for thromboprophylaxis in Fontan patients is proposed. Additionally, the current state of knowledge is reviewed with respect to the epidemiology, pathophysiology, and detection of thromboembolic events in Fontan patients, and important evidence gaps are highlighted.

Background Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the Fibrillin-1 gene (FBN1). Here, we undertook the first epigenome-wide association study (EWAS) in patients with MFS aiming at identifying DNA methylation loci associated with MFS phenotypes that may shed light on the disease process. Methods The Illumina 450 k DNA-methylation array was used on stored peripheral whole-blood samples of 190 patients with MFS originally included in the COMPARE trial. An unbiased genome-wide approach was used, and methylation of CpG-sites across the entire genome was evaluated. Additionally, we investigated CpG-sites across the FBN1-locus (15q21.1) more closely, since this is the gene defective in MFS. Differentially Methylated Positions (DMPs) and Differentially Methylated Regions (DMRs) were identified through regression analysis. Associations between methylation levels and aortic diameters and presence or absence of 21 clinical features of MFS at baseline were analyzed. Moreover, associations between aortic diameter change, and the occurrence of clinical events (death any cause, type-A or -B dissection/rupture, or aortic surgery) and methylation levels were analyzed. Results We identified 28 DMPs that are significantly associated with aortic diameters in patients with MFS. Seven of these DMPs (25%) could be allocated to a gene that was previously associated with cardiovascular diseases (HDAC4, IGF2BP3, CASZ1, SDK1, PCDHGA1, DIO3, PTPRN2). Moreover, we identified seven DMPs that were significantly associated with aortic diameter change and five DMP’s that associated with clinical events. No significant associations at p –8 or p –6 were found with any of the non-cardiovascular phenotypic MFS features. Investigating DMRs, clusters were seen mostly on X- and Y, and chromosome 18–22. The remaining DMRs indicated involvement of a large family of protocadherins on chromosome 5, which were not reported in MFS before. Conclusion This EWAS in patients with MFS has identified a number of methylation loci significantly associated with aortic diameters, aortic dilatation rate and aortic events. Our findings add to the slowly growing literature on the regulation of gene expression in MFS patients.

ObjectivesPatients with Marfan syndrome (MFS) are prone to develop aortic aneurysms due to fragmentation of elastic fibres, resulting in reduced distensibility of the aorta. Reduced distensibility was previously shown to predict progressive descending aorta dilatation. Here, we investigated longitudinal changes in distensibility, as a potential predictor of aortic events.MethodsThis retrospective study included all patients with MFS with at least four cardiac magnetic resonance examinations performed between 1996 and 2012. Aortic distensibility was assessed, in the ascending (level 1), proximal descending (level 2) and distal descending (level 3) aorta. Changes in distensibility were studied using linear mixed-effects regression models.ResultsIn total, 35 patients with MFS (age at inclusion 28 (IQR 23–32) years, 54% men) were included. Mean aortic distensibility was already low (between 2.9×10–3/mm Hg/year and 6.4×10–3/mm Hg/year) at all levels at baseline, and significantly decreased over time at levels 2 and 3 (respectively, p=0.012 and p=0.002). The rate of distensibility loss per year (×10-3/mm Hg/year) was 0.01, 0.03 and 0.06×10–3/mm Hg at levels 1, 2 and 3, respectively. At inclusion, men exhibited very low distensibility, whereas women showed moderately reduced distensibility, gradually decreasing with age.Aortic dilatation rate at level 2 was associated with reduced aortic distensibility. However, we could not demonstrate a direct correlation between distensibility and clinical events during a follow-up of 22 years.ConclusionPatients with MFS display reduced aortic distensibility already at an early age, inversely relating to aortic dilatation rate. However, in this selected patient group, distensibility seems less suitable as an individual predictor of aortic events.

Objective Adult congenital heart disease (ACHD) patients are at risk of sudden cardiac death (SCD). However, methods for risk stratification are not yet well‐defined. The Tpeak‐Tend (TpTe) interval, a measure of dispersion of ventricular repolarization, is a risk factor for SCD in non‐ACHD patients. We aim to evaluate whether TpTe can be used in risk stratification for SCD in ACHD patients. Design From an international multicenter cohort of 25 790 ACHD patients, we identified all SCD cases. Cases were matched to controls by age, gender, congenital defect, and (surgical) intervention. Outcome Measures TpTe was measured on a standard 12‐lead ECG. The maximum TpTe of all ECG leads (TpTe‐max), mean (TpTe‐mean), and TpTe dispersion (maximum minus minimum) were obtained. Odds ratios (OR) for SCD cases vs controls were calculated using conditional logistic regression analysis. Results ECGs were available for 147 cases (median age at death 33.5 years (quartiles 26.2, 48.7), 66% male) and 267 controls. The mean TpTe‐max was 97 ± 24 ms in cases vs 84 ± 17 ms in controls (P

With recent advances in medical and surgical management, most patients with congenital heart disease (CHD) survive to reproductive age. Current guidelines recommend counseling about inheritance and transmission of CHD to offspring. We evaluated whether adult CHD patients recalled having received information about the inheritance of their CHD, patients' knowledge about inheritance and their concerns in this regard. A questionnaire was sent to 486 non-syndromic CHD patients aged 20-45 years. We received 332 useful questionnaires (response rate 68%). One-third (33%) of patients recalled receiving information about inheritance of CHD from their cardiologist, and 13% had consulted a clinical geneticist. Eight percent of patients who were considering having children estimated the recurrence risk for their own offspring to be 1% or lower, whereas one-fourth (25%) estimated it to be higher than 10%. According to our classification, 44% estimated the recurrence risk in a correct range of magnitude. Additional information about inheritance of CHD was desired by 41% of patients. Forty-two percent of patients considering having children reported concerns about transmitting CHD to offspring. We conclude that a substantial proportion of adult CHD patients lacks knowledge and desires more information about inheritance, indicating a need for better patient education. Current guidelines and/or their implementation do not seem to meet the needs of these patients. A dedicated program of counseling for adults with CHD has to be developed to optimize knowledge and satisfaction with information provision and to reduce or manage concerns regarding inheritance of CHD.

Congenital heart defects (CHDs) occur mostly sporadic, but familial CHD cases have been reported. Mutations in several genes, including NKX2.5, GATA4 and NOTCH1, were identified in families and patients with CHD, but the mechanisms underlying CHD are largely unknown. We performed genome-wide linkage analysis in a large four-generation family with autosomal dominant CHD (including atrial septal defect type I and II, tetralogy of Fallot and persistent left superior vena cava) and low atrial rhythm, a unique phenotype that has not been described before. We obtained phenotypic information including electrocardiography, echocardiography and DNA of 23 family members. Genome-wide linkage analysis on 12 affected, 5 unaffected individuals and 1 obligate carrier demonstrated significant linkage only to chromosome 9q21-33 with a multipoint maximum LOD score of 4.1 at marker D9S1690, between markers D9S167 and D9S1682. This 48-cM critical interval corresponds to 39 Mb and contains 402 genes. Sequence analysis of nine candidate genes in this region (INVS, TMOD1, TGFBR1, KLF4, IPPK, BARX1, PTCH1, MEGF9 and S1PR3) revealed no mutations, nor were genomic imbalances detected using array comparative genomic hybridization. In conclusion, we describe a large family with CHD and low atrial rhythm with a significant LOD score to chromosome 9q. The phenotype is representative of a mild form of left atrial isomerism or a developmental defect of the sinus node and surrounding tissue. Because the mechanisms underlying CHD are largely unknown, this study represents an important step towards the discovery of genes implied in cardiogenesis.

Item does not contain fulltext OBJECTIVE: A high prevalence of migraine has been described in various forms of congenital heart disease, with and without shunt. In this study we investigated the prevalence of migraine in patients with Marfan syndrome (MFS). METHODS: All 457 adult patients with MFS from the participating centres and 194 controls received a validated questionnaire about headache. Migraine was diagnosed according to the International Headache Society criteria, by three independent neurologists, blinded to patient files. RESULTS: Response rate was 68% and 56% in Marfan patients and controls, respectively. Forty percent of the 309 responding MFS patients (mean age 40+/-14 years; 51% females) and 28% of the 102 controls (mean age 43+/-15 years; 58% females), suffered from migraine (p=0.03). The prevalence of migraine with aura (MA) was 22% in MFS patients and 14% in controls (p=0.06). We found MFS to be an independent risk factor for having overall migraine (OR 1.7; 95%CI 1.1-2.8), also after adjustment for age and gender (OR 1.9; 95%CI 1.1-3.1; p=0.02) and for MA after adjustment for gender (OR 2.0; 95%CI 1.1-3.7; p=0.04). In patient with MFS, previous aortic root surgery appeared to be an independent risk factor for having MA (OR 2.2; 95%CI; 1.2.-4.0, p=0.01) adjusted for gender. CONCLUSION: MFS is an independent risk factor for having overall migraine and MA. Moreover, we found that a history of aortic root surgery seems to be associated with an increased risk of MA.

Vis JC, Thoonsen H, Duffels MG, de Bruin-Bon RA, Huisman SA, van Dijk AP, Hoendermis ES, Berger RM, Bouma BJ, Mulder BJ. Six-minute walk test in patients with Down syndrome: validity and reproducibility. Arch Phys Med Rehabil 2009;90:1423-7. Objectives: To examine the validity of the six-minute walk test (6MWT) as a tool to evaluate functional exercise performance in patients with Down syndrome (DS). Design: Comparison of the six-minute walk distance (6MWD) in 2 distinct groups of DS patients: with and without severe cardiac disease. To test reproducibility, a group of patients with DS performed the 6MWT twice. Setting: Tertiary referral centers for patients with congenital heart defects and outpatient clinics for people with intellectual disabilities. Participants: Adult patients with DS with (n=29) and without (n=52) severe cardiac disease categorized by cardiac echocardiography. Interventions: Not applicable. Main Outcome Measure: Distance walked on the 6MWT. Results: The mean 6MWD in the group with severe cardiac disease was 289 +/- 104m and in the group without severe cardiac disease 280 +/- 104m (P=.70). Older age, female sex, and severe level of intellectual disability were all found to be independently and significantly correlated with a lower 6MWD (r=.67, P

Contains fulltext : 51420.pdf (Publisher’s version ) (Closed access) AIMS: To investigate outcome and complications of implantable cardioverter defibrillators (ICDs) in adults with congenital heart disease (CHD) and to identify predictors of (in-) appropriate shocks. METHODS AND RESULTS: Sixty-four CHD patients >/= 18 years at first ICD implantation [63% tetralogy of Fallot (TOF) and age at implantation 37 +/- 13 years] were identified using the Dutch adult CHD registry and a Belgian tertiary care centre database. Median follow-up duration was 3.7 years. Early complications included pocket haematoma (n = 3), lead failure (n = 2), and pneumothorax (n = 2). Late complications occurred in 11 (17%) patients, including lead failure (n = 6) and and electrical storm (n = 3). Overall, 30 device-related re-interventions were performed in 20 patients (31%), including four premature generator changes and seven lead replacements. Half of the patients received one or more shocks, and 46 shocks in 15 patients (23%) were classified as appropriate. One hundred and sixty shocks in 26 patients (41%) were classified as inappropriate. No predictors of (in-)appropriate shocks were identified, except TOF being associated with less appropriate shocks than patients with other CHD (HR 0.29, P = 0.02). CONCLUSION: The ICD provided effective therapy in a quarter of adults with CHD with low complication rates. The incidence of inappropriate shocks, however, appeared to be excessive and warrants further attention.

OBJECTIVES: To evaluate our results of valve-sparing aortic root replacement and associated (multiple) valve repair. METHODS: From September 2003 to September 2013, 97 patients had valve-sparing aortic root replacement procedures. Patient records and preoperative, postoperative and recent echocardiograms were reviewed. Median age was 40.3 (range: 13.4–68.6) years and 67 (69.1%) were male. Seven (7.2%) patients were younger than 18 years, the youngest being 13.4 years. Fifty-four (55.7%) had Marfan syndrome, 2( 2.1%) otherfibrous tissue diseases, 15 (15.5%) bicuspid aortic valve and 3 (3.1%) had earlier Fallot repair. The reimplantation technique was used in all, with a straight vascular prosthesis in 11 (26–34 mm) and the Valsalva prosthesis in 86 (26–32 mm). Concomitant aortic valve repair was performed in 43 (44.3%), mitral valve repair in 10 (10.3%), tricuspid valve repair in 5 (5.2%) and aortic arch replacement in 3 (3.1%). RESULTS: Mean follow-up was 4.2±2.4 years. Follow-up was complete in all. One 14-year old patient died 1.3 years post-surgery presumably of ventricular arrhythmia. One patient underwent reoperation for aneurysm of the proximal right coronary artery after 4.9 years and 4 patients required aortic valve replacement, 3 of which because of endocarditis after 0.1, 0.8 and 1.3 years and 1 because of cusp prolapse after 3.8 years. No thrombo-embolic complications occurred. Mortality, root reoperation and aortic regurgitation were absent in 88.0±0.5% at 5-year follow-up. CONCLUSIONS: Results of valve-sparing root replacement are good, even in association with a high incidence of concomitant valve repair. Valve-sparing aortic root replacement can be performed at a very young age as long as an adult size prosthesis can be implanted.

To evaluate differences in functional parameters and reproducibility between short axis and axial slice orientation in the quantitative evaluation of the systemic right ventricle by cardiovascular magnetic resonance.Cross-sectional evaluation comparing two methods (Bland-Altman).Tertiary care outpatients.Quantitative cardiovascular magnetic resonance evaluation using short axis or axial slice orientation.Intraobserver variance, interobserver variance and systematic differences in systemic right ventricular volumes, ejection fraction, and mass between both methods.Twenty-two patients (mean age 33 ± 7 years) with systemic right ventricle (three with congenitally corrected transposition of the great arteries and 19 with atrially switched transposition of the great arteries).Compared with short axis slices, analysis of axial slices resulted in higher end systolic volume (6.6%, P.01), while mass (-10.8%, P.01) and ejection fraction (-8.9%, P.01) turned out lower. Intraobserver and interobserver reproducibility were similar for both methods when measuring end-diastolic and end-systolic volumes. However, ejection fraction and stroke volume were measured more consistently in axial orientation, while ventricular mass was measured more consistently in short axis orientation.There are significant differences in volume, mass, and function between measurements in axial and short axis orientation. Ejection fraction and stroke volume, which have a high clinical relevance, were measured more consistently in axial slice orientation. Consequently, we recommend using axial slice orientation in patients with a systemic right ventricle.

Objective Patients with repaired tetralogy of Fallot (TOF) experience increased rates of mortality and morbidity in adulthood. This study was designed to identify risk factors for death and ventricular tachycardia (VT) in a large contemporary cohort of patients with repaired TOF. Methods Subjects with repaired TOF from four large congenital heart centres in the USA, Canada and Europe were enrolled. Clinical, ECG, exercise, cardiac magnetic resonance (CMR) and outcome data were analysed. Results Of the 873 patients (median age 24.4 years), 32 (3.7%) reached the primary outcome (28 deaths, 4 sustained VT; median age at outcome 38 years; median time from CMR to outcome 1.9 years). Cox proportional-hazards regression identified RV mass-to-volume ratio >= 0.3 g/mL (HR, 5.04; 95% CI 2.3 to 11.0; p

For adult patients with congenital heart disease (CHD), knowledge about the origin and inheritance of their CHD is important. Clinical geneticists may play a significant role in their care. We explored the diagnostic yield of clinical genetic consultation of adult CHD patients, patients' motivations for the consultation, implications for reproductive decisions, patients' evaluation of the impact of provided information, and satisfaction with counseling. Chart review was performed on all adult patients referred for CHD to our clinical genetics department between 2000 and 2011 (n=90). Additionally, a questionnaire was sent to those patients referred between 2005 and 2011 (n=64), of which 46 useful questionnaires were returned (72% response). Of patients without an etiological diagnosis at referral (n=83), 17 (20%) were eventually diagnosed with syndromic CHD, 6 (7%) with nonsyndromic monogenetic CHD and 45 (54%) with nonsyndromic multifactorial CHD. The diagnosis remained undetermined in 15 (18%) patients. Half of patients who returned the questionnaire had purposefully postponed having children until after genetic consultation and 13% had changed their mind about having children or not after the consultation. Counseling was valued positively. In this study, we showed the added value of clinical genetic consultation in the care for adult CHD patients: it improves diagnostics by establishing an etiological diagnosis and associated recurrence risk in a substantial proportion of patients and leads to more informed reproductive decisions. With new genetic testing technologies an etiological diagnosis may be established in an increasing number of patients in the near future.

To assess the reproducibility of aortic volume estimates and to serially test their use in patients with Marfan syndrome.The study was approved by the medical ethics committee and all subjects gave written informed consent. In 81 patients with Marfan syndrome and seven healthy control subjects, aortic volumes and diameters at baseline were estimated by means of contrast material-enhanced magnetic resonance (MR) imaging. At 3 years of follow-up, aortic expansion rate were calculated in a subgroup of 22 patients with Marfan syndrome. Total aortic volume was defined as volume measurement from the level of the aortic annulus to the aortic bifurcation. Intra- and interobserver agreement of aortic volume were calculated by using the intraclass correlation coefficient. Differences in variables were analyzed with the Student t test and logistic regression. Effect size was calculated.Intra- and interobserver agreement of aortic volume calculation was 0.996 and 0.980, respectively. Mean aortic volume was significantly greater in patients with Marfan syndrome than in control subjects (104 mL/m(2); 95% confidence interval [CI]: 95, 114 mL/m(2) vs 74 mL/m(2); 95% CI: 62, 87 mL/m(2); P.001). In 22 patients with Marfan syndrome, mean aortic volume was increased at 3 years of follow-up (17 mL; 95% CI: 8, 26 mL; P = .001; effect size, 0.29), while mean aortic diameter did not increase significantly (0.4 mm; 95% CI: 0.0, 0.9 mm; P = .171; effect size, 0.13).Assessment of aortic volume is highly reproducible and may be suited for use in the detection of aortic expansion in patients with Marfan syndrome.http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13122310/-/DC1.

The study objectives were to analyze sex differences in hospital mortality of adult patients with congenital heart disease (CHD) and to determine the impact of health services associated with pregnancy on outcomes in women.The determinants of sex differences in the demographic distribution of CHD are poorly understood.The Quebec CHD database and the Dutch CONCOR (CONgenital CORvitia) registry were used to identify patients with CHD aged 18 to 65 years who were hospitalized between 1996 and 2005. Regression analyses were used to compare 30-day in-hospital mortality in men versus women and in women aged 18 to 45 years with versus without a pregnancy history, after adjustment for age, CHD severity, comorbidities, and admission diagnosis.Of 39,776 patients followed for 259,741 patient years, 19,099 patients (48%) had 54,195 admissions (62% among women). In those aged 18 to 45 years, 30-day in-hospital mortality was higher in men compared with women with nonpregnancy admissions (adjusted rate ratio: 1.36; 95% confidence interval: 1.02 to 1.81). The adjusted rate ratio for 30-day in-hospital mortality in women with a pregnancy history compared with those without was 0.49 (95% confidence interval: 0.24 to 0.99). A history of pregnancy was not associated with an overall increase in medical encounters.We demonstrated a protective effect of sex on in-hospital mortality in women with CHD of reproductive age that did not correlate with increased medical surveillance. Future studies need to explore other mechanisms to account for our observations. Understanding the determinants of the sex distribution of adults with CHD is important for our ability to predict demographic changes in the population with CHD.

NKX2-5 is a homeodomain-containing transcription factor implied in both heart and thyroid development. Numerous mutations in NKX2-5 have been reported in individuals with congenital heart disease (CHD), but recently a select few have been associated with thyroid dysgenesis, among which the p.A119S variation. We sequenced NKX2-5 in 303 sporadic CHD patients and 38 families with at least two individuals with CHD. The p.A119S variation was identified in two unrelated patients: one was found in the proband of a family with four affected individuals with CHD and the other in a sporadic CHD patient. Clinical evaluation of heart and thyroid showed that the mutation did not segregate with CHD in the familial case, nor did any of the seven mutation carriers have thyroid abnormalities. We tested the functional consequences of the p.A119S variation in a cellular context by performing transactivation assays with promoters relevant for both heart and thyroid development in rat heart derived H10 cells and HELA cells. There was no difference between wildtype NKX2-5 and p.A119S NKX2-5 in activation of the investigated promoters in both cell lines. Additionally, we reviewed the current literature on the topic, showing that there is no clear evidence for a major pathogenic role of NKX2-5 mutations in thyroid dysgenesis. In conclusion, our study demonstrates that p.A119S does not cause CHD or TD and that it is a rare variation that behaves equal to wildtype NKX2-5. Furthermore, given the wealth of published evidence, we suggest that NKX2-5 mutations do not play a major pathogenic role in thyroid dysgenesis, and that genetic testing of NKX2-5 in TD is not warranted.

Pulmonary arterial hypertension due to congenital heart disease (CHD-PAH) has a poor prognosis. We sought to determine whether the biomarker high-sensitivity troponin T (hsTnT) measured on routine visit at the outpatient clinic is associated with prognosis.Consecutive adult CHD-PAH (86% Eisenmenger syndrome) patients referred for advanced medical therapy between January 2005 and March 2007 in the Academic Medical Center in Amsterdam. Patients with severe renal impairment were excluded.The primary outcome was mortality.Of all 31 patients (mean age 45 ± 12 years) with CHD-PAH, eight patients died during a median follow-up of 5.6 (range 1.6 to 6.8) years. A hsTnT level0.014 μg/L was the 99th percentile cutoff of the normal distribution and therefore defined as elevated. At baseline, elevated levels of hsTnT were found in eight patients (26%). In univariate Cox regression, hsTnT elevated at baseline, NT-pro-BNP and right ventricular function were determinants of death (P.05 for all). Patients with elevated levels of hsTnT showed a significantly higher mortality rate as compared to patients with normal hsTnT levels (62% vs. 13%, P = .005).Levels of hsTnT were abnormal in a substantial proportion of CHD-PAH patients. A significant inverse relationship was found between hsTnT and survival.

Identification of adults with congenital heart disease (CHD) who were lost to cardiological follow-up.Cross-sectional study.Adults with CHD and not under cardiological follow-up were asked via a nationwide publicity campaign to contact the CONCOR (CONgenital CORvitia) project group.A total of 593 patients with mild (85%) to moderate-severe (15%) CHD were registered via the nationwide campaign. Of these patients, 66% were examined within 1 year by a cardiologist. Additional cardiac follow-up was necessary within 1 year in 22% of these patients. In 16% of the patients, new residual lesions were found; and in three of these patients the pulmonary valve required replacement.During this comprehensive nationwide campaign it became clear that a considerable number of adults with CDH fail to receive regular cardiac care. However, after surgical correction of CHD in childhood, residual lesions are common in this population. Threatening residual lesions can be present asymptomatically. Cardiological follow-up is therefore almost always necessary, also in patients without symptoms. Patients with CHD as well as their medical care personnel need to be well informed of this.

A first step in the delivery of tailored care is answering the following question: does health care meet the needs of patients? Therefore patients' perspective on health care use and their needs was examined. The design used was cross-sectional questionnaire study.A total of 1109 adult congenital heart defect (CHD) patients attending one of eight Dutch hospitals were randomly selected from a national database (10% of all registered patients).Patient reported questionnaires on in- and outpatient health care use during the past year and need for additional care.A total of 66% and 40% of patients had contact with their cardiologist and general practitioner, respectively. Six to 10 percent were hospitalized, operated upon, or visited the emergency room. For the majority, the amount of contact was sufficient. Most patients indicated that the communication skills and expertise of the cardiologist and general practitioner were sufficient, and health care improvements were not necessary. Frequent health care users had a poor functional status and frequent contact with their cardiologist and general practitioner. Patients who want more contact with their cardiologist rated the communication skills of the cardiologist as insufficient.For most patients, the amount and quality of care are both sufficient. Patients who rate the communication skills of the cardiologist as insufficient have need more contact. In addition to the recommended training program as described in the American College of Cardiology/American Heart Association (ACC/AHA) and European Society of Cardiology (ESC) guidelines, we recommend the incorporation of communication training. This is the first study to provide insight into health care use and needs of CHD patients in countries with a compulsory health insurance system from the patient perspective.

Background— Ebstein anomaly is a rare congenital heart malformation characterized by adherence of the septal and posterior leaflets of the tricuspid valve to the underlying myocardium. An association between Ebstein anomaly with left ventricular noncompaction (LVNC) and mutations in MYH7 encoding β-myosin heavy chain has been shown; in this report, we have screened for MYH7 mutations in a cohort of probands with Ebstein anomaly in a large population-based study. Methods and Results— Mutational analysis in a cohort of 141 unrelated probands with Ebstein anomaly was performed by next-generation sequencing and direct DNA sequencing of MYH7 . Heterozygous mutations were identified in 8 of 141 samples (6%). Seven distinct mutations were found; 5 were novel and 2 were known to cause hypertrophic cardiomyopathy. All mutations except for 1 3-bp deletion were missense mutations; 1 was a de novo change. Mutation-positive probands and family members showed various congenital heart malformations as well as LVNC. Among 8 mutation-positive probands, 6 had LVNC, whereas among 133 mutation-negative probands, none had LVNC. The frequency of MYH7 mutations was significantly different between probands with and without LVNC accompanying Ebstein anomaly ( P MYH7 mutation in the pedigrees of 3 of the probands, 1 of which also included another individual with Ebstein anomaly. Conclusions— Ebstein anomaly is a congenital heart malformation that is associated with mutations in MYH7 . MYH7 mutations are predominantly found in Ebstein anomaly associated with LVNC and may warrant genetic testing and family evaluation in this subset of patients.

Ventricular systolic and diastolic function, as measured by echocardiography, are diminished in patients with a systemic right ventricle (RV). As the clinical implications of these finding remained unknown, we aimed to identify echocardiographic parameters of systolic and diastolic ventricular function that are independent determinants of the clinical condition in these patients.Forty-six adult patients (61% male; mean age 33 [range 18-69] years) with a systemic RV underwent echocardiography to assess qualitative and quantitative systolic and diastolic function of the systemic RV and the subpulmonary left ventricle (LV). Uni- and multivariate linear regression analyses were performed to identify independent echocardiographic determinants for NYHA class, maximal exercise capacity (V'O(2peak)) and NT-proBNP levels.We found qualitative assessment of RV and LV function to be significantly associated with NYHA class (RV: β= 0.26; P = 0.05 and LV: β= 0.82; P0.01), V'O(2peak) (RV: β=-10.4; P0.05 and LV: β=-18.4; P0.05) and NT-proBNP levels (RV: β= 0.58; P0.01 and LV: β= 1.40; P0.001). Tricuspid annulus plane systolic excursion (TAPSE) was significantly associated with NYHA class (β=-0.92; P = 0.001), V'O(2peak) (β= 18.5; P = 0.05), and serum NT-proBNP levels (β=-1.00; P0.05). Associations between quantitative parameters of systolic subpulmonary LV function and clinical parameters were less distinct. We found no associations between RV and LV diastolic function and clinical parameters.Qualitative function of the systemic RV and the subpulmonary LV, and TAPSE, are determinants of clinical condition in patients with a systemic RV. These patients' clinical condition could not be determined by echocardiographically measured diastolic RV function, and systolic and diastolic LV function.

Contains fulltext : 89235.pdf (Publisher’s version ) (Closed access) AIMS: Mortality in adults with congenital heart disease is known to be increased, yet its extent and the major mortality risks are unclear. METHODS AND RESULTS: The Dutch CONCOR national registry for adult congenital heart disease was linked to the national mortality registry. Cox's regression was used to assess mortality predictors. Of 6933 patients, 197 (2.8%) died during a follow-up of 24 865 patient-years. Compared with the general national population, there was excess mortality, particularly in the young. Median age at death was 48.8 years. Of all deaths, 77% had a cardiovascular origin; 45% were due to chronic heart failure (26%, age 51.0 years) or sudden death (19%, age 39.1 years). Age predicted mortality, as did gender, severity of defect, number of interventions, and number of complications [hazard ratio (HR) range 1.1-5.9, P < 0.05]. Several complications predicted all-cause mortality beyond the effects of age, gender, and congenital heart disease severity, i.e. endocarditis, supraventricular arrhythmias, ventricular arrhythmias, conduction disturbances, myocardial infarction, and pulmonary hypertension (HR range 1.4-3.1, P < 0.05). These risks were similar in patients above and below 40 years of age. Almost all complications predicted death due to heart failure (HR range 2.0-5.1, P < 0.05); conduction disturbances and pulmonary hypertension predicted sudden death (HR range 2.0-4.7, P < 0.05). CONCLUSION: Mortality is increased in adults with congenital heart disease, particularly in the young. The vast majority die from cardiovascular causes. Mortality risk, particularly by heart failure, is increased by virtually all complications. Complications are equally hazardous in younger as in older patients. 01 mei 2010

The aim of this study was to analyze whether QRS duration, before and after pulmonary valve replacement (PVR), is related to long-term outcome in patients with tetralogy of Fallot (TOF).Key factors that determine outcome after PVR in adult TOF patients are largely unknown. Recognition of such factors assists the identification of patients at increased risk of adverse events.Adults who previously underwent total correction for TOF (n=90; age 31.4±10.3 years) and required PVR for pulmonary regurgitation were included. The QRS duration was measured pre-operatively and 6 months after PVR. The post-operative changes in QRS duration were calculated. Adverse events (death, re-PVR, ventricular tachycardia, and symptomatic heart failure) were noted during follow-up.During 5.5±3.5 years of follow-up, 13 adverse events occurred. The 5-year event-free survival rate was 76% for patients with a pre-operative QRS duration180 ms and 90% in patients with a QRS duration≤180 ms (p=0.037). For patients with a post-operative QRS duration180 ms, 5-year event-free survival was 71%, whereas it was 91% for patients with a post-operative QRS duration≤180 ms (p=0.004). After multivariate correction, a post-operative QRS duration180 ms (hazard ratio: 3.685, 95% confidence interval: 1.104 to 12.304, p0.05) and the absence of a reduction in QRS duration post-PVR (hazard ratio: 6.767, 95% confidence interval: 1.704 to 26.878, p0.01), was significantly associated with adverse outcome.Severe QRS prolongation, before or after PVR, and the absence of a reduction in QRS duration after PVR, are major determinants of adverse outcome during long-term follow-up of patients with TOF.

Background: Previous studies have shown that patients with congenital heart disease (ConHD) report a diminished health-related quality of life. Purpose: This study examines the mechanisms by which ConHD affects health-related quality of life. We hypothesize that (1) the relation between trait anxiety and quality of life is mediated by a negative interpretation bias for heart sensations, specifically in ConHD, and that (2) the relation between trait anxiety, and interpretation bias is mediated by state anxiety. Method: Sixty-six patients with ConHD and 50 healthy participants read a vignette about a person experiencing ambiguous heart-related sensations. Interpretation bias to these sensations was assessed with the Implicit Models of Illness Questionnaire. Participants completed Spielberger trait and state anxiety questionnaires and the physical subscales of a quality-of-life questionnaire. Results: Path-analysis demonstrated that interpretation bias mediated the relation between trait anxiety and daily functioning. However, trait anxiety and interpretation bias were less influential with respect to gross motor functioning. Moreover, state anxiety mediated the relation between trait anxiety and interpretation bias. Conclusion: These results suggest that patients with ConHD who display both elevated levels of trait and state anxiety exhibit the most pronounced negative interpretation bias for heart sensations and in turn diminished daily functioning.

To delineate the risk factors for rupture of congenital aneurysmal fistulas in adult patients.We conducted a literature search of the Medline database using Pubmed search interface to identify reports dealing with rupture of congenital aneurysmal fistulas in an adult population. The search included the English and non-English languages between 1963 and 2005.Fourteen adult patients (12 females) with serious and life-threatening complications secondary to aneurysmal fistulas were reported. Mean age was 62.9 years. The ethnic origins of these 14 patients were 9 Asian and 5 Caucasian. Most patients have had no other cardiac malformations. Five patients had a history of hypertension. One patient was asymptomatic. In 13 symptomatic patients, the clinical presentation was cardiac tamponade, pericardial effusion, syncope, heart failure, chest pain, dyspnea, fatigue, distal thromboembolic events with infarction, shock, and/or sudden death. Aneurysmal fistulas were identified in 10 patients; of these 6 were of the saccular type. Rupture occurred in 9 patients (8 females and 1 male). Eleven patients were treated surgically with 1 late death. Two male subjects experienced sudden unexpected cardiac death.Rupture of congenital aneurysmal fistulas occurred more often in females. Identified risk factors for rupture, hemopericardium, tamponade, and death were among others saccular aneurysm, Asian ethnic race, origin of the aneurysmal fistulas from the left coronary artery and a history of hypertension may play a role. In this article, we present a literature review of congenital aneurysmal fistulas associated with or without rupture and a case report of a woman with unruptured aneurysmal fistula.

A search of peer-reviewed literature was conducted to identify reports that provide data on complications associated with pregnancy in women with structural congenital heart disease (CHD). This review describes the outcome of 2,491 pregnancies, including 377 miscarriages (15%) and 114 elective abortions (5%). Important cardiac complications were seen in 11% of the pregnancies. Obstetric complications do not appear to be more prevalent. In complex CHD, premature delivery rates are high, and more children are small for gestational age. The offspring mortality was high throughout the spectrum and was related to the relatively high rate of premature delivery and recurrence of CHD.

Contains fulltext : 71123.pdf (Publisher’s version ) (Closed access) BACKGROUND: Pregnancy in women with congenital aortic stenosis (AS) is associated with increased cardiac complications. Data on non-cardiac complications are limited, and this information is crucial for prenatal counselling and perinatal care. The aim of this study was to present the maternal and perinatal outcome of pregnancy in women with congenital AS. METHODS: By review of the Dutch CONCOR national registry and a local Belgian tertiary care centre database, 35 women with congenital AS with a history of completed pregnancy before aortic valve replacement were enrolled in this study. Medical history and maternal and perinatal outcome were determined. RESULTS: Thirty-five women had 58 pregnancies resulting in 53 successful pregnancies, three miscarriages, and two abortions. The most serious cardiac complications were heart failure (n=2, 3.8%) and atrial arrhythmia (n=3, 5.7%). Although cardiac complications were present (9.4%), obstetric (22.6%) and perinatal (24.5%) complications were observed more often. A total of six pregnancies (11.3%) were complicated by hypertension-related disorders, including one case of eclampsia. Furthermore, 7 premature births (13.2%) and 7 small-for-gestational-age births (13.2%) were encountered. Pregnancy in women with severe AS was characterized by an increased incidence of heart failure and premature labour, and shorter pregnancy duration. Older women (>30 years) were at increased risk of perinatal events (odds ratio 4.38, 95% confidence interval 1.02 to 18.81). CONCLUSIONS: Pregnancy is generally well tolerated in women with congenital AS. Importantly, an excess of obstetric and perinatal complications was found, requiring more meticulous attention.

PURPOSE: To evaluate retrospectively the presence of fibrosis and largest diameter of the right ventricular outflow tract (RVOT) by using delayed enhancement magnetic resonance (MR) imaging in patients who had undergone initial correction for tetralogy of Fallot. MATERIALS AND METHODS: MR imaging was performed in 24 consecutive patients (16 male, eight female; mean age, 25 years; age range, 13-47 years) with corrected tetralogy of Fallot. The study protocol was approved by the local ethics committee, and informed consent was not required. Fifteen minutes after injection of 0.2 mmol/kg gadopentetate dimeglumine, an inversion-recovery turbo field-echo sequence was applied for detection of delayed enhancement. Right ventricular volumes, ejection fraction, and anterior-posterior diameter of the RVOT were calculated. Mann-Whitney nonparametric testing was used to compare measurements of ventricular volume, function, and anterior-posterior diameter of the RVOT in the presence or absence of delayed enhancement. Correlation was tested with Pearson coefficient. RESULTS: Delayed enhancement was seen in 17 patients in the RVOT. During initial surgery, transannular patching was performed in 13 (76%) of 17 patients, RVOT patching in one (6%) of 17 patients, and the Brock procedure in two (12%) of 17 patients. In one patient, the type of initial RVOT repair was unknown. Patients with delayed enhancement in the RVOT, as compared with those without delayed enhancement in the RVOT, had increased RVOT diameter (32 mm +/- 7 [standard deviation] vs 22 mm +/- 3, P < .01), decreased right ventricular ejection fraction (43% +/- 6.3 vs 54% +/- 10, P < .001), and increased end-diastolic volume (175 mL/m2 +/- 42 vs 118 mL/m2 +/- 34, P < .01). The diameter of the RVOT correlated with increased right ventricular end-systolic volume (R = 0.86) and was inversely related to ejection fraction (R = -0.65). CONCLUSION: Delayed enhancement occurs frequently in patients after correction for tetralogy of Fallot. Delayed enhancement in the RVOT was associated with RVOT dilatation, which adversely affects right ventricular hemodynamics

Introduction: Survival of patients with congenital heart disease has dramatically improved after surgical repair became available 40 years ago. Instead of a mortality of 85% during childhood following the natural course, over 85% of these infants are now expected to reach adulthood. However, data on long-term outcome is scarce due to the lack of large, national registries. Moreover, little is known about the genetic basis of congenital heart defects. In 2000, the Interuniversity Cardiology Institute of the Netherlands and the Netherlands Heart Foundation have taken the initiative to develop a national registry and DNA-bank of patients with congenital heart disease in the Netherlands named CONCOR. Objectives: The aims of the CONCOR project are to facilitate investigation of the prevalence and long-term outcome of specific congenital heart defects and their treatment, to develop an efficient organisational structure for the improvement of healthcare for patients with congenital heart disease, and to allow investigation of the molecular basis of congenital heart defects. Methods: After informed consent, research nurses enter data of participating patients into the CONCOR database using a web application. Data is transferred over the Internet via a secure connection. About 20 ml blood is withdrawn from the patient, and the DNA is isolated and stored. From each participating patient family history on congenital heart disease is obtained. Results: Within two and a half years more than 4200 patients have agreed to participate. More than 99% of the patients that were asked have given their consent to participate in CONCOR. From 60% of these patients DNA has already been obtained. Mean age of the patients included is 34 years; more than 85% of the patients are younger than 45 years. Late complications occur frequently and the incidence increases with advancing age. 18% of the patients are known with supraventricular or ventricular arrhythmias. 2% of the included patients suffered a cerebrovascular accident, 139 (3%) had endocarditis. 6% of the patients has pulmonary hypertension or Eisenmenger syndrome. More than 15% of the patients reported an affected family member with congenital heart disease in the first, second, or third degree. 6% has an affected first-degree relative, and 4% a second-degree relative. Already 10 research projects have started using the CONCOR data and DNA. Conclusion: The population of patients with congenital heart disease is young and rapidly growing. Late complications occur frequently and the incidence increases with advances age. The CONCOR registry and DNA-bank facilitates research on prevalence and long-term outcome and allows investigation of the molecular basis of congenital heart disease