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Background: Sudden cardiac death (SCD) is a major cause of mortality in adult congenital heart disease (ACHD) patients. SCD may be prevented by implantable cardioverter-defibrillator (ICD) implantation, but patient stratification remains troublesome. The 2014 Consensus Statement on Arrhythmias in ACHD patients and the 2015 European Society of Cardiology Guidelines specified recommendations for ICD implantation in ACHD patients for the first time. We assess the discriminative ability of these ICD recommendations for SCD in ACHD patients.Methods and Results: Of 25 790 ACHD patients in an international multicenter registry, we identified all SCD cases, matched to living controls by age, sex, congenital defect, and surgical repair. We assessed all primary prevention ICD recommendations listed in both documents. We used conditional logistic regression models to calculate odds ratios and receiver operating characteristic curves with area under the curve. Consensus Statement: One hundred twenty-four cases (median age at death, 33 years [26-44]; 67% men) and 230 controls were studied. In total, 41% of SCD cases and 17% of controls had an ICD recommendation (odds ratio, 5.9; P<0.001). European Society of Cardiology Guidelines: Of one hundred fifty-seven cases (median age at death, 33 years [26-48]; 64% men) and 292 controls, 35% and 14% had an ICD recommendation, respectively (odds ratio, 4.8; P<0.001).Conclusions: A minority of SCD cases had an ICD recommendation according to these guidelines, whereas the majority of SCD victims remained unrecognized. With an area under the curve of 0.6 to 0.7, the discriminative ability of both guidelines was mediocre. Critical clinical reasoning when deciding on ICD implantation in ACHD patients, therefore, remains vital. [ABSTRACT FROM AUTHOR]

Background—Exercise echocardiography is often applied as a noninvasive strategy to screen for abnormal pulmonary hemodynamic response, but it is technically challenging, and limited data exist regarding its accuracy to estimate pulmonary arterial pressure during exercise. Methods and Results—Among 65 patients with exertional intolerance undergoing upright invasive exercise testing, tricuspid regurgitation (TR) Doppler estimates and invasive measurement of pulmonary arterial pressure at rest and peak exercise were simultaneously obtained. TR Doppler envelopes were assessed for quality. Correlation, Bland–Altman, and receiveroperating characteristic curve analyses were performed to evaluate agreement and diagnostic accuracy. Mean age was 62±13 years, and 31% were male. High-quality (grade A) TR Doppler was present in 68% at rest and 34% at peak exercise. For grade A TR signals, echocardiographic measures of systolic pulmonary arterial pressure correlated reasonably well with invasive measurement at rest (r=0.72, P<0.001; bias, −2.9±8.0 mm Hg) and peak exercise (r=0.75, P<0.001; bias, −1.9±15.6 mm Hg). Lower quality TR signals (grade B and C) correlated poorly with invasive measurements overall. In patients with grade A TR signals, mean pulmonary arterial pressure-to-workload ratio at a threshold of 1.4 mm Hg/10 W was able to identify abnormal pulmonary hemodynamic response during exercise (>3.0 mm Hg/L per minute increase), with 91% sensitivity and 82% specificity (area under the curve, 0.90; 95% confidence interval, 0.77–1.0; P=0.001). Conclusions—Agreement between echocardiographic and invasive measures of pulmonary pressures during upright exercise is good among the subset of patients with high-quality TR Doppler signal. While the limits of agreement are broad, our results suggest that in those patients, sensitivity is adequate to screen for abnormal pulmonary hemodynamic response during exercise. [ABSTRACT FROM AUTHOR]

The article discusses a research which examines the effect of losartan on aortic root dilatation rate between Marfan syndrome patient with haploinsufficient FBN1 mutation and Marfan patient with an FBN1 mutation leading to a dominant negative fibrillin-1 effect. It shows that losartan significantly reduced aortic root dilatation rate only in haploinsufficient patients and not in patients with dominant negative FBN1 mutations.

The author reflects on the risk of infective endocarditis (IE) in patients with congenital heart disease (CHD). She reveals that the overall incidence of endocarditis in adults with CHD is 11% per 100,000 person. She notes on the guidelines on IE prophylaxis which emphasized the role of primary prevention. She discusses a study which reports the cumulative incidence and predictors of IE in children 0-18 years old with CHD.

The article examines the outcome of 136 adults with congenital heart disease in the Netherlands and Belgium after the implantable cardioverter defibrillator (ICD) therapy. Secondary prevention indication, symptomatic nonsustained ventricular tachycardia and coronary artery disease were linked with appropriate ICD shocks. The eight-year survival rates for low-, intermediate- and high-risk patients are also mentioned. About 29% of the patients had 45 complications associated with ICD.

The article describes the case of a 47-year-old woman who was born with tricuspid atresia with normally connected great arteries without pulmonary stenosis. She had a Fontan-Bjork procedure when she was 14-years old and at age of 38 she had atrioventricular block for which a dual-chamber pacemaker system was implanted. In the last two years she had progressive heart failure and diarrhea and was clinically diagnosed with protein-losing enteropathy (PLE). The tricuspid valve function was restored by placement of a Melody transcatheter valve.

A letter to the editor is presented in response to the article "Long-Term Nationwide Follow-up Study of Simple Congenital Heart Disease Diagnosed in Otherwise Healthy Children" by M. Olsen and others in the 2016 issue.

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., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: Marfan syndrome (MFS) is caused by mutations in FBN1 (fibrillin-1), an extracellular matrix (ECM) component, which is modified post-translationally by glycosylation. This study aimed to characterize the glycoproteome of the aortic ECM from patients with MFS and relate it to aortopathy. Approach and Results: ECM extracts of aneurysmal ascending aortic tissue from patients with and without MFS were enriched for glycopeptides. Direct N-glycopeptide analysis by mass spectrometry identified 141 glycoforms from 47 glycosites within 35 glycoproteins in the human aortic ECM. Notably, MFAP4 (microfibril-associated glycoprotein 4) showed increased and more diverse N-glycosylation in patients with MFS compared with control patients. MFAP4 mRNA levels were markedly higher in MFS aortic tissue. MFAP4 protein levels were also increased at the predilection (convexity) site for ascending aorta aneurysm in bicuspid aortic valve patients, preceding aortic dilatation. In human aortic smooth muscle cells, MFAP4 mRNA expression was induced by TGF (transforming growth factor)-β1 whereas siRNA knockdown of MFAP4 decreased FBN1 but increased elastin expression. These ECM changes were accompanied by differential gene expression and protein abundance of proteases from ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family and their proteoglycan substrates, respectively. Finally, high plasma MFAP4 concentrations in patients with MFS were associated with a lower thoracic descending aorta distensibility and greater incidence of type B aortic dissection during 68 months follow-up., Conclusions: Our glycoproteomics analysis revealed that MFAP4 glycosylation is enhanced, as well as its expression during the advanced, aneurysmal stages of MFS compared with control aneurysms from patients without MFS.

Rationale: Familial recurrence studies provide strong evidence for a genetic component to the predisposition to sporadic, nonsyndromic Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease phenotype. Rare genetic variants have been identified as important contributors to the risk of congenital heart disease, but relatively small numbers of TOF cases have been studied to date., Objective: We used whole exome sequencing to assess the prevalence of unique, deleterious variants in the largest cohort of nonsyndromic TOF patients reported to date., Methods and Results: Eight hundred twenty-nine TOF patients underwent whole exome sequencing. The presence of unique, deleterious variants was determined; defined by their absence in the Genome Aggregation Database and a scaled combined annotation-dependent depletion score of ≥20. The clustering of variants in 2 genes, NOTCH1 and FLT4, surpassed thresholds for genome-wide significance (assigned as P<5×10 -8 ) after correction for multiple comparisons. NOTCH1 was most frequently found to harbor unique, deleterious variants. Thirty-one changes were observed in 37 probands (4.5%; 95% CI, 3.2%-6.1%) and included 7 loss-of-function variants 22 missense variants and 2 in-frame indels. Sanger sequencing of the unaffected parents of 7 cases identified 5 de novo variants. Three NOTCH1 variants (p.G200R, p.C607Y, and p.N1875S) were subjected to functional evaluation, and 2 showed a reduction in Jagged1-induced NOTCH signaling. FLT4 variants were found in 2.4% (95% CI, 1.6%-3.8%) of TOF patients, with 21 patients harboring 22 unique, deleterious variants. The variants identified were distinct to those that cause the congenital lymphoedema syndrome Milroy disease. In addition to NOTCH1, FLT4 and the well-established TOF gene, TBX1, we identified potential association with variants in several other candidates, including RYR1, ZFPM1, CAMTA2, DLX6, and PCM1., Conclusions: The NOTCH1 locus is the most frequent site of genetic variants predisposing to nonsyndromic TOF, followed by FLT4. Together, variants in these genes are found in almost 7% of TOF patients.

Objective: Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin-1 gene. Patients with MFS are at risk of aortic aneurysm formation and dissection. Usually, blood pressure-lowering drugs are used to reduce aortic events; however, this is not sufficient for most patients. In the aorta of smooth muscle cell-specific sirtuin-1-deficient mice, spontaneous aneurysm formation and senescence are observed. Resveratrol is known to enhance sirtuin-1 activity and to reduce senescence, which prompted us to investigate the effectiveness of resveratrol in inhibition of aortic dilatation in the Fbn1(C1039G/+) MFS mouse model., Approach and Results: Aortic senescence strongly correlates with aortic root dilatation rate in MFS mice. However, although resveratrol inhibits aortic dilatation, it only shows a trend toward reduced aortic senescence. Resveratrol enhances nuclear localization of sirtuin-1 in the vessel wall and, in contrast to losartan, does not affect leukocyte infiltration nor activation of SMAD2 and extracellular signal-regulated kinases 1/2 (ERK1/2). Interestingly, specific sirtuin-1 activation (SRT1720) or inhibition (sirtinol) in MFS mice does not affect aortic root dilatation rate, although senescence is changed. Resveratrol reduces aortic elastin breaks and decreases micro-RNA-29b expression coinciding with enhanced antiapoptotic Bcl-2 expression and decreased number of terminal apoptotic cells. In cultured smooth muscle cells, the resveratrol effect on micro-RNA-29b downregulation is endothelial cell and nuclear factor κB-dependent., Conclusions: Resveratrol inhibits aortic root dilatation in MFS mice by promoting elastin integrity and smooth muscle cell survival, involving downregulation of the aneurysm-related micro-RNA-29b in the aorta. On the basis of these data, resveratrol holds promise as a novel intervention strategy for patients with MFS., (© 2016 The Authors.)

Background: Association between the C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene and congenital heart disease (CHD) is contentious., Methods and Results: We compared genotypes between CHD cases and controls and between mothers of CHD cases and controls. We placed our results in context by conducting meta-analyses of previously published studies. Among 5814 cases with primary genotype data and 10 056 controls, there was no evidence of association between MTHFR C677T genotype and CHD risk (odds ratio [OR], 0.96 [95% confidence interval, 0.87-1.07]). A random-effects meta-analysis of all studies (involving 7697 cases and 13 125 controls) suggested the presence of association (OR, 1.25 [95% confidence interval, 1.03-1.51]; P=0.022) but with substantial heterogeneity among contributing studies (I(2)=64.4%) and evidence of publication bias. Meta-analysis of large studies only (defined by a variance of the log OR <0.05), which together contributed 83% of all cases, yielded no evidence of association (OR, 0.97 [95% confidence interval, 0.91-1.03]) without significant heterogeneity (I(2)=0). Moreover, meta-analysis of 1781 mothers of CHD cases (829 of whom were genotyped in this study) and 19 861 controls revealed no evidence of association between maternal C677T genotype and risk of CHD in offspring (OR, 1.13 [95% confidence interval, 0.87-1.47]). There was no significant association between MTHFR genotype and CHD risk in large studies from regions with different levels of dietary folate., Conclusions: The MTHFR C677T polymorphism, which directly influences plasma folate levels, is not associated with CHD risk. Publication biases appear to substantially contaminate the literature with regard to this genetic association.

Background: Incidence and prevalence rates for pediatric pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH) are unknown. This study describes the nationwide epidemiological features of pediatric PH in the Netherlands during a 15-year period and the clinical course of pediatric PAH., Methods and Results: Two registries were used to retrospectively identify children (0-17 years) with PH. Overall, 3263 pediatric patients were identified with PH due to left heart disease (n=160; 5%), lung disease/hypoxemia (n=253; 8%), thromboembolic disease (n=5; <1%), and transient (n=2691; 82%) and progressive (n=154; 5%) PAH. Transient PAH included persistent PH of the newborn and children with congenital heart defects (CHD) and systemic-to-pulmonary shunt, in whom PAH resolved after successful shunt correction. Progressive PAH mainly included idiopathic PAH (n=36; iPAH) and PAH associated with CHD (n=111; PAH-CHD). Pulmonary arterial hypertension associated with CHD represented highly heterogeneous subgroups. Syndromes were frequently present, especially in progressive PAH (n=60; 39%). Survival for PAH-CHD varied depending on the subgroups, some showing better and others showing worse survival than for iPAH. Survival of children with Eisenmenger syndrome appeared worse than reported in adults. For iPAH and PAH-CHD, annual incidence and point prevalence averaged, respectively, 0.7 and 4.4 (iPAH) and 2.2 and 15.6 (PAH-CHD) cases per million children. Compared to studies in adults, iPAH occurred less whereas PAH-CHD occurred more frequently., Conclusions: Pediatric PH is characterized by various age-specific diagnoses, the majority of which comprise transient forms of PAH. Incidence of pediatric iPAH is lower whereas incidence of pediatric PAH-CHD is higher than reported in adults. Pediatric PAH-CHD represents a heterogeneous group with highly variable clinical courses.

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<0.0001). LVNC segregated with the 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.

Background: Gender differences in prognosis have frequently been reported in cardiovascular disease but less so in congenital heart disease. We investigated whether gender is associated with outcome in adult patients with congenital heart disease., Methods and Results: From the CONgenital CORvitia (CONCOR) national registry for adults with congenital heart disease, 7414 patients were identified. All outcomes before entry into the registry and during subsequent follow-up were recorded, and differences between men and women were analyzed with the underlying congenital heart defect taken into account. Median age at the end of follow-up was 35 years (range, 17 to 91 years); 49.8% were female. No gender difference in mortality was found. Women had a 33% higher risk of pulmonary hypertension (odds ratio [OR]=1.33; 95% CI, 1.07 to 1.65; P=0.01), a 33% lower risk of aortic outcomes (OR=0.67; 95% CI, 0.50 to 0.90; P=0.007), a 47% lower risk of endocarditis (OR=0.53; 95% CI, 0.40 to 0.70; P<0.001), and a 55% lower risk of an implantable cardioverter-defibrillator (OR=0.45; 95% CI, 0.26 to 0.80; P=0.006). Furthermore, the risk of arrhythmias appeared to be lower in women (OR=0.88; 95% CI, 0.77 to 1.02; P=0.08)., Conclusions: The risk of several major cardiac outcomes in adult patients with congenital heart disease appears to vary by gender.

Background: To facilitate the optimal timing of pulmonary valve replacement, we analyzed preoperative thresholds of right ventricular (RV) volumes above which no decrease or normalization of RV size takes place after surgery., Methods and Results: Between 1993 and 2006, 71 adult patients with corrected tetralogy of Fallot underwent pulmonary valve replacement in a nationwide, prospective follow-up study. Patients were evaluated with cardiovascular magnetic resonance both preoperatively and postoperatively. Changes in RV volumes were expressed as relative change from baseline. RV volumes decreased with a mean of 28%. RV ejection fraction did not change significantly after surgery (from 42+/-10% to 43+/-10%; P=0.34). Concomitant RV outflow tract reduction resulted in a 25% larger decrease of RV volumes. After correction for surgical RV outflow tract reduction, higher preoperative RV volumes (mL/m2) were independently associated with a larger decrease of RV volumes (RV end-diastolic volume: beta=0.41; P<0.001). Receiver operating characteristic analysis revealed a cutoff value of 160 mL/m2 for normalization of RV end-diastolic volume or 82 mL/m2 for RV end-systolic volume., Conclusions: Overall, we could not find a threshold above which RV volumes did not decrease after surgery. Preoperative RV volumes were independently associated with RV remodeling and also when corrected for a surgical reduction of the RV outflow tract. However, normalization could be achieved when preoperative RV end-diastolic volume was <160 mL/m2 or RV end-systolic volume was <82 mL/m2.