BACKGROUND:Pregnancy in women with a Fontan circulation carries increased risk. Given the relative evidence void, pregnancy counseling requires considerable nuance and experience. OBJECTIVES:This study aimed to identify risk factors for maternal and fetal complications and to contrast risk estimates obtained from existing risk stratification tools, including the modified WHO, CARPREG II, and ZAHARA risk scores. METHODS:Pregnant women (>20 weeks of gestation) with a Fontan circulation were retrospectively included from 13 international centers. Univariate and multivariable analyses identified predictors of complications, and the performance of risk stratification tools was assessed. RESULTS:From 2006 to 2018, 84 women with Fontan physiology had 108 pregnancies, and form the basis of this investigation. Maternal cardiovascular complications occurred in 32 (30%) of all pregnancies including Fontan circulatory failure (17%), supraventricular tachycardia (7.4%), and thromboembolic events (3.7%). No maternal deaths occurred. Premature birth constituted 68% of neonatal complications, with a fetal and neonatal mortality of 13%. Multivariable analysis linked adverse maternal outcomes to pre-pregnancy oxygen saturation (adjusted OR 0.77; 95%CI 0.61-0.96; p=0.02). None of the risk models showed good discriminative ability. The modified WHO classification was the only risk model significantly associated with adverse fetal outcomes. CONCLUSIONS:Pregnancy in women with Fontan circulation poses a significant cardiovascular risk for the mother and a high burden of fetal and neonatal complications. The existing predictive risk stratification models do not discriminate hazard between well-functioning patients with Fontan from those with additional hemodynamic burden. This underscores the necessity for large-scale studies to refine risk stratification.

BACKGROUND:New treatment strategies are required to reduce aortic events in Marfan syndrome (MFS). Resveratrol is a dietary supplement that intervenes in aortic wall cellular metabolism and may benefit MFS patients. PURPOSE:To evaluate whether treatment with Resveratrol affects aorta hemodynamics derived from 4D flow MRI in MFS. STUDY TYPE:Prospective single-arm open-label multicenter trial. POPULATION:46 MFS patients (mean age 36 ± 9 years, 23 female), 20 with and 26 without a history of aortic root surgery (RR and native MFS), and 25 age- and sex-matched healthy controls. FIELD STRENGTH/SEQUENCE:3T, temporally resolved 3D phase contrast (4D flow MRI) and 3D mDixon sequences. ASSESSMENT:MFS patients underwent 4D flow MRI before (baseline) and after 1 year of 500 mg daily Resveratrol treatment (follow-up). Velocity magnitude and wall shear stress (WSS) in six regions in the thoracic aorta were evaluated. Incidence maps showing abnormal hemodynamics compared to healthy controls were generated. Pulse wave velocity (PWV) was assessed in 45 subjects. The relationships between MRI parameters and annual aortic growth from the 3D mDixon scans and age were investigated. STATISTICAL TESTS:Student's paired and unpaired t-tests, Fisher's exact tests, McNemar's exact test, and Pearson correlation coefficients (r). Statistical significance was defined as p < 0.05. RESULTS:No significant changes in any of the hemodynamic parameters were observed: inner descending aorta WSS (Pa), native: from 1.08 ± 0.21 to 1.08 ± 0.17, p = 0.818, RR: from 1.02 ± 0.29 to 0.98 ± 0.21, p = 0.270; velocity (m/s), native: from 0.64 ± 0.10 to 0.65 ± 0.10, p = 0.359, RR: 0.68 ± 0.15, to 0.67 ± 0.12, p = 0.629; abnormally directed WSS incidence: native: from 17 (65%) to 14 (54%), p = 0.453, RR: 13 (65%) to 13 (65%), p = 1.000; PWV (m/s) native: from 7.7 ± 1.9 to 7.9 ± 1.8, p = 0.582, RR: 9.2 ± 1.6 to 8.2 ± 3.2, p = 0.184. PWV correlated with age in RR MFS patients (r = 0.59, n = 19). DATA CONCLUSION:No significant changes in aortic hemodynamics derived from 4D flow MRI were observed after 1 year of Resveratrol treatment. EVIDENCE LEVEL:1. TECHNICAL EFFICACY:Stage 4.

Background:The number of patients with an arterial switch operation (ASO) for transposition of the great arteries (TGA) is steadily growing; limited information is available regarding the clinical course in the current era. Objectives:The purpose was to describe clinical outcome late after ASO in a national cohort, including survival, rates of (re-)interventions, and clinical events. Methods:A total of 1,061 TGA-ASO patients (median age 10.7 years [IQR: 2.0-18.2 years]) from a nationwide prospective registry with a median follow-up of 8.0 years (IQR: 5.4-8.8 years) were included. Using an analysis with age as the primary time scale, cumulative incidence of survival, (re)interventions, and clinical events were determined. Results:At the age of 35 years, late survival was 93% (95% CI: 88%-98%). The cumulative re-intervention rate at the right ventricular outflow tract and pulmonary branches was 36% (95% CI: 31%-41%). Other cumulative re-intervention rates at 35 years were on the left ventricular outflow tract (neo-aortic root and valve) 16% (95% CI: 10%-22%), aortic arch 9% (95% CI: 5%-13%), and coronary arteries 3% (95% CI: 1%-6%). Furthermore, 11% (95% CI: 6%-16%) of the patients required electrophysiological interventions. Clinical events, including heart failure, endocarditis, and myocardial infarction occurred in 8% (95% CI: 5%-11%). Independent risk factors for any (re-)intervention were TGA morphological subtype (Taussig-Bing double outlet right ventricle [HR: 4.9, 95% CI: 2.9-8.1]) and previous pulmonary artery banding (HR: 1.6, 95% CI: 1.0-2.2). Conclusions:TGA-ASO patients have an excellent survival. However, their clinical course is characterized by an ongoing need for (re-)interventions, especially on the right ventricular outflow tract and the left ventricular outflow tract indicating a strict lifelong surveillance, also in adulthood.

The European Society of Cardiology guidelines for the management of adult congenital heart disease patients recommend screening for arrhythmias and bradycardias in symptomatic patients, often being done by means of an ambulatory 24-48 -hour Holter or implantable loop recorder (ILR). However, nowadays non-invasive instruments, such as patches, smartwatches and smartphones based on single -lead ECGs that perform extended monitoring, are also available. The aim of this narrative review was to assess whether these instruments, when they detect arrhythmias and bradycardias in patients with adult congenital heart disease, will lead to meaningful changes in clinical care. Clinically meaningful changes include adjustment of medication, cardioversion, electrophysiology study, ablation or implantation of a cardiovascular implantable electronic device. The following monitoring instruments are discussed: cumulative Holter, 2 -week continuous monitor, smartwatchand smartphone-based single -lead ECG, and ILR. The diagnostic yield of extended rhythm monitoring is high, and varies between 18% (smartphone-based single -lead ECG) and 41% with ILR. In conclusion, contemporary arrhythmia screening includes various new non-invasive technologies that are promising new tools as an alternative to Holter monitoring or ILR. However, the optimal mode of detection is still unclear due to the lack of head -to -head comparisons.

Background: Systemic right ventricular (sRV) physiology occurs in patients with congenitally corrected transposition of the great arteries (ccTGA) and D-TGA post atrial switch repair, and the natural history is of progressive sRV dysfunction. No study has assessed longitudinal changes in sRV remodeling by serial cardiovascular magnetic resonance (CMR). Methods: Patients evaluated at two adult congenital heart disease centers and who underwent >= 2 CMR exams were studied. Indexed sRV end-diastolic volume (sRVEDVi), end-systolic volume (sRVESVi), and ejection fraction (sRVEF) were determined by a core laboratory. Concurrent echocardiograms were assessed for degree of systemic tricuspid regurgitation (sTR). Tricuspid valve events were defined as >= moderate sTR, or interval tricuspid valve replacement (TVR). Generally, the earliest and most recent studies were compared. A subset of patients were followed with >= moderate sTR, and then subsequently underwent interval TVR. For these patients, two study time intervals were defined to analyze the impact of each event independently. Results: Sixty-seven patients were studied (33 +/- 11 years, 48% [32/67] male, 33% [22/67] ccTGA), with 72 total time intervals studied (median interval 9.0 years [interquartile range 4.6-13.3]). There was a small increase in sRVEDVi over time (AsRVEDVi 5.5 +/- 15.8 mL/m2, p < 0.001), but mean change in sRVEF was not significant (AsRVEF 0.1 +/- 6.9%, p = 0.86); notably, confidence intervals (CI) were wide for both. ccTGA patients had a trend toward greater decrement in sRVEF (AsRVEF -1.7 +/- 6.8 vs 1.3 +/- 6.7%, p = 0.06). For each 25 mL/m2 increase in baseline sRVEDVi, there was a 1.8% decrease in sRVEF (95% CI -3.2% to -0.5%, p = 0.01). Patients without significant sTR had lesser deterioration in sRVEF compared to those with >= moderate sTR or with interval TR intervention (AsRVEF 1.8 +/- 6.9% vs -2.1 +/- 6.6% and -2.6 +/- 4.5, p < 0.05). Interval sRV conduction delay was associated with a trend toward greater decrements in sRVEF (AsRVEF -3.9 +/- 6.3 vs 0.9 +/- 6.8%, p = 0.07). Overall, underlying congenital anatomy, baseline sRVEDVi, advanced sTR or interval TVR, and sRV conduction delay explained only 16% of the variability in AsRVEF over time. Conclusion: Longitudinal changes in sRV remodeling were small, with great heterogeneity. Apparent risk factors in our study, namely underlying congenital anatomy, baseline sRVEDVi, TR events, and sRV conduction disease accounted for only 16% of the variability seen in the longitudinal change of sRVEF.

BACKGROUND:In patients with transposition of the great arteries and an arterial switch operation (TGA-ASO) right ventricular outflow tract (RVOT) obstruction is a common complication requiring one or more RVOT interventions. OBJECTIVES:We aimed to assess cardiopulmonary exercise capacity and right ventricular function in patients stratified for type of RVOT intervention. METHODS:TGA-ASO patients (≥16 years) were stratified by type of RVOT intervention. The following outcome parameters were included: predicted (%) peak oxygen uptake (peak VO2), tricuspid annular plane systolic excursion (TAPSE), tricuspid Lateral Annular Systolic Velocity (TV S'), right ventricle (RV)-arterial coupling (defined as TAPSE/RV systolic pressure ratio), and N-terminal proBNP (NT-proBNP). RESULTS:447 TGA patients with a mean age of 25.0 (interquartile range (IQR) 21-29) years were included. Patients without previous RVOT intervention (n = 338, 76%) had a significantly higher predicted peak VO2 (78.0 ± 17.4%) compared to patients with single approach catheter-based RVOT intervention (73.7 ± 12.7%), single approach surgical RVOT intervention (73.8 ± 28.1%), and patients with multiple approach RVOT intervention (66.2 ± 14.0%, p = 0.021). RV-arterial coupling was found to be significantly lower in patients with prior catheter-based and/or surgical RVOT intervention compared to patients without any RVOT intervention (p = 0.029). CONCLUSIONS:TGA patients after a successful arterial switch repair have a decreased exercise capacity. A considerable amount of TGA patients with either catheter or surgical RVOT intervention perform significantly worse compared to patients without RVOT interventions.

BACKGROUND:Resveratrol, a dietary supplement that intervenes in cellular metabolism, has been shown to reduce aortic growth rate in a mouse model of Marfan syndrome (MFS), a condition associated in humans with life-threatening aortic complications, often preceded by aortic dilatation. The primary objective of this study was to investigate the effects of resveratrol on aortic growth rate in patients with MFS . METHODS:In this investigator-initiated, single-arm open-label multicentre trial, we analysed resveratrol treatment in adults aged 18-50 years with MFS. The primary endpoint was the change in estimated annual aortic growth at five predefined levels in the thoracic aorta after 1 year of resveratrol treatment, evaluated using a linear mixed model. Aortic diameters were measured by cardiac MRI at three time points to analyse the annual aortic expansion rate before and after initiation of treatment. Additionally, annual aortic growth was compared with growth in a previously conducted losartan randomised clinical trial. RESULTS:898 patients were screened of which 19% (168/898) patients met the inclusion criteria.36% (61/168) patients signed informed consent and 93% (57/61) aged 37±9 years, of which 28 males (49%) were included in the final analysis of the study. 46% (26/57) had undergone aortic root replacement prior to the study. Aortic root diameters remained stable after 1.2±0.3 years of resveratrol administration. A trend towards a decrease in estimated growth rate (mm/year) was observed in the aortic root (from 0.39±0.06 to -0.13±0.23, p=0.072), ascending aorta (from 0.40±0.05 to -0.01±0.18, p=0.072) and distal descending aorta (from 0.32±0.04 to 0.01±0.14, p=0.072). CONCLUSION:Resveratrol treatment for 1 year may stabilise the aortic growth rate in adult patients with MFS. However, a subsequent randomised clinical trial with a longer follow-up duration and a larger study cohort is needed to establish an actual long-term beneficial effect of this dietary supplement in patients with MFS. TRIAL REGISTRATION NUMBER:NL66127.018.18.

The European guidelines advocate a goal-oriented treatment approach in pulmonary arterial hypertension (PAH), based on a comprehensive risk assessment instrument, which has been validated in several PAH subgroups. We investigated its discriminatory ability and explored tricuspid annular plane systolic excursion and revised thresholds to improve its predictability within the adult congenital heart disease (CHD) population. In total, 223 adults (42 ± 16 years, 66% women, 68% Eisenmenger) were enrolled from 5 European PAH-CHD expert centers. Patients were classified as low, intermediate, or high risk at the baseline visit and at follow-up within 4 to 18 months. By the general PAH guidelines instrument, survival did not differ between the risk groups (p-value not significant), mostly because of the skewed group distribution. Reclassifying patients using revised thresholds for N-terminal pro-brain natriuretic peptide and 6-minute walk distance (i.e., low, intermediate, and high as <500, 500 to 1,400, >1,400 ng/L and >400, and 165 to 400 and <165 m, respectively) and use of tricuspid annular plane systolic excursion (low, intermediate, and high as >20, 16 to 20, and <16 mm, respectively) significantly improved the discrimination between the risk groups at baseline and follow-up (p = 0.001, receiver operating characteristic increase from 0.648 to 0.701), reclassifying 64 patients (29%). Irrespective of follow-up risk group, survival was better for patients with higher proportions of low-risk variables. Improvement to a low-risk profile at a median of 9 months of follow-up provided improved survival compared with the survival of patients who remained in the low-risk group. In conclusion, the external validity of general risk instrument for PAH appeared to be of limited discriminatory value in patients with PAH-CHD. We propose a refined risk instrument with improved discrimination for PAH-CHD.

Background Robust risk assessment is crucial for the growing repaired tetralogy of Fallot population at risk of major adverse clinical outcomes; however, current tools are hindered by lack of validation. This study aims to develop and validate a risk prediction model for death in the repaired tetralogy of Fallot population. Methods and Results Patients with repaired tetralogy of Fallot enrolled in the INDICATOR (International Multicenter Tetralogy of Fallot Registry) cohort with clinical, arrhythmia, cardiac magnetic resonance, and outcome data were included. Patients from London, Amsterdam, and Boston sites were placed in the development cohort; patients from the Toronto site were used for external validation. Multivariable Cox regression was used to evaluate factors associated with time from cardiac magnetic resonance until the primary outcome: all‐cause death. Of 1552 eligible patients (n=1221 in development, n=331 in validation; median age at cardiac magnetic resonance 23.4 [interquartile range, 15.6–35.6] years; median follow up 9.5 years), 102 (6.6%) experienced the primary outcome. The multivariable Cox model performed similarly during development (concordance index, 0.83 [95% CI, 0.78–0.88]) and external validation (concordance index, 0.80 [95% CI, 0.71–0.90]) and identified older age at cardiac magnetic resonance, obesity, type of tetralogy of Fallot repair, higher right ventricular end‐systolic volume index, and lower biventricular global function index as independent predictors of death. A risk‐scoring algorithm dividing patients into low‐risk (score ≤4) versus high‐risk (score >4) groups was validated to effectively discriminate risk of death (15‐year survival of 95% versus 74%, respectively; P <0.001). Conclusions This externally validated mortality risk prediction algorithm can help identify vulnerable patients with repaired tetralogy of Fallot who may benefit from targeted interventions.

La congestión desempeña un papel fundamental en la patogénesis, la presentación y el pronóstico de la insuficiencia cardiaca y es un objetivo terapéutico importante. Sin embargo, su gravedad y su distribución por órganos y compartimentos varían mucho entre los pacientes, lo que ilustra la complejidad de este fenómeno. Aunque los síntomas y signos clínicos son útiles para evaluar la congestión y controlar el estado del volumen en un paciente individual, tienen poca sensibilidad y no permiten fenotipificar la congestión. Esto conduce a la incertidumbre diagnóstica y dificulta la toma de decisiones terapéuticas. En este artículo se ofrece una visión general actualizada de los biomarcadores circulantes, las modalidades de imagen (es decir, la ecografía cardiaca y extracardiaca) y las técnicas invasivas que podrían ayudar a los clínicos a identificar los diferentes perfiles de congestión y guiar la estrategia de tratamiento para esta población diversa de pacientes de alto riesgo con insuficiencia cardiaca.Congestion plays a major role in the pathogenesis, presentation, and prognosis of heart failure and is an important therapeutic target. However, its severity and organ and compartment distribution vary widely among patients, illustrating the complexity of this phenomenon. Although clinical symptoms and signs are useful to assess congestion and manage volume status in individual patients, they have limited sensitivity and do not allow identification of congestion phenotype. This leads to diagnostic uncertainty and hampers therapeutic decision-making. The present article provides an updated overview of circulating biomarkers, imaging modalities (ie, cardiac and extracardiac ultrasound), and invasive techniques that might help clinicians to identify different congestion profiles and guide the management strategy in this diverse population of high-risk patients with heart failure.

Although major breakthroughs in the field of pediatric cardiology, cardiac surgery, intervention, and overall care improved the outlook of congenital heart disease, Eisenmenger syndrome (ES) is still encountered and remains a complex clinical entity with multisystem involvement, including secondary erythrocytosis, increased thrombotic and bleeding diathesis, high arrhythmogenic risk, progressive heart failure, and premature death. Clearly, care for ES is best delivered in multidisciplinary expert centers. In this review, we discuss the considerable recent progress in understanding the complex pathophysiology of ES, means of prognostication, and improvement in clinical outcomes achieved with pulmonary arterial hypertension-targeted therapies. Additionally, we delineate areas of uncertainty in various aspects of care, discuss gaps in current evidence, and review current status in less privileged countries and propose initiatives to reduce disease burden. Finally, we propose the application of emerging technologies to enhance the delivery and quality of health care related to ES and beyond. (C) 2022 by the American College of Cardiology Foundation.

Background The European Society of Cardiology (ESC) guidelines for the management of adult congenital heart disease (ACHD) recommend screening in patients at risk for arrhythmic events. However, the optimal mode of detection is unknown. Methods Baseline and follow-up data of symptomatic ACHD patients who received an implantable loop recorder (ILR) or who participated in a smartphone based single-lead electrocardiogram study were collected. The primary endpoint was time to first detected arrhythmia. Results In total 116 ACHD patients (mean age 42 years, 44% male) were studied. The ILR group (n = 23) differed from the smartphone based single-lead electrocardiogram group (n = 93) in having a greater part of males and had more severe CHD and (near) syncope as qualifying diagnosis. In the smartphone based single-lead electrocardiogram group history of arrhythmia and palpitations were more frequent (all p < 0.05). Monitoring was performed for 40 and 79 patient-years for the ILR- and smartphone based single-lead electrocardiogram group, respectively. Arrhythmias occurred in 33 patients with an equal median time for both groups to first arrhythmia of 3 months (HR of 0.7, p = 0.81). Furthermore, atrial fibrillation occurred most often (n = 16) and common therapy changes included medication changes (n = 7) and implantation of pacemaker or Implantable Cardioverter Defibrillator (ICD) (N = 4). Symptoms or mode of detection were not a determinant of the first event. Conclusion Non-invasive smartphone based single-lead electrocardiogram monitoring could be an acceptable alternative for ILR implantation in detecting arrhythmia in symptomatic ACHD patients in respect to diagnostic yield, safety and management decisions, especially in those without syncope.

In the transposition of the great arteries (TGA), alterations in hemodynamics and oxygen saturation could result in fibrotic remodeling, but histological studies are scarce. We aimed to investigate fibrosis and innervation state in the full spectrum of TGA and correlate findings to clinical literature. Twenty-two human postmortem TGA hearts, including TGA without surgical correction (n = 8), after Mustard/Senning (n = 6), and arterial switch operation (ASO, n = 8), were studied. In newborn uncorrected TGA specimens (1 day–1.5 months), significantly more interstitial fibrosis (8.6% ± 3.0) was observed compared to control hearts (5.4% ± 0.8, p = 0.016). After the Mustard/Senning procedure, the amount of interstitial fibrosis was significantly higher (19.8% ± 5.1, p = 0.002), remarkably more in the subpulmonary left ventricle (LV) than in the systemic right ventricle (RV). In TGA-ASO, an increased amount of fibrosis was found in one adult specimen. The amount of innervation was diminished from 3 days after ASO (0.034% ± 0.017) compared to uncorrected TGA (0.082% ± 0.026, p = 0.036). In conclusion, in these selected postmortem TGA specimens, diffuse interstitial fibrosis was already present in newborn hearts, suggesting that altered oxygen saturations may already impact myocardial structure in the fetal phase. TGA-Mustard/Senning specimens showed diffuse myocardial fibrosis in the systemic RV and, remarkably, in the LV. Post-ASO, decreased uptake of nerve staining was observed, implicating (partial) myocardial denervation after ASO.

BACKGROUND The impact of pulmonary valve replacement (PVR) on major adverse clinical outcomes in patients with repaired tetralogy of Fallot (rTOF) is unknown.OBJECTIVES The purpose of this study was to determine whether PVR is associated with improved survival and freedom from sustained ventricular tachycardia (VT) in rTOF.METHODS A PVR propensity score was created to adjust for baseline differences between PVR and non-PVR patients enrolled in INDICATOR (International Multicenter TOF Registry). The primary outcome was time to the earliest occurrence of death or sustained VT. PVR and non-PVR patients were matched 1:1 on PVR propensity score (matched cohort) and in the full cohort, modeling was performed with propensity score as a covariate adjustment.RESULTS Among 1,143 patients with rTOF (age 27 & PLUSMN; 14 years, 47% PVR, follow-up 8.3 & PLUSMN; 5.2 years), the primary outcome occurred in 82. The adjusted HR for the primary outcome for PVR vs no-PVR (matched cohort n = 524) was 0.41 (95% CI: 0.21-0.81; multivariable model P = 0.010). Full cohort analysis revealed similar results. Subgroup analysis suggested beneficial effects in patients with advanced right ventricular (RV) dilatation (interaction P = 0.046; full cohort). In patients with RV end-systolic volume index >80 mL/m2, PVR was associated with a lower primary outcome risk (HR: 0.32; 95% CI: 0.16-0.62; P < 0.001). There was no association between PVR and the primary outcome in patients with RV end-systolic volume index #80 mL/m2 (HR: 0.86; 95% CI: 0.38-1.92; P = 0.70). CONCLUSIONS Compared with rTOF patients who did not receive PVR, propensity score-matched individuals receiving PVR had lower risk of a composite endpoint of death or sustained VT. (J Am Coll Cardiol 2023;81:2075-2085) & COPY; 2023 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the extracellular matrix gene coding for fibrillin-1 (FBN1). MFS leads to aortic aneurysms as key feature. Due to the high genetic diversity within the MFS patient population, genotype-phenotype predictions on disease progression and response to therapy remain challenging. Furthermore, current preclinical murine models represent only a subset of FBN1 mutations, which limits translational studies. In this study, we developed a preclinical model using primary cells of MFS patients that represent genetic and clinical variability in order to develop improved drug strategies. Human primary fibroblasts were isolated from skin biopsies derived from MFS patients (n=56) participating in the COMPARE trial. Human aortic smooth muscle cells (AoSMCs) were isolated from aortic tissue derived from MFS patients undergoing prophylactic aortic surgery (n=4). Long-term cultures in 384-well plates were assessed for the extracellular matrix and disease associated pathways. Analysis of all MFS fibroblasts showed either a reduced or abolished fibrillin-1 extracellular matrix network. Moreover, substantially reduced secretion of fibrillin-1 and asprosin in the culture medium was measured, as compared to healthy control fibroblasts. MFS fibroblasts with an abolished fibrillin-1 matrix were associated with patients with more rapid aortic root diameter growth. Exploring disease-relevant pathways revealed reduced nuclear localization of transcription factor KLF4 in MFS fibroblasts, which associated with the level of fibrillin-1 matrix. As a marker for myofibroblasts, α-smooth muscle actin (ASMA) staining was increased in these MFS fibroblasts. These findings were validated in AoSMC cultures, showing similar MFS fibrillin-1 matrix, nuclear KLF4, and ASMA expression profiles. In conclusion, phenotypic screening of patient-derived cells contributes to improved understanding of disease development and is valuable as preclinical tool for risk assessment and drug development for MFS and related conditions.

Marfan syndrome (MFS) is a connective tissue disorder affecting the cardiovascular, ocular, and skeletal system, which may be accompanied by psychological features. This study aimed to determine the prevalence of fatigue, anxiety, and symptoms of depression in MFS patients, and to assess the degree to which sociodemographic and clinical variables are associated with fatigue and psychological aspects. The prevalence of fatigue, anxiety, and symptoms of depression were assessed in two cohorts of MFS patients and compared with healthy controls. The checklist individual strength (CIS), and hospital anxiety and depression scale (HADS) questionnaires were utilized. Medical status was assessed (family history of MFS, aortic root dilatation >40 mm, previous aortic surgery, aortic dissection, chronic pain, skeletal involvement, and scoliosis). Severe fatigue was experienced by 37% of the total MFS cohort (n = 155). MFS patients scored significantly higher on the CIS questionnaire, concerning severe fatigue, as compared with the general Dutch population (p < 0.0001). There were no differences in HADS anxiety or depression scores. In older MFS patients, with a more severe cardiovascular phenotype, chronic pain, and a higher unemployment rate, significantly more symptoms of depression were observed, when compared with the general population (p = 0.027) or compared with younger MFS patients (p = 0.026). Multivariate analysis, showed that anxiety was associated with chronic pain (p = 0.022) and symptoms of depression with unemployment (p = 0.024). MFS patients report significantly more severe fatigue as compared with the general population. Since the cause of fatigue is unclear, more research may be needed. Psychological intervention, for example, cognitive behavioral therapy, may contribute to a reduction in psychological symptoms.

BACKGROUND:Clinical factors are used to estimate late complication risk in adults after atrial switch operation (AtrSO) for transposition of the great arteries (TGA), but heterogeneity in clinical course remains. We studied whether common genetic variants are associated with outcome and add value to a clinical risk score in TGA-AtrSO patients. METHODS AND RESULTS:This multicenter study followed 133 TGA-AtrSO patients (aged 28 [IQR 24-35] years) for 13 (IQR 9-16) years and examined the association of genome-wide single-nucleotide polymorphisms (SNPs) with a composite endpoint of symptomatic ventricular arrhythmia, heart failure hospitalization, ventricular assist device implantation, heart transplantation, or mortality. Thirty-two patients (24%) reached the endpoint. The genome-wide association study yielded one genome-wide significant (p < 1 × 10-8) locus and 18 suggestive loci (p < 1 × 10-5). A genetic risk score constructed on the basis of independent SNPs with p < 1 × 10-5 was associated with outcome after correction for the clinical risk score (HR = 1.26/point increase [95%CI 1.17-1.35]). Risk stratification improved with a combined risk score (clinical score + genetic score) compared to the clinical score alone (p = 2 × 10-16, C-statistic 0.95 vs 0.85). In 51 patients with a clinical intermediate (5-20%) 5-year risk of events, the combined score reclassified 32 patients to low (<5%) and 5 to high (>20%) risk. Stratified by the combined score, observed 5-year event-free survival was 100%, 79% and 31% for low, intermediate, and high-risk patients, respectively. CONCLUSIONS:Common genetic variants may explain some variation in the clinical course in TGA-AtrSO and improve risk stratification over clinical factors alone, especially in patients at intermediate clinical risk. These findings support the hypothesis that including genetic variants in risk assessment may be beneficial.

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.