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Background: To date, the pathophysiology of first-ever and recurrent stroke/TIA still remains unclear in young patients with embolic stroke/TIA of undetermined source (ESUS). Clinical studies with long-term follow-up in young ESUS patients are necessary to investigate the underlying pathophysiology of first-ever and recurrent stroke/TIA in this patient population, in particular the role of new-onset atrial fibrillation. Aims: Our aim was to study the long-term (>10-year) clinical outcome of young patients (<50 years) with ESUS. Methods: This cohort study included all patients aged ≤ 50 years who underwent transoesophageal echocardiography for diagnostic work-up of ESUS during 1996–2008 from one tertiary center. All patients were contacted by telephone between September–November 2018 to update clinical information from medical records. The clinical outcomes of this study were incidence rates of all-cause and cardiovascular mortality, recurrent stroke/TIA, new-onset clinical AF, and ischemic vascular events. Results: In total, 108 patients (57% female, mean age 40 ± 7.2 years [range 19–50 years], n = 72 stroke) were included. Across clinical follow-up (median 13[IQR 10–16] years), 24 patients died (n = 14 cardiovascular). The 15-year incidence rate of recurrent stroke/TIA was 15% (incidence rate = 1.09[95%CI 0.54–1.65]/100 patient-years) and a 5.5% incidence of new-onset clinical AF (incidence rate = 0.44[95%CI 0.09–0.79]/100 patient-years) following ESUS. Conclusions: The incidence of recurrent stroke/TIA is relatively high during long-term clinical follow-up of young patients with ESUS. In contrast, new-onset clinical AF is relatively low and therefore may not play an important part in the pathophysiology of first-ever and recurrent stroke/TIA of these patients. [ABSTRACT FROM AUTHOR]

This study tested the hypothesis that patients with a congenital heart disease are sensitive regarding heartbeat perception, reflected in enhanced attention for heartbeat, estimation of own heart rate, and a vulnerability to become anxious by listening to heartbeat sounds. Twenty adults with a congenital heart disease, and 20 healthy controls conducted 3 experimental tasks: a concentration task during distraction by heartbeat sounds, own heart rate estimation, and exposure to different patterns of heartbeat sounds. The results showed that patients were more distracted by heartbeat, and were also worse at estimating heart rate than controls. However, heartbeat sounds did not evoke anxiety. In conclusion, patients with a congenital heart disease may differ from controls in heartbeat perception, but there was no support for obsessive monitoring for heartbeat or excessive reactions to heartbeat sounds. [ABSTRACT FROM AUTHOR]

Objective: To investigate liver function and coagulation disorders in patients with a Fontan circulation at different time intervals after surgery.Design: Retrospective analysis of clinical data and cross sectional study relating liver function and coagulation profile to time since surgery, in 28 surviving patients after the modified Fontan procedure.Patients: 20 patients (71%) with atriopulmonary anastomosis, seven (25%) with atrioventricular anastomosis, and one (4%) with total cavopulmonary connection. Follow up ranged from 2.0 to 21.8 years (mean 11.1).Results: Abnormal liver function tests, mainly reflecting cholestasis, were present in 21 patients who had a significantly longer follow up (p < 0.01). Protein synthesis was normal in almost all patients. Coagulation profile showed abnormalities in 22 patients. "Procoagulant" abnormalities-that is, decreased plasminogen and protein C activity-were found in 11 and five patients, respectively. The extent of these abnormalities was less in patients with a longer follow up. Anticoagulant abnormalities were factor V deficiency in 16 patients and factor VII deficiency in 17, resulting in a prolonged prothrombin time in 19 patients. Thirteen patients had both pro- and anticoagulant abnormalities. A prethrombotic state was present in five patients, with a significantly longer mean time interval since surgery (p = 0.05). Thus, although the individual procoagulant indices decreased with increasing time intervals since surgery, a prethrombotic state was found particularly in patients with a long term follow up.Conclusions: Mild cholestasis was mainly present in Fontan patients with a long duration of follow up. Along with laboratory procoagulant abnormalities indicating a prethrombotic state, anticoagulant abnormalities were also present. The coagulation profile varied at different time intervals after surgery. Thus detailed evaluation should be performed regularly, and the use of anticoagulants should be considered in every patient. Long term prospective studies are needed to evaluate the individual fluctuations of coagulation profile over time following a Fontan procedure. [ABSTRACT FROM AUTHOR]

The leading cause of premature death in patients with Marfan's syndrome (MS) is type A aortic dissection or rupture due to progressive aortic root dilation. The aim of this study was to analyze aortic root growth in 113 men and 108 women with MS. All patients were prospectively followed with serial echocardiograms of the native aortic root. At baseline, women had on average a 5-mm smaller aortic root diameter adjusted for age than men. Average aortic root growth was 0.42 mm/year (SE 0.05) in men and 0.38 mm/year (SE 0.04) in women. On the basis of aortic root growth rates, the men and women could be divided into 2 normally distributed subgroups: fast and slow growers. Approximately 1 in 7 men (1.5 mm/year, SE 0.5) and approximately 1 in 9 women (1.8 mm/year, SE 0.3) had fast-growing aortic root diameters. Significantly more type A dissections (25% vs 4%, p <0.001) were observed in fast growers than in slow growers; this was found in men and women. Type A dissections were observed in 4 men and 9 women. By reducing the cut-off value by 5 mm for elective aortic root replacement in women, type A dissections could have been prevented in 3 women. In conclusion, guidelines should take gender differences into account, and therefore, the investigators propose reducing the threshold for elective aortic root replacement in women with MS by 5 mm. [ABSTRACT FROM AUTHOR]

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., Competing Interests: Declaration of competing interest Dr. Bouma reports financial support was provided by Janssen-Cilag. The remaining authors have no competing interests to declare., (Copyright © 2024. Published by Elsevier Inc.)

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., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: Support was received from the Netherlands Cardiovascular Research lnitiative: An initiative with support of the Dutch Heart Foundation and Hartekind, CVON2019-002 OUTREACH. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

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 ± 14 years, 47% PVR, follow-up 8.3 ± 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/m 2 , 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/m 2 (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., Competing Interests: Funding Support and Author Disclosures This work was supported in part by National Institutes of Health/NLHBI/CCHMC 2UO1HL098147-12 and the Alexander S. Nadas Chair at Harvard Medical School (to Dr Geva), the Lerner Research Award and the Sarah Marie Liamos Fund (to Dr Valente), British Heart Foundation EX/18/1/34296 (to Dr Babu-Narayan), the Canadian Institutes of Health Research MOP 119353 (to Dr Wald), and by the Amsterdam Cardiovascular Sciences (to Dr Bokma). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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: 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., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

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., (© 2022 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Background: It is difficult to assess the risk for aortic dissection beyond the aortic root in patients with Marfan syndrome (MFS). To aid risk assessment in these patients, we investigated aortic flow and wall shear stress (WSS) by 4D flow magnetic resonance imaging (MRI) in patients with MFS and compared the results with healthy volunteers. We hypothesized that MFS patients with a high-risk profile for aortic dissection would show abnormal hemodynamics in aortic regions associated with aortic dissection., Methods: MFS patients (n = 55) and healthy subjects (n = 25), matched for age and sex, prospectively underwent 4D flow MRI. 4D flow maps were constructed to detect elevated (defined as higher than the three-dimensional 95 % confidence interval) and deviant directed (defined as vector angle differences higher than 120°) WSS in MFS patients as compared to the controls. Univariate and multivariate associations with risk factors for aortic dissection in MFS patients were assessed., Results: The maximum incidence for elevated WSS was 20 % (CI 9 %-31 %) and found in the ascending aorta. The maximum for deviant directed WSS was 39 % (CI 26 %-52 %) and found in the inner descending aorta. Significantly more male patients had deviant directed WSS in the inner proximal descending aorta (63 % vs 24 %, p = 0.014). Multivariate analysis showed that deviant directed WSS was associated with male sex (p = 0.019), and a haplo-insufficient FBN1 mutation type (p = 0.040). In 60 % of MFS patients with a previous aortic root replacement surgery, abnormal hemodynamics were found in the ascending aorta. No significant differences between hemodynamics were found in the descending aorta between operated and non-operated patients., Conclusion: Deviant directed WSS in the proximal descending aorta is associated with known risk factors for aortic dissection in MFS patients, namely male sex and a haploinsufficient FBN1 mutation type., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

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., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The clinical and prognostic implications of a hypertensive response to exercise after repair of coarctation of the aorta (CoA) remain controversial. We aimed to determine the prevalence of a hypertensive response to exercise, identify factors associated with peak exercise systolic blood pressure (SBP) and explore the association of peak exercise SBP with resting blood pressure and cardiovascular events during follow-up., Methods: From the Dutch national CONgenital CORvitia (CONCOR) registry, adults with repaired CoA who underwent exercise stress testing were included. A hypertensive response to exercise was defined as a peak exercise SBP ≥210 mm Hg in men and ≥190 mm Hg in women. Cardiovascular events consisted of coronary artery disease, stroke, aortic complications and cardiovascular death., Results: Of the original cohort of 920 adults with repaired CoA, 675 patients (median age 24 years (range 16-72 years)) underwent exercise stress testing. Of these, 299 patients (44%) had a hypertensive response to exercise. Mean follow-up duration was 10.1 years. Male sex, absence of a bicuspid aortic valve and elevated resting SBP were independently associated with increased peak exercise SBP. Peak exercise SBP was positively predictive of office SBP (β=0.11, p<0.001) and 24-hour SBP (β=0.05, p=0.03) at follow-up, despite correction for baseline SBP. During follow-up, 100 patients (15%) developed at least 1 cardiovascular event. Peak exercise SBP was not significantly associated with the occurrence of cardiovascular events (HR 0.994 (95% CI 0.987 to 1.001), p=0.11)., Conclusions: A hypertensive response to exercise was present in nearly half of the patients in this large, prospective cohort of adults with repaired CoA. Risk factors for increased peak exercise SBP were male sex, absence of a bicuspid aortic valve and elevated resting SBP. Increased peak exercise SBP independently predicted hypertension at follow-up. These results support close follow-up of patients with a hypertensive response to exercise to ensure timely diagnosis and treatment of future hypertension., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)