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Patent foramen ovale (PFO) has been associated with migraine, especially migraine with aura, and 30-50% of individuals with migraine with aura have a PFO, suggesting it could be more than just an "innocent bystander''. Observational data showed a reduction of the frequency and severity of migraine attacks, particularly those with aura, following transcatheter PFO closure for established indications. Three small randomized controlled trials have demonstrated significant benefits of PFO closure in most of their secondary endpoints, such as reductions in the mean number of monthly migraine attacks and migraine days. Since a significant proportion of patients experience important side effects from traditional migraine medications and newer highly effective migraine prevention strategies may need to be instituted. PFO closure could in this regard to be a valuable add-on in the armamentarium of migraine treatment, improving the quality of life by alleviating the need for medications. The effect of percutaneous PFO closure on migraine treatment is needed to be clarified. As the underlying pathophysiology remains poorly understood and largely hypothetical, future investigations, focusing on the causal relationship between PFO and migraine, will help to define the subgroup of patients most likely to benefit from PFO closure. More accurate patient recruitment may lead to greater postprocedural benefits and more significant symptom improvement. Additionally, randomized controlled trials need to be reported adequately with more realistic endpoints, sufficient duration of follow-up, and statistical power to detect differences between closure and placebo groups to ensure precise and reliable findings., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Imaging fusion technology is promising as it is radiation and contrast sparing. Herein, we compare conventional biplane angiography to multimodality image fusion with live fluoroscopy using two-dimensional (2D)-three-dimensional (3D) registration (MMIF 2D-3D ) and assess MMIF 2D-3D impact on radiation exposure and contrast volume during cardiac catheterization of patients with congenital heart disease (CHD)., Methods: We matched institutional MMIF 2D-3D procedures and controls according to patient characteristics (body mass index, age, and gender) and the seven procedure-type subgroups. Then, we matched the number of tests and controls per subgroup using chronological ordering or propensity score matching. Subsequently, we combined the matched subgroups into larger subgroups of similar procedure type, keeping subgroups with at least 10 test and 10 control cases. Air kerma (AK) and dose area product (DAP) were normalized by body weight (BW), product of body weight and fluoroscopy time (BW × FT), or product of body weight and number of frames (BW × FR), and stratified by acquisition plane and irradiation event type (fluoroscopy or acquisition). Three senior interventionists evaluated the relevance of MMIF 2D-3D (5-point Likert scale)., Results: The Overall group consisted of 54 MMIF 2D-3D cases. The combined and matched subgroups were pulmonary artery stenting (Stent PUL ), aorta angioplasty (Plasty AO ), pulmonary artery angioplasty (Plasty PUL ), or a combination of the latter two (Plasty). The FT of the lateral plane reduced significantly by 69.6% for the Overall MMIF 2D-3D population. AK BW and DAP BW decreased, respectively, by 43.9% and 39.3% (Overall group), 49.3% and 54.9% (Plasty AO ), and 36.7% and 44.4% for the Plasty subgroup. All the aforementioned reductions were statistically significant except for DAP BW in the Overall and Plasty (sub)groups. The decrease of AK BW and DAP BW in the Stent PUL and Plasty PUL subgroups was not statistically significant. The decrease in the median values of the weight-normalized contrast volume (CMC BW ) in all five subgroups was not significant. Cardiologists considered MMIF 2D-3D very useful with a median score of 4., Conclusion: In our institution, MMIF 2D-3D overall enabled significant AK BW reduction during the catheterization of CHD patients and was mainly driven by reduced FT in the lateral plane. We observed significant AK BW reduction in the Plasty and Plasty AO subgroups and DAP BW reduction in the Plasty AO subgroup. However, the decrease in CMC BW was not significant., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer-review process and the final decision., (© 2024 Buytaert, Vandekerckhove, Panzer, Campens, Bacher and De Wolf.)

Objective: To evaluate the effectiveness of the transition program for adolescents with congenital heart disease (CHD) 'Transition With a Heart' (TWAH) on disease-related knowledge, quality of life (QoL), transition experiences, and gaps in follow-up., Methods: A study with pre-posttest and control group (post-test) using consecutive sampling, including adolescents with moderate to severely complex CHD, without intellectual disability, aged≥ 12 y, and parents. After weighting, t-tests were performed. A multivariable regression analysis explored the outcomes' determinants., Results: In the intervention group, 28 adolescents and 25 parents were included, and 53 adolescents and 18 parents as controls. Adolescents' knowledge significantly increased after completing TWAH (from 59.8% to 75.7%;p < 0.01). Their knowledge was positively correlated with TWAH (β = +13.3;p < 0.01). Adolescents' transition experiences were also positively related to TWAH (general experience: β = +5.5;p < 0.01; transfer satisfaction: β = +0.8; p < 0.01). Adolescents' QoL was mainly determined by CHD complexity and not by TWAH. No one showed gaps in follow-up. TWAH was not associated with parents' transition experiences., Conclusion: Implementing TWAH substantially improved adolescents' disease-related knowledge and transition experiences., Practice Implications: The results regarding transition experiences need to be confirmed by further research. The TWAH design with the person-tailored educational program, skills training, and the transition coordinator can be used in settings with other chronic diseases., Competing Interests: Declaration of Competing Interest 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., (Copyright © 2023 Elsevier B.V. All rights reserved.)

A higher incidence of conduction disturbances and permanent pacemaker implantation (PPI) has been observed after transcatheter aortic valve implantation (TAVI) in patients with bicuspid aortic valves (BAVs) as compared to those with tricuspid aortic valves (TAVs). This study aimed to provide an anatomical explanation for this observation, supported by an in-depth anatomical mapping of the membranous septum (MS) in a large cohort of BAVs and TAVs using cardiac computed tomography (CT). A total of 300 cardiac CT scans were analysed, revealing a significantly shorter sub-annular length of the MS in BAVs at all measuring points compared to TAVs (p < 0.001). In the current BAV cohort, the MS was found to be at its shortest at the RCC site, measuring less than 1 mm in depth. In addition, the MS was located more anteriorly towards the RCC in BAVs, where the transcatheter aortic valve tends to be implanted deeper, and we observed a trend towards a higher PPI rate in BAVs. Future studies should investigate whether anatomical mapping of the MS in patients undergoing TAVI could be a useful tool for decision-making and potentially mitigate the risk of conduction disturbances., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Humans have a larger energy budget than great apes, allowing the combination of the metabolically expensive traits that define our life history. This budget is ultimately related to the cardiac output, the product of the blood pumped from the ventricle and the number of heart beats per minute, a measure of the blood available for the whole organism physiological activity. To show the relationship between cardiac output and energy expenditure in hominid evolution, we study a surrogate measure of cardiac output, the aortic root diameter, in humans and great apes. When compared to gorillas and chimpanzees, humans present an increased body mass adjusted aortic root diameter. We also use data from the literature to show that over the human lifespan, cardiac output and total energy expenditure follow almost identical trajectories, with a marked increase during the period of brain growth, and a plateau during most of the adult life. The limited variation of adjusted cardiac output with sex, age and physical activity supports the compensation model of energy expenditure in humans. Finally, we present a first study of cardiac output in the skeleton through the study of the aortic impression in the vertebral bodies of the spine. It is absent in great apes, and present in humans and Neanderthals, large-brained hominins with an extended life cycle. An increased adjusted cardiac output, underlying higher total energy expenditure, would have been a key process in human evolution., (© 2023. The Author(s).)

Background: At the beginning of the COVID-19 pandemic, professionals in charge of particularly vulnerable populations, such as adult congenital heart disease (ACHD) patients, were confronted with difficult decision-making. We aimed to assess changes in risk stratification and outcomes of ACHD patients suffering from COVID-19 between March 2020 and April 2021., Methods and Results: Risk stratification among ACHD experts (before and after the first outcome data were available) was assessed by means of questionnaires. In addition, COVID-19 cases and the corresponding patient characteristics were recorded among participating centres. Predictors for the outcome of interest (complicated disease course) were assessed by means of multivariable logistic regression models calculated with cluster-robust standard errors. When assessing the importance of general and ACHD specific risk factors for a complicated disease course, their overall importance and the corresponding risk perception among ACHD experts decreased over time. Overall, 638 patients (n = 168 during the first wave and n = 470 during the subsequent waves) were included (median age 34 years, 52% women). Main independent predictors for a complicated disease course were male sex, increasing age, a BMI >25 kg/m2, having ≥2 comorbidities, suffering from a cyanotic heart disease or having suffered COVID-19 in the first wave vs. subsequent waves., Conclusions: Apart from cyanotic heart disease, general risk factors for poor outcome in case of COVID-19 reported in the general population are equally important among ACHD patients. Risk perception among ACHD experts decreased during the course of the pandemic., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Professor Werner Budts reports financial support was provided by Abbott and Occlutech. Following co-authors: Dr. Pastora Gallego, Dr. Magalie Ladouceur, Dr. Massimo Chessa, Professor Werner Budts and Prof. Helmut Baumgartner are Associate Editors and, therefore, members of the Editorial Board of the International Journal of Cardiology Congenital Heart Disease., (© 2022 The Authors.)

Introduction: Bicuspid aortic valve is difficult to detect on standard transverse images., Purpose: We aimed to investigate the usefulness of the hammock sign for detection of bicuspid aortic valve., Methods: We retrospectively investigated the usefulness of a newly proposed 'hammock sign' in a population of 45 contrast enhanced computer tomographic studies to discern tricuspid (22) from anatomical bicuspid aortic (23) valves. The gold standard of aortic morphology was the definite diagnosis in the patient's medical file, established by computed tomography, magnetic resonance, or surgery., Results: Computer tomographic (CT) studies of each aortic morphology were randomly evaluated for the presence of the hammock sign on coronal and sagittal images, by two readers blinded to the diagnosis. Sensitivity for detecting an anatomic bicuspid valve was 86%, and specificity was 100%., Conclusion: The hammock sign allows for a quick and easy diagnosis of an anatomical bicuspid aortic valve, merely by scrolling through the standard coronal reconstructions of any type of contrast-enhanced thoracic CT study, and regardless of any other findings associated with bicuspid aortic valve. Functional bicuspid aortic valves were not the scope of this study., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2023 The Author(s).)

Most transcatheter aortic valve replacement-related procedures (eg, transcatheter aortic valve replacement implantation depth, commissural alignment, coronary access, bioprosthetic or native aortic scallop intentional laceration to prevent iatrogenic coronary artery obstruction, paravalvular leak closure) require an optimal fluoroscopic viewing angle located somewhere along the aortic annulus S-curve. Chamber views, coronary cusp and coronary anatomy, can be understood along the aortic annulus S-curve. A better understanding of the optimal fluoroscopic viewing angles along the S-curve may translate into increased operator confidence and improved safety and efficacy while reducing procedural time, radiation dose, contrast volume, and complication rates., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Pseudoxanthoma elasticum (PXE) is a currently intractable genetic disorder characterized by progressive ectopic calcification in the skin, eyes and arteries. Therapeutic trials in PXE are severely hampered by the lack of reliable biomarkers. Serum calcification propensity T50 is a blood test measuring the functional anticalcifying buffer capacity of serum. Here, we evaluated T50 in PXE patients aiming to investigate its determinants and suitability as a potential biomarker for disease severity. Fifty-seven PXE patients were included in this cross-sectional study, and demographic, clinical, imaging and biochemical data were collected from medical health records. PXE severity was assessed using Phenodex scores. T50 was measured using a validated, nephelometry-based assay. Multivariate models were then created to investigate T50 determinants and associations with disease severity. In short, the mean age of patients was 45.2 years, 68.4% was female and mean serum T50 was 347 min. Multivariate regression analysis identified serum fetuin-A (p < 0.001), phosphorus (p = 0.007) and magnesium levels (p = 0.034) as significant determinants of T50, while no correlations were identified with serum calcium, eGFR, plasma PPi levels or the ABCC6 genotype. After correction for covariates, T50 was found to be an independent determinant of ocular (p = 0.013), vascular (p = 0.013) and overall disease severity (p = 0.016) in PXE. To conclude, shorter serum T50—indicative of a higher calcification propensity—was associated with a more severe phenotype in PXE patients. This study indicates, for the first time, that serum T50 might be a clinically relevant biomarker in PXE and may thus be of importance to future therapeutic trials.

Background: Biallelic pathogenic variants in the ATP-binding cassette subfamily C member 6 ( ABCC6 ) gene cause pseudoxanthoma elasticum, a multisystemic ectopic calcification disorder, while heterozygous ABCC6 variants are associated with an increased risk of cardiovascular and cerebrovascular disease. As the prevalence of pathogenic ABCC6 variants in the general population is estimated at ~1%, identifying additional ABCC6 -related (sub)clinical manifestations in heterozygous carriers is of the utmost importance to reduce this burden of disease. Here, we present a large Belgian cohort of heterozygous ABCC6 carriers with comprehensive clinical, biochemical and imaging data. Based on these results, we formulate clinical practice guidelines regarding screening, preventive measures and follow-up of ABCC6 carriers., Methods: The phenotype of 56 individuals carrying heterozygous pathogenic ABCC6 variants was assessed using clinical (eg, detailed ophthalmological examinations), biochemical, imaging (eg, cardiovascular and abdominal ultrasound) and genetic data. Clinical practice guidelines were then drawn up., Results: We found that ABCC6 heterozygosity is associated with distinct retinal alterations ('comet-like') (24%), high prevalence of hypercholesterolaemia (>75%) and diastolic dysfunction (33%), accelerated lower limb atherosclerosis and medial vascular disease, abdominal organ calcification (26%) and testicular microlithiasis (28%), though with highly variable expression., Conclusion: In this study, we delineated the multisystemic ABCC6 heterozygosity phenotype characterised by retinal alterations, aberrant lipid metabolism, diastolic dysfunction and increased vascular, abdominal and testicular calcifications. Our clinical practice guidelines aimed to improve early diagnosis, treatment and follow-up of ABCC6 -related health problems., Competing Interests: Competing interests: LN is a PhD fellow of the Research Foundation Flanders (FWO), Belgium (11F2121N), and was also supported by a Special Research Fund (BOF) grant from the Ghent University, Belgium (BOF19/DOC/253). OV and BL are senior clinical investigators of the FWO, Belgium., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Background: Peripheral arterial disease (PAD) is a manifestation of systemic atherosclerosis. Intermittent claudication is a symptomatic form of PAD that is characterized by pain in the lower limbs caused by chronic occlusive arterial disease. This pain develops in a limb during exercise and is relieved with rest. Propionyl-L-carnitine (PLC) is a drug that may alleviate the symptoms of PAD through a metabolic pathway, thereby improving exercise performance., Objectives: The objective of this review is to determine whether propionyl-L-carnitine is efficacious compared with placebo, other drugs, or other interventions used for treatment of intermittent claudication (e.g. exercise, endovascular intervention, surgery) in increasing pain-free and maximum walking distance for people with stable intermittent claudication, Fontaine stage II., Search Methods: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL databases and the World Health Organization International Clinical Trials Registry Platform and the ClinicalTrials.gov trials register to July 7, 2021. We undertook reference checking and contact with study authors and pharmaceutical companies to identify additional unpublished and ongoing studies., Selection Criteria: Double-blind randomized controlled trials (RCTs) in people with intermittent claudication (Fontaine stage II) receiving PLC compared with placebo or another intervention. Outcomes included pain-free walking performance (initial claudication distance - ICD) and maximal walking performance (absolute claudication distance - ACD), analyzed by standardized treadmill exercise test, as well as ankle brachial index (ABI), quality of life, progression of disease, and adverse events., Data Collection and Analysis: Two review authors independently selected trials, extracted data, and evaluated trials for risk of bias. We contacted study authors for additional information. We resolved any disagreements by consensus. We performed fixed-effect model meta-analyses with mean differences (MDs) and 95% confidence intervals (CIs). We graded the certainty of evidence according to GRADE., Main Results: We included 12 studies in this review with a total number of 1423 randomized participants. A majority of the included studies assessed PLC versus placebo (11 studies, 1395 participants), and one study assessed PLC versus L-carnitine (1 study, 26 participants). We identified no RCTs that assessed PLC versus any other medication, exercise, endovascular intervention, or surgery. Participants received PLC 1 grams to 2 grams orally (9 studies) or intravenously (3 studies) per day or placebo. For the comparison PLC versus placebo, there was a high level of both clinical and statistical heterogeneity due to study size, participants coming from different countries and centres, the combination of participants with and without diabetes, and use of different treadmill protocols. We found a high proportion of drug company-backed studies. The overall certainty of the evidence was moderate. For PLC compared with placebo, improvement in maximal walking performance (ACD) was greater for PLC than for placebo, with a mean difference in absolute improvement of 50.86 meters (95% CI 50.34 to 51.38; 9 studies, 1121 participants), or a 26% relative improvement (95% CI 23% to 28%). Improvement in pain-free walking distance (ICD) was also greater for PLC than for placebo, with a mean difference in absolute improvement of 32.98 meters (95% CI 32.60 to 33.37; 9 studies, 1151 participants), or a 31% relative improvement (95% CI 28% to 34%). Improvement in ABI was greater for PLC than for placebo, with a mean difference in improvement of 0.09 (95% CI 0.08 to 0.09; 4 studies, 369 participants). Quality of life improvement was greater with PLC (MD 0.06, 95% CI 0.05 to 0.07; 1 study, 126 participants). Progression of disease and adverse events including nausea, gastric intolerance, and flu-like symptoms did not differ greatly between PLC and placebo. For the comparison of PLC with L-carnitine, the certainty of evidence was low because this included a single, very small, cross-over study. Mean improvement in ACD was slightly greater for PLC compared to L-carnitine, with a mean difference in absolute improvement of 20.00 meters (95% CI 0.47 to 39.53; 1 study, 14 participants) or a 16% relative improvement (95% CI 0.4% to 31.6%). We found no evidence of a clear difference in the ICD (absolute improvement 4.00 meters, 95% CI -9.86 to 17.86; 1 study, 14 participants); or a 3% relative improvement (95% CI -7.4% to 13.4%). None of the other outcomes of this review were reported in this study., Authors' Conclusions: When PLC was compared with placebo, improvement in walking distance was mild to moderate and safety profiles were similar, with moderate overall certainty of evidence. Although In clinical practice, PLC might be considered as an alternative or an adjuvant to standard treatment when such therapies are found to be contraindicated or ineffective, we found no RCT evidence comparing PLC with standard treatment to directly support such use., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Cardiovascular disease is the leading cause of death during pregnancy with thoracic aortic dissection being one of the main causes. Thoracic aortic disease is commonly related to hereditary disorders and congenital heart malformations such as bicuspid aortic valve (BAV). Pregnancy is considered a high risk period in women with underlying aortopathy., Methods: The ESC EORP Registry Of Pregnancy And Cardiac disease (ROPAC) is a prospective global registry that enrolled 5739 women with pre-existing cardiac disease. With this analysis, we aim to study the maternal and fetal outcome of pregnancy in women with thoracic aortic disease., Results: Thoracic aortic disease was reported in 189 women (3.3%). Half of them were patients with Marfan syndrome (MFS), 26% had a BAV, 8% Turner syndrome, 2% vascular Ehlers-Danlos syndrome and 11% had no underlying genetic defect or associated congenital heart defect. Aortic dilatation was reported in 58% of patients and 6% had a history of aortic dissection. Four patients, of whom three were patients with MFS, had an acute aortic dissection (three type A and one type B aortic dissection) without maternal or fetal mortality. No complications occurred in women with a history of aortic dissection. There was no significant difference in median fetal birth weight if treated with a beta-blocker or not (2960 g (2358-3390 g) vs 3270 g (2750-3570 g), p value 0.25)., Conclusion: This ancillary analysis provides the largest prospective data review on pregnancy risk for patients with thoracic aortic disease. Overall pregnancy outcomes in women with thoracic aortic disease followed according to current guidelines are good., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Long-term results after tetralogy of Fallot (TOF) repair are determined by the extent of right ventricular remodeling to chronic pulmonary regurgitation entailing progressive RV dysfunction and a risk of developing ventricular arrhythmia. Pulmonary valve replacement (PVR) can alleviate this burden. As a predictor of ventricular arrhythmia, QRS duration remains a strong parameter in this decision. We performed a retrospective analysis of all PVR patients between 2005 and 2018, studying the time evolution of electrocardiographic parameters before and after PVR through linear mixed model analysis. 42 TOF patients underwent PVR. The median timespan between primary repair and PVR was 18 years (IQR 13-30). The indication for PVR was primarily based on the association of exercise intolerance (67%) and significant RV dilation on cMRI (median RVEDVi 161 ml/m 2 IQR 133-181). Median QRS length was 155 ms (IQR 138-164), 4 (10%) patients had a QRS > 180 ms. QRS duration increased significantly before PVR, but barely showed regression after PVR. Changes of QRS duration after PVR were independent of RV dilation. In conclusion, when the decision for PVR in TOF patients is primarily based on RV volume and/or function threshold, QRS duration > 180 ms is rarely observed. In contrast with the significant increase of QRS duration before PVR, QRS length regression appears to be independent of the extent of RV dilation or QRS > 160 ms. Considering that the decision for PVR is based on mechanical RV characteristics, the utility of serial follow-up of QRS duration in contemporary operated TOF patients becomes questionable in absence of clinical arguments for ventricular arrhythmia., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aims: Patients with adult congenital heart disease (ACHD) are a potentially vulnerable patient cohort in case of COVID-19. Some cardiac defects may be associated with a poor COVID-19 outcome. Risk estimation in ACHD is currently based on expert opinion. The aim of this study was to collect clinical outcome data and to identify risk factors for a complicated course of COVID-19 in patients with ACHD., Methods: Twenty-five ACHD centres in nine European countries participated in the study. Consecutive patients with ACHD diagnosed with COVID-19 presenting to one of the participating centres between 27 March and 6 June 2020 were included. A complicated disease course was defined as hospitalisation for COVID-19 requiring non-invasive or invasive ventilation and/or inotropic support, or a fatal outcome., Results: Of 105 patients with a mean age of 38±13 years (58% women), 13 had a complicated disease course, of whom 5 died. In univariable analysis, age (OR 1.3, 95% CI 1.1 to 1.7, per 5 years), ≥2 comorbidities (OR 7.1, 95% CI 2.1 to 24.5), body mass index of >25 kg/m 2 (OR 7.2, 95% CI 1.9 to 28.3) and cyanotic heart disease (OR 13.2, 95% CI 2.5 to 68.4) were associated with a complicated disease course. In a multivariable logistic regression model, cyanotic heart disease was the most important predictor (OR 60.0, 95% CI 7.6 to 474.0)., Conclusions: Among patients with ACHD, general risk factors (age, obesity and multiple comorbidities) are associated with an increased risk of complicated COVID-19 course. Congenital cardiac defects at particularly high risk were cyanotic lesions, including unrepaired cyanotic defects or Eisenmenger syndrome., Competing Interests: Competing interests: WB declared being proctor of Abbott and Occlutech., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Upregulation of the RAS-RAF-MEK-ERK-MAPK pathway is involved in the development of several human tumors, aortic aneurysms, atherosclerosis, and cardiomyopathy. Refametinib, a highly selective MEK-inhibitor, has already shown antineoplastic activity in phase II trials. Furthermore, it showed potency to attenuate aortic root growth in murine models. Current formulations of this drug however necessitate oral gavage as a delivery method for long-term studies, which is labor-intensive and induces stress and occasional injury, potentially confounding results. Therefore, we developed a novel oral administration method for refametinib. A 2-hydroxypropyl-beta-cyclodextrin (HPBCD) based drinking water preparation of refametinib was formulated, for which a selective, analytical UHPLC-UV method was developed to assess the in-use stability. Next, 16 week old male wild-type C57Bl/6J mice received either a daily dose of 50 or 75 mg/kg/day refametinib or were given regular drinking water during 7 days. In both dosage groups the refametinib plasma levels were measured (n = 10 or 7, respectively). Furthermore, pERK/total ERK protein levels were calculated in the myocardial and aortic tissue of mice receiving a daily dose of 50 mg/kg/day refametinib and untreated mice (n = 4/group). After 7 days no significant degradation of refametinib was observed when dissolved in drinking water provided that drinking bottles were protected from UV/visible light. Furthermore, a dose-dependent increase in refametinib plasma levels was found whereby active plasma levels (> 1.2 µg/mL) were obtained even in the lowest dose-group of 50 mg/kg/day. A significant reduction of pERK/total ERK protein levels compared to untreated mice was observed in aortic and myocardial tissue of mice receiving a daily dose of 50 mg/kg/day refametinib. Importantly, a relatively high mortality rate was noted in the highest dose group (n = 5). This approach provides a valid alternative oral administration method for refametinib with a reduced risk of complications due to animal manipulation and without loss of functionality, which can be implemented in future research regarding the malignant upregulation of the RAS-RAF-MEK-ERK-MAPK pathway. However, care must be taken not to exceed the toxic dose., (Copyright © 2020 Steijns, Bracke, Renard, De Backer, Sips, Debunne, Wynendaele, Verbeke, De Spiegeleer and Campens.)

Background: Detailed multidimensional assessment of patent foramen ovale (PFO) size with transesophageal echocardiography (TOE) may help to determine PFO pathogenicity in cryptogenic stroke patients. We explored the potential additive value of Live xPlane and three-dimensional (3D) TOE anatomical PFO sizing techniques., Methods: Imaging data of 45 patients who underwent a 3D TOE-assisted percutaneous PFO closure were studied. The two-dimensional (2D) PFO separation distance and right-to-left (RL) contrast shunt magnitude were assessed on preprocedural TOE recordings. Peri-procedural measurements of the triangular anatomical PFO opening (base, height, and area) were performed after positioning of a stiff guidewire (SW) through the PFO, using Live xPlane imaging and 3D Zoom mode., Results: The PFO SW base appeared on average 5 times larger than the preprocedural 2D PFO separation (median difference [IQR] = 13[5] mm; P < .001). For a same PFO separation, the width of the PFO base may vary significantly. The PFO SW base was significantly larger in patients with a large versus a small-to-moderate PFO RL contrast shunt (18 vs 15 mm; P = .007) and in those with a spontaneous versus a provoked shunt (18 vs 14 mm; P = .003)., Conclusion: Live xPlane and 3D Zoom TOE allow peri-procedural measurement of the largest dimension of a PFO, which is the PFO base. Patients with a large or spontaneous RL contrast shunt appear to have a larger PFO base. The anatomical PFO base dimension may be taken into account for optimization of device and patient selection strategies., (© 2020 Wiley Periodicals LLC.)

Background: Marfan syndrome (MFS) is a multisystemic hereditary connective tissue disease. Aortic root aneurysms and dissections are the most common and life-threatening cardiovascular disorders affecting these patients. Other cardiac manifestations include mitral valve prolapse, ventricular dysfunction and arrhythmias. Medical treatment of cardiovascular features is ultimately aimed at slowing down aortic root growth rate and preventing dissection. Losartan has been proposed as a new therapeutic tool for this purpose. To which extent losartan affects cardiac function has not been studied previously., Methods: We designed a prospective, double-blind, randomized placebo-controlled trial to evaluate the effect of losartan added to beta-blocker therapy on aortic growth and ventricular function in patients with MFS. Secondary outcomes were aortic dissection, prophylactic aortic surgery and death., Results: Twenty-two patients were enrolled in the trial. There was a mild and similar increase in the aortic root during the 3 years of follow-up in both groups (median 1 mm, IQR [-1-1.5] and 1 mm, IQR [-0.25-1] in the losartan and placebo group, respectively, p = 1). Diastolic and systolic ventricular function was normal at baseline in both groups and remained stable during the study. One patient in the placebo group presented a subclavian artery dissection during follow-up., Conclusion: Losartan on top of beta-blocker therapy has no additional effect on aortic growth or on cardiac function in patients with MFS. Our results are underpowered but are in line with the result from other groups. In order to have a better insight on whether a group of patients could benefit more from losartan therapy, the outcome of an on-going meta-analysis should be awaited.

Background: Mild intrinsic cardiomyopathy in patients with Marfan syndrome (MFS) has consistently been evidenced by independent research groups. So far, little is known about the long-term evolution and pathophysiology of this finding., Methods: To gain more insights into the pathophysiology of MFS-related cardiomyopathy, we performed in-vivo and ex-vivo studies of 11 Fbn1(C1039G/+) mice and 9 wild-type (WT) littermates. Serial ultrasound findings obtained in mice were correlated to the human phenotype. We therefore reassessed left ventricular (LV) function parameters over a 6-y follow-up period in 19 previously reported MFS patients, in whom we documented mild LV dysfunction., Results: Fbn1(C1039G/+) mice demonstrated LV contractile dysfunction. Subsequent ex-vivo studies of the myocardium of adult mutant mice revealed upregulation of TGFβ-related pathways and consistent abnormalities of the microfibrillar network, implicating a role for microfibrils in the mechanical properties of the myocardium. Echocardiographic parameters did not indicate clinical significant deterioration of LV function during follow-up in our patient cohort., Conclusion: In analogy with what is observed in the majority of MFS patients, the Fbn1(C1039G/+) mouse model demonstrates mild intrinsic LV dysfunction. Both extracellular matrix and molecular alterations are implicated in MFS-related cardiomyopathy. This model may now enable us to study therapeutic interventions on the myocardium in MFS.

Background: Heritable Thoracic Aortic Disorders (H-TAD) may present clinically as part of a syndromic entity or as an isolated (nonsyndromic) manifestation. About one dozen genes are now available for clinical molecular testing. Targeted single gene testing is hampered by significant clinical overlap between syndromic H-TAD entities and the absence of discriminating features in isolated cases. Therefore panel testing of multiple genes has now emerged as the preferred approach. So far, no data on mutation detection rate with this technique have been reported., Methods: We performed Next Generation Sequencing (NGS) based screening of the seven currently most prevalent H-TAD-associated genes (FBN1, TGFBR1/2, TGFB2, SMAD3, ACTA2 and COL3A1) on 264 samples from unrelated probands referred for H-TAD and related entities. Patients fulfilling the criteria for Marfan syndrome (MFS) were only included if targeted FBN1 sequencing and MLPA analysis were negative., Results: A mutation was identified in 34 patients (13%): 12 FBN1, one TGFBR1, two TGFBR2, three TGFB2, nine SMAD3, four ACTA2 and three COL3A1 mutations. We found mutations in FBN1 (N = 3), TGFBR2 (N = 1) and COL3A1 (N = 2) in patients without characteristic clinical features of syndromal H-TAD. Six TAD patients harboring a mutation in SMAD3 and one TAD patient with a TGFB2 mutation fulfilled the diagnostic criteria for MFS., Conclusion: NGS based H-TAD panel testing efficiently reveals a mutation in 13% of patients. Our observations emphasize the clinical overlap between patients harboring mutations in syndromic and nonsyndromic H-TAD related genes as well as within syndromic H-TAD entities, justifying a widespread application of this technique.

In this overview we aim to address a number of recent insights and developments regarding clinical aspects, etiology, and treatment of Heritable Thoracic Aortic Disease (H-TAD). We will focus on monogenetic disorders related to aortic aneurysms. H-TADs are rare but they provide a unique basis for the study of underlying pathogenetic pathways in the complex disease process of aneurysm formation. The understanding of pathomechanisms may help us to identify medical treatment targets to improve prognosis. Among the monogenetic aneurysm disorders, Marfan syndrome is considered as a paradigm entity and many insights are derived from the study of clinical, genetic and animal models for Marfan syndrome. We will therefore first provide a detailed overview of the various aspects of Marfan syndrome after which we will give an overview of related H-TAD entities.

Thoracic aortic dilatation requires accurate and timely detection to prevent progression to thoracic aortic aneurysm and aortic dissection. The detection of thoracic aortic dilatation necessitates the availability of cut-off values for normal aortic diameters. Tools to evaluate aortic dimension above the root are scarce and inconsistent regarding age groups. The aim of this study was to provide reference values for aortic root and ascending aortic diameters on the basis of transthoracic echocardiographic measurements in a large cohort of children and adults. Diameters at the level of the sinuses of Valsalva (SoV) and ascending aorta (AA) were assessed with transthoracic echocardiography in 849 subjects (453 females, age range 1 to 85 years, mean 40.1 ± 21.3 years) and measured according to published guidelines. Linear regression analysis was applied to create nomograms, as well as equations for upper limits of normal and z-scores. SoV and AA diameters were strongly correlated with age, body surface area (BSA), and weight (r = 0.67 to 0.79, p <0.001 for all). Male subjects had significantly larger aortic dimensions at all levels in adulthood, even after BSA correction (p ≤0.004 for all age intervals). Gender-, age-, and BSA-specific upper limits of normal and z-score equations were developed from a multivariate regression model, which strongly predicts SoV and AA diameters (adjusted R(2) for SoV = 0.84 and 0.67 and for AA = 0.82 and 0.74, for male and female subjects, respectively). In conclusion, this study provides widely applicable reference values for thoracic aortic dilatation screening purposes. Age, BSA, and gender must be taken into account when assessing an individual patient., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Loeys-Dietz syndrome (LDS) is an autosomal dominant arterial aneurysm disease belonging to the spectrum of transforming growth factor β (TGFβ)-associated vasculopathies. In its most typical form it is characterized by the presence of hypertelorism, bifid uvula/cleft palate and aortic aneurysm and/or arterial tortuosity. LDS is caused by heterozygous loss of function mutations in the genes encoding TGFβ receptor 1 and 2 (TGFBR1 and -2), which lead to a paradoxical increase in TGFβ signaling. To address this apparent paradox and to gain more insight into the pathophysiology of aneurysmal disease, we characterized a new Tgfbr1 mouse model carrying a p.Y378* nonsense mutation. Study of the natural history in this model showed that homozygous mutant mice die during embryonic development due to defective vascularization. Heterozygous mutant mice aged 6 and 12 months were morphologically and (immuno)histochemically indistinguishable from wild-type mice. We show that the mutant allele is degraded by nonsense mediated mRNA decay, expected to result in haploinsufficiency of the mutant allele. Since this haploinsufficiency model does not result in cardiovascular malformations, it does not allow further study of the process of aneurysm formation. In addition to providing a comprehensive method for cardiovascular phenotyping in mice, the results of this study confirm that haploinsuffciency is not the underlying genetic mechanism in human LDS.

Objective: Pseudoxanthoma elasticum (PXE) is an autosomal recessive connective tissue disorder with involvement of the skin, the retina, and the cardiovascular system. Cardiovascular involvement is mainly characterized by mineralization and fragmentation of elastic fibers of blood vessels and premature atherosclerosis. We conducted an ultrasound study to investigate the cardiovascular phenotype and to propose recommendations for the management of patients with PXE and heterozygous ABCC6 mutation carriers., Approach and Results: Thirty-two patients, 23 carriers, and 28 healthy volunteers underwent cardiac and vascular ultrasound studies. Cardiac imaging revealed left ventricular diastolic dysfunction in patients with PXE with a significantly prolonged deceleration time and lower septal early diastolic velocities of the mitral annulus compared with controls. Carriers also demonstrated significantly prolonged deceleration time. Carotid-to-femoral pulse wave velocity was significantly increased in patients with PXE when compared with carriers and controls. Vascular imaging revealed a high prevalence of peripheral artery disease in both patients and carriers and a significantly higher carotid intima-media thickness compared with controls., Conclusions: The results of this study clearly demonstrate impaired left ventricular diastolic function, impairment of the elastic properties of the aorta, and a high prevalence of peripheral artery disease in patients with PXE. Carriers also seem to exhibit a cardiovascular phenotype with mainly mild diastolic dysfunction and accelerated atherosclerosis. Increased awareness for cardiovascular events in both patients and heterozygous carriers is warranted.

Since the identification of the fibrillin-1 gene as the causal gene for Marfan syndrome, our knowledge of molecular genetics and the applicability of genetic testing in clinical practice have expanded dramatically. Several new syndromes related to thoracic aortic aneurysms and dissections (TAAD) have been described and the list of underlying genes in syndromal and nonsyndromal TAAD already includes more than 10 different genes and is rapidly expanding. Based on this knowledge, our insights into the underlying pathophysiology of TAAD have improved significantly, and new opportunities for targeted treatment have emerged. Clinicians involved in the care of TAAD patients require a basic knowledge of the disease entities and need to be informed on the applicability of genetic testing in their patients and families. Gene-tailored treatment and management is indeed no science fiction anymore and should now be considered as part of good clinical practice. We provide a systematic overview of genetic TAAD entities and practical recommendations for genetic testing and patient management.

Background: Thoracic aortic aneurysm/dissection (TAAD) is a common phenotype that may occur as an isolated manifestation or within the constellation of a defined syndrome. In contrast to syndromic TAAD, the elucidation of the genetic basis of isolated TAAD has only recently started. To date, defects have been found in genes encoding extracellular matrix proteins (fibrillin-1, FBN1; collagen type III alpha 1, COL3A1), proteins involved in transforming growth factor beta (TGFβ) signaling (TGFβ receptor 1 and 2, TGFBR1/2; and SMAD3) or proteins that build up the contractile apparatus of aortic smooth muscle cells (myosin heavy chain 11, MYH11; smooth muscle actin alpha 2, ACTA2; and MYLK)., Methods and Result: In 110 non-syndromic TAAD patients that previously tested negative for FBN1 or TGFBR1/2 mutations, we identified 7 ACTA2 mutations in a cohort of 43 familial TAAD patients, including 2 premature truncating mutations. Sequencing of MYH11 revealed an in frame splice-site alteration in one out of two probands with TAA(D) associated with PDA but none in the series of 22 probands from the cohort of 110 patients with non-syndromic TAAD. Interestingly, immunohistochemical staining of aortic biopsies of a patient and a family member with MYH11 and patients with ACTA2 missense mutations showed upregulation of the TGFβ signaling pathway., Conclusions: MYH11 mutations are rare and typically identified in patients with TAAD associated with PDA. ACTA2 mutations were identified in 16% of a cohort presenting familial TAAD. Different molecular defects in TAAD may account for a different pathogenic mechanism of enhanced TGFβ signaling., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Since the identification of the fibrillin‑1 gene as the causal gene for Marfan syndrome, our knowledge of molecular genetics and the applicability of genetic testing for heritable thoracic aneurysms and dissections (H-TAD) in clinical practice have increased substantially. Several new syndromes related to H-TAD have been described and the list of mutated genes in syndromal and nonsyndromal H-TAD is rapidly expanding. This knowledge has led to a significant improvement of our insight into the underlying pathophysiology of H-TAD resulting in new opportunities for targeted treatment, as well as in improved risk stratification. Clinicians involved in the care for H-TAD patients require a basic knowledge of the disease entities and need to be correctly informed on the applicability of genetic testing in their patients and families. Gene‑tailored treatment and management should now be considered as part of good clinical practice. We provide a systematic overview of genetic H-TAD entities and practical recommendations for genetic testing and patient management.