Evaluation of a nurse-led multi-component transition program for adolescents with congenital heart disease.

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 (ß = +13.3;p < 0.01). Adolescents' transition experiences were also positively related to TWAH (general experience: ß = +5.5;p < 0.01; transfer satisfaction: ß = +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.

Orbital atherectomy to facilitate transfemoral transcatheter aortic valve implantation in patients with calcified iliofemoral arteries: a case series.

Background: The transfemoral (TF) approach drives most of the advantages of transcatheter aortic valve implantation (TAVI) over surgical aortic valve replacement. Alternative accesses for TAVI are associated with higher complication rates, but are still considered in ∼5% of cases due to peripheral arterial disease (PAD). Percutaneous transluminal angioplasty can still allow TF-TAVI in selected cases with severe calcific PAD; however, ancillary techniques for calcium management are often needed. Case Summary: Orbital atherectomy was selected to facilitate TF-TAVI in two patients with different degrees and aspects of calcific PAD. Pre-procedural computed tomography analysis was key to choose the most appropriate technique for calcium management. We describe our experience with a step-by-step procedural approach to orbital atherectomy-assisted TF-TAVI. Discussion: PAD is not uncommon in patients affected by severe symptomatic aortic valve stenosis. Orbital atherectomy can still allow TF-TAVI in selected cases with severe calcific PAD. A meticulous patient selection and a standardized, step-wise procedural execution are mandatory to optimize outcomes.

Anatomical mapping of the membranous septum in tricuspid and bicuspid aortic valves by cardiac computed tomography.

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.

The aorta in humans and African great apes, and cardiac output and metabolic levels in human evolution.

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.

The Hammock Sign in Computed Tomography as a Detection Aid for Bicuspid Aortic Valves.

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.

The coronavirus disease pandemic among adult congenital heart disease patients and the lessons learnt - results of a prospective multicenter european registry.

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.

Multimodality 3D image fusion with live fluoroscopy reduces radiation dose during catheterization of congenital heart defects.

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 (MMIF2D-3D) and assess MMIF2D-3D impact on radiation exposure and contrast volume during cardiac catheterization of patients with congenital heart disease (CHD). Methods: We matched institutional MMIF2D-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 MMIF2D-3D (5-point Likert scale). Results: The Overall group consisted of 54 MMIF2D-3D cases. The combined and matched subgroups were pulmonary artery stenting (StentPUL), aorta angioplasty (PlastyAO), pulmonary artery angioplasty (PlastyPUL), or a combination of the latter two (Plasty). The FT of the lateral plane reduced significantly by 69.6% for the Overall MMIF2D-3D population. AKBW and DAPBW decreased, respectively, by 43.9% and 39.3% (Overall group), 49.3% and 54.9% (PlastyAO), and 36.7% and 44.4% for the Plasty subgroup. All the aforementioned reductions were statistically significant except for DAPBW in the Overall and Plasty (sub)groups. The decrease of AKBW and DAPBW in the StentPUL and PlastyPUL subgroups was not statistically significant. The decrease in the median values of the weight-normalized contrast volume (CMCBW) in all five subgroups was not significant. Cardiologists considered MMIF2D-3D very useful with a median score of 4. Conclusion: In our institution, MMIF2D-3D overall enabled significant AKBW reduction during the catheterization of CHD patients and was mainly driven by reduced FT in the lateral plane. We observed significant AKBW reduction in the Plasty and PlastyAO subgroups and DAPBW reduction in the PlastyAO subgroup. However, the decrease in CMCBW was not significant.

Aortic Annulus S-Curve: Implications for Transcatheter Aortic Valve Replacement and Related Procedures, Part 1.

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.

Serum Calcification Propensity T50 Associates with Disease Severity in Patients with Pseudoxanthoma Elasticum.

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 T50­indicative of a higher calcification propensity­was 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.

Clinical and subclinical findings in heterozygous ABCC6 carriers: results from a Belgian cohort and clinical practice guidelines.

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.

Propionyl-L-carnitine for intermittent claudication.

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.

QRS Duration During Follow-Up of Tetralogy of Fallot: How Valuable is it? Analysis of ECG Changes in Relation to Pulmonary Valve Implantation.

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/m2 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.

Clinical outcome of COVID-19 in patients with adult congenital heart disease.

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/m2 (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.

Pregnancy outcome in thoracic aortic disease data from the Registry Of Pregnancy And Cardiac disease.

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.

MEK1/2 Inhibition in Murine Heart and Aorta After Oral Administration of Refametinib Supplemented Drinking Water.

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.

A new dimension in patent foramen ovale size estimation.

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.

Efficacy of losartan as add-on therapy to prevent aortic growth and ventricular dysfunction in patients with Marfan syndrome: a randomized, double-blind clinical trial.

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.

Marfan Syndrome and Related Heritable Thoracic Aortic Aneurysms and Dissections.

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.