Adult congenital heart disease training in Europe: current status, disparities and potential solutions.

OBJECTIVES: This study aimed to determine the status of training of adult congenital heart disease (ACHD) cardiologists in Europe. METHODS: A questionnaire was sent to ACHD cardiologists from 34 European countries. RESULTS: Representatives from 31 of 34 countries (91%) responded. ACHD cardiology was recognised by the respective ministry of Health in two countries (7%) as a subspecialty. Two countries (7%) have formally recognised ACHD training programmes, 15 (48%) have informal (neither accredited nor certified) training and 14 (45%) have very limited or no programme. Twenty-five countries (81%) described training ACHD doctors 'on the job'. The median number of ACHD centres per country was 4 (range 0-28), median number of ACHD surgical centres was 3 (0-26) and the median number of ACHD training centres was 2 (range 0-28). An established exit examination in ACHD was conducted in only one country (3%) and formal certification provided by two countries (7%). ACHD cardiologist number versus gross domestic product Pearson correlation coefficient=0.789 (p<0.001). CONCLUSION: Formal or accredited training in ACHD is rare among European countries. Many countries have very limited or no training and resort to 'train people on the job'. Few countries provide either an exit examination or certification. Efforts to harmonise training and establish standards in exit examination and certification may improve training and consequently promote the alignment of high-quality patient care.

The multi-faceted food odorant 4-methylphenol selectively activates evolutionary conserved receptor OR9Q2.

4-Methylphenol is a food-related odor-active volatile with a high recognition factor, due to its horse stable-like, fecal odor quality. Its ambivalent hedonic impact as key aroma compound, malodor, and semiochemical has spurred the search for its cognate, chemosensory odorant receptors across species. A human odorant receptor for the highly characteristic 4-methylphenol has been elusive. Here, we identified and characterized human receptor OR9Q2 to be tuned to purified 4-methylphenol, but not to its contaminant isomer 3-methylphenol. This highly selective function of OR9Q2 complements an exclusive phenol detection gap in the ancient, most broadly tuned human odorant receptor OR2W1. Moreover, a 4-methylphenol function is evolutionary conserved in phylogenetically related OR9Q2 orthologs from chimpanzee, mouse, and cow. Notably, the cow receptor outperformed human OR9Q2 10-fold in signal strength, consonant with previous reports of 4-methylphenol as a bovine pheromone. Our results suggest OR9Q2 as best sensor for the key food odorant, malodor, and semiochemical 4-methylphenol.

Modeling the Orthosteric Binding Site of the G Protein-Coupled Odorant Receptor OR5K1.

With approximately 400 encoding genes in humans, odorant receptors (ORs) are the largest subfamily of class A G protein-coupled receptors (GPCRs). Despite its high relevance and representation, the odorant-GPCRome is structurally poorly characterized: no experimental structures are available, and the low sequence identity of ORs to experimentally solved GPCRs is a significant challenge for their modeling. Moreover, the receptive range of most ORs is unknown. The odorant receptor OR5K1 was recently and comprehensively characterized in terms of cognate agonists. Here, we report two additional agonists and functional data of the most potent compound on two mutants, L1043.32 and L2556.51. Experimental data was used to guide the investigation of the binding modes of OR5K1 ligands into the orthosteric binding site using structural information from AI-driven modeling, as recently released in the AlphaFold Protein Structure Database, and from homology modeling. Induced-fit docking simulations were used to sample the binding site conformational space for ensemble docking. Mutagenesis data guided side chain residue sampling and model selection. We obtained models that could better rationalize the different activity of active (agonist) versus inactive molecules with respect to starting models and also capture differences in activity related to minor structural differences. Therefore, we provide a model refinement protocol that can be applied to model the orthosteric binding site of ORs as well as that of GPCRs with low sequence identity to available templates.

Outcomes in CME/CPD - Special Collection: How to make the "pyramid" a perpetuum mobile.

Continuing medical education (CME) should not be an end in itself, but as expressed in Moore's pyramid, help to improve both individual patient and ultimately community, health. However, there are numerous barriers to translation of physician competence into improvements in community health. To enhance the effect CME may achieve in improving community health the authors suggest a kick-off/keep-on continuum of medical competence, and integration of aspects of public health at all levels from planning to delivery and outcomes measurement in CME.

Outcome of pregnancy in patients with structural or ischaemic heart disease: results of a registry of the European Society of Cardiology.

AIMS: To describe the outcome of pregnancy in patients with structural or ischaemic heart disease. METHODS AND RESULTS: In 2007, the European Registry on Pregnancy and Heart disease was initiated by the European Society of Cardiology. Consecutive patients with valvular heart disease, congenital heart disease, ischaemic heart disease (IHD), or cardiomyopathy (CMP) presenting with pregnancy were enrolled. Data for the normal population were derived from the literature. Sixty hospitals in 28 countries enrolled 1321 pregnant women between 2007 and 2011. Median maternal age was 30 years (range 16-53). Most patients were in NYHA class I (72%). Congenital heart disease (66%) was most prevalent, followed by valvular heart disease 25%, CMP 7%, and IHD in 2%. Maternal death occurred in 1%, compared with 0.007% in the normal population. Highest maternal mortality was found in patients with CMP. During pregnancy, 338 patients (26%) were hospitalized, 133 for heart failure. Caesarean section was performed in 41%. Foetal mortality occurred in 1.7% and neonatal mortality in 0.6%, both higher than in the normal population. Median duration of pregnancy was 38 weeks (range 24-42) and median birth weight 3010 g (range 300-4850). In centres of developing countries, maternal and foetal mortality was higher than in centres of developed countries (3.9 vs. 0.6%, P < 0.001 and 6.5 vs. 0.9% P < 0.001) CONCLUSION: The vast majority of patients can go safely through pregnancy and delivery as long as adequate pre-pregnancy evaluation and specialized high-quality care during pregnancy and delivery are available. Pregnancy outcomes were markedly worse in patients with CMP and in developing countries.

Heart Transplantation in a 14-Year-Old Boy in the Presence of Severe Out-of-Proportion Pulmonary Hypertension due to Restrictive Left Heart Disease: A Case Report.

A 14-year-old boy after balloon valvuloplasty of severe aortic valve stenosis in the neonatal period was referred for heart-lung transplantation because of high grade pulmonary hypertension and left heart dysfunction due to endocardial fibroelastosis with severe mitral insufficiency. After heart catheterization, hemodynamic parameters were invasively monitored: a course of levosimendan and initiation of diuretics led to a decrease of pulmonary capillary wedge pressure (from maximum 35 to 24 mmHg). Instead of an expected decrease, mean pulmonary artery pressures (mPAP) increased up to 80 mmHg with increasing transpulmonary pressure gradient (TPG) up to 55 mmHg. Oral bosentan and intravenous epoprostenol then led to a ~50% decrease of mPAP (TPG between 16 and 22 mmHg). The boy was listed solely for heart transplantation which was successfully accomplished 1 month later.

Acute lung failure during mechanical circulatory support.

The use of venoarterial extracorporal membrane oxygenation and ventricular assist-devices in children with end stage heart failure is well established. The use of a bridge-to-bridge strategy leads to excellent survival rates in pediatric patients. We present an adolescent, who acquired acute respiratory failure, due to possible transfusion related lung injury, and who was successfully treated with venovenous extracorporal membrane oxygenation while on ventricular assist-device support.

Brain-type natriuretic peptide secretion following febrile and afebrile seizures - a new marker in childhood epilepsy?

PURPOSE: Markers for epileptic seizures are rare and their use has not been established in the evaluation of seizures and febrile convulsions (FC). Brain-type natriuretic peptide (BNP) is a natriuretic, diuretic, and vasodilator compound first discovered in the hypothalamus but mainly synthesized in the myocardium. The aim of this study was to assess whether epileptic seizures or FC are related to increased secretion of the N-terminal fragment of BNP (NT-proBNP). METHODS: Sixty-five postictal children (43 boys, 22 girls) and 31 children with epilepsy (20 boys, 11 girls) after a seizure-free period for at least 2 months serving as controls were enrolled. Postictal NT-proBNP levels were analyzed and controlled 24-48 h thereafter. RESULTS: Plasma concentration of NT-proBNP was significantly higher 4 h postictal compared to 24-48 h postictal (p < 0.001). Subgroup analysis revealed increased NT-proBNP levels in children with tonic-clonic seizures and FC compared to children with partial motor seizures (p < 0.001), syncope (SYN; p < 0.01), or control population (p < 0.001). CONCLUSIONS: Our results suggest that elevated plasma NT-proBNP levels are not specific for cardiac dysfunction. Postictal measurement of plasma NT-proBNP seems to be useful in discriminating different types of epilepsy, FC, and SYN in childhood.

Prolonged QTc intervals and decreased left ventricular contractility in patients with propionic acidemia.

OBJECTIVE: To investigate electrophysiological and functional signs of myocardial damage in patients with propionic acidemia (PA), an inborn error of metabolism caused by deficiency of propionyl CoA carboxylase (PCC). STUDY DESIGN: In an observational longitudinal study 10 patients with PA (6 boys and 4 girls) ranging between 2.5 and 20.2 (median 9.0) years of age at last follow-up were investigated over a period of up to 20 (mean 7.4) years using 12-lead electrocardiograms (ECGs), 24-hour continuous ECG recordings, bicycle exercise testings, and echocardiography with special focus on repolarization abnormalities such as corrected QT interval (QTc) prolongation, ventricular dysrhythmias, and left ventricular systolic function. RESULTS: QTc interval was prolonged (>440 ms) in 70% of patients beyond infanthood. Continuous ECG recordings revealed rhythm disturbances in 20% of patients. M-mode echocardiographic left ventricular function was reduced (fractional shortening [FS] <30%) in 40%. One patient showed signs of dilated cardiomyopathy. CONCLUSIONS: The majority of patients with PA (even in clinically stable situations) have disturbances in cardiac electrophysiology that can contribute to cardiac complications. Possible mechanisms include effects of toxic metabolites or deprivation of essential substrates. To avoid life-threatening complications, we recommend regular cardiological evaluations in this group of patients.

Different patterns of aortic wall elasticity in patients with Marfan syndrome: a noninvasive follow-up study.

OBJECTIVE: Aortic complications determine the life expectancy of most patients with Marfan syndrome. To find out whether there is heterogenous aortic involvement among patients and, if there is, to characterize aortic patterns and response to long-term beta-blocker therapy, we investigated aortic elastic properties before and during beta-blocker treatment. METHODS: In 46 patients with Marfan syndrome (age, 17.4 +/- 11.1 years) and 46 healthy control subjects, ascending and descending aortic elastic parameters were determined noninvasively before and after 39 +/- 16 months of beta-blocker treatment with atenolol. RESULTS: Aortic diameters and distensibility distinguished Marfan patients and controls with a sensitivity of 85% and a specificity of 87%. Cluster analysis revealed 4 patterns of aortic phenotypic expression: (1) reduced ascending aortic elasticity (46% of patients), (2) diminished ascending and descending aortic elasticity (17%), (3) minimal alterations of ascending and descending aortic elasticity (20%), and (4) reduced descending aortic elasticity (17%). During follow-up, aortic elastic properties improved in 21 (70%) of 30 patients and deteriorated in 9 (30%) irrespective of beta-blocker dosage. Improvement was observed in 100% of patients (n = 7; age, 5.3 +/- 4.2 years) with end-diastolic aortic root diameters between 20 and 30 mm and in 61% of patients (14/23; age, 20.5 +/- 10.0 years) with root diameters between 30 and 52 mm. CONCLUSIONS: Aortic elastic parameters distinguish between patients with Marfan syndrome and healthy controls and show the pattern of regional aortic involvement. Improvement or deterioration during follow-up can influence therapeutic decisions to prevent aortic dissection and rupture. Young age, small root diameter, and high distensibility are favorable prognostic factors.

A bioinformatics framework for genotype-phenotype correlation in humans with Marfan syndrome caused by FBN1 gene mutations.

Mutations in the human FBN1 gene are known to be associated with the Marfan syndrome, an autosomal dominant inherited multi-systemic connective tissue disorder. However, in the absence of solid genotype-phenotype correlations, the identification of an FBN1 mutation has only little prognostic value. We propose a bioinformatics framework for the mutated FBN1 gene which comprises the collection, management, and analysis of mutation data identified by molecular genetic analysis (DHPLC) and data of the clinical phenotype. To query our database at different levels of information, a relational data model, describing mutational events at the cDNA and protein levels, and the disease's phenotypic expression from two alternative views, was implemented. For database similarity requests, a query model which uses a distance measure based on log-likelihood weights for each clinical manifestation, was introduced. A data mining strategy for discovering diagnostic markers, classification and clustering of phenotypic expressions was provided which enabled us to confirm some known and to identify some new genotype-phenotype correlations.

Reduced aortic elastic properties in a child with Takayasu arteritis: case report and literature review.

UNLABELLED: Takayasu arteritis (TA) is a chronic inflammatory vasculitis of the aorta and its major branches with a very low incidence in Europe and North America. Our objective was to determine the elastic properties of the affected ascending and descending aortic walls non-invasively in a 14-year-old Iraqi girl with a 3-year history of fever, fatigue, malaise and diffuse pain. Ultrasound and magnetic resonance angiography showed marked thickening of the aortic wall, dilatation of the aortic arch, and decreased luminal diameters of the abdominal aorta and both subclavian arteries, consistent with TA. Ascending and descending aortic elastic properties such as distensibility and stiffness index were markedly reduced compared to a group of healthy controls (n=39): ascending aortic distensibility was 20 kPa(-1) x 10(-3) versus 63+/-23 kPa(-1) x 10(-3) in controls, and the ascending aortic stiffness index 9.6 versus 3.5+/-1.3 in controls. Although the patient's general condition improved rapidly on oral prednisolone and azathioprine and inflammatory parameters normalised within 3 weeks, the aortic elastic parameters did not change during the first 2 weeks of anti-inflammatory treatment. Unfortunately, no further follow-up was possible. CONCLUSION: In patients with Takayasu arteritis, non-invasive quantification of reduced aortic elastic properties can help to assess aortic involvement, and possibly to follow disease activity and vascular response to therapy.

Interventional occlusion of a large pulmonary arteriovenous malformation with an Amplatzer septal occluder.

Interventional occlusion of pulmonary arteriovenous malformations with large feeding arteries may be associated with an increased risk of device embolization. In a 40-year-old patient with a solitary pulmonary arteriovenous malformation one large feeding artery was successfully closed by means of an Amplatzer septal occluder and detachable coils. The use of an Amplatzer septal occluder should be considered as an alternative therapeutic option in cases of huge pulmonary arteriovenous malformation to reduce the risk of device embolization.

Transesophageal echocardiography for quantifying size of patent foramen ovale in patients with cryptogenic cerebrovascular events.

BACKGROUND AND PURPOSE: Patent foramen ovale (PFO) is a risk factor for paradoxical embolism, and severe shunting and wide opening of PFO are risk factors for severe and recurrent cerebrovascular events. Neither contrast echocardiography nor 2-dimensional (2D) measurement of PFO size have been validated or compared with invasive balloon sizing. METHODS: We performed transesophageal echocardiography (TEE) in 100 patients with cryptogenic stroke and catheter closure of PFO. The amount of contrast shunting through the PFO during cubital and femoral contrast delivery and the PFO size measured by 2D TEE were compared with balloon sizing. RESULTS: There was a significant correlation (r(2)=0.8; P<0.0001) between 2D TEE measurement and invasive balloon sizing. Mean balloon-sized PFO diameter was significantly larger than mean PFO diameter measured by 2D TEE (8.3+/-2.6 versus 5.2+/-1.7 mm). Semiquantitative contrast TEE correlated with PFO size (r(2)=0.7; P<0.0001) only if the contrast agent was administered through a femoral vein. Correlation was poor when the contrast agent was administered via a cubital vein. CONCLUSIONS: We conclude that 2D TEE measurement of a PFO size is more accurate than the traditionally used contrast technique.