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The 12-lead electrocardiogram is a key component of cardiac screening in elite adolescent footballers. Current technology hampers mobile electrocardiogram monitoring that could reduce the time-to-diagnosis in symptomatic athletes. Recently, a 22-lead mobile electrocardiogram monitor, CardioSecur (Personal MedSystems GmbH), has been approved for use in adults. In this study, the differences in parameter accuracy between CardioSecur’s 22-lead electrocardiogram and the gold standard 12-lead electrocardiogram were assessed in elite adolescent footballers (n=31) using Bland-Altman and paired t-tests/Wilcoxon analysis. Agreement between the two devices was clinically acceptable for heart rate (bias=− 0.633 bpm), PR Interval (bias=− 1.73 ms), Bazzett’s corrected QTc interval (bias=2.03 ms), T-wave axis (bias=6.55°), P-wave duration (bias=− 0.941 ms), Q-wave amplitude (bias=0.0195 mV), Q-wave duration (bias=1.98 ms), rhythm (bias=0.0333), ST-segment (bias=− 0.0629), J-point analysis (bias=− 0.01) and extended T wave and QRS duration analysis. Unsatisfactory agreement was observed in QRS axis (bias=− 19.4°), P-wave axis (bias=− 0.670°), QRS amplitude (bias=− 0.660 mV), P-wave amplitude (bias=0.0400 mV) and T-wave amplitude (bias=− 0.0675 mV). CardioSecur’s 22-lead electrocardiogram agrees with the gold standard in rhythm, durations, T-wave determination in all leads assessed, permitting its use in adolescent footballers for immediate pitch- or track-side analysis.

Current echocardiographic criteria cannot accurately differentiate exercise induced left ventricular (LV) hypertrabeculation in athletes from LV non-compaction cardiomyopathy (LVNC). This study aims to evaluate the role of speckle tracking echocardiography (STE) in characterising LV myocardial mechanics in healthy adolescent athletes with and without LVNC echocardiographic criteria.Adolescent athletes evaluated at three sports academies between 2014 and 2019 were considered for this observational study. Those meeting the Jenni criteria for LVNC (end-systolic non-compacted/compacted myocardium ratio 2 in any short axis segment) were considered LVNC+ and the rest LVNC-. Peak systolic LV longitudinal strain (SA total of 417 participants were included, mean age 14.5 ± 1.7 years, of which 6.5% were LVNC+ (n = 27). None of the athletes showed any additional LVNC clinical criteria. All average SAmong healthy adolescent athletes, 6.5% met the echocardiographic criteria for LVNC, but showed normal LV STE parameters, in contrast to available data on paediatric LVNC describing abnormal myocardial function. STE could better characterise the myocardial mechanics of athletes with LV hypertrabeculation, thus allowing the transition from structural to functional LVNC diagnosis, especially in suspected physiological remodelling.

Purpose Few data exist on the descriptions of LV myocardial mechanics and reserve during dynamic exercise of adolescent athletes. The aim of this study was to describe the LV myocardial and cardiopulmonary changes during exercise using 2-D strain deformation imaging. Methods Elite adolescent male football players (n = 42) completed simultaneous cardiopulmonary exercise testing (CPET) and exercise echocardiography measurement of LV myocardial deformation by 2-D strain imaging. LV longitudinal and circumferential 2-D strain and strain rates were analyzed at each stage during incremental exercise to a work rate of 150 W. Additionally, exercise LV myocardial deformation and its relation to metabolic exercise parameters were evaluated at each exercise stage and in recovery using repeated measures ANOVA, linear regression and paired t tests. Results LV peak systolic baseline 2-D strain (longitudinal: − 15.4 ± 2.5%, circumferential: − 22.5 ± 3.1%) increased with each exercise stage, but longitudinal strain plateaued at 50 W (mean strain reserve − 7.8 ± 3.0) and did not significantly increase compared to subsequent exercise stages (P > 0.05), whilst circumferential strain (mean strain reserve − 11.6 ± 3.3) significantly increased (P 2 and O2 pulse (P Conclusion This study describes LV myocardial deformation dynamics by 2-D strain and provides reference values for LV myocardial strain and strain rate during exercise in adolescent footballers. It found important differences between LV longitudinal and circumferential myocardial mechanics during exercise and introduces a methodology that can be used to quantify LV function and cardiac reserve during exercise in adolescent athletes.

SARS-CoV-2 is the causative virus responsible for the COVID-19 pandemic. This pandemic has necessitated that all professional and elite sport is either suspended, postponed or cancelled altogether to minimise the risk of viral spread. As infection rates drop and quarantine restrictions are lifted, the question how athletes can safely resume competitive sport is being asked. Given the rapidly evolving knowledge base about the virus and changing governmental and public health recommendations, a precise answer to this question is fraught with complexity and nuance. Without robust data to inform policy, return-to-play (RTP) decisions are especially difficult for elite athletes on the suspicion that the COVID-19 virus could result in significant cardiorespiratory compromise in a minority of afflicted athletes. There are now consistent reports of athletes reporting persistent and residual symptoms many weeks to months after initial COVID-19 infection. These symptoms include cough, tachycardia and extreme fatigue. To support safe RTP, we provide sport and exercise medicine physicians with practical recommendations on how to exclude cardiorespiratory complications of COVID-19 in elite athletes who place high demand on their cardiorespiratory system. As new evidence emerges, guidance for a safe RTP should be updated.

Background Numerous studies have measured the prognostic associations between cardiorespiratory fitness and patient outcomes in congenital heart disease, but no systematic review has assessed these associations for all types of congenital heart disease. It is therefore a timely opportunity to syntheses all available data using a systematic review methodology. The aim of this study is to detail the protocol for a systematic review and meta-analysis. Objectives Within this paper we have developed a protocol for a prognostic factors systematic review and meta-analysis, to assess the role of cardiopulmonary exercise testing/cardiorespiratory fitness, in the prognosis of mortality and morbidity in congenital heart disease. Methods We have outlined, in detail, the process for this systematic review using the latest accepted methodological guidelines for prognostic factors research, such as the PICOTS system, CHARMS-PF data extraction, QUIPS risk of bias assessments and the prognostic GRADE guidelines (see list of abbreviations). Conclusion The implications of this review will aid future treatments, interventions and individual patient risk prediction. The publication of this protocol aims to improve scientific rigour by ensuring transparency in the systematic review and meta-analysis process.

The success of systematic early age talent development has led to the professionalisation of youth sports academies used by clubs and governing bodies alike, and sports physicians are nowadays commonly confronted with paediatric cardiological problems. Medical cardiac care of the paediatric athlete is however in its infancy, and the international guidelines that are present for adult athletes, are not yet available. Similarly, reference data for ECG and echocardiography are incomplete. The aim of this article is to provide and introduction to the cardiac care of the paediatric athlete to facilitate healthy and above all, safe talent development, but also provide guidance on how to distinguish adaptive, beneficial cardiovascular remodelling from underlying pathology of congenital or inherited cardiovascular disease. Differences in presentation, diagnosis and treatment between childhood and adult athletes are highlighted and can educate the reader in the emerging field of paediatric sports cardiology.

Sports Cardiology practice commonly involves the evaluation of athletes for genetically determined cardiac conditions that may predispose to malignant arrhythmias, heart failure, and sudden cardiac death. High-level exercise can lead to electrical and structural cardiac remodelling which mimics inherited cardiac conditions (ICCs). Differentiation between 'athlete's heart' and pathology can be challenging and often requires the whole armamentarium of available investigations. Genetic studies over the last 30 years have identified many of the genetic variants that underpin ICCs and technological advances have transformed genetic testing to a more readily available and affordable clinical tool which may aid diagnosis, management, and prognosis. The role of genetic testing in the evaluation and management of athletes with suspected cardiac conditions is often unclear beyond the context of specialist cardio-genetics centres. This document is aimed at physicians, nurses, and allied health professionals involved in the athlete's care. With the expanding role and availability of genetic testing in mind, this document was created to address the needs of the broader sports cardiology community, most of whom work outside specialized cardio-genetics centres, when faced with the evaluation and management of athletes with suspected ICC. The first part of the document provides an overview of basic terminology and principles and offers guidance on the appropriate use of genetic testing in the assessment of such athletes. It outlines key considerations when contemplating genetic testing, highlighting the potential benefits and pitfalls, and offers a roadmap to genetic testing. The second part of the document presents common clinical scenarios in Sports Cardiology practice, outlining the diagnostic, prognostic, and therapeutic implications of genetic testing, including impact on exercise recommendations. The scope of this document does not extend to a comprehensive description of the genetic basis, investigation, or management of ICCs.

While invasive assessment of hemodynamics and testing of acute vasoreactivity in the catheterization laboratory is the gold standard for diagnosing pulmonary hypertension (PH) and pulmonary vascular disease (PVD) in children, transthoracic echocardiography (TTE) serves as the initial diagnostic tool. International guidelines suggest several key echocardiographic variables and indices for the screening studies when PH is suspected. However, due to the complex anatomy and special physiological considerations, these may not apply to patients with congenital heart disease (CHD). Misinterpretation of TTE variables can lead to delayed diagnosis and therapy, with fatal consequences, or–on the other hand-unnecessary invasive diagnostic procedures that have relevant risks, especially in the pediatric age group. We herein provide an overview of the echocardiographic workup of children and adolescents with PH with a special focus on children with CHD, such as ventricular/atrial septal defects, tetralogy of Fallot or univentricular physiology. In addition, we address the use of echocardiography as a tool to assess eligibility for exercise and sports, a major determinant of quality of life and outcome in patients with PH associated with CHD.

Congenital heart disease (ConHD) represents 1% of global births (95% CI 0.86% to 1.02%), and due to improved medical care, long-term survival rates have substantially improved, leading to growing ConHD populations across the life span.1 2 People with ConHD can have reduced cardiorespiratory fitness (CRF), health-related quality of life (HRQoL) and physical activity (PA) levels when compared with healthy populations. This is important because CRF has been significantly associated with future mortality and morbidity in healthy and ConHD populations.3 4 ### Objective There is currently no high-level evidence evaluating the effect of exercise in patients with ConHD. To inform current practice and policy, we therefore sought to undertake a systematic review and meta-analysis of randomised controlled trials (RCTs) to assess the effectiveness and safety of all types of PA interventions in people with ConHD.5 ### Searches A search was performed through to September 2019 in the following databases: Cochrane Central Register of Controlled Trials, MEDLINE, Embase and CINAHL, AMED, BIOSIS, Web of Science, LILACS and DARE. ### Study selection We included any type of RCT that compared a PA intervention to a usual care (no PA) comparator. We included all types of interventions, all settings (hospital and home) and both paediatric (5–18 years old) and adult (>18) populations. Our outcomes of interest were maximal and submaximal CRF, HRQoL, PA, muscular strength, hospital admissions during follow-up, time off work/education and any adverse events (AEs), although these did not limit study inclusion. ### Data extraction and risk of bias (RoB) assessment Data extraction and RoB assessment were carried out independently by two authors. We used piloted data extraction templates and assessed study RoB using the revised Cochrane RoB 2 tool. Any disagreements were resolved by consensus and decisions were independently checked by a third author. ### Data analysis Where possible, study outcomes were pooled using meta-analysis. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was used to assess …

Background Barth syndrome (BS) is a life-threatening genetic disease caused by abnormal lipids in the mitochondria of cells and mostly affects young males. Those living with BS have severe exercise intolerance, lethargy and fatigue due to muscle disease which affect their daily life. Previous research suggests a need for qualitative exploration of self-regulation in BS and the inter-personal processes at play in family life. Therefore this study aimed to explore self-regulation and coping strategies and inter-personal responses in individuals and families affected by Barth syndrome. A multi-perspective qualitative study based on face to face, semi-structured, in-depth interviews with 11 participants (9–27 years, mean 15 years) with BS and/or their parents participating in a randomised double-blind clinical drug trial (CARDIOMAN). Interviews were transcribed verbatim and managed in NVivo prior to conducting a thematic analysis (AS and GH). Results Four key themes were identified: diagnosis and treatment, social support, identity and social integration, symptoms and self-regulation. The present findings suggest that self-regulation and coping in boys with BS was interpersonal and contingent on parental awareness such that parents were aware that their child had a limited energy reserve and that had to be managed due to the implications of fatigue for daily living. Conclusion The findings support previous quantitative work demonstrating that children and parents tend to share a coherent view of BS. However, there is a need for greater awareness from others within the wider context of social and employment networks to minimise adverse implications for future life choices.

Exercise and physical activity (PA) have been shown to be effective, safe and feasible in both healthy children and children with congenital heart disease (CHD). However, implementing exercise training as an intervention is still not routine in children with CHD despite considerable evidence of health benefits and well-being. Understanding how children with CHD can safely participate in exercise can boost participation in PA and subsequently reduce inactivity-related diseases. Home-based exercise intervention, with the use of personal wearable activity trackers, and high-intensity interval training have been beneficial in adults’ cardiac rehabilitation programmes. However, these remain underutilised in paediatric care. Therefore, the aims of this narrative review were to synthesise prescribed exercise interventions in children with CHD, identify possible limitation to exercise training prescription and provide an overview on how to best integrate exercise intervention effectively for this population into daily practice.

Aims The role of cardiopulmonary exercise testing (CPET) in predicting major adverse cardiovascular events (MACE) in people with congenital heart disease (ConHD) is unknown. A systematic review with meta-analysis was conducted to report the associations between CPET parameters and MACE in people with ConHD. Methods and results Electronic databases were systematically searched on 30 April 2020 for eligible publications. Two authors independently screened publications for inclusion, extracted study data, and performed risk of bias assessment. Primary meta-analysis pooled univariate hazard ratios across studies. A total of 34 studies (18 335 participants; 26.2 ± 10.1 years; 54% ± 16% male) were pooled into a meta-analysis. More than 20 different CPET prognostic factors were reported across 6 ConHD types. Of the 34 studies included in the meta-analysis, 10 (29%), 23 (68%), and 1 (3%) were judged as a low, medium, and high risk of bias, respectively. Primary univariate meta-analysis showed consistent evidence that improved peak and submaximal CPET measures are associated with a reduce risk of MACE. This association was supported by a secondary meta-analysis of multivariate estimates and individual studies that could not be numerically pooled. Conclusion Various maximal and submaximal CPET measures are prognostic of MACE across a variety of ConHD diagnoses. Further well-conducted prospective multicentre cohort studies are needed to confirm these findings.

Speckle tracking echocardiography (STE) has gained importance in the evaluation of adult inherited cardiomyopathies, but its utility in children is not well characterized. We conducted a systematic review to evaluate the role of STE in pediatric inherited cardiomyopathies. PubMed, EMBASE, Web of Science, Scopus, CENTRAL and CINAHL databases were searched up to May 2020, for terms related to inherited cardiomyopathies and STE. Included were dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), left ventricular non-compaction (LVNC) and arrhythmogenic cardiomyopathy (ACM). A total of 14 cohorts were identified, of which six were in DCM, four in HCM, three in LVNC and one in ACM. The most commonly reported STE measurements were left ventricular longitudinal strain (Sl), circumferential strain (Sc), radial strain (Sr) and rotation/torsion/twist. Sl, Sc and were abnormal in all DCM and LVNC cohorts, but not in all HCM. Apical rotation and twist/torsion were increased in HCM, and decreased in LVNC. Abnormal STE parameters were reported even in cohorts with normal non-STE systolic/diastolic measurements. STE in childhood cardiomyopathies can detect early changes which may not be associated with changes in cardiac function detectable by non-STE methods. Longitudinal and circumferential strain should be introduced in the cardiomyopathy echocardiography protocol, reflecting current practice in adults.

Athlete preparticipation screening focuses on preventing sudden cardiac death (SCD) by detecting diseases such as arrhythmogenic ventricular cardiomyopathy (AVC), which affects primarily the right ventricular myocardium. Diagnosis may be obscured by physiological remodeling of the athlete heart. Healthy athletes may meet the 2010 Task Force Criteria right ventricular outflow tract (RVOT) dimension cut-offs, questioning the suitability of the modified Task Force Criteria (mTFC) in adolescent athletes. In this study, 67 male adolescent footballers undergoing preparticipation screening were reviewed. All athletes underwent a screening for resting ECG and echocardiogram according to the English FA protocol, as well as cardiopulmonary exercise testing, stress ECG, and exercise echocardiography. Athletes’ right ventricular outflow tract (RVOT) that met the major AVC diagnostic criteria for dilatation were identified. Of 67 evaluated athletes, 7 had RVOT dilatation that met the major criteria, all in the long axis parasternal view measurement. All had normal right ventricular systolic function, including normal free-wall longitudinal strain (ranging from − 21.5 to − 32.7%). Left ventricular ejection fraction ranged from 52 to 67%, without evidence of structural changes. Resting ECGs and cardiopulmonary exercise tests were normal in all individuals. In a series of healthy athletes meeting the major AVC diagnostic criteria for RVOT dilatation, none had any other pathological changes on a detailed screening including ECG, exercise testing, and echocardiography. This report highlights that current AVC echocardiographic diagnosis criteria have limitations in this population.

Funding Acknowledgements Type of funding sources: Other. Main funding source(s): The study was support by a contractual research partnership between the University of Bristol and Canon Medical Systems UK Background Left ventricular non-compaction (LVNC) is a rare cardiomyopathy, with hypertrabeculation often observed in athletes. In confirmed LVNC, LV systolic strain and rotational mechanics have been shown to be abnormal. Whether healthy athletes meeting echocardiographic LVNC criteria exhibit abnormal myocardial mechanics is not known. Purpose The aim of this study is to evaluate the prevalence of healthy paediatric athletes meeting the Jenni criteria for LVNC and how this relates to LV systolic function and rotational mechanics. Methods Professional athletes under 18 years undergoing comprehensive pre-participation screening (2014-2017) at two sports academies were included. Jenni criteria for LVNC were assessed from short axis LV views. Global and segmental peak systolic longitudinal (Sl) and circumferential strain (Sc), basal rotation (basal Rot) and apical rotation (apical Rot) were calculated using speckle tracking imaging. Results A total of 201 boys (11.9-18 years, median 15.1 years) were included, with diverse ethnicity (47.7% Arab, 28.5% Black, 21.8% White, and 2% other) and sports background (60% football, 21.2% athletics, 18.8% other). Of these n = 16 (8%) met the Jenni criteria for LVNC and were more likely to be of Black ethnicity than Arab or White (12.7% vs 4.4% or 9.5%). There were no differences in global, lateral or septal Sl, basal, mid or apical Sc, basal Rot or apical Rot between participants with or without Jenni criteria for LVNC (Table 1). Conclusions In healthy paediatric athletes, those meeting the criteria for LVNC (8%) do not have abnormal longitudinal, circumferential strain and rotational mechanics, compared to those without LVNC criteria. This finding supports the use of speckle tracking echocardiography as a tool in differentiating pathological changes reported in LVNC from exercise associated adaptations observed in athletes during preparticipation screening. LV mechanics Jenni criteria presence With Jenni criteria Median (IQR) Without Jenni criteria Median (IQR) p value Global LV Sl -18.6% (-19.1;-17.7) -18.6% (-19.7;-17.8) 0.7 Lateral Sl -18.3% (-18.8;-17.2) -18.5% (-19.8;-17.6) 0.5 Septal Sl -18.6% (-20.6;-17.3) -18.7% (-20.1;-17.7) 0.7 Basal LV Sc -23% (-24.6;-21.6) -23.3% (-25.7;-21.6) 0.7 Mid LV Sc -24.9% (-27.1;-23.2) -25.1% (-27.1;-22.5) 0.9 Apical LV Sc -27.8% (-32.3;-24.8) -26% (30.5;-22.4) 0.2 Basal Rot -4o (-4.7;-2.5) -3.8o (-5.3;-2.5) 0.9 Apical Rot 6.4o (5.2;7.1) 4.4 (2.9;7.1) 0.2

Funding Acknowledgements Type of funding sources: Other. Main funding source(s): The study was support by a contractual research partnership between the University of Bristol and Canon Medical Systems UK. Background Arrhytmogenic cardiomyopathy (ACM) is a major cause of sudden cardiac death among young athletes. Screening these individuals can be challenging due to right ventricular (RV) exercise-related remodelling, particularly right ventricular outflow tract (RVOT) dilation. Recent studies have also shown that peak RV longitudinal strain (Sl) measured by speckle tracking echocardiography (STE) is reduced in adolescents with definite and borderline ACM. The prevalence of RV changes meeting ACM criteria in healthy paediatric athletes, and whether these changes are associated with abnormal RV strain values is not known. Purpose The aim of this study is to evaluate the prevalence of healthy paediatric athletes meeting the ACM echocardiographic modified Task Force Criteria (mTFC) for RVOT dilation, and how this relates to RV longitudinal systolic function. Methods Athletes under 18 years old undergoing comprehensive pre-participation screening (2014-2017) at two sports academies were included. Global (RV-Sl) and free wall peak systolic strain (FW-Sl) were calculated using STE. Three groups were defined: meeting the major mTFC for RVOT size (M-mTFC), meeting the minor mTFC (m-mTFC) and not meeting the mTFC (no-mTFC). RV-Sl and FW-Sl were compared using the Kruskall Wallis test. Results A total of 247 boys (11.1-18 years, median 14.6 years) were included, with diverse ethnicity (53.1% Arab, 27.6% Black, 17.6% White, and 1.7% other) and sports background (50.6% football, 27.9% athletics, 21.5% other). Of these n = 22 were in the M-mTFC group (8.9%), n = 93 in the m-mTFC group (37.7%) and n = 132 in the no-mTFC group (53.4%). No regional RV wall motion abnormalities were observed. There were no differences in RV-Sl or FW-Sl by mTFC Group (Table 1). Conclusions In healthy paediatric athletes, 9% met the major mTFC, and 38% met the minor mTFC for RVOT size. RV longitudinal strain was found to be similar between those who met the mTFC and those who did not. This highlights the probable non-pathological adaptations reflected by RVOT dilation in these individuals, as opposed to those seen in ACM. The results of this study suggest that STE can be a valuable tool in ACM screening in paediatric athletes, especially in cases where RV remodelling is present. RV peak longitudinal strain by mTFC All M-mTFC n = 22 m-mTFC n = 93 no-mTFC n = 132 p value for between group comparison Global RV Sl (median, IQR) -23.3% (-25.2;-21.7) -23.3% (-25.5;-21.7) -23.4% (-25;-21.7) -23.3% (-25.5;-21.7) p = 0.8 Free wall RV Sl (median, IQR) 27.7% (-30;-25.2) -27.6% (-29.3;-25.2%) -28.1% (-29.7;-25) -27.5 (-30.5;-25.4) p = 0.9

IntroductionSurgical repair of congenital heart defects often requires the use of cardiopulmonary bypass (CPB) and cardioplegic arrest. Cardioplegia is used during cardiac surgery requiring CPB to keep the heart still and to reduce myocardial damage as a result of ischaemia–reperfusion injury. Cold cardioplegia is the prevalent method of myocardial protection in paediatric patients; however, warm cardioplegia is used as part of usual care throughout the UK in adults. We aim to provide evidence to support the use of warm versus cold blood cardioplegia on clinical and biochemical outcomes during and after paediatric congenital heart surgery.Methods and analysisWe are conducting a single-centre randomised controlled trial in paediatric patients undergoing operations requiring CPB and cardioplegic arrest at the Bristol Royal Hospital for Children. We will randomise participants in a 1:1 ratio to receive either ‘cold-blood cardioplegia’ or ‘warm-blood cardioplegia’. The primary outcome will be the difference between groups with respect to Troponin T levels over the first 48 postoperative hours. Secondary outcomes will include measures of cardiac function; renal function; cerebral function; arrythmias during and postoperative hours; postoperative blood loss in the first 12 hours; vasoactive-inotrope score in the first 48 hours; intubation time; chest and wound infections; time from return from theatre until fit for discharge; length of postoperative hospital stay; all-cause mortality to 3 months postoperative; myocardial injury at the molecular and cellular level.Ethics and disseminationThis trial has been approved by the London – Central Research Ethics Committee. Findings will be disseminated to the academic community through peer-reviewed publications and presentation at national and international meetings. Patients will be informed of the results through patient organisations and newsletters to participants.Trial registration numberISRCTN13467772; Pre-results.

BACKGROUND Barth syndrome is a rare, life-threatening, X-linked recessive genetic disease that predominantly affects young males and is caused by abnormal mitochondrial lipid metabolism. Currently, there is no definitive treatment for Barth syndrome other than interventions to ameliorate acute symptoms, such as heart failure, cardiac arrhythmias, neutropenia, and severe muscle fatigue. Previous mechanistic studies have identified the lipid-lowering drug bezafibrate as a promising potential treatment; however, to date, no human trials have been performed in this population. OBJECTIVE The aim of this study is to determine whether bezafibrate (and resveratrol in vitro) will increase mitochondrial biogenesis and potentially modify the cellular ratio of monolysocardiolipin (MLCL) to tetralinoleoyl-cardiolipin (L4-CL), ameliorating the disease phenotype in those living with the disease. METHODS The CARDIOMAN (Cardiolipin Manipulation) study is a UK single-center, double-blinded, randomized, placebo-controlled crossover study investigating the efficacy of bezafibrate in participants with Barth syndrome. Treatment was administered in two 15-week phases with a minimum washout period of 1 month between the phases where no treatment was administered. The primary outcome is peak oxygen consumption (VO2 peak). Secondary outcomes include MLCL/L4-CL ratio and CL profile in blood cells, amino acid expression, phosphocreatine to adenosine triphosphate ratio in cardiac muscle and skeletal muscle oxidative function on phosphorus-31 magnetic resonance spectroscopy, quality of life using the Pediatric Quality of Life Inventory questionnaire, absolute neutrophil count, cardiac function and rhythm profiles at rest and during exercise, and mitochondrial organization and function assessments. Outcomes were assessed at baseline and during the final week of each treatment phase. RESULTS A total of 12 patients were scheduled to participate across three consecutive research clinics between March and April 2019. In total, 11 participants were recruited, and the follow-up was completed in January 2020. Data analysis is ongoing, with publication expected in 2021. CONCLUSIONS This trial was approved by the United Kingdom National Research Ethics Service Committee and the Medicines and Healthcare products Regulatory Agency. The feasibility of the CARDIOMAN study will help to inform the future conduct of randomized controlled trials in rare disease populations as well as testing the efficacy of bezafibrate as a potential treatment for the disease and advancing the mechanistic understanding of Barth syndrome. CLINICALTRIAL International Standard Randomized Controlled Trial Number (ISRCTN): 58006579; https://www.isrctn.com/ISRCTN58006579 INTERNATIONAL REGISTERED REPORT DERR1-10.2196/22533

Improved clinical care has led to an increase in the number of adults with congenital heart disease (CHD) engaging in leisure time and competitive sports activities. Although the benefits of exercise in patients with CHD are well established, there is a low but appreciable risk of exercise-related complications. Published exercise recommendations for individuals with CHD are predominantly centred on anatomic lesions, hampering an individualized approach to exercise advice in this heterogeneous population. This document presents an update of the recommendations for competitive sports participation in athletes with cardiovascular disease published by the Sports Cardiology & Exercise section of the European Association of Preventive Cardiology (EAPC) in 2005. It introduces an approach which is based on the assessment of haemodynamic, electrophysiological and functional parameters, rather than anatomic lesions. The recommendations provide a comprehensive assessment algorithm which allows for patient-specific assessment and risk stratification of athletes with CHD who wish to participate in competitive sports.

The success of systematic early age talent development has led to the professionalisation of youth sports academies used by clubs and governing bodies alike, and sports physicians are nowadays commonly confronted with paediatric cardiological problems. This has led to calls from the International Olympic Committee, amongst others, for more diligence to safeguard the psycho-physiological development of the paediatric athlete. Medical cardiac care of the paediatric athlete however is in its infancy and international guidelines, present for many common adult sports cardiology scenarios, are not available yet. The aim of this chapter is to provide a practical approach to the cardiac care of the paediatric athlete to facilitate healthy and above all, safe talent development, but also provide guidance on how to distinguish adaptive, beneficial cardiovascular remodelling from underlying pathology of congenital or inherited cardiovascular disease, including cardiomyopathies and arrhythmias. Differences in presentation, diagnosis and treatment between childhood and adult athletes are highlighted and can educate the reader in the emerging field of paediatric sports cardiology.

ObjectiveHistorically, electrocardiographic (ECG) interpretation criteria for athletes were only applicable to adults. New international recommendations now account for athletes ≤16 years, but their clinical appropriateness is unknown. We sought to establish the diagnostic accuracy of new international ECG recommendations against the Seattle criteria and 2010 European Society of Cardiology (ESC) recommendations in paediatric athletes using receiver operator curve analysis. Clinical context was calculated using Bayesian analysis.Methods876 Arab and 428 black male paediatric athletes (11–18 years) were evaluated by medical questionnaire, physical examination, ECG and echocardiographic assessment. ECGs were retrospectively analysed according to the three criteria.ResultsThirteen (1.0%) athletes were diagnosed with cardiac pathology that may predispose to sudden cardiac arrest/death (SCA/D) (8 (0.9%) Arab and (5 (1.2%) black)). Diagnostic accuracy was poor (0.68, 95% CI 0.54 to 0.82) for 2010 ESC recommendations, fair (0.70, 95% CI 0.54 to 0.85) for Seattle criteria and fair (0.77, 95% CI 0.61 to 0.93) for international recommendations. False-positive rates were 41.0% for 2010 ESC recommendations, 21.8% for Seattle criteria and 6.8% for international recommendations. International recommendations provided a positive (+LR) and negative (−LR) post-test likelihood ratio of 9.0 (95% CI 5.1 to 13.1) and 0.4 (95% CI 0.2 to 0.7), respectively.ConclusionIn Arab and black male paediatric athletes, new international recommendations outperform both the Seattle criteria and 2010 ESC recommendations, reducing false positive rates, while yielding a ‘fair’ diagnostic accuracy for cardiac pathology that may predispose to SCA/D. In clinical context, the ‘chance’ of detecting cardiac pathology within a paediatric male athlete with a positive ECG (+LR=9.0) was 8.3%, whereas a negative ECG (−LR=0.4) was 0.4%.

The European Pediatric Pulmonary Vascular Disease Network is a registered, non-profit organization that strives to define and develop effective, innovative diagnostic methods and treatment options in all forms of pediatric pulmonary hypertensive vascular disease, including pulmonary hypertension (PH) associated with bronchopulmonary dysplasia, PH associated with congenital heart disease (CHD), persistent PH of the newborn, and related cardiac dysfunction. The executive writing group members conducted searches of the PubMed/MEDLINE bibliographic database (1990-2018) and held face-to-face and web-based meetings. Ten section task forces voted on the updated recommendations, based on the 2016 executive summary. Clinical trials, meta-analyses, guidelines, and other articles that include pediatric data were searched using the term "pulmonary hypertension" and other keywords. Class of recommendation (COR) and level of evidence (LOE) were assigned based on European Society of Cardiology/American Heart Association definitions and on pediatric data only, or on adult studies that included >10% children or studies that enrolled adults with CHD. New definitions by the World Symposium on Pulmonary Hypertension 2018 were included. We generated 10 tables with graded recommendations (COR/LOE). The topics include diagnosis/monitoring, genetics/biomarkers, cardiac catheterization, echocardiography, cardiac magnetic resonance/chest computed tomography, associated forms of PH, intensive care unit/lung transplantation, and treatment of pediatric PH. For the first time, a set of specific recommendations on the management of PH in middle- and low-income regions was developed. Taken together, these executive, up-to-date guidelines provide a specific, comprehensive, detailed but practical framework for the optimal clinical care of children and young adults with PH.

Background International electrocardiographic (ECG) recommendations regard anterior T-wave inversion (ATWI) in athletes under 16 years to be normal. Design The aim of this study was to identify the prevalence, distribution and determinants of TWI by ethnicity, chronological and biological age within paediatric athletes. A second aim was to establish the diagnostic accuracy of international ECG recommendations against refinement within athletes who present with ECG variants isolated to ATWI (V1–V4) using receiver operator curve analysis. Clinical context was calculated using Bayesian analysis. Methods Four hundred and eighteen Arab and 314 black male athletes (11–18 years) were evaluated by ECG, echocardiogram and biological age (by radiological X-ray) assessment. Results A total of 116 (15.8%) athletes presented with ATWI (V1–V4), of which 96 (82.8%) were observed in the absence of other ECG findings considered to be abnormal as per international recommendations for ECG interpretation in athletes; 91 (12.4%) athletes presented with ATWI confined to V1–V3, with prevalence predicted by black ethnicity (odds ratio (OR) 2.2, 95% confidence interval (CI) 1.3–3.5) and biological age under 16 years (OR 2.0, 95% CI 1.2–3.3). Of the 96 with ATWI (V1–V4) observed in the absence of other ECG findings considered to be abnormal, as per international recommendations for ECG interpretation in athletes, diagnostic accuracy was ‘fail’ (OR 0.47, 95% CI 0.00–1.00) for international recommendations and ‘excellent’ (OR 0.97, 95% CI 0.92–1.00) when governed by biological age under 16 years, providing a positive and negative likelihood ratio of 15.8 (95% CI 1.8–28.1) and 0.0 (95% CI 0.0–0.8), respectively. Conclusion Interpretation of ECG variants isolated with ATWI (V1–V4) using international recommendations (chronological age

An increasing number of patients with congenital heart disease (CHD) are participating in regular sport at levels ranging from gentle recreational activities to elite professional sport. In general, children and adults with CHD should be encouraged to engage in regular physical activity, but long-term complications, such as heart failure, arrhythmias, and the need for re-operation, can occur. The sports cardiologist must be alert to the presence of underlying CHD, as physiology, haemodynamics, and functional status can change with time even after correction or palliation and intervention may be necessary before the onset of major symptoms. Although consensus management guidelines for adults with CHD are available, there is very little lesion-specific advice on sports and exercise. The wide range of diagnoses and pathophysiology make regular and individualized assessment essential. Assessment tools include ECG, echocardiogram, and CMR, but regular comprehensive functional exercise assessment is recommended. Care of the athlete with CHD should be coordinated in close collaboration with congenital heart specialists.

Athlete’s heart occurs in childhood but is less well understood than in adults. In children, exercise-related cardiac remodelling occurs but with more heterogeneity than in adults. It can be difficult to distinguish age-related cardiac maturation, exercise-related adaptation, and the early manifestation of cardiac disease such as cardiomyopathy. The initial assessment of a child with possible athlete’s heart includes a detailed history (medical, family, and exercise), comprehensive physical examination, ECG, and echocardiography. Congenital and structural heart disease should be excluded and the pubertal stage should be considered when interpreting findings. Investigations should be interpreted according to somatic size (using centiles) and pubertal stage rather than chronological age. Ethnic variations in physiology should be identified. If in doubt, child athletes with possible ethnically related changes should be followed up until maturity. T-wave inversion in anteroseptal leads is usually normal before puberty but abnormal after puberty. Lateral T-wave inversion is usually abnormal at any age. Voltage criteria for left ventricular hypertrophy are common in healthy child athletes. The presence of pathological Q waves, T-wave inversion, and ST-segment depression requires exclusion of cardiomyopathy. Most child athletes’ heart chamber size is within the normal reference ranges for age/gender, but hypertrophic cardiomyopathy should be considered in adolescent athletes with wall thickness >12mm (girls >11mm).

Background Barth syndrome is a rare, life-threatening, X-linked recessive genetic disease that predominantly affects young males and is caused by abnormal mitochondrial lipid metabolism. Currently, there is no definitive treatment for Barth syndrome other than interventions to ameliorate acute symptoms, such as heart failure, cardiac arrhythmias, neutropenia, and severe muscle fatigue. Previous mechanistic studies have identified the lipid-lowering drug bezafibrate as a promising potential treatment; however, to date, no human trials have been performed in this population. Objective The aim of this study is to determine whether bezafibrate (and resveratrol in vitro) will increase mitochondrial biogenesis and potentially modify the cellular ratio of monolysocardiolipin (MLCL) to tetralinoleoyl-cardiolipin (L4-CL), ameliorating the disease phenotype in those living with the disease. Methods The CARDIOMAN (Cardiolipin Manipulation) study is a UK single-center, double-blinded, randomized, placebo-controlled crossover study investigating the efficacy of bezafibrate in participants with Barth syndrome. Treatment was administered in two 15-week phases with a minimum washout period of 1 month between the phases where no treatment was administered. The primary outcome is peak oxygen consumption (VO2 peak). Secondary outcomes include MLCL/L4-CL ratio and CL profile in blood cells, amino acid expression, phosphocreatine to adenosine triphosphate ratio in cardiac muscle and skeletal muscle oxidative function on phosphorus-31 magnetic resonance spectroscopy, quality of life using the Pediatric Quality of Life Inventory questionnaire, absolute neutrophil count, cardiac function and rhythm profiles at rest and during exercise, and mitochondrial organization and function assessments. Outcomes were assessed at baseline and during the final week of each treatment phase. Results A total of 12 patients were scheduled to participate across three consecutive research clinics between March and April 2019. In total, 11 participants were recruited, and the follow-up was completed in January 2020. Data analysis is ongoing, with publication expected in 2021. Conclusions This trial was approved by the United Kingdom National Research Ethics Service Committee and the Medicines and Healthcare products Regulatory Agency. The feasibility of the CARDIOMAN study will help to inform the future conduct of randomized controlled trials in rare disease populations as well as testing the efficacy of bezafibrate as a potential treatment for the disease and advancing the mechanistic understanding of Barth syndrome. Trial Registration International Standard Randomized Controlled Trial Number (ISRCTN): 58006579; https://www.isrctn.com/ISRCTN58006579 International Registered Report Identifier (IRRID) DERR1-10.2196/22533

BACKGROUND The aim of this study was to quantify the degree of the effect of in-plane partial volume averaging on recorded peak velocity in phase contrast magnetic resonance angiography (PCMRA). METHODS Using cardiac optimized 1.5 Tesla MRI scanners (Siemens Symphony and Avanto), 145 flow measurements (14 anatomical locations; ventricular outlets, aortic valve (AorV), aorta (5 sites), pulmonary arteries (3 sites), pulmonary veins, superior and inferior vena cava)- in 37 subjects (consisting of healthy volunteers, congenital and acquired heart disease patients) were analyzed by Siemens Argus default voxel averaging technique (where peak velocity = mean of highest velocity voxel and four neighbouring voxels) and by single voxel technique (1.3×1.3×5 or 1.7×1.7×5.5 mm3) (where peak velocity = highest velocity voxel only). The effect of scan protocol (breath hold versus free breathing) and scanner type (Siemens Symphony versus Siemens Avanto) were also assessed. Statistical significance was defined as P

Theme park operators and medical professionals advise children with heart conditions against using rollercoaster rides, but these recommendations are not evidence-based. The underlying assumption is that the combination of adrenergic stimulation through stress and acceleration might trigger arrhythmias in susceptible individuals. We conducted a cross-sectional observational study to assess heart rate and rhythm in healthy children during commercial rollercoaster rides. 20 healthy children (9 male) aged 11–15 (mean 13.3±1.4) years underwent continuous heart rate and rhythm monitoring (2-lead ECG) from 5mins before until 10mins after each of 4 high speed (>50km∙h-1), high G force (Gz>4) commercial rollercoaster rides. Total recording time was 13 h 20 min. No arrhythmic events were detected. Resting heart rate was 81 ± 10 b·min-1 and increased to 158 ± 20 b·min-1 during rides. The highest mean HR (165 ±23 b·min-1) was observed on the ride with the lowest g-force (4.5 g), but one of the highest speeds (100 km∙h-1). Anticipatory tachycardia (126 ±15 b·min-1) within 5 min was frequently observed. A 10 min recovery HR (124 ±17 b·min-1) was 56 % greater than resting HR. The speed and G-force experienced on rollercoasters induce sinus tachycardia but do not elicit pathological arrhythmias in healthy children.

BACKGROUND: Reports on the incidence and causes of sudden cardiac death among young athletes have relied largely on estimated rates of participation and varied methods of reporting. We sought to investigate the incidence and causes of sudden cardiac death among adolescent soccer players in the United Kingdom. METHODS: From 1996 through 2016, we screened 11,168 adolescent athletes with a mean (±SD) age of 16.4±1.2 years (95% of whom were male) in the English Football Association (FA) cardiac screening program, which consisted of a health questionnaire, physical examination, electrocardiography, and echocardiography. The FA registry was interrogated to identify sudden cardiac deaths, which were confirmed with autopsy reports. RESULTS: During screening, 42 athletes (0.38%) were found to have cardiac disorders that are associated with sudden cardiac death. A further 225 athletes (2%) with congenital or valvular abnormalities were identified. After screening, there were 23 deaths from any cause, of which 8 (35%) were sudden deaths attributed to cardiac disease. Cardiomyopathy accounted for 7 of 8 sudden cardiac deaths (88%). Six athletes (75%) with sudden cardiac death had had normal cardiac screening results. The mean time between screening and sudden cardiac death was 6.8 years. On the basis of a total of 118,351 person-years, the incidence of sudden cardiac death among previously screened adolescent soccer players was 1 per 14,794 person-years (6.8 per 100,000 athletes). CONCLUSIONS: Diseases that are associated with sudden cardiac death were identified in 0.38% of adolescent soccer players in a cohort that underwent cardiovascular screening. The incidence of sudden cardiac death was 1 per 14,794 person-years, or 6.8 per 100,000 athletes; most of these deaths were due to cardiomyopathies that had not been detected on screening. (Funded by the English Football Association and others.).

Background left ventricular (LV) and right ventricular (RV) myocardial reserve during exercise in adolescents has not been directly characterized. The aim of this study was to quantify myocardial performance response to exercise by using two-dimensional (2-D) speckle tracking echocardiography and describe the relationship between myocardial reserve, respiratory, and metabolic exercise parameters. A total of 23 healthy boys and girls (mean age 13.2 ± 2.7 yr; stature 159.1 ± 16.4 cm; body mass 49.5 ± 16.6 kg; BSA 1.47 ± 0.33 m2) completed an incremental cardiopulmonary exercise test (25 W·3 min increments) with simultaneous acquisition of 2-D transthoracic echocardiography at rest, each exercise stage up to 100 W, and in recovery at 2 min and 10 min. Two-dimensional LV (LV Sl) and RV (RV Sl) longitudinal strain and LV circumferential strain (LV Sc) were analyzed to define the relationship between myocardial performance reserve and metabolic exercise parameters. Participants achieved a peak oxygen uptake (V̇o2peak) of 40.6 ± 8.9 ml·kg−1·min−1 and a work rate of 154 ± 42 W. LV Sl and LV Sc and RV Sl increased significantly across work rates ( P < 0.05). LV Sl during exercise was significantly correlated to resting strain, V̇o2peak, oxygen pulse, and work rate (0.530 ≤ r ≤ 0.784, P < 0.05). This study identifies a positive and moderate relationship between LV and RV myocardial performance and metabolic parameters during exercise by using a novel methodology. Relationships detected present novel data directly describing myocardial adaptation at different stages of exercise and recovery that in the future can help directly assess cardiac reserve in patients with cardiac pathology.

AimTo describe the electrocardiographic (ECG) and echocardiographic manifestations of the paediatric athlete’s heart, and examine the impact of age, race and sex on cardiac remodelling responses to competitive sport.DesignSystematic review with meta-analysis.Data sourcesSix electronic databases were searched to May 2016: MEDLINE, PubMed, EMBASE, Web of Science, CINAHL and SPORTDiscus.Inclusion criteria(1) Male and/or female competitive athletes, (2) participants aged 6–18 years, (3) original research article published in English language.ResultsData from 14 278 athletes and 1668 non-athletes were included for qualitative (43 articles) and quantitative synthesis (40 articles). Paediatric athletes demonstrated a greater prevalence of training-related and training-unrelated ECG changes than non-athletes. Athletes ≥14 years were 15.8 times more likely to have inferolateral T-wave inversion than athletes ConclusionsThe paediatric athlete’s heart undergoes significant remodelling both before and during ‘maturational years’. Paediatric athletes have a greater prevalence of training related and training-unrelated ECG changes than non-athletes, with age, race and sex mediating factors on cardiac electrical and LV structural remodelling.

Increased oxygen uptake and utilisation during exercise depend on adequate adaptations of systemic and pulmonary vasculature. Recent advances in magnetic resonance imaging techniques allow for direct quantification of aortic and pulmonary blood flow using phase-contrast magnetic resonance angiography (PCMRA). This pilot study tested quantification of aortic and pulmonary haemodynamic adaptations to moderate aerobic supine leg exercise using PCMRA.Nine adult healthy volunteers underwent pulse gated free breathing PCMRA while performing heart rate targeted aerobic lower limb exercise. Flow was assessed in mid ascending and mid descending thoracic aorta (AO) and main pulmonary artery (MPA) during exercise at 180 % of individual resting heart rate. Flow sequence analysis was performed by experienced operators using commercial offline software (Argus, Siemens Medical Systems).Exercise related increase in HR (rest: 69 ± 10 b min(-1), exercise: 120 ± 13 b min(-1)) resulted in cardiac output increase (from 6.5 ± 1.4 to 12.5 ± 1.8 L min(-1)). At exercise, ascending aorta systolic peak velocity increased from 89 ± 14 to 122 ± 34 cm s(-1) (p = 0.016), descending thoracic aorta systolic peak velocity increased from 104 ± 14 to 144 ± 33 cm s(-1) (p = 0.004), MPA systolic peak velocity from 86 ± 18 to 140 ± 48 cm s(-1) (p = 0.007), ascending aorta systolic peak flow rate from 415 ± 83 to 550 ± 135 mL s(-1) (p = 0.002), descending thoracic aorta systolic peak flow rate from 264 ± 70 to 351 ± 82 mL s(-1) (p = 0.004) and MPA systolic peak flow rate from 410 ± 80 to 577 ± 180 mL s(-1) (p = 0.006).Quantitative blood flow and velocity analysis during exercise using PCMRA is feasible and detected a steep exercise flow and velocity increase in the aorta and MPA. Exercise PCMRA can serve as a research and clinical tool to help quantify exercise blood flow adaptations in health and disease and investigate patho-physiological mechanisms in cardio-pulmonary disease.

Exercise training is an underused intervention in paediatric healthcare. This is surprising, since initial evidence demonstrates its effectiveness and safety; furthermore it confers socioeconomic benefits for healthcare systems. Pilot studies have assessed and confirmed the feasibility of exercise training in many paediatric disease settings. However, more research is needed to understand the pathophysiology, quantify treatment effects and monitor outcomes. A concerted effort from researchers, health professionals and police makers will be necessary to make exercise training an evidence-based and cost-effective intervention in paediatric care.

Williams-Beuren syndrome (WBS) is a multisystem genetic disorder comprising of craniofacial, developmental, and cardiac malformations. The most common cardiac defects found are supravalvar aortic stenosis and peripheral pulmonary stenosis. However, WBS should be regarded as a general arteriopathy consisting of stenoses of medium- and large-sized arteries including the coronary arteries. Cardiac manifestations are often the initial reason for referral and careful cardiovascular assessment is important as coronary artery involvement confers a significant anesthetic risk and may be associated with ischemia and resultant ventricular dysfunction. Here we review the literature and describe a 2-year-old boy with evolving clinical features of WBS. He presented to our pediatric cardiology department for a routine assessment of peripheral pulmonary branch stenosis. A 12-lead electrocardiogram showed changes consistent with left ventricular ischemia and a two-dimensional echocardiogram showed reduced left ventricular function and mild supravalvar aortic stenosis. Subsequent cardiac catheterization diagnosed severe left main coronary artery stenosis. Deteriorating ventricular function secondary to acute ischemia postcatheterization required intensive care treatment from which the patient did not recover. This case report highlights the necessity of careful cardiology assessment without delay in patients with a suspicion of WBS. Isolated coronary stenosis though rare in WBS should be considered in the presence of ischemia or reduced ventricular function. Larger case series are needed to further characterize the correlation between WBS and acute coronary events.

Tricuspid atresia and common truncus arteriosus are rare forms of congenital heart disease; the coexistence of both anomalies is therefore an extremely uncommon event. Without treatment, early mortality is the natural course so diagnostic and therapeutic management must be performed without delay. We report a case of a newborn with a postnatal diagnosis of coexistent tricuspid atresia and common arterial trunk in whom successful palliation was performed using a staged surgical approach.

To assess the prognostic value of the baseline C-reactive protein (CRP) level in patients undergoing percutaneous coronary intervention (PCI) after pre-treatment with 600 mg of clopidogrel and whether there is an interaction between CRP level and abciximab in terms of outcome.Pooled analysis from the ISAR-SWEET, SMART-2, ISAR-REACT and REACT-2 trials. SETTING, METHODS: The study included 4847 patients with coronary artery disease (CAD) undergoing PCI after pre-treatment with 600 mg of clopidogrel. The primary outcome was one-year mortality. The combined incidence of death, myocardial infarction and target lesion revascularisation was the secondary outcome.Based on the median value of CRP (2.3 mg/l), patients were divided into two groups: the high-CRP group (n = 2448) and the low-CRP group (n = 2399). During one year, there were 141 deaths (5.8%) in the high-CRP group compared with 51 deaths (2.1%) in the low-CRP group (OR = 2.77, 95% CI 2.04 to 3.77; p0.001). The incidence of major adverse cardiac events (MACE) was 28% in the high-CRP group compared with 25% in the low-CRP group (OR = 1.13, 95% CI 1.01 to 1.26; p = 0.034). The Cox proportional hazards model showed that high CRP was an independent predictor of one-year mortality (hazard ratio 2.20, 95% CI 1.54 to 3.15; p0.001 for CRP level2.3 mg/l vs CRP levelor =2.3 mg/l). No significant interaction was observed between CRP level and abciximab regarding one-year mortality (p = 0.08) or MACE (p = 0.68).In patients with CAD undergoing PCI after pretreatment with 600 mg of clopidogrel, baseline CRP level predicts one-year mortality and MACE. Abciximab therapy did not confer any particular beneficial effect in patients with a higher inflammatory burden.

We have identified an ethylnitrosourea (ENU)-induced recessive mouse mutation (Vcc) with a pleiotropic phenotype that includes cardiac, tracheoesophageal, anorectal, anteroposterior patterning defects, exomphalos, hindlimb hypoplasia, a presacral mass, renal and palatal agenesis, and pulmonary hypoplasia. It results from a C470R mutation in the proprotein convertase PCSK5 (PC5/6). Compound mutants (Pcsk5Vcc/null) completely recapitulate the Pcsk5Vcc/Vcc phenotype, as does an epiblast-specific conditional deletion of Pcsk5. The C470R mutation ablates a disulfide bond in the P domain, and blocks export from the endoplasmic reticulum and proprotein convertase activity. We show that GDF11 is cleaved and activated by PCSK5A, but not by PCSK5A-C470R, and that Gdf11-deficient embryos, in addition to having anteroposterior patterning defects and renal and palatal agenesis, also have a presacral mass, anorectal malformation, and exomphalos. Pcsk5 mutation results in abnormal expression of several paralogous Hox genes (Hoxa, Hoxc, and Hoxd), and of Mnx1 (Hlxb9). These include known Gdf11 targets, and are necessary for caudal embryo development. We identified nonsynonymous mutations in PCSK5 in patients with VACTERL (vertebral, anorectal, cardiac, tracheoesophageal, renal, limb malformation OMIM 192350) and caudal regression syndrome, the phenotypic features of which resemble the mouse mutation. We propose that Pcsk5, at least in part via GDF11, coordinately regulates caudal Hox paralogs, to control anteroposterior patterning, nephrogenesis, skeletal, and anorectal development.

Rapid and precise phenotyping analysis of large numbers of wild-type and mutant mouse embryos is essential for characterizing the genetic and epigenetic factors regulating embryogenesis. We present a novel methodology that permits precise high-throughput screening of the phenotype of embryos with both targeted and randomly generated mutations. To demonstrate the potential of this methodology we show embryo phenotyping results produced in a large-scale ENU-mutagenesis study. In essence this represents an analysis pipeline, which starts with simultaneous micro-magentic resonance imaging (microMRI) screening (voxel size: 25.4 x 25.4 x 24.4 microm) of 32 embryos in one run. Embryos with an indistinct phenotype are then cut into parts and suspect organs and structures are analysed with HREM (high-resolution episcopic microscopy). HREM is an imaging technique that employs 'positive' eosin staining and episcopic imaging for generating three-dimensional (3D) high-resolution (voxel size: 1.07 x 1.07 x 2 microm) digital data of near histological contrast and quality. The results show that our method guarantees the rapid availability of comprehensive phenotype information for high numbers of embryos in, if necessary, histological quality and detail. The combination of high-throughput microMRI with HREM provides an alternative screening pipeline with advantages over existing 3D phenotype screening methods as well as traditional histology. Thus, the microMRI-HREM phenotype analysis pipeline recommends itself as a routine tool for analysing the phenotype of transgenic and mutant embryos.

Monosomy of the human chromosome 6p terminal region results in a variety of congenital malformations that include brain, craniofacial, and organogenesis abnormalities. To examine the genetic basis of these phenotypes, we have carried out an unbiased functional analysis of the syntenic region of the mouse genome (proximal Mmu13). A genetic screen for recessive mutations in this region recovered thirteen lines with phenotypes relevant to a variety of clinical conditions. These include two loci that cause holoprosencephaly, two that underlie anophthalmia, one of which also contributes to other craniofacial abnormalities such as microcephaly, agnathia, and palatogenesis defects, and one locus responsible for developmental heart and kidney defects. Analysis of heterozygous carriers of these mutations shows that a high proportion of these loci manifest with behavioral activity and sensorimotor deficits in the heterozygous state. This finding argues for the systematic, reciprocal phenotypic assessment of dominant and recessive mouse mutants. In addition to providing a resource of single gene mutants that model 6p-associated disorders, the work reveals unsuspected genetic complexity at this region. In particular, many of the phenotypes associated with 6p deletions can be elicited by mutation in one of a number of genes. This finding implies that phenotypes associated with contiguous gene deletion syndromes can result not only from dosage sensitivity of one gene in the region but also from the combined effect of monosomy for multiple genes that function within the same biological process.

Williams-Beuren syndrome (WBS) is a multisystem genetic disorder comprising of craniofacial, developmental, and cardiac malformations. The most common cardiac defects found are supravalvar aortic stenosis and peripheral pulmonary stenosis. However, WBS should be regarded as a general arteriopathy consisting of stenoses of medium- and large-sized arteries including the coronary arteries. Cardiac manifestations are often the initial reason for referral and careful cardiovascular assessment is important as coronary artery involvement confers a significant anesthetic risk and may be associated with ischemia and resultant ventricular dysfunction. Here we review the literature and describe a 2-year-old boy with evolving clinical features of WBS. He presented to our pediatric cardiology department for a routine assessment of peripheral pulmonary branch stenosis. A 12-lead electrocardiogram showed changes consistent with left ventricular ischemia and a two-dimensional echocardiogram showed reduced left ventricular function and mild supravalvar aortic stenosis. Subsequent cardiac catheterization diagnosed severe left main coronary artery stenosis. Deteriorating ventricular function secondary to acute ischemia postcatheterization required intensive care treatment from which the patient did not recover. This case report highlights the necessity of careful cardiology assessment without delay in patients with a suspicion of WBS. Isolated coronary stenosis though rare in WBS should be considered in the presence of ischemia or reduced ventricular function. Larger case series are needed to further characterize the correlation between WBS and acute coronary events.

OBJECTIVES— To identify, map, clone, and functionally validate a novel mouse model for impaired glucose tolerance and insulin secretion. RESEARCH DESIGN AND METHODS— Haploinsufficiency of the insulin receptor and associated mild insulin resistance has been used to sensitize an N-ethyl-N-nitrosourea (ENU) screen to identify novel mutations resulting in impaired glucose tolerance and diabetes. The new impaired glucose tolerance 4 (IGT4) model was selected using an intraperitoneal glucose tolerance test and inheritance of the phenotype confirmed by generation of backcross progeny. Segregation of the phenotype was correlated with genotype information to map the location of the gene and candidates sequenced for mutations. The function of the SRY-related high mobility group (HMG)-box 4 (Sox4) gene in insulin secretion was tested using another ENU allele and by small interfering RNA silencing in insulinoma cells. RESULTS— We describe two allelic autosomal dominant mutations in the highly conserved HMG box of the transcription factor Sox4. Previously associated with pancreas development, Sox4 mutations in the adult mouse result in an insulin secretory defect, which exhibits impaired glucose tolerance in association with insulin receptor+/−–induced insulin resistance. Elimination of the Sox4 transcript in INS1 and Min6 cells resulted in the abolition of glucose-stimulated insulin release similar to that observed for silencing of the key metabolic enzyme glucokinase. Intracellular calcium measurements in treated cells indicate that this defect lies downstream of the ATP-sensitive K+ channel (KATP channel) and calcium influx. CONCLUSIONS— IGT4 represents a novel digenic model of insulin resistance coupled with an insulin secretory defect. The Sox4 gene has a role in insulin secretion in the adult β-cell downstream of the KATP channel.

Background Cardiovascular adaptations to aerobic exercise are mediated through interactions of cardiac, hormonal, metabolic, and muscular mechanisms with a dominant role for increase in cardiac output to enhance oxygen delivery. However, increased demands for oxygen uptake and use during exercise depend on adequate adaptations of systemic and pulmonary vasculature. Assessment of exercise response is crucial in various cardiac and pulmonary diseases. Recent advances in MRI techniques allow for direct measurement of aortic and pulmonary blood flow with phase-contrast magnetic resonance angiography (PCMRA). We have studied aortic and pulmonary flow in healthy individuals to assess haemodynamic adaptations to exercise using PCMRA. Methods Nine adult healthy volunteers underwent PCMRA while doing heart-rate-targeted (180% of resting heart rate) aerobic supine leg exercise. Aortic flow was reassessed post exercise after 2 min rest. All flow variables were assessed by retrospective free-breathing pulse-gated PCMRA in the mid ascending aorta and main pulmonary artery (field of view [FOV] 320 mm, FOV phase 75%, base resolution 256, voxel 1·3 × 1·3 × 5·0 mm, TE 2·2 ms, TR 29·9 ms, slice thickness 5 mm, three averages, and 30 reconstructed phases, Venc 150 cm/s at rest, 300 cm/s during exercise). All images were assessed by three individuals trained in MRI flow evaluation and independently checked by an experienced cardiac radiologist. Flow sequence analysis was done with offline software (Argus, Siemens Medical Systems), by manually contouring the vessel of interest so that all flow was accounted for. Pulmonary and aortic blood flow was determined from the flow velocities in individual voxels in the region of interest. Findings Increase in heart rate during exercise (from a mean of 69 beats per min [SD 10] at rest to 120 [14] after exercise) resulted in increased cardiac output (mean 6·5 L/min [SD 1·4] to 12·4 [1·8]). All flow variables significantly increased with exercise compared with rest: aorta systolic peak velocity increased from mean 89 cm/s [SD 14] to 122 [34] (p=0·016); pulmonary artery systolic peak velocity 86 cm/s [18] to 140 [48] (p=0·007); aorta systolic peak flow rate 415 mL/s [83] to 550 [135] (p=0·002); and pulmonary artery systolic peak flow rate 410 mL/s [80] to 577 [180] (p=0·006). These variables showed a trend to normalisation at 2 min recovery. Interpretation Use of free-breathing pulse-gated PCMRA to measure aortic and pulmonary blood flow and velocity during exercise is feasible. Moderate aerobic exercise leads to a steep increase in blood flow and flow velocities in aorta and main pulmonary artery facilitating increased oxygen uptake. Exercise PCMRA could help in diagnosis, assessment of treatment response, and follow-up in many patient groups with pulmonary and cardiovascular disease. Funding Bristol NIHR Cardiovascular Biomedical Research Unit, NIHR Academic Clinical Lectureship to GEP