The use of 2-D speckle tracking echocardiography in differentiating healthy adolescent athletes with right ventricular outflow tract dilation from patients with arrhythmogenic cardiomyopathy.

AIMS: Echocardiographic assessment of adolescent athletes for arrhythmogenic cardiomyopathy (ACM) can be challenging owing to right ventricular (RV) exercise-related remodelling, particularly RV outflow tract (RVOT) dilation. The aim of this study is to evaluate the role of RV 2-D speckle tracking echocardiography (STE) in comparing healthy adolescent athletes with and without RVOT dilation to patients with ACM. METHODS AND RESULTS: A total of 391 adolescent athletes, mean age 14.5 ± 1.7 years, evaluated at three sports academies between 2014 and 2019 were included, and compared to previously reported ACM patients (n = 38 definite and n = 39 borderline). Peak systolic RV free wall (RVFW-Sl), global and segmental strain (Sl), and corresponding strain rates (SRl) were calculated. The participants meeting the major modified Task Force Criteria (mTFC) for RVOT dilation were defined as mTFC+ (n = 58, 14.8%), and the rest as mTFC- (n = 333, 85.2%). Mean RVFW-Sl was -27.6 ± 3.4% overall, -28.2 ± 4.1% in the mTFC+ group and - 27.5 ± 3.3% in the mTFC- group. mTFC+ athletes had normal RV-FW-Sl when compared to definite (-29% vs -19%, p < 0.001) and borderline ACM (-29% vs -21%, p < 0.001) cohorts. In addition, all mean global and regional Sl and SRl values were no worse in the mTFC+ group compared to the mTFC- (p values range < 0.0001 to 0.1, inferiority margin of 2% and 0.1 s-1 respectively). CONCLUSIONS: In athletes with RVOT dilation meeting the major mTFC, STE evaluation of the RV can demostrate normal function and differentiate physiological remodelling from pathological changes found in ACM, improving screening in grey-area cases.

A New Tool to Aid the Differential Diagnosis of Physiological Remodelling from Cardiac Pathology When Assessing Left Ventricle, Left Atrial and Aortic Structure and Function in Male Arab and Black Paediatric Athletes.

Aim: To determine if published Z-scores for left ventricular (LV), left atrial (LA) and aortic structure as well as indices of LV function (Doppler and TDI) in paediatric athletes and non-athletes are appropriate for application in male Arab and black paediatric athletes. If inappropriate, we aim to provide new nomograms and Z-scores for clinical application. Methods: 417 (297 Arab, 120 black) male paediatric (11-18 years) athletes, were evaluated by 2D echocardiography as per British Society of Echocardiography recommendations, and biological age (by radiological X-ray) assessment. Z-scores were tested by residual and correlation analysis together with visual inspection. New Z-scores involved allometric (a*BSA(b+c*chronological age)) and second-order polynomial (y=a*chronological age2+b*chronological age+c) equations for measures of cardiac size and indices of LV function, respectively. Results: Residual linear regression, correlation analysis and visual inspection revealed published z-scores in white peri-pubertal footballers and paediatric non-athletes to be inappropriate for application in male Arab and black paediatric athletes. Residual linear regression revealed new Z-scores for measures of LV, LA and aortic root size to be independent of BSA, ethnicity, chronological and biological age. Residual linear regression revealed new Z-scores for measures of function to be independent of chronological age. Conclusion: Our new z-scores may aid differential diagnosis of suspected pathology versus physiology remodelling, in cardiac screening of the Arab and black paediatric athlete. Nomograms are provided to assist the tracking of the paediatric athlete necessitating annual follow-up and Excel z-score calculation to facilitate use in day-to-day practice.

Getting the best from the Heart Team: guidance for cardiac multidisciplinary meetings.

The purpose of this document is to update the existing joint British Societies recommendations on multidisciplinary meetings (MDMs) published in 2015 to reflect changes in practice. We aim to provide guidance on the structure and function of MDMs which should be taking place in every cardiac surgical centre. Out of scope are MDMs that do not require the routine presence of a cardiac surgeon such as electrophysiology MDMs and those which are not provided in every centre, such as complex aortic surgery.

Prevalence and significance of T-wave inversion in Arab and Black paediatric athletes: Should anterior T-wave inversion interpretation be governed by biological or chronological age?

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 <16 years) warrants caution, but governance by biological age yielded an 'excellent' diagnostic accuracy. In the clinical context, the 'chance' of detecting cardiac pathology within a paediatric male athlete presenting with ATWI in the absence of other ECG findings considered to be abnormal, as per international recommendations for ECG interpretation in athletes (positive likelihood ratio 15.8), was 14.4%, whereas a negative ECG (negative likelihood ratio 0.0) was 0%.

Diagnostic accuracy and Bayesian analysis of new international ECG recommendations in paediatric athletes.

OBJECTIVE: Historically, 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. METHODS: 876 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. RESULTS: Thirteen (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. CONCLUSION: In 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%.

Impact of geographical origin upon the electrical and structural manifestations of the black athlete's heart.

Aims: Black athletes demonstrate an increased prevalence of repolarization anomalies and left ventricular hypertrophy compared to their white counterparts. Recent international recommendations for electrocardiogram (ECG) interpretation in athletes now account for some of these observations, but little attention is given to whether the heart of the black athlete is universal, or whether substantial differences exist according to geographic origin. Our aim was to examine the impact of geographical origin upon the electrical-and structural manifestations of the black athlete's heart. Methods and results: A total of 1698 male competitive athletes participating in mixed sports presented at our organization for 12 lead-ECG led pre-participation screening, with 1222 athletes undergoing systematic echocardiography. Black athletes were categorized against United Nations defined geographical regions (North, East, Middle and West Africa, African American/Caribbean, South American, and West Asia) and compared with a cohort of non-black athletes who shared a close geographical boarder with Africa (South European White and Arabic North African). The prevalence of an abnormal ECG suggestive of cardiac pathology significantly varied by geographical origin. Repolarization abnormalities were significantly more common among West (6.4%) and Middle African (8.5%) athletes than East (1.5%) and North Africans (1.2%) (P < 0.05). Left ventricular hypertrophy was significantly more common among African-American/Caribbean (9.5%) and West African (5%) athletes than West Asian (0.8%), East African (0%), and North African (0%) athletes (P < 0.05). This result remained after accounting for body size. Conclusion: The collective term 'black' should not imply that the hearts of all black athletes are universally comparable. There is considerable variability in the cardiac electrical and structural remodelling response to exercise that appears to be dependent on geographic origin.

Electrical and structural adaptations of the paediatric athlete's heart: a systematic review with meta-analysis.

AIM: To 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. DESIGN: Systematic review with meta-analysis. DATA SOURCES: Six 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. RESULTS: Data 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 <14 years. Paediatric black athletes had significantly more training-related and training-unrelated ECG changes than Caucasian athletes. Age was a positive predictor of left ventricular (LV) internal diameter during diastole, interventricular septum thickness during diastole, relative wall thickness and LV mass. When age was accounted for, these parameters remained significantly larger in athletes than non-athletes. Paediatric black athletes presented larger posterior wall thickness during diastole (PWTd) than Caucasian athletes. Paediatric male athletes also presented larger PWTd than females. CONCLUSIONS: The 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.

Comparison of three current sets of electrocardiographic interpretation criteria for use in screening athletes.

BACKGROUND: An increasing number of sporting bodies report unacceptably high levels of false-positive ECGs when undertaking pre-participation cardiac screening. To address this issue, modified ECG interpretation criteria have become available for use within athletes. OBJECTIVE: This study assessed the accuracy of the new 2014 'Refined Criteria' against the 2013 Seattle Criteria and the 2010 European Society of Cardiology (ESC) recommendations in a cohort of Arabic, black and Caucasian athletes. METHODS: 2491 male athletes (1367 Arabic, 748 black and 376 Caucasian) undertook pre-participation screening including a 12-lead ECG, with further investigation(s) upon indication. RESULTS: Ten athletes (0.4%) were identified with cardiac pathology; seven with hypertrophic cardiomyopathy (HCM; five black and two Arabic) and three Arabs with Wolff-Parkinson-White syndrome (WPW). All three ECG criteria were 100% sensitive identifying all cases of HCM and WPW. The 2014 Refined Criteria reduced (p<0.0001) the prevalence of an abnormal ECG to 5.3% vs 11.6% (Seattle Criteria) and 22.3% (2010 ESC recommendations). The 2014 Refined Criteria significantly (p<0.0001) improved specificity (94.0%) across all ethnicities compared with the Seattle Criteria (87.5%) and ESC recommendations (76.6%). Black athletes continue to present a higher prevalence (p<0.0001) of abnormal ECGs compared with Arabic and Caucasian athletes (10% vs 3.6% and 2.1%). CONCLUSIONS: The 2014 Refined Criteria for athlete ECG interpretation outperformed both the 2013 Seattle Criteria and the 2010 ESC recommendations by significantly reducing the number of false-positive ECGs in Arabic, black and Caucasian athletes while maintaining 100% sensitivity for serious cardiac pathologies.

Type F Congenital Quadricuspid Aortic Valve: A Very Rare Case Diagnosed by 3-dimenional Transoesophageal Echocardiography.

Congenital quadricuspid aortic valve (QAV) is a rare cardiac anomaly. Several different anatomical variations of a quadricuspid aortic valve have been described. Aortic regurgitation is the predominant valvular dysfunction associated with QAV and patients tend to present in their 5(th) or 6(th) decade of life. This anomaly is rarely picked up by transthoracic echocardiogram (TTE). A comprehensive transoesophageal echocardiography (TOE) study is more likely to diagnose it. We describe a very rare type of QAV - Type F in a 52-year-old lady who presented with symptoms of shortness of breath and pre-syncope. We include TOE images and intra-operative valve images.

TRAIL attenuates the development of atherosclerosis in apolipoprotein E deficient mice.

TRAIL (tumour necrosis factor-related apoptosis inducing ligand) is most often reported to induce apoptosis in tumour cells. It is expressed in artery walls but its role and regulation in vascular pathologies is little studied. We aimed to measure the effect of genetic deletion of TRAIL on atherosclerosis in a mouse model. TRAIL was mainly expressed in endothelium, smooth muscle cells and macrophages within plaques. The absence of TRAIL in chow and in fat-fed mice led to greater lesion coverage in aortae (8 weeks, % area ± SEM), n=7-8, 1.24 ± 0.2 (no TRAIL, chow diet) vs. 0.42 ± 0.1, p<0.01 and 3.4 ± 0.8 (no TRAIL, Western diet) vs. 0.94 ± 0.2, p<0.01 and larger, smooth muscle cell rich lesions at aortic roots than control mice (8 weeks, mean lesion area/total cross sectional area ± SEM, n=7-8, 0.17 ± 0.01 (no TRAIL, chow diet) vs. 0.135 ± 0.006, p<0.05 and 0.36 ± 0.03 (no TRAIL, Western diet) vs. 0.23 ± 0.02, p<0.05) particularly at early time points. The larger early lesions appeared to be as a result of increased smooth muscle cells in lesions of TRAIL deficient, pro-atherosclerotic animals. We conclude that TRAIL attenuates plaque size at early stages of atherosclerosis.

Resting B cells suppress tumor immunity via an MHC class-II dependent mechanism.

Resting B cells have been variously shown to induce direct tolerance of antigen specific CD8+ T cells, induce T-cell anergy via transforming growth factor-beta production, down-regulate interleukin-12 production by dendritic cells (DC) and influence TH1/TH2 differentiation via the production of regulatory cytokines. Through these mechanisms, B cells can exert a regulatory function in in vivo models of T-cell immunity including, experimental autoimmune encephalitis and rheumatoid arthritis. Here, we show that the resting B cells inhibit the ability of DC vaccination to provide protection from tumor growth. Inhibition of DC induced immunity by B cells was independent of presentation of major histocompatibility molecule (MHC) class-I bound tumor antigen but dependent on B-cell expression of MHC class-II. Administration of B cells did not alter the ability of DC to migrate from the injection site or impair DC-T cell interactions within the draining lymph node. The inhibitory effect of B cells was lost when they were activated by CD40L and partially reversed by the depletion of CD4+/CD25+ regulatory T cells. Together our findings indicate that the resting B cells are capable of limiting CD8+ T-cell effector function induced by DC vaccination via a mechanism that is dependent on the expression of MHC class-II molecules.

Nuclear factor of activated T (NFAT) cells activity within CD4+ T cells is influenced by activation status and tissue localisation.

Nuclear factor of activated T (NFAT) cells is a family of transcription factors important for the regulation of cytokine expression by CD4+ T cells. Whilst a number of studies have examined NFAT activity of in vitro generated CD4+ T helper (Th)1 and Th2 cells, regulation of NFAT during in vivo immune responses has yet to be elucidated. We show that NFAT activity in CD4+ T cells peaked at early time-points in the draining mediastinal lymph node of mice infected with influenza A (Flu) or Nippostrongylus brasiliensis (Nb). In contrast, low NFAT transcriptional activity was detected in CD4+ T cells isolated from the lung of either Flu or Nb infected mice, despite a greater proportion of cytokine-producing cells being present at this site. These findings indicate that the activation status and tissue microenvironment of effector CD4+ T cells can determine their requirement for NFAT-mediated transcription.

Prospective monitoring of tumor necrosis factor alpha and interferon gamma to predict the onset of acute and chronic graft-versus-host disease after allogeneic stem cell transplantation.

Peripheral blood T cells were isolated from 19 allogeneic and 4 autologous stem cell transplant (SCT) recipients and assessed for tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma transcription by reverse transcription-polymerase chain reaction. Levels were compared with resting donor T-cell transcription levels. Increased production of TNF-alpha predicted for the onset of severe (grade II-IV) graft-versus-host disease (GVHD) (P = .001). Increased TNF-alpha (P = .025) and IFN-gamma (P = .001) transcription also independently predicted for the eventual onset of extensive chronic GVHD. Increased TNF-alpha or IFN-gamma transcription was not seen in either a syngeneic SCT recipient or 4 autologous SCT controls. These findings provide a means by which GVHD can be predicted before it is clinically evident, thus allowing for accurate diagnosis and monitoring of GVHD and possibly more cost-effective management of post-SCT immunosuppression.

Differential T cell function and fate in lymph node and nonlymphoid tissues.

The functions and fate of antigen-experienced T cells isolated from lymph node or nonlymphoid tissues were analyzed in a system involving adoptive transfer of in vitro-activated T cells into mice. Activated T cells present in the lymph nodes could be stimulated by antigen to divide, produce effector cytokines, and migrate to peripheral tissues. By contrast, activated T cells that had migrated into nonlymphoid tissues (lung and airway) produced substantial effector cytokines upon antigen challenge, but were completely unable to divide or migrate back to the lymph nodes. Therefore, activated T cells can undergo clonal expansion in the lymph node, but are recruited and retained as nondividing cells in nonlymphoid tissues. These distinct regulatory events in lymph node and nonlymphoid tissues reveal simple key mechanisms for both inducing and limiting T cell immunity.