Cardiac Death In Young Athletes Research Articles

β-MYHC Mutations Linked to Early-Onset HCM and DCM Show Differences in Pre-Steady and Steady State Kinetic Parameters

Hypertrophic Cardiomyopathy (HCM) is the leading cause of sudden cardiac death in young athletes and has an incidence of 1 in 500 people. Dilated cardiomyopathy (DCM) has a prevalence of 1 in 2000 people. Both diseases can be inherited, with HCM being autosomal dominant, and DCM having different genotypic profiles. There are over 400 mutations in cardiac myosin (MYH7) that have been linked to both diseases. Also noteworthy, early-onset HCM and DCM patients typically have a worse prognosis than adult-onset patients. The only intervention for these pediatric patients is a heart transplant. Here we describe the kinetic analysis of several cardiac myosin mutations that have been identified to be unique to early-onset patients. One set of mutations has been identified in pediatric HCM and the other set is DCM. Steady-state characterization of ATP hydrolysis for both mutant sets using an NADH coupled ATPase assay is reported. Additionally, transient kinetic analysis for several mutants was conducted illustrating differences in the cross-bridge kinetics between HCM and DCM mutants, namely ATP-induced dissociation, ADP release, and the binding constants of actin and the different nucleotide states. This data suggests that the motor activity is different among mutants and may provide insight into the mechanistic defects that can lead to both diseases.

Surgical Unroofing for Anomalous Aortic Origin of Coronary Arteries

Anomalous aortic origin of a coronary artery (AAOCA) from an opposite sinus of Valsalva is an uncommon congenital defect that is typically only discovered on cardiac catheterization or on autopsy following sudden cardiac death. Conjectured mechanisms for the ischemia are generally believed to relate to the unique and easily obstructed geometry of the coronary ostium and the stenotic intramural coronary segment. Given the potentially devastating consequences of not repairing an AAOCA—that is, sudden cardiac death—these patients should undergo repair of the anomaly when it is discovered. Multiple options for surgically correcting the AAOCA have been developed, and the most used approaches include coronary artery bypass grafting, coronary reimplantation, and unroofing of the intramural segment. Here we present the technique for surgical unroofing of the intramural segment of an anomalous coronary artery of aortic origin.

Abstract 16387: Preventing Cardiovascular Disease and Sudden Cardiac Death by Pre-screening Athletes

Background: Cardiovascular disease (CVD) and sudden cardiac death (SCD) among young athletes (YA) remains consistent and continues to influence preventative practices and pre-screening debate. In the United States, screening for SCD in young athletes follows the American Heart Association 12-step screening questions focusing on personal history, family history, and physical examination. The European Society of Cardiology (ESC) outlines a pre-participation screening (PPS) method to minimize SCD and cardiac arrest (CA) by using family history, athlete’s history in sports, physical examination, and a resting 12-lead ECG. Negative findings allow athlete to continue with sports, whereas positive findings require athletes to continue with additional diagnostic tests (echo, stress test, etc.) Method: Using the U.S. National Registry of Sudden Death in Athletes from the National Heart, Lung, and Blood Institute Working Group, we analyzed the annual mortality rates of sudden cardiac death in young athletes in the U.S. compared to the sudden cardiac death rates as reported through the Veneto study. Results: In a 1980-2006 study, using the U.S. National Registry of Sudden Death in Athletes, 1866 sudden deaths were evaluated finding 690 cases were correlated to CVD, with a leading cause of hypertrophic cardiomyopathy. Research shows that every 3 days in the U.S., we lose an athlete to SCD. A study from 1979-2004 in the Veneto region in Italy reported an annual SCD incidence of 1.9 deaths/100,000 person-years in screened young athletes and 0.79 deaths/100,000 person-years in unscreened nonathletic participants. Additionally, the study found an 89% decrease in SCD in athletes with 3.6/100,000 person-years from 1979-1980 and a reported 0.4/100,000 person-years in 2003-2004. Conclusion: In the U.S., 690 sudden cardiac deaths out of 1866 sudden deaths (leading cause as hypertrophic cardiomyopathy) may have been detected using the PPS by adding an ECG to the pre-screening examination. It remains significant that the Veneto study demonstrated little change in SCD in unscreened non-athletes throughout 1979-2004 but notes a significant 89% decrease in SCD in screened athletes paralleling with the 1982 implementation of pre-participation screening.

Abstract 10114: Cardiovascular Magnetic Resonance Measurement of Myocardial Extracellular Volume by T1 Mapping Differentiates Athlete's Heart From Hypertrophic Cardiomyopathy

Introduction: Athletes who train regularly can develop left ventricular (LV) hypertrophy, which can be difficult to differentiate from hypertrophic cardiomyopathy (HCM), the leading cause of sudden cardiac death in young athletes. Cardiovascular magnetic resonance (CMR) T1 and extracellular volume (ECV) mapping provide quantitative assessment of myocardial composition. Hypothesis: ECV can differentiate athletic from pathological remodelling. Methods: 35 athletes, 25 HCM patients and 35 volunteers underwent 3.0T CMR protocol including 5b(3s)3b Modified Look-Locker Inversion (MOLLI) T1 maps before and 15 minutes after administration of 0.15mmol/kg intravenous gadobutrol. Native T1 and ECV were measured for each subject and each segment of the American Heart Association model. Results: Native T1 and ECV were both significantly lower in athletes than HCM (1182.8±38.1ms vs 1264.6±50.3ms, P<0.001 and 23.2±2.9% vs 32.3±5.9%, P<0.001 respectively). On receiver operator curve analysis the area under the curve (AUC) to differentiate HCM from athlete for native T1 was 0.91 and ECV 0.95. The AUC to differentiate indeterminate 8-15mm thick segments (Figure) were native T1 0.83, ECV 0.92 and segment thickness 0.80 (P<0.001 for all). The diagnostic accuracy of ECV was superior to native T1 and segment thickness (P=0.001 for both). The optimal cut-off to diagnose HCM in an indeterminate segment was ECV>24.7% (sensitivity 91.7% & specificity 83.2%) and native T1>1226ms (sensitivity 60.0% & specificity 96.7%). Conclusions: ECV measurement by CMR is able to distinguish HCM and athletic remodelling with high diagnostic accuracy and has a potential role in the exclusion of HCM in athletes presenting with left ventricular hypertrophy. Figure: ROC curves for segmental wall thickness (mm), native T1 (ms) and ECV (%) for the detection of HCM against athletes in intermediate wall thickness segments (8-15mm thick). AUCs were 0.80, 0.83, and 0.92 respectively (P<0.001 for all).

81 The Financial Implications of Application of the Refined ECG Criteria in Pre-Participation Screening of Elite Athletes: Abstract 81 Table 1

<h3>Introduction</h3> Sudden cardiac death in young athletes is commonly due to inherited cardiac diseases that can be detected during life. The International Olympic Committee (IOC) and European Society of Cardiology (ESC) recommend pre-participation screening with ECG in young athletes to detect those at risk. The 2010 ESC recommendations and Seattle criteria recommendations were developed to aid the ECG interpretation in athletes given that cardiovascular remodelling in the conditioned athlete is associated with physiological ECG changes. Antagonists of ECG inclusive pre-participation screening have questioned the high rates of false positive ECG’s in athletes despite these recommendations, as well as the cost effectiveness of such practice. The recently published refined criteria for ECG interpretation in athletes have demonstrated a significant reduction in the false positive ECG rate without compromising sensitivity of diagnosis. The aim of this study was to report the financial implications of application of the three ECG interpretation criteria in detecting potentially sinister diseases in young UK athletes. <h3>Methods</h3> Between 2011–2013, 2,493 consecutive asymptomatic and apparently healthy elite athletes aged 14–35 years underwent pre-participation screening with ECG conducted by a cardiologist at a cost of £35 per athlete. ECG interpretation was in line with 2010 ESC recommendations. Athletes with ECG abnormalities warranted further evaluation which would be facilitated in secondary care as recommended by the ESC. The Seattle criteria and refined criteria for ECG interpretation were applied to this cohort retrospectively. <h3>Results</h3> 2,493 athletes (mean age 19.8 ± 4 years, 1934 (78%) male, 2,214 white (88.9%), 72 black (3%), 227 mixed/other (8.1%)) from 23 sporting disciplines were screened. 7 athletes (0.3%) were diagnosed with a potentially sinister cardiac condition by ECG irrespective of the ECG criteria used (4 HCM, 1 LQTS, 2 WPW). The refined criteria would reduce the minimum overall cost per sinister cardiac condition identified from £31,191 to £17,459, equating to a 44% reduction. <h3>Conclusion</h3> The refined criteria for ECG interpretation could reduce the overall cost of pre-participation screening by a minimum by £39 per athlete (Table 1). In the current financial climate, the refined criteria provides a welcome cost saving practice without compromising efficacy of screening. The data is based on heavily subsidised preliminary investigations and modest tariffs of further investigations in the National Health Service (NHS); therefore the refined criteria is likely to have a greater impact in other healthcare models.

Percutaneous Angioplasty of the Right Coronary Artery Originating from the Left Coronary Sinus

Congenital anomalies of the coronary arteries are relatively rare - they are found in 1.3% of all patients undergoing coronary arteriography. They are a common cause of sudden cardiac death in young athletes and hard labor workers. The atypical origin of the right coronary artery from the left coronary sinus has a clinical significance when the anomalous artery is compressed between the aorta and the pulmonary artery causing intermittent ischemia. Atherosclerosis and rupture of the atherosclerotic plaque could be a common cause for ischemia too. The atypical origin of the coronary artery is a challenge for the interventional cardiologist.

Clinical Case Session I: Sunday 3 May 2015, 10:00-11:00 * Room: Venecia

Clinical Case Session I: Sunday 3 May 2015, 10:00-11:00 * Room: Venecia

STANDARDIZED APPROACH TO PATIENTS WITH ANOMALOUS AORTIC ORIGIN OF A CORONARY ARTERY: RESULTS FROM THE CORONARY ANOMALIES PROGRAM AT TEXAS CHILDREN’S HOSPITAL

Anomalous aortic origin of a coronary artery (AAOCA) is the second leading cause of sudden cardiac death in young athletes. Management is controversial and longitudinal follow-up data is lacking. Prospective, observational study of patients (pts) seen with AAOCA from 12/2012 to 04/2014. The

Additive value of dobutamine stress echocardiography in patients with an anomalous origin of a coronary artery.

An anomalous origin of a coronary artery (AOCA) is the second most common cause of non-traumatic sudden cardiac death in young athletes. Patients with a malignant course of an AOCA of the right coronary artery only need surgical correction when myocardial ischaemia is detected. An AOCA and its malignant or benign course can be detected by coronary angiography, coronary computed tomography or cardiac magnetic resonance imaging. Detection of ischaemia can be more difficult since even a negative maximal-effort stress ECG does not exclude a potential lethal coronary anomaly. Also, there are no case series or trials showing sensitivity or specificity for any form of ischaemia detection for AOCA in the literature. Although not described previously in adults, dobutamine stress echocardiography was previously described in a paediatric population with AOCA. We are the first to describe ischaemia detection by dobutamine stress echocardiography in three adult patients with an AOCA of the right coronary artery who were subsequently referred for surgery.Electronic supplementary materialThe online version of this article (doi: 10.1007/s12471-014-0648-3) contains supplementary material, which is available to authorized users.

Sudden Cardiac Death in Young Adults

Sudden cardiac death is defined as death from unexpected circulatory arrest resulting from cardiac arrhythmia which occurs within one hour of the onset of symptoms. Hypertrophic cardiomyopathy (HCM) is the leading cause of sudden cardiac death in young athletes in the United States and the most common genetic cardiovascular disorder. HCM is characterized by a heavy muscular hyper contracting heart and is a diastolic disorder of heart with asymmetric hypertrophy of ventricular septum. HCM is mostly asymptomatic until sudden cardiac death occurs. Sudden death due to cardiac failure is the most common cause of death and particularly likely in young males with familial HCM or with a family history of sudden death. Major risk factors for sudden death in individuals with Hypertrophic cardiomyopathy include prior history of cardiac arrest, ventricular fibrillation, spontaneous sustained ventricular tachycardia, family history of premature sudden death, unexplained syncope, left ventricular thickness more than or equal to 30mm, abnormal exercise blood pressure and non-sustained ventricular tachycardia. We are hereby reporting few rare cases of sudden cardiac deaths, the bodies of which were brought to the mortuary of S.C.B Medical College, Cuttack for autopsy.

MYBPC3 Gene Therapy for Neonatal Sarcomeric Cardiomyopathies

Hypertrophic cardiomyopathy (HCM) is mainly characterized by left ventricular hypertrophy (LVH), diastolic dysfunction and increased interstitial fibrosis. HCM has an estimated prevalence in a young adult population of 1:500 and is the leading cause of sudden cardiac death in young athletes. HCM is transmitted in an autosomal-dominant fashion and often caused by mutations in MYBPC3, encoding cardiac myosin-binding protein C (cMyBP-C). Most MYBPC3 mutations result in truncated proteins. Findings in humans and in cat/mouse models indicate that haploinsufficiency is the most prevalent HCM mechanism. The presence of double truncating MYBPC3 mutations in infants has been shown to result in severe heart failure and death within 1 year. One of our goals is to prevent the development of the severe cardiac disease phenotype by gene therapy. We developed a mouse model that genetically mimics some human neonatal forms of HCM. The Mybpc3-targeted knock-in (KI) mice carry a homozygous G>A transition in exon 6, resulting in 3 different aberrant mRNAs and proteins.I will present the results of the different gene therapy approaches we performed in this mouse model, which include 5′-trans-splicing, exon skipping and overexpression. The different strategies were evaluated in isolated cardiac myocytes, engineered heart tissue or in vivo in the homozygous KI mice. With the 3 approaches, we provided proof-of-concept studies that paved the way to evaluate the concept in larger animal models and then in severe forms of human neonatal cardioymyopathies.ReferencesGedicke-Hornung, Behrens-Gawlik et al., EMBO Mol Med 2013Mearini, Stimpel et al., Mol Therapy - Nucl Acids 2013Behrens-Gawlik et al., Pflugers Arch - Eur J Physiol 2014Mearini, Stimpel et al., Nat Commun, in press

Abstract 15362: Pre-participation Screening of Young Competitive Athletes for the Prevention of Sudden Cardiac Death Using a New Electrocardiographic Device

Introduction: Routine 12-lead electrocardiogram screening for the prevention of sudden cardiac death in young athletes is not recommended due to the enormous cost per life saved. The application of less expensive electrocardiographic devices has not been investigated. Hypothesis: The purpose of this pilot study was to investigate the utility of a new 3-lead wireless electrocardiographic device for the pre-participation screening of young competitive athletes. Methods: Twenty-seven college football players were enrolled in this study. During the pre-participation screening sessions, each player underwent evaluation using a conventional 12-lead electrocardiogram and a new 3-lead electrocardiogram coupled to our wireless electrocardiographic device. The new 3-lead electrocardiography is a compact device that yields high quality electrocardiographic signals. We compared several electrocardiographic parameters (QRS duration, QRS amplitude, left ventricular hypertrophy, ST deviation and corrected QT interval) using Pearson’s correlation coefficient. Results: The QRS duration, QRS amplitude and corrected QT interval values exhibited significant correlation between the two types of electrocardiograms (correlation coefficient 0.723, 0.537 and 0.734, respectively with P value of 0.01, 0.004 and 0.01, respectively). ST deviation in V1 was weakly correlated with ST deviation in lead Z without statistical significance (correlation coefficient 0.227 with P value of 0.256). Assessment of left ventricular hypertrophy using the Cornell voltage or Sokolow-Lyon criteria and average QRS amplitude also revealed weak correlation without statistical significance (correlation coefficient 0.221 and 0.246, respectively with P value of 0.268 and 0.216, respectively). Conclusions: Our newly developed 3-lead electrocardiogram results correlated well with those of a conventional 12-lead electrocardiogram in terms of QRS duration, QRS amplitude and corrected QT interval. Thus, the 3-lead electrocardiogram might represent a useful screening tool for the prevention of sudden cardiac death in young competitive athletes.

The ECG of high-level junior soccer players: comparing the ESC vs the Seattle criteria

IntroductionSudden cardiac death in young athletes is a devastating event. The screening and detection of potentially life-threatening cardiac pathology by ECG is difficult due to high numbers of false-positive results,...

Pathologies cardiaques à risque chez le jeune sportif

Physical training significantly reduces all cause mortality in the general population. Eligibility for competitive sport participation in athletes with cardiovascular diseases is based on recommendations. Incidence of sudden cardiac death in young athletes is low (0.5to 2/100,000athletes/year). The most common cardiac diseases at risk are hypertrophic cardiomyopathies, congenital coronary arteries abnormalities, arrhythmogenic right ventricular cardiomyopathy and acute myocarditis. Pre-participation screening is based on the cardiovascular evaluation, including ECG (repeated every 3years since the age of 12and every 5years since the age of 20to the age of 35). Some events are unpredictable (idiopathic ventricular fibrillation, sudden death related to congenital coronary arteries abnormalities or commotio cordis). A better access to public defibrillation is needed.

LEFT VENTRICULAR HYPERTROPHY IN ELITE ADOLESCENT ATHLETES: GEORGIAN EXPERIENCE OF PRE-PARTICIPATION SCREENING

BackgroundAthlete's heart should be differentiated from the hypertrophic cardiomyopathy (HCM)-leading cause of exercise related sudden cardiac death in young athletes. Some genetic variations of HCM are characterized by a benign...

Anomalous Aortic Origin of a Coronary Artery: Toward a Standardized Approach

Anomalous aortic origin of a coronary artery (AAOCA) is a congenital abnormality of the origin or course of a coronary artery that arises from the aorta. It is the second most common cause of sudden cardiac death in young athletes. Its exact prevalence, the pathophysiological mechanisms that cause sudden cardiac death, the actual risk of death for the different types of AAOCA, the optimal way to evaluate these patients, and whether any treatment strategies decrease the risk of sudden cardiac death in patients diagnosed with AAOCA are unknown. This article analyzes what is currently known and unknown about this disease. It also describes the creation of a dedicated multidisciplinary coronary anomalies program and the development of a framework in an initial attempt to standardize the evaluation and management of these patients.

Sports preparticipation cardiac screening: what about children?

Sudden cardiac death in young athletes is a devastating event. Screening programs have been proposed to prevent sudden cardiac death in young athletes. Mortality rates and causes of death differ among young adults and children. Children have a considerably lower incidence of sudden cardiac death. Data lack to compare athletes and non-athletes in childhood, but 40-50 % of sudden cardiac death in this age group seems to be related to exercise. Screening programs including history and physical exam are not very sensitive or specific and will result in important numbers of false-positives and false-negatives. Especially, interpretation of ECG in children is different from ECG in adults, with less accurate diagnoses as a consequence. Secondary prevention by widespread education of simple resuscitation techniques and use of automatic external defibrillators if available will probably save as many lives as any screening program. Sufficient data are lacking to support general preparticipation screening with history, physical exam, and ECG in competitive children. Nevertheless, the impact of such a program, together with secondary preventive measures, should be evaluated in large prospective studies.

Active Surveillance of Sudden Cardiac Death in Young Athletes by Periodic Internet Searches

The authors hypothesized that prospective, systematic Internet searches could identify occurrences of sudden cardiac death (SCD) in athletes and would be useful for establishing a system of active surveillance. Weekly advanced Google searches of the Internet were conducted for cases of SCD in young athletes during a 12-month period (2007-2008). Athletes ages 11-30 years who collapsed during a game, practice, or within an hour of exercise were included in the study. Individuals with known histories of cardiac issues and events occurring outside the United States were excluded. Verification of SCD was by autopsy reports and death certificates from county coroner offices and vital record agencies. Initially, 71 events were identified. Verification for the cause of death by coroner reports was possible in 45 cases, 43 (96 %) of which were confirmed to be SCDs. A total of 69 individuals 11-30 years of age (mean 17 ± 5 years) died suddenly of cardiovascular causes while participating in 15 different organized sports and a variety of nonorganized physical activities. The most common cause of death was hypertrophic cardiomyopathy (30 %), followed by coronary artery anomalies (9 %), and myocarditis (9 %). The incidence of athlete SCD, the types of sports involved, and the cardiac causes of death in our study were comparable with those of previous reports. Readily available Internet searches have the potential to be a powerful tool for identifying occurrences of athlete SCD. An active surveillance system using Google searches followed by coroner report verification can provide important epidemiologic and clinical information.

Transgenic Mouse α- and β-Cardiac Myosins Containing the R403Q Mutation Show Isoform-dependent Transient Kinetic Differences

Familial hypertrophic cardiomyopathy (FHC) is a major cause of sudden cardiac death in young athletes. The discovery in 1990 that a point mutation at residue 403 (R403Q) in the β-myosin heavy chain (MHC) caused a severe form of FHC was the first of many demonstrations linking FHC to mutations in muscle proteins. A mouse model for FHC has been widely used to study the mechanochemical properties of mutated cardiac myosin, but mouse hearts express α-MHC, whereas the ventricles of larger mammals express predominantly β-MHC. To address the role of the isoform backbone on function, we generated a transgenic mouse in which the endogenous α-MHC was partially replaced with transgenically encoded β-MHC or α-MHC. A His6 tag was cloned at the N terminus, along with R403Q, to facilitate isolation of myosin subfragment 1 (S1). Stopped flow kinetics were used to measure the equilibrium constants and rates of nucleotide binding and release for the mouse S1 isoforms bound to actin. For the wild-type isoforms, we found that the affinity of MgADP for α-S1 (100 μM) is ~ 4-fold weaker than for β-S1 (25 μM). Correspondingly, the MgADP release rate for α-S1 (350 s(-1)) is ~3-fold greater than for β-S1 (120 s(-1)). Introducing the R403Q mutation caused only a minor reduction in kinetics for β-S1, but R403Q in α-S1 caused the ADP release rate to increase by 20% (430 s(-1)). These transient kinetic studies on mouse cardiac myosins provide strong evidence that the functional impact of an FHC mutation on myosin depends on the isoform backbone.

Differentiating Athlete's Heart from Inherited Cardiac Pathology: The Challenge of Repolarisation Abnormalities Presenting during Anaesthesia

This case report describes an asymptomatic healthy male professional athlete who underwent general anaesthesia for a routine orthopaedic operation. Peri-procedure, pronounced ST elevation suggestive of myocardial ischaemia manifested on the electrocardiogram lasting for four hours post-procedure, upon which the athlete developed deep and diffuse inferolateral T-wave inversion. These changes resolved spontaneously and the patient remained clinically stable throughout. This case demonstrates the clinical conundrum facing anaesthetists attempting to differentiate between repolarisation anomalies that are commonly observed in high-level athletes and those of inherited cardiac pathology, namely hypertrophic cardiomyopathy, which is the leading cause of sudden cardiac death in young athletes.