Electrocardiographic Right Ventricular Hypertrophy in Athletes
Electrocardiographic Right Ventricular Hypertrophy in Athletes
Athletes. In the UK, the charitable organization Cardiac Risk in the Young subsidizes cardiovascular evaluations for several elite sporting organizations that mandate pre-participation screening of all member athletes. Between 2010 and 2012, 627 athletes competing at international (77.0%), national (9.1%), or regional level (13.9%) were recruited to the present study, and underwent assessment by health questionnaire, physical examination, ECG, and two-dimensional echocardiography. The cohort was aged between 14 and 35 years, and 438/627 (69.9%) were male. All participants provided written consent for screening and study enrolment, and ethical approval was obtained from the local Research Ethics Committee in accordance with the Declaration of Helsinki. Athletes with any previous history of cardiac or pulmonary disease, systemic hypertension, diabetes mellitus, family history of cardiomyopathy, or family history of pre-mature (≤40 years) sudden cardiac death were excluded from the study. Athletes with electrocardiographic evidence of ventricular pre-excitation or complete bundle branch block were also excluded.
Non-athletic Controls. Cardiac risk in the young also offers cardiovascular evaluation to any young individual (aged 14–35 years), irrespective of the athletic status, wishing to be tested for conditions pre-disposing to sudden cardiac death. The protocol comprises of a health questionnaire, physical examination, and 12-lead ECG. Non-athletic control cases were recruited for additional echocardiography if they led a sedentary lifestyle (≤3 h of organized physical activity per week). Control subjects and athletes were matched for age, gender, and ethnicity. Exclusion criteria were identical to those applied in athletes. The final control cohort composed of 241 sedentary individuals, of whom 159/241 (66.0%) were male.
Pathological Cohorts. Two disease groups with established RV pathology, an ARVC cohort (n = 68) and a pulmonary hypertensive cohort (n = 30), were evaluated on the basis of their propensity to cause pathological RV dilatation and/or hypertrophy as well as sports-related sudden cardiac death. Both groups consisted of adult patients under follow-up in a UK tertiary cardiac referral centre. To simulate cases that might be detected during the screening of athletes, the pulmonary hypertensive cohort was restricted to asymptomatic, mild cases (invasively measured mean pulmonary artery pressure between 26 and 40 mmHg) that had been detected through surveillance echocardiography (congenital, thromboembolic, and connective tissue disease-related aetiologies) The 2010 Modified Task Force criteria were used to define ARVC. Approximately two-fifths of the ARVC cohort (39.7%) consisted of asymptomatic individuals detected through family screening. To prevent comparison with compound pathologies, exclusion criteria for the pathological cohorts included ischaemic heart disease, LV dysfunction or hypertrophy, arterial hypertension, and chronic primary lung diseases.
A standard 12-lead ECG was performed in the supine position using either a MAC 5000 or MAC 5500 digital resting recorder (GE Medical Systems, Milwaukee, WI, USA) as described elsewhere. Measurements were made on anonymized recordings using callipers. Current international guidelines and consensus statements were used to define abnormal electrocardiograms. Left ventricular hypertrophy (LVH) was defined according to the Sokolow-Lyon voltage criterion (SV1 + RV5/6 > 3.5 mV). The normal frontal cardiac axis was considered to be >−30° but <120°. T-wave inversion (TWI) ≥ −0.1 mV in ≥2 contiguous leads was considered significant. Leads V1-V4 were subclassified as anterior precordial leads. Partial right bundle branch block was defined as QRS duration >100 ms but <120 ms, with rSR' morphology in lead V1 and qRS in V6. Right ventricular hypertrophy was defined according to several established diagnostic criteria, including the R:S ratio (V1) > 1, R:S ratio (V5) < 1, R:S ratio (V6) < 1, R' > 1.0 mV if rSR' in V1, and R(V1) > 0.7 mV. The Sokolow-Lyon voltage criterion for RVH (R-wave in lead V1 + S-wave in lead V5 or V6 > 1.05 mV) was studied in detail, since it is referred to specifically in guidelines for ECG interpretation in athletes. In addition, the Sokolow-Lyon RVH criterion in combination with right-axis deviation (>120°) was studied, since it is cited as a potential marker of RV pathology in the most recent international consensus document relating to abnormal ECG findings in athletes (the 'Seattle Criteria'). The term 'isolated' is used to describe electrocardiographic anomalies observed in the absence of other ECG features considered 'uncommon and training-unrelated' in athletes.
Echocardiographic examinations were performed with the subject at rest, in the left lateral decubitus position using the following commercially available ultrasound systems; Vivid-I (GE Healthcare, Milwaukee, WI, USA), CX50, or iE33 (Philips Medical, Bothel, WA, USA). A complete echocardiographic study of the left and right sides of the heart was performed according to current guidelines from the European Society of Cardiology and the American Society of Echocardiography. Echocardiographic studies were saved to compact discs as numeric files to generate anonymity, and cardiac measurements were repeated independently by an experienced cardiologist (A.Z.) blinded to the identity of the subject. Right ventricular end-diastolic wall thickness (RVWT) was measured in the focused subcostal view at the level of the tip of the anterior tricuspid leaflet, taking care to exclude the pericardium and trabeculations from the measurement. Echocardiographic RVH was defined as RVWT > 5 mm. Right ventricular regional wall motion abnormalities were defined as akinetic, dyskinetic, or aneurysmal, in accordance with diagnostic criteria for ARVC.
Athletes with suspected cardiac pathology on the basis of history, physical examination, 12-lead ECG, and echocardiography were subjected to more comprehensive assessment (exercise ECG, ambulatory monitoring, signal-averaged ECG, and cardiac magnetic resonance imaging), as has been described elsewhere. Specific triggers for additional evaluation included RV regional wall motion abnormalities, and TWI in ≥2 contiguous leads. Athletes exhibiting substantial LV hypertrophy (males with maximal LV wall thickness >12 mm; females >11 mm) were assessed further to exclude hypertrophic cardiomyopathy. Echocardiographic RVH (RVWT > 5 mm) was investigated further if accompanied by cardiovascular symptoms, electrocardiographic TWI, or abnormal indices of RV systolic or diastolic function (fractional area change <35%, tricuspid annular plane systolic excursion <16 cm, or early myocardial relaxation velocity [E'] <8 cm/s). In the absence of prolonged longitudinal data relating to ethnic differences in athletic cardiac remodelling, identical referral criteria were applied to athletes of all ethnicities.
Values are expressed as means ± standard deviation or percentages, as appropriate. The Kolmogorov–Smirnov test was used to assess normality of distributions. Group differences were tested using the unpaired Student's T-test or Mann–Whitney U test. The χ test or Fisher's exact test were used to test proportional differences between groups. Multivariable linear regression models were constructed to identify independent determinants of RVWT. Inter-observer and intra-observer reproducibility of RVWT measurements were assessed using intraclass correlation coefficient analysis and reported as: coefficient (95% confidence interval). Our findings in athletes and ARVC patients were used to generate a hypothetical athletic screening population, to test the utility of various ECG markers for the detection of ARVC. Although estimates for the prevalence of ARVC are variable, we used the commonly quoted value of 1 in 2000 of the general population. Statistical analysis was performed using the SPSS software, version 20 (Chicago, IL, USA). Two-tailed P-values < 0.05 were considered to indicate significance throughout.
Methods
Subjects
Athletes. In the UK, the charitable organization Cardiac Risk in the Young subsidizes cardiovascular evaluations for several elite sporting organizations that mandate pre-participation screening of all member athletes. Between 2010 and 2012, 627 athletes competing at international (77.0%), national (9.1%), or regional level (13.9%) were recruited to the present study, and underwent assessment by health questionnaire, physical examination, ECG, and two-dimensional echocardiography. The cohort was aged between 14 and 35 years, and 438/627 (69.9%) were male. All participants provided written consent for screening and study enrolment, and ethical approval was obtained from the local Research Ethics Committee in accordance with the Declaration of Helsinki. Athletes with any previous history of cardiac or pulmonary disease, systemic hypertension, diabetes mellitus, family history of cardiomyopathy, or family history of pre-mature (≤40 years) sudden cardiac death were excluded from the study. Athletes with electrocardiographic evidence of ventricular pre-excitation or complete bundle branch block were also excluded.
Non-athletic Controls. Cardiac risk in the young also offers cardiovascular evaluation to any young individual (aged 14–35 years), irrespective of the athletic status, wishing to be tested for conditions pre-disposing to sudden cardiac death. The protocol comprises of a health questionnaire, physical examination, and 12-lead ECG. Non-athletic control cases were recruited for additional echocardiography if they led a sedentary lifestyle (≤3 h of organized physical activity per week). Control subjects and athletes were matched for age, gender, and ethnicity. Exclusion criteria were identical to those applied in athletes. The final control cohort composed of 241 sedentary individuals, of whom 159/241 (66.0%) were male.
Pathological Cohorts. Two disease groups with established RV pathology, an ARVC cohort (n = 68) and a pulmonary hypertensive cohort (n = 30), were evaluated on the basis of their propensity to cause pathological RV dilatation and/or hypertrophy as well as sports-related sudden cardiac death. Both groups consisted of adult patients under follow-up in a UK tertiary cardiac referral centre. To simulate cases that might be detected during the screening of athletes, the pulmonary hypertensive cohort was restricted to asymptomatic, mild cases (invasively measured mean pulmonary artery pressure between 26 and 40 mmHg) that had been detected through surveillance echocardiography (congenital, thromboembolic, and connective tissue disease-related aetiologies) The 2010 Modified Task Force criteria were used to define ARVC. Approximately two-fifths of the ARVC cohort (39.7%) consisted of asymptomatic individuals detected through family screening. To prevent comparison with compound pathologies, exclusion criteria for the pathological cohorts included ischaemic heart disease, LV dysfunction or hypertrophy, arterial hypertension, and chronic primary lung diseases.
Twelve-lead Electrocardiography
A standard 12-lead ECG was performed in the supine position using either a MAC 5000 or MAC 5500 digital resting recorder (GE Medical Systems, Milwaukee, WI, USA) as described elsewhere. Measurements were made on anonymized recordings using callipers. Current international guidelines and consensus statements were used to define abnormal electrocardiograms. Left ventricular hypertrophy (LVH) was defined according to the Sokolow-Lyon voltage criterion (SV1 + RV5/6 > 3.5 mV). The normal frontal cardiac axis was considered to be >−30° but <120°. T-wave inversion (TWI) ≥ −0.1 mV in ≥2 contiguous leads was considered significant. Leads V1-V4 were subclassified as anterior precordial leads. Partial right bundle branch block was defined as QRS duration >100 ms but <120 ms, with rSR' morphology in lead V1 and qRS in V6. Right ventricular hypertrophy was defined according to several established diagnostic criteria, including the R:S ratio (V1) > 1, R:S ratio (V5) < 1, R:S ratio (V6) < 1, R' > 1.0 mV if rSR' in V1, and R(V1) > 0.7 mV. The Sokolow-Lyon voltage criterion for RVH (R-wave in lead V1 + S-wave in lead V5 or V6 > 1.05 mV) was studied in detail, since it is referred to specifically in guidelines for ECG interpretation in athletes. In addition, the Sokolow-Lyon RVH criterion in combination with right-axis deviation (>120°) was studied, since it is cited as a potential marker of RV pathology in the most recent international consensus document relating to abnormal ECG findings in athletes (the 'Seattle Criteria'). The term 'isolated' is used to describe electrocardiographic anomalies observed in the absence of other ECG features considered 'uncommon and training-unrelated' in athletes.
Transthoracic Echocardiography
Echocardiographic examinations were performed with the subject at rest, in the left lateral decubitus position using the following commercially available ultrasound systems; Vivid-I (GE Healthcare, Milwaukee, WI, USA), CX50, or iE33 (Philips Medical, Bothel, WA, USA). A complete echocardiographic study of the left and right sides of the heart was performed according to current guidelines from the European Society of Cardiology and the American Society of Echocardiography. Echocardiographic studies were saved to compact discs as numeric files to generate anonymity, and cardiac measurements were repeated independently by an experienced cardiologist (A.Z.) blinded to the identity of the subject. Right ventricular end-diastolic wall thickness (RVWT) was measured in the focused subcostal view at the level of the tip of the anterior tricuspid leaflet, taking care to exclude the pericardium and trabeculations from the measurement. Echocardiographic RVH was defined as RVWT > 5 mm. Right ventricular regional wall motion abnormalities were defined as akinetic, dyskinetic, or aneurysmal, in accordance with diagnostic criteria for ARVC.
Further Evaluation
Athletes with suspected cardiac pathology on the basis of history, physical examination, 12-lead ECG, and echocardiography were subjected to more comprehensive assessment (exercise ECG, ambulatory monitoring, signal-averaged ECG, and cardiac magnetic resonance imaging), as has been described elsewhere. Specific triggers for additional evaluation included RV regional wall motion abnormalities, and TWI in ≥2 contiguous leads. Athletes exhibiting substantial LV hypertrophy (males with maximal LV wall thickness >12 mm; females >11 mm) were assessed further to exclude hypertrophic cardiomyopathy. Echocardiographic RVH (RVWT > 5 mm) was investigated further if accompanied by cardiovascular symptoms, electrocardiographic TWI, or abnormal indices of RV systolic or diastolic function (fractional area change <35%, tricuspid annular plane systolic excursion <16 cm, or early myocardial relaxation velocity [E'] <8 cm/s). In the absence of prolonged longitudinal data relating to ethnic differences in athletic cardiac remodelling, identical referral criteria were applied to athletes of all ethnicities.
Statistical Analysis
Values are expressed as means ± standard deviation or percentages, as appropriate. The Kolmogorov–Smirnov test was used to assess normality of distributions. Group differences were tested using the unpaired Student's T-test or Mann–Whitney U test. The χ test or Fisher's exact test were used to test proportional differences between groups. Multivariable linear regression models were constructed to identify independent determinants of RVWT. Inter-observer and intra-observer reproducibility of RVWT measurements were assessed using intraclass correlation coefficient analysis and reported as: coefficient (95% confidence interval). Our findings in athletes and ARVC patients were used to generate a hypothetical athletic screening population, to test the utility of various ECG markers for the detection of ARVC. Although estimates for the prevalence of ARVC are variable, we used the commonly quoted value of 1 in 2000 of the general population. Statistical analysis was performed using the SPSS software, version 20 (Chicago, IL, USA). Two-tailed P-values < 0.05 were considered to indicate significance throughout.
