Cardiovascular preparticipation evaluation has long been suggested in young athletes to reduce the risk of exercise-related fatal events (7), and previous studies have indicated that its systematic implementation may decrease the incidence of sudden cardiac death in young competitive sportsmen (6). However, despite the traditional focus of research and media on risk prevention in the young, the risk of suffering an adverse cardiovascular event in association with exercise is higher in middle and older age (29). It also appears that the growing popularity of endurance events has been paralleled by declining fitness among participants (2), which is important as individuals that are less accustomed to exercise have the highest risk for cardiac events during sports (29).
Consequently, a recent European consensus document recommends preparticipation evaluation also in all middle-age and older individuals planning to undertake high-intensity sports, even in the absence of cardiovascular symptoms or risk factors and regardless of their previous level of habitual physical activity (4). A similar approach has been advocated by the American Heart Association (AHA) (22).
Because of the increasing popularity of intense sport activities, particularly in higher age (2,15), for example, 2 million runners annually complete a marathon (1), the implementation of such strategies would pose logistical challenges and have important implications for routine clinical practice. Because the above recommendations are largely based on expert group consensus, it appears crucial that the results of implementing such a strategy are thoroughly assessed.
Therefore, the present study aimed to describe for the first time the cardiovascular findings of a preparticipation evaluation in male middle-age individuals planning to participate for their first time in a competitive running event, a subgroup considered at particularly high risk of exercise-related adverse cardiac events (29). To enable a comprehensive assessment of cardiovascular risk, participants were screened using published European recommendations for such evaluation (4), in conjunction with echocardiography and additional blood tests including N-terminal pro-brain natriuretic peptide (NT-proBNP). Further workup was conducted as clinically justified based on initial examination findings.
The study was performed within 3 wk before the world’s largest cross-country running race, Lidingöloppet, held annually in the hilly terrain of the Lidingö island outside Stockholm. All men age 45 yr and older making an entry for first-time participation in the 2010 event (10 km, 15 km, or 30 km races) and who, for logistical reasons, were living in the greater Stockholm area were invited by mail and e-mail. Participants who did not respond to the initial invitation received up to three additional reminders via e-mail and/or phone. Because the study focused on novice runners, participants were asked about participation in other similar endurance events, and those with a history of two or more participations in any endurance race ≥10 km in the last 2 yr were excluded from study participation. The study protocol adhered to the Declaration of Helsinki and was approved by the regional ethical review board. All participants provided written informed consent before participation.
The prerace evaluation comprised a 12-lead ECG, blood pressure, echocardiography, blood testing, comprehensive medical history and physical examination, and estimation of the cardiovascular risk SCORE (32). Cuff blood pressure was recorded as the mean of measurements from both arms after 5 min of rest in a supine position. Body weight and height were also measured to calculate the body mass index (BMI; kg·m−2). The tests were always performed within a single visit, which was concluded by the physician examination, allowing findings from other diagnostic tests to be taken into account. Participants were instructed not to train on the examination day. Participants with abnormal results deemed of clinical relevance underwent further assessment (se next section). Official results list monitoring and personal communication with participants were used to determine the race outcome.
Medical history, physical examination, and risk SCORE
Medical history and physical evaluation were performed in a standardized fashion by a qualified physician, following the 12-element AHA recommendations (23). Runners were also interviewed about their training and smoking habits, the latter categorized as current, past, or never smokers and quantified in pack-years. Age, blood pressure, lipid levels, and smoking status were later incorporated into the SCORE chart developed by the European Society of Cardiology to estimate the 10-yr risk of fatal cardiovascular events both at current age and when extrapolated to age 60 yr. A Swedish adaptation of the SCORE chart according to national information on cardiovascular risk profile and mortality was used (32).
Standard 12-lead ECGs were recorded at a paper speed of 50 mm·s−1 after 5 min of rest in a supine position (GE Medical Systems, Milwaukee, WI) and checked by a physician on acquisition. All ECG tracings were later reassessed, and changes were classified as “common and training-related” or “uncommon and training-unrelated” based on the recent European Society of Cardiology recommendations for 12-lead ECG interpretation in athletes (8), based on the consensus of two electrophysiologists (FB and LB). Early repolarization was defined as >1 mm ST elevation in two adjacent leads. The PQ, QRS, and QT intervals and electrical axis were measured automatically by the ECG recorder and verified or modified by the two electrophysiologists using calipers. Abnormal QT intervals (≥440 ms) or those with a suspicion of incorrect measurements by the ECG recorder were manually rechecked following established standards (18). QT intervals were corrected according to Bazett’s, QTc = QT × R to R interval (RR)½ (RR in seconds).
All participants underwent transthoracic echocardiography (VIVID E9 or VIVID 7; GE-Vingmed Ultrasound AS, Horten, Norway) using views and measurements recommended by the American Society of Echocardiography (17). A dedicated EchoPAC (version 7.0; GE-Vingmed Ultrasound AS) workstation was used for postacquisition analyses. In brief, cardiac dimensions including left ventricular mass (LVM) were obtained in a two-dimensional parasternal long axis view and indexed for body surface area as indicated in using the letter I (e.g., LVMI). LV hypertrophy was defined as LVMI > 115 g·m−2, and eccentric morphology was deemed to be present for a relative wall thickness ≤0.42 based on the American Society of Echocardiography guidelines (17). The E/A ratio was calculated from the mitral inflow E and A wave velocities. Tissue velocities including peak systolic (Sm), early diastolic (Em), and late diastolic lengthening velocity (Am) were recorded as the median of three beats using color-coded tissue Doppler in the basal septum.
Interobserver (PA and AS) and intraobserver (PA) reproducibility was tested in a random sample (n = 26) using coefficient of variability. Interobserver variability was 9.4% (95% confidence interval [CI], 7.7–11.1) and 10.4% (95% CI, 6.5–14.3) for cardiac dimensions and tissue velocity imaging, respectively. Intraobserver variability was 7.2% (95% CI, 4.7–11.1) and 8.1% (95% CI, 5.1–11.1) for cardiac dimensions and tissue velocities, respectively.
Blood laboratory studies
Blood samples with normal ranges as defined per local laboratory standards (given within parenthesis) were drawn from the antecubital vein and analyzed without prior freezing or hemoglobin (134–170 g·dL−1), creatinine (<100 μmol·L−1), sodium (137–145 mmol·L−1), potassium (3.6–4.6 mmol·L−1), direct low-density lipoprotein (direct LDL) (1.4–4.1 mmol·L−1), and NT-proBNP (<84 and <192 ng·L−1 in age <50 and ≥ 50 yr respectively; Roche Diagnostics, Bromma, Sweden). Direct LDL testing was chosen over a conventional lipoprotein profile because overnight fasting could not be ensured within the protocol. To approximate the risk SCORE, we substituted total cholesterol values of 4, 5, 6, 7, and 8 with direct LDL levels of <2.6, 2.7–3.3, 3.4–4.1, 4.2–4.9, and >5, respectively, corresponding to the Adult Treatment Panel III classification of LDL as optimal, near optimal, borderline high, high, and very high (12).
Criteria for further assessment after initial evaluation.
Criteria defined a priori for further evaluation with maximum exercise testing largely conformed with European recommendations (4) and included symptoms of coronary artery disease (CAD; e.g., exertional chest pain), blood pressure > 180/110, ECG changes suggestive of CAD (e.g., ST segment depression and T-wave inversions), presence of multiple cardiac risk-factors yielding a current risk SCORE ≥5%, diabetes mellitus, markedly raised LDL (>6 mmol·L−1), or a strong family history of CAD in first-degree relatives. Marked echocardiographic abnormalities (e.g., hemodynamically significant valvular disorders), abnormal cardiac hypertrophy (e.g., interventricular septal diameter >15 mm), and elevated NT-proBNP formed additional criteria.
Participants with minor T-wave inversions (<2 mm), right bundle branch block, left- and right-axis deviation, or signs of left atrial enlargement on the ECG were not deemed to require further workup if present in isolation and when history, physical status (including blood pressure), and echocardiography were normal.
In some individuals with non-pre-specified findings, further diagnostic workup was initiated based on physician judgment.
Data are presented as mean ± SD or median [interquartile range] as appropriate. For baseline characteristics, the data range is also presented. Data distribution was analyzed by the Kolmogorov–Smirnov test. The Student t-test or the Mann–Whitney U-test was applied to compare means of groups. All statistical analyses were performed using PASW Statistics, version 18 (IBM Corporation, Armonk, NY). A two-tailed P < 0.05 was considered statistically significant.
In the 2010 Lidingöloppet, 13,625, 1528, and 1050 male runners were registered to participate in the 30-, 15-, and 10-km races, respectively. There were 1001 first-time male participants age ≥45 yr, of whom 265 fulfilled the inclusion criteria. Of these, 58 did not respond, 42 declined participation, and 12 did not attend the scheduled appointment. Thus, 153 runners with a mean age of 51 ± 5 yr (range, 45–69 yr) completed the evaluation 10 ± 4 d before the race (30 km, n = 93; 15 km, n = 35; 10 km, n = 25) (Fig. 1). Their baseline characteristics are shown in Table 1. There were no significant differences between participants in the longer (30 km) and shorter races (15 and 10 km), except for the amount of weekly training (2.8 ± 3.1 vs 1.8 ± 2.0 h·wk−1, P = 0.03).
Overall, 14 runners had abnormal findings in the prerace diagnostic evaluation requiring further workup. Details are summarized in Table 2.
Medical history and physical examination, risk SCORE
Medical history, physical examination, and risk SCORE estimation led to further workup of six participants (Table 2). During medical history taking, one participant admitted to syncopal episodes with a suspected cardiac etiology. His 12-lead ECG showed a first-degree atrioventricular block (PQ interval, 260 ms), and during a 48-h Holter monitoring, he had sinus arrests up to 7 s and intermittent third-degree atrioventricular block at daytime. He was discouraged from strenuous physical activity pending pacemaker implantation. In addition, this participant underwent an unremarkable exercise test because of a risk SCORE ≥ 5%.
Palpitations (n = 2), a history of myocardial infarction and DM (n = 1), and exertional chest pain (n = 1) led to further cardiovascular workup by exercise testing and Holter monitoring in four participants. None had findings suggestive of exercise-induced myocardial ischemia, but three had paroxysmal atrial fibrillation (all CHA2DS2-VASc score = 0) (19).
Among 11 participants (7%) with medically treated hypertension, all but 1 (180/110 mm Hg) had well-controlled blood pressure during the physical examination. A consecutive 24-h blood pressure recording in this participant was within acceptable limits, and an exercise test (due to a risk SCORE ≥5%) did not show any pathologic findings.
Eighteen participants (12%) reported physical inactivity (less than 30 min of physical activity at least three times per week), 21 participants (34%) had a BMI higher than 25, and 9 participants (6%) had a BMI higher than 30 kg·m−2. Thirty-five participants (23%) were past smokers, and one participant (1%) was a current smoker.
The median 10-yr risk SCORE was 1% (0%–1%) at current age and 3% (2%–3%) when extrapolated to age 60 yr. Two participants with a current risk SCORE ≥ 5% (5% and 6%, respectively) underwent unremarkable exercise testing (see previous paragraphs). The proportion of participants with an estimated risk ≥5% at age 60 was 9%. These individuals were advised to consult their general practitioner regarding management of future cardiac risk.
At the evaluation visit, all runners were in sinus rhythm with a heart rate of 58 ± 9 bpm and PQ, QRS, and QTc intervals of 168 ± 25, 100 ± 11, and 416 ± 23 ms, respectively. The prevalence of “common and training-related” and “uncommon and training-unrelated” ECG changes (8) was 82% and 24%, respectively (Fig. 2). Forty-nine participants (32%) showed features of early repolarization.
Prolonged QTc intervals (≥440 ms), present in 20 participants (13%), was the most common ECG abnormality considered training unrelated (Fig. 2). Electrolyte status (Na and K), age, LVMI, and BMI did not differ significantly between participants with and without QTc prolongation.
Because of abnormal ECG findings, six runners were referred for further cardiovascular workup (Table 2), including four participants with prolonged QTc intervals, one with 464 ms (in combination with mitral valve prolapse and moderate mitral regurgitation at rest and during exercise echocardiography), and three with 484, 505, and 550 ms, respectively. All were asymptomatic, were not taking QT-prolonging substances, had normal electrolyte status, denied previous syncopal events, and had no family history of long-QT syndrome or sudden cardiac death. Further assessment by exercise test and 48 h of Holter monitoring confirmed the prolonged repolarization intervals (QTc max of 470, 473, 522, and 530 ms, respectively). The two participants with QTc > 500 ms also had aberrant T-wave morphology and were discouraged from participation in the race. Genetic testing was declined by one of them and was negative in the other.
One asymptomatic individual had T-wave inversions that extended beyond lead V3. His echocardiography was normal. Further assessment by exercise test, Holter monitoring, signal averaged ECG, and cardiac MRI did not show any evidence of arrhythmogenic right ventricular cardiomyopathy or ischemic heart disease. Another runner with ST depression had an otherwise normal evaluation and a normal exercise test.
Selected echocardiographic variables are shown in Table 1. Eccentric LV hypertrophy was found in 9 participants (6%), all deemed to be present for a relative wall thickness ≤ 0.42. There were no significant differences with regard to age, hours of training per week, BMI, blood pressure, left ventricular ejection fraction, relative wall thickness, tissue velocities, or NT-proBNP between left ventricular hypertrophy (LVH) and non-LVH participants. Measures of cardiac diastolic function was within normal limits in all participants. E/A ratio and Em showed weak but significant inverse correlations with age (r = −0.29 and r = −0.25, P < 0.05 for both) but no significant correlations with training volume or blood pressure measurements.
Abnormal echocardiographic findings led to further cardiovascular workup in two individuals (Table 2). One had mild aortic regurgitation at rest and preserved cardiac function during exercise stress echocardiography and was cleared for participation. In another individual, echocardiography revealed a tumor (15 × 20 mm) that originated from the anterior tricuspid leaflet, with no hemodynamic compromise at rest. After further examination by contrast-enhanced echocardiography and computed tomography, the nature of this intracardiac mass remained unclear. After surgical removal, the mass was histopathologically determined to be a lipoma. Race participation was discouraged, pending surgery.
Blood tests revealed mildly abnormal results in a significant proportion of participants. These findings had no effect on race eligibility. Selected values are shown in Table 1. According to the local laboratory standards, 12% had anemia, 33% hypokalemia, 7% hyponatremia, and 5% elevated LDL levels, none had LDL >6 mmol·L−1. NT-proBNP was within the normal range in all participants.
On the race day, the temperature ranged from 14°C to 20°C with overcast skies and light winds. Of the study participants, 130 (85%) completed the race, 19 (12%) did not start for various reasons (e.g., common cold, musculoskeletal problems), and 4 (3%) did not complete the race (all due to musculoskeletal problems). One study participant developed atrial fibrillation during the race but no other serious medical events occurred in any study participant, nor were there any significant medical emergencies in any race participant according to information provided by the race organizers.
The increasing popularity of endurance events has led many individuals to start vigorous exercise and competitive sports in middle and older age, a lifestyle undisputedly associated with overall health benefits (5). However, because some individuals may harbor undetected cardiovascular conditions associated with an increased risk of adverse cardiac events during exercise, a preparticipation cardiovascular evaluation has been recommended (4). This study, which focuses on the presumed “high-risk group” of men age ≥45 yr planning first-time endurance race participation, is the first to report results from such a procedure. Further medical workup was deemed necessary in 9%, and 2% of the participants were discouraged from vigorous exercise, the same proportions as in a large Italian screening program of young athletes (6). This analogy may be taken as support of the usefulness of cardiovascular evaluation in the studied target group. Furthermore, our findings confirm the usefulness of a thorough physician examination and a 12-lead ECG as first line tests in preparticipation evaluation. Combined, these tests identified 12 of the 14 runners requiring further diagnostic evaluation, whereas blood testing and echocardiography did not add substantially to the diagnostic yield.
Medical history, physical examination, and risk SCORE
The addition of the modified risk SCORE (32) did not contribute significantly to the evaluation process, likely because of its inherently low-risk estimates in lower age categories, particularly among nonsmokers. Notably, 12% of the participants reported being physically inactive, and 6% of the participants were obese; however, they registered to participate in a challenging cross-country running race. This may concur with our recent finding that the growing popularity of endurance events has been paralleled by declining fitness among participants, suggesting a lowered threshold for participation (2).
Athletes frequently have training-induced ECG changes that may complicate ECG interpretation and raise concern of an underlying cardiac abnormality (8). These changes can occur already within a few months of training (11), which likely explains their frequent presence also in our population of first-time participants. For example, 32% showed early repolarization phenomena, which is generally considered a benign finding and part of athletic heart syndrome (8). Knowledge of these typical ECG features is important for all physicians involved in both preparticipation evaluation and routine care of physically active individuals. However, although guidelines exist to help clinicians interpret ECG changes in athletes (8), there is currently no consensus as to how such abnormalities should be worked up.
Interestingly, training-unrelated ECG abnormalities were noted in 24% of participants, a proportion markedly greater compared with a previous report in younger athletes (<5%) (8). This difference was largely driven by the high prevalence of prolonged QTc intervals in our cohort with a mean QTc of 416 ± 23 ms and 13% exceeding 440 ms. By comparison, a group of young competitive athletes (mean age, 20 yr) had QTc intervals of 397 ± 28 ms, with only 0.4% higher than 440 ms (3). QTc intervals may be prolonged by 10%–15% because of endurance training (33) and also increase with older age and higher BMI (20), which could explain some of this discrepancy. Our findings may suggest that more liberal cutoff values for prolonged QTc are appropriate in middle-age and older endurance athletes, at least in the asymptomatic individuals with no pertinent medical history. Still, following current recommendations (34), the two individuals with QTc > 500 ms were discouraged from vigorous exercise.
Although all runners had sinus rhythm at baseline, further evaluation because of palpitations and exertional chest pain identified three participants (2%) with lone atrial fibrillation. Because only a minority of participants were assessed by Holter monitoring, it is likely that the present study underestimated the actual prevalence of atrial fibrillation, which is known to be higher in middle-age and older endurance athletes compared with the general population (16). However, there is no evidence to support limiting of physical activity in such individuals.
To better characterize the study population, our diagnostic evaluation included echocardiography, which is not recommended as a first-line test. Six percent had eccentric LVH with preserved cardiac function and an otherwise normal workup, suggestive of athletic heart syndrome. Although measures of cardiac diastolic function was within normal limits in all participants, the inverse correlation with age suggests that, despite their training, our group did not escape from the age-related decline in diastolic function (25). However, as this study focused on novice runners, this may be expected. The unexpected finding of a cardiac lipoma in one participant was likely without relevance in the general context but illustrates that any widely applied test can lead to incidental findings requiring additional testing and/or treatment.
Blood laboratory tests
Many runners had blood laboratory values outside the normal range, for example, mild anemia, hyponatremia, and hypokalemia, which likely correlates with the long-term dilutional effects of training on plasma volume (9). Other contributing factors to anemia, particularly in runners, include hemolysis from foot strike, gastrointestinal blood loss, and hematuria (28).
NT-proBNP, a well-established marker of myocardial dysfunction and a strong predictor of cardiovascular events (31), was within the normal range in all runners, which is in keeping with the absence of structural abnormalities on echocardiography. However, in a previous study among self-reportedly healthy elderly runners, elevated NT-proBNP identified a group of participants with severe undetected cardiovascular disease (26), suggesting that the diagnostic properties of natriuretic peptides are maintained in the athletic population.
Coronary artery disease
Of note, no participant was diagnosed with CAD, the most common underlying etiology of sudden cardiac death in athletes age >35 yr (21). One retrospective study showed that acute coronary events during leisure time sports are not uncommon in middle-age men without previously known CAD (10). Furthermore, one study reported a higher than expected prevalence of CAD in endurance runners (24), although that study has been criticized for self-selection bias with a large proportion of former smokers.
For these reasons, our study could be criticized for not assessing all participants by an exercise test. However, various forms of exercise tests have poor sensitivity and specificity for finding CAD in asymptomatic patients with a low pretest likelihood of disease (13,14,22). Thus, based on the recommendations of the European (4) and U.S. Preventative Task Force (13) recommendations, exercise testing was not included in the initial evaluation.
Finally, as many individuals today start exercise late in life, it is possible that they harbor previously undetected cardiac conditions typically associated with adverse events in young competitive athletes, such as cardiomyopathies and channelopathies, and therefore preparticipation evaluation in middle and older age should not exclusively focus on identifying participants with CAD.
The study is limited by a small sample size, and the prevalence of cardiovascular conditions should thus be interpreted with caution. Of the participants, 22%, 16%, and 5% did not respond, declined to participate, or did not attend the scheduled appointment, respectively, which introduces the possibility of self-selection bias. However, keeping in mind that these individuals were middle-age urban professionals who volunteered to participate in a time consuming protocol, the observed response must be considered good. These numbers could also be viewed as a useful finding in the planning of future studies in the field. Importantly, there was no difference in age and runtimes between study participants and those who abstained (51 ± 5 vs 52 ± 6 yr, NS; 201 ± 31 vs 205 ± 28 min in the 30-km race, NS), suggesting that a representative sample was evaluated.
Because of their higher risk of exercise-related adverse cardiac events, our study focused on male runners (20), and consequently, no conclusions can be drawn as regard women. Furthermore, the current EACPR (4) and AHA (22) recommendations for preparticipation evaluation of middle-age athletes also include those age 35–44 and 40–44 yr, respectively, who were not represented in this study. It is possible that including women, runners with larger previous endurance racing experience, and younger participants would have affected the proportion of abnormal findings.
Participants with uncommon and training-unrelated ECG changes, such as left atrial hypertrophy and electrical axis deviation, could be reassured by echocardiography. If strictly adhering to the EACPR guidelines, that is, not using echocardiography as a first-line test, more participants with abnormal ECGs may have required further workup. However, some experts are beginning to question the need for further evaluation of such ECG alterations, when present in isolation (27,30).
The relatively high prevalence of abnormal findings in this study supports the value of cardiovascular evaluation in middle-age and older individuals before intense physical activity. A thorough physician examination together with a 12-lead ECG is effective in identifying individuals in need for further diagnostic workup. However, the detection of CAD, the most important cause of exercise-related cardiovascular events in middle and older age, is limited by the absence of a reliable screening tool. Therefore, the effect of the present approach on clinical outcome and its cost-effectiveness remains to be explored.
The authors are indebted to Eva Wallgren, the Cardiovascular Research Unit staff, and Peter Matha and colleagues at the Clinical Trial Centre, Karolinska University Hospital, who provided invaluable technical and logistic support.
This work was supported by grants from the Swedish Heart and Lung Foundation, the Swedish Centre for Sports Research, and Roche Diagnostics.
The authors declare no conflict of interest.
The results of the present study do not constitute endorsement by the American College of Sports Medicine.
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