Department of Medicine, McLean Hospital, Belmont, MA; Clinical Laboratory and Nuclear Medicine Divisions, Massachusetts General Hospital and Harvard Medical School, Boston, MA
In contrast to nonspecific elevations of myoglobin and creatine kinase MB (CK-MB) in athletes due to exertional rhabdomyolysis of trained skeletal muscle(1,2), reported increases in cardiospecific troponins after competition may indicate silent injury to the myocardium (3,4,5,6,7,8). We therefore undertook serial testing of multiple cardiac markers used to diagnose early- and late-stage myocardial injury in the same group of middle-aged runners before and sequentially after five Boston Marathons over 4 years. In addition to creatinine kinase MB (CK-MB) and myoglobin, cardiac TnI (cTnI) was tested by a qualitative rapid assay in 1997, a high-sensitivity reference method in 1998-2000, and a rapid quantitative method to detect acute myocardial infarction (AMI) in 2001 together with cardiac troponin T (cTnT). Selective post-race single photon emission computed tomography (SPECT) Tc-99m sestamibi myocardial scintigraphy and B-natriuretic peptide (BNP) levels were used to assess microinfarction and transient left ventricular dysfunction respectively.
Participants were 82 runners with a mean age of 47 + 8 years attending the pre-race Scientific Symposia of the American Medical Athletic Association as entrants in the 10 1st to 10 5th Boston Athletic Association Marathons from 1997 to 2001. Medical and running histories obtained yearly by questionnaire indicated no smoking or known coronary heart disease, 25 training miles per week, and five prior marathons completed including a qualifying race under four hours in the prior year.
Blood samples were drawn the day before and within four and 24 hours after the race. In 1997, whole blood was immediately tested by rapid assay for CK-MB, myoglobin and cTnI using Cardiac STATus' CK-MB/Myoglobin and Cardiac STATus' Troponin I Point-of-Care Test Kits (Princeton Bio Meditech Corp., Princeton, NJ) with sera frozen at -70o for reference testing. Sequential sera were similarly obtained and frozen from 20, 17, and 14 runners in 1998-2000 for measurement of CK-MB, myoglobin and cTnI by an ACS: 180 instrument (Bayer Corporation, Tarrytown, NY). In 2001, CK-MB, myoglobin, and cTnI were measured by a rapid quantitative fluorescence immunoassay using Triage[R] Cardiac Panel (Biosite[R] Diagnostics, Inc., San Diego, CA), cTnT by an electrochemiluminescence immunoassay on the Elecsys 1010 analyzer (Roche Diagnostics Corp., Indianapolis, IN), and BNP by the Triage[R] BNP Test (Biosite[R] Diagnostics, Inc., San Diego, CA). SPECT sestamibi myocardial perfusion imaging was performed at rest the morning after the 1998 race in five finishers after injection with 30m Ci Tc-99m sestamibi (Cardiolite[R], Dupont Pharmaceuticals, North Billerica, MA). The student-paired T test (Sigma Stat, Jandal Scientific) was used to compare results from runners providing three sequential samples.
Changes in cardiac markers were measured before and after a total of 104 races among 82 runners with 15 subjects participating multiple times over four years. Results of qualitative rapid assays for CK-MB, myoglobin, and cTnI before and sequentially after the 1997 Boston Marathon are shown in Table 1 with positive tests confirmed by corresponding reference methods. CK-MB/myoglobin rapid assays were positive pre-race in 17 and 14 of 40 runners respectively and in all runners (n=41) within four and 24 hours (n= 13) post race. Rapid assays for cTnI were positive in two asymptomatic runners with levels remaining elevated up to 72 hours post-race.
Using the same reference method in 51 runners in 1998-2000, there were significant increases from pre-race to within four hours after competition for all markers with persistent increases in CK-MB and cTnI within 24 hours post-race (see Figure 1). Serum myoglobin (nl<110ng/ml) rose 38.4-fold from 47 + 5 ng/ml pre-race to 1811 + 340 ng/ml (p<.0001) within four hours post-race, returning to baseline within 24 hours (n=37, 1998-1999). Serum CK-MB (nl<6.6 ng/ml) rose 4.9-fold from 2.8 + .5 ng/ml pre-race to 13.8 + 1.4 ng/ml (p<.0001) within four hours and 13.5-fold to 38 + 6.9 ng/ml (p<.0001) within 24 hours post-race (n=51, 1998-2000). Mean values for cTnI (nl<1.5ng/ml) rose 6.5-fold within the normal range from .02 + .005 ng/ml pre-race to .14 + .02 ng/ml (p=.0013) and 0.14 + 0.4 ng/ml (p=.0013) within four and 24 hours post-race, respectively (n=51, 1998-2000).
Post-race SPECT sestamibi myocardial imaging was normal in five runners in 1998 including a 47 year old asymptomatic subject concurrent with a cTnI of 3.1 ng/ml selected because of positive rapid assays for cTnI in the prior year. A 72 year old runner with a normal post-race scan was hospitalized for transient chest pain later the same day with nondiagnostic electrocardiograms and a two-fold increase in cTnI from 0.6 ng/ml pre-race to 1.2 ng/ml post-race. Stress SPECT sestamibi cardiac imaging remained normal in both of these runners six weeks later. Three other runners with normal scans showed no post-race increase in cTnI, including a 56 year old Iron Man triathlete with a custom-programmed permanent cardiac pacemaker (Telectronics 1256, Denver, CO) placed in 1995 for idiopathic complete heart block.
Quantitative rapid assays in 2001 showed increases in CK-MB and myoglobin at both post-race time points (p<0.005) with no change in cTnI or cTnT (see Figure 2). BNP levels were within normal limits (<100 pg/ml) post-race in all subjects but increased from 16.7 + 4.5 pg/ml to 48.6 + 10.2 pg/ml within 24 hours post-race (p=0.0006). All runners remained free of cardiac events over four years while completing subsequent marathons with comparable finishing times averaging four hours and 20 minutes.
In contrast to reported increases in cardiac troponins in endurance athletes based on single values after competition (6,7,8), we extended previous studies using serial testing to assess the time course of release in the same group of runners over four years. Because of positive qualitative rapid assays for cTnI in some runners in 1997, we undertook subsequent testing with an assay for cTnI providing low-end analytical sensitivity designed to detect minor degrees of myocardial damage as used to differentiate unstable angina from non-ST segment elevation myocardial infarction in patients with acute coronary syndromes (9, 10). This high-sensitivity showed a 6.5-fold increase in cTnI at both post-race time points in each subgroup and in 51 runners over three years with a consistency seen with true-positive rather than sporadic or spurious elevations(11). SPECT sestamibi Tc-99m myocardial imaging was negative in five runners in 1998 concurrent in one asymptomatic subject with a cTnI level of 3.1 ng/ml, which may represent necrosis of cardiomyocytes below the threshold for detection by SPECT myocardial imaging as with prior antimyosin myocardial scintigraphy(12). Another 72 year old runner with normal imaging was hospitalized hours later for transient chest pain, with a two-fold post-race increase in cTnI to 1.2 ng/ml compatible with unstable angina. Follow-up stress SPECT sestamibi cardiac imaging was negative six weeks later in both of these runners who remained asymptomatic while completing subsequent races with comparable finishing times.
Based upon changes in cTnI in runners as predictive of poor prognosis in patients with acute coronary syndromes(13,14), we undertook testing for cTnI and cTnT in 2001 using rapid quantitative methods designed to detect AMI (15). While confirming post-race increases in myoglobin and CK-MB as early-stage markers of AMI, there was no change in cTnT or cTnI as late-stage markers up to 24 hours after competition. Despite post-race increases in novel inflammatory markers for cardiovascular risk in these same runners (16), there was no apparent increase in cardiac events in these middle-aged male runners over four years. Further studies including younger and elite athletes and runners rehabilitated after treatment for ischemic or other heart disease are indicated to assess the prognostic role of cardiac troponins as shown in patients with heart disease (13, 17).
Regarding exercise-related myocardial stunning as reported in endurance athletes after competition(7), BNP as a surrogate marker of transient left ventricular dysfunction (18, 19) remained normal. An increase in BNP within the normal range at 24 hours post-race (p = 0.006) deserves study as a possible mechanism for hyponatremia and noncardiogenic pulmonary edema as may occur in endurance athletes after competition (20).
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"Reprinted from The American Journal of Cardiology, Vol. 88, pp. 918-920, Copyright 2001, with permission from Excerpia Medica, Inc."
Contents in Brief: In contrast to non-specific post-race elevations in myoglobin and CK-MB as early-stage markers for AMI due to exertional rhabdomyolysis of trained skeletal muscle, late-stage markers including cTnI and cTnT remained negative by rapid quantitative methods within 24 hours after competition. A 6.5-fold increase in cTnI by high-sensitivity methods as predictive of poor outcome in patients with acute coronary syndromes occurred in these middle-aged male runners without evidence for microinfarction by SPECT-sestamibi myocardial scintigraphy, left ventricular dysfunction by BNP, or apparent risk for cardiac events over four years.
Address correspondence and reprint requests to:
Kent Lewandrowski, M.D.
Department of Clinical
Laboratories, Gray 5
Massachusetts General Hospital
Fruit Street, Belmont MA 02114 (USA)
Telephone: (617) 726-2275
Fax: (617) 726-9206
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