Arthur J. Siegel

Myocardial Injury and Ventricular Dysfunction Related to Training Levels Among Nonelite Participants in the Boston Marathon

Background— Multiple studies have individually documented cardiac dysfunction and biochemical evidence of cardiac injury after endurance sports; however, convincing associations between the two are lacking. We aimed to determine the associations between the observed transient cardiac dysfunction and biochemical evidence of cardiac injury in amateur participants in endurance sports and to elicit the risk factors for the observed injury and dysfunction. Methods and Results— We screened 60 nonelite participants, before and after the 2004 and 2005 Boston Marathons, with echocardiography and serum biomarkers. Echocardiography included conventional measures as well as tissue Doppler–derived strain and strain rate imaging. Biomarkers included cardiac troponin T (cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP). All subjects completed the race. Echocardiographic abnormalities after the race included altered diastolic filling, increased pulmonary pressures and right ventricular dimensions, and decreased right ventricular systolic function. At baseline, all had unmeasurable troponin. After the race, >60% of participants had increased cTnT >99th percentile of normal (>0.01 ng/mL), whereas 40% had a cTnT level at or above the decision limit for acute myocardial necrosis (≥0.03 ng/mL). After the race, NT-proBNP concentrations increased from 63 (interquartile range [IQR] 21 to 81) pg/mL to 131 (IQR 82 to 193) pg/mL (P<0.001). The increase in biomarkers correlated with post-race diastolic dysfunction, increased pulmonary pressures, and right ventricular dysfunction (right ventricular mid strain, r=−0.70, P<0.001) and inversely with training mileage (r=−0.71, P<0.001). Compared with athletes training >45 miles/wk, athletes who trained ≤35 miles/wk demonstrated increased pulmonary pressures, right ventricular dysfunction (mid strain 16±5% versus 25±4%, P<0.001), myocyte injury (cTnT 0.09 versus <0.01 ng/mL, P<0.001), and stress (NT-proBNP 182 versus 106 pg/mL, P<0.001). Conclusions— Completion of a marathon is associated with correlative biochemical and echocardiographic evidence of cardiac dysfunction and injury, and this risk is increased in those participants with less training.

Effect of Marathon Running on Hematologic and Biochemical Laboratory Parameters, Including Cardiac Markers

Participants in marathon races may require medical attention and the performance of laboratory assays. We report the changes in basic biochemical parameters, cardiac markers, CBC counts, and WBC differentials observed in participants in a marathon before, within 4 hours, and 24 hours after a race. The concentrations of glucose, total protein, albumin, uric acid, calcium, phosphorus, serum urea nitrogen, creatinine, bilirubin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, total creatine kinase, creatine kinase-MB, myoglobin, and the anion gap were increased after the race, consistent with the effects of exertional rhabdomyolysis and hemolysis. The increase in WBC counts was due mainly to neutrophilia and monocytosis, with a relative decrease in circulating lymphocytes, consistent with an inflammatory reaction to tissue injury. A significant percentage of laboratory results were outside the standard reference ranges, indicating that modified reference ranges derivedfrom marathon runners might be more appropriatefor this population. We provide a table of modified reference ranges (or expected ranges) for basic biochemical, cardiac, and hematologic laboratory parameters for marathon runners.

Statement of the Second International Exercise-Associated Hyponatremia Consensus Development Conference, New Zealand, 2007.

Tamara Hew-Butler, DPM, PhD,* J. Carlos Ayus, MD,† Courtney Kipps, BMBS, MSc,‡ Ronald J. Maughan, PhD,§ Samuel Mettler, MSc,¶ Willem H. Meeuwisse, MD, PhD (chair),k Anthony J. Page, MBChB, MD,** Stephen A. Reid, MBBS, PhD,†† Nancy J. Rehrer, PhD,‡‡ William O. Roberts, MD, MSc,§§ Ian R. Rogers, MBBS,¶¶ Mitchell H. Rosner, MD,kk Arthur J. Siegel, MD,*** Dale B. Speedy, MBChB, MD,††† Kristin J. Stuempfle, PhD,‡‡‡ Joseph G. Verbalis, MD,§§§ Louise B. Weschler, MAT, PT,¶¶¶ and Paul Wharam, MMedSckkk

Consensus statement of the 1st International Exercise-Associated Hyponatremia Consensus Development Conference, Cape Town, South Africa 2005.

Over the past decade, exercise-associated hyponatremia (EAH) has emerged as an important complication of prolonged endurance activity. Prior to 1985, this condition was not reported, and runners generally finished marathons with weight loss but without serious medical complications. Abnormalities of serum sodium concentrations ([Na]), when measured, were confined to elevated levels consistent with varying degrees of volume depletion. In March 2005, a panel of twelve international experts on exercise physiology, sport medicine, water metabolism and body fluid homeostasis convened in Cape Town, South Africa, for the 1st International Exercise-Associated Hyponatremia Consensus Development Conference. The primary goal of this panel was to review all of the existing data on EAH and formulate an evidence-based analysis that would define the current understanding of the pathophysiology of EAH. In particular, the panel was constituted to facilitate integration of existing medical and scientific knowledge of other forms of hyponatremia with the occurrence of this homeostatic imbalance during endurance exercise. A secondary goal of the EAH Consensus Development Conference was to prepare a statement that would serve to curtail the growing problem of EAH by disseminating the most current information to both medical personnel and the greater public on the prevalence, nature and treatment of this disorder. The panel strived to clearly articulate what we agreed upon, debate issues that we did not agree upon, and describe in detail what we did and did not know, including minority viewpoints that were supported by clinical and experimental data. The following statement reflects a concise summary of the data deliberated and synthesized by the panel and provides a ‘‘snapshot in time’’ of the current state of knowledge on EAH. New knowledge will continue to advance regarding our understanding of EAH, and will mandate future updates to this consensus statement.

Effect of Marathon Running on Inflammatory and Hemostatic Markers

A lthough increasing levels of regular physical activity are incrementally cardioprotective, prolonged strenuous exercise such as marathon running may trigger acute myocardial infarction and sudden cardiac death. The mechanism of such events is not well understood but may be due to hemodynamic, vasoconstrictive, and prothrombotic effects with disruption of unstable coronary plaques leading to acute coronary thrombosis. Although several studies have demonstrated exercise-induced activation of fibrinolysis and coagulation, the effect of marathon running on hemostatic balance has not been well studied. We therefore measured changes in C-reactive protein (CRP), von Willebrand factor (vWF), D-dimer, fibrinogen, fibrinolytic activity, white blood cell (WBC) counts, and platelet activation in middle-aged runners before and after the Boston Marathon. An imbalance in prothrombotic and fibrinolytic factors after strenuous physical exertion may transiently increase the risk for intravascular—including coronary—thrombosis and trigger acute ischemic events. • • • Subjects were attendees at the prerace Scientific Symposia of the American Medical Athletic Association as entrants in the 100th to 105th Boston Athletic Association Marathons from 1966 to 2001 (mean age 47.6 years), who reported no smoking or known coronary heart disease by yearly questionnaire. Blood samples were drawn without stasis from an antecubital vein using a 21-gauge butterfly needle the morning before, within 4 hours after the race, and the next morning. Samples were drawn at the same time points for platelet studies in the year 2000 from subjects reporting no use of anti-inflammatory drugs in the prior 2 weeks and for complete blood counts in the year 2001. Whole blood was collected in 3.2% sodium citrate (9:1, vol/vol), and centrifuged at 2,500 g for 20 minutes at 4°C to obtain platelet-poor plasma for the measurement of CRP, vWF, D-dimer, fibrinolytic activity, and fibrinogen. Whole blood was similarly collected and processed in 15% (K3) ethylenediaminetetraacetic acid at a final concentration of 1 mg/ml for determination of vWF. CRP and D-dimer levels were determined using commercially available enzymelinked immunosorbant assays by TintEliza Biopool (Ventura, California) and Diagnostica Stago (Persippany, New Jersey), respectively. The vWF was determined by an enzyme-linked immunoassay procedure described by Penny et al, fibrinolytic activity by a fibrin plate assay as described by Brackman, and fibrinogen levels by the Clauss method. Whole blood for platelet aggregation studies was collected in 3.2% sodium citrate (9:1, vol/vol), and centrifuged within 1 hour of collection at 125 g for 10 minutes at room temperature to obtain platelet-rich plasma for testing after 30 minutes. Platelet aggregation testing was performed using a platelet aggregometer (PACKS-4 Platelet Aggregation Chromogenic Kinetic System, Helena Laboratories, Beaumont, Texas) in response to 10 ug/ml collagen, 10 uM adenosine diphosphate, 10 uM epinephrine, 500 ug/ml arachidonate, and 1.5 mg/ml ristocetin. Complete blood counts were performed in an ADVIA 120 automated hematology autoanalyzer (Bayer Diagnostics, Tarrytown, New York). Total and high-density lipoprotein cholesterol levels were measured using an Abbot Diagnostics ABA-200 biochromatic analyzer and Abbot A-Gent enzymatic reagents (Abbott Lab., Chicago, Illinois). Creatinine, blood urea nitrogen, and electrolytes were determined using a Hitachi 917 chemistry autoanalyzer (Roche Diagnostics, Indianapolis, Indiana). The Student paired t test was used to compare results from pooled data before and after the 1996 and 1997 marathons becausea there were no significant differences in baseline values between the 2 races. In comparing prerace values with those within 4 hours after the race in 55 finishers in 1996 to 1997, marathon running resulted in a twofold or greater increase in CRP (343 611 to 762 973 ng/ml [p 0.001]), vWF (109 47% to 233 65% [p 0.001]), D-dimer (177 137 to 529 279 ng/ml [p 0.001]), and fibrinolytic activity (75 48 to 213 95 mm [p 0.001]), whereas fibrinogen levels decreased (278 52 to 260 45 mg/dl [p 0.001]; Table 1). When comparing prerace specimens with those within 4 hours after the marathon in 32 runners in 2001, WBC and platelet counts increased (5.5 0.2 to 17.4 1.5 th/mm [p 0.005] and 226 25 to 253 27 th/mm [p 0.05]), respectively, whereas hematocrit and hemoglobin levels were unchanged. Platelet studies showed a shortened lag time to aggregation with collagen and an increase with epinephrine (n 5, year 2000). When comparing prerace values with those the morning after the race in 13 runners in 1997, vWF and From the Department of Medicine, McLean Hospital, Belmont; Institute for Prevention of Cardiovascular Disease; Massachusetts General Hospital and Brigham and Women’s Hospital, Boston, Massachusetts; Royal North Shore Hospital, Sydney, Australia; and Harvard Medical School, Boston, Massachusetts. Dr. Siegel’s address is: McLean Hospital, Department of Internal Medicine, 115 Mill Street, Belmont, Massachusetts 02478. E-mail: ajsiegel@mclean.harvard.edu. Manuscript received December 29, 2000; revised manuscript received and accepted May 23, 2001.

Effects of Low- and High-Nicotine Cigarette Smoking on Mood States and the HPA Axis in Men

The acute effects of smoking a low- or high-nicotine cigarette on hypothalamic–pituitary–adrenal (HPA) hormones, subjective responses, and cardiovascular measures were studied in 20 healthy men who met American Psychiatric Association Diagnostic and Statistical Manual IV criteria for nicotine dependence. Within four puffs (or 2 min) after cigarette smoking began, plasma nicotine levels and heart rate increased significantly (P<0.01), and peak ratings of ‘high’ and ‘rush’ on a Visual Analogue Scale were reported. Reports of ‘high,’ ‘rush,’ and ‘liking’ and reduction of ‘craving’ were significantly greater after smoking a high-nicotine cigarette than a low-nicotine cigarette (P<0.05). Peak plasma nicotine levels after high-nicotine cigarette smoking (23.9±2.6 ng/ml) were significantly greater than after low-nicotine cigarette smoking (3.63±0.59 ng/ml) (P<0.001). After smoking a low-nicotine cigarette, adrenocorticotropin hormone (ACTH), cortisol, dehydroepiandrosterone (DHEA), and epinephrine did not change significantly from baseline. After high-nicotine cigarette smoking began, plasma ACTH levels increased significantly above baseline within 12 min and reached peak levels of 21.88±5.34 pmol/l within 20 min. ACTH increases were significantly correlated with increases in plasma nicotine (r=0.85; P<0.0001), DHEA (r=0.66; P=0.002), and epinephrine (r=0.86; P<0.0001). Cortisol and DHEA increased significantly within 20 min (P<0.05) and reached peak levels of 424±48 and 21.13±2.55 ng/ml within 60 and 30 min, respectively. Thus cigarette smoking produced nicotine dose-related effects on HPA hormones and subjective and cardiovascular measures. These data suggest that activation of the HPA axis may contribute to the abuse-related effects of cigarette smoking.

Elevated Serum Cardiac Markers in Asymptomatic Marathon Runners after Competition: Is the Myocardium Stunned?

Prolonged strenuous exercise may trigger acute myocardial infarction (AMI), as exemplified by the occurrence of sudden cardiac death during marathon running. Serum creatine kinase MB (CK-MB) may be elevated in asymptomatic marathon runners after competition from exertional rhabdomyolysis of skeletal muscle altered by training, limiting its utility for evaluating acute cardiac injury in such athletes. Myoglobin and CK-MB2 isoform levels are emerging as earlier markers of AMI and troponin subunits as more specific than serum CK-MB mass. We tested runners before and sequentially after the 1995 Boston Marathon for conventional and newer markers including myoglobin, CK-MB mass and isoforms, cardiac troponin T, and cardiac troponin I using standard laboratory methods and rapid format assays if available. The mean serum values for myoglobin, CK-MB mass, CK-MB/myoglobin rapid panel tests, and CK-MB2 isoforms were normal or negative pre-race and elevated or positive 4 and 24 h after competition. These markers lack specificity for acute cardiac injury in trained runners. While the mean serum values for cardiac troponins T and I remained normal, 9 of 45 runners (20%) showed an increase in subunits by first-generation assays. All runners remained asymptomatic for cardiac disease and completed subsequent marathons 1 year later, making reversible myocardial injury or stunning unlikely. Elevated values of serum markers for AMI, including first-generation assays for both troponin subunits should be interpreted with caution in trained runners.

Measurement of a Plasma Stroke Biomarker Panel and Cardiac Troponin T in Marathon Runners Before and After the 2005 Boston Marathon

We report changes in cardiac troponin-T (TnT) and a new plasma stroke biomarker panel (D-dimer, B-natriuretic peptide [BNP], matrix metalloproteinase-9 [MMP-9], S-100 b, Biosite Diagnostics, San Diego, CA) in 30 nonprofessional marathon runners before and immediately after the 2005 Boston Marathon. Following competition, there was a statistically significant increase in MMP-9 (P < .001) and D dimer (P < .001). Nonsignificant changes in S-100 b and BNP were observed. Premarathon and postmarathon values for a multimarker stroke index increased from 0.97 (normal) to 3.5 (low risk or more; P < .001). Two subjects had index values more than the high-risk cutoff value. Mean TnT premarathon and postmarathon levels increased (from <0.01 to 0.03 ng/mL; P < .0001). After the marathon, with a cutoff value of 0.05 ng/mL, 7 runners (23%) had values above the manufacturers recommended cutoff for myocardial damage. Although biochemical evidence of myocardial damage following strenuous exercise may reflect myocardial stunning or subclinical ischemia, the changes in the stroke index and values for individual stroke markers may reflect a systemic inflammatory response to exertional rhabdomyolysis which is common, but the possibility of subclinical central nervous system damage cannot be excluded.

Effects of marathon running on platelet activation markers : direct evidence for in vivo platelet activation.

We used the ADVIA 2120 Hematology System (Bayer HealthCare, Diagnostics Division, Tarrytown, NY) to study the effects of vigorous exercise on CBC count, WBC differential, RBC fragmentation, and platelet activation parameters in 32 healthy participants in a 26.2-mile (42.2-km) marathon. The runners demonstrated increases in hematocrit and platelet count consistent with dehydration and leukocytosis indicative of demargination of neutrophils or inflammation secondary to tissue destruction (eg, rhabdomyolysis). The number of RBC fragments was increased after the race (P = .008), consistent with exercise-induced hemolysis. The mean platelet component, a measure of platelet granularity, was decreased (P < .0001), and the number of platelet clumps was increased (P = .0026), providing evidence for in vivo platelet activation during the marathon. By using direct measurement of platelet granularity, our study confirms the in vivo activation of platelets by vigorous exercise and establishes the usefulness of automated cell counters for the assessment of platelet activation and of RBC fragmentation in this setting.

Effects of Smoking Successive Low- and High-Nicotine Cigarettes on Hypothalamic–Pituitary–Adrenal Axis Hormones and Mood in Men

Smoking one cigarette produces rapid nicotine dose-related increases in hypothalamic–pituitary–adrenal (HPA) axis hormones, mood, and heart rate, but relatively little is known about the effects of smoking several cigarettes successively. Twenty-four healthy adult men who met Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria for nicotine dependence provided informed consent. After overnight abstinence from smoking, men smoked three low- or high-nicotine cigarettes for 4 min each at 60 min intervals. Samples for nicotine and hormone analysis, Visual Analog Scale (VAS) ratings of subjective effects and heart rate were collected at 4, 8, 12, 16, 20, 30, 40, and 50 min after each cigarette. After low-nicotine cigarettes, nicotine levels, adrenocorticotropin hormone, and heart rate did not increase significantly, cortisol and dehydroepiandrosterone decreased significantly, and positive VAS ratings were lower but parallel to ratings after high-nicotine cigarette smoking. After high-nicotine cigarettes, peak nicotine levels increased monotonically. HPA axis hormones increased after smoking, but peak levels did not differ significantly after successive high-nicotine cigarettes. Positive VAS ratings and heart rate increased after each high-nicotine cigarette, but peak levels were lower after smoking the second and third cigarette. ‘Craving’ decreased significantly after smoking both low- and high-nicotine cigarettes, then gradually increased during the 60 min interval between cigarettes. These data are consistent with clinical reports that the first cigarette after overnight nicotine abstinence is most salient. Tolerance to the subjective and cardiovascular effects of nicotine developed rapidly during repeated cigarette smoking, but nicotine-stimulated increases in HPA axis hormones did not change significantly.