We measured the serum levels of myoglobin, total creatine kinase (CK), and the CK myocardial (CK-MB), muscle (CK-MM), and brain (CK-BB) isoenzymes in 37 subjects treated with statins and 43 nonstatin-treated controls running the 2011 Boston Marathon. Venous blood samples were obtained the day before (PRE) and within 1 hour (FINISH) and 24 hours after (POST) the race. The hematocrit and hemoglobin values were used to adjust for changes in the plasma volume. The CK distribution was normalized using log transformation before analysis. The exercise-related increase in CK 24 hours after exercise, adjusted for changes in plasma volume, was greater in the statin users (PRE to POST 133 ± 15 to 1,104 ± 150 U/L) than in the controls (PRE to POST 125 ± 12 to 813 ± 137 U/L; p = 0.03 for comparison). The increase in CK-MB 24 hours after exercise was also greater in the statin users (PRE to POST 1.1 ± 3.9 to 8.9 ± 7.0 U/L) than in the controls (PRE to POST 0.0 ± 0.0 to 4.2 ± 5.0 U/L; p <0.05 for comparison). However, the increases in muscle myoglobin did not differ at any point between the 2 groups. Increases in CK at both FINISH and POST race measurements were directly related to age in the statin users ( r 2 = 0.13 and r 2 = 0.14, respectively; p <0.05) but not in the controls ( r 2 = 0.02 and r 2 = 0.00, respectively; p >0.42), suggesting that susceptibility to exercise-induced muscle injury with statins increases with age. In conclusion, our results show that statins increase exercise-related muscle injury.
Approximately 468,000 persons completed a marathon, a 42-km footrace, in the United States in 2009, a 10% increase from 2008. Serious adverse events with marathon running are rare, but such exercise can produce marked increases in the serum markers of skeletal muscle damage. The average serum creatine kinase (CK) levels, for example, can be ∼2,000% higher after a marathon. Statins can increase resting creatine kinase levels, and we have previously shown increases in CK levels after unaccustomed exercise in physically untrained subjects treated with lovastatin. Regular physical exercise, and even a single bout of vigorous exercise, protects the skeletal muscle from exercise-induced injury, as measured by the serum CK levels. Because both participation in marathons and statin use are prevalent, we sought to determine whether statin users running a marathon exhibited greater evidence of muscle damage as assessed by serum CK levels than marathon runners not using these medications.
Methods
A total of 37 statin-using athletes (29 men and 8 women) and 43 controls (30 men and 13 women) were recruited through an e-mail sent to all participants registered for the 115th Boston Athletic Association Marathon held on April 18, 2011. The subjects were recruited if they had either continuously received statin therapy for >6 months or not used any lipid-lowering medication. Subjects were nonsmokers, aged ≥35 years, and free of known cardiovascular or metabolic disease, except hypercholesterolemia. They were not taking oral contraceptives and/or hormonal therapy and had agreed to abstain for 24 hours before the race from taking any nonstatin medications such as aspirin or nonsteroidal anti-inflammatory drugs that could affect the skeletal muscle biomarker levels. The subjects provided written, informed consent to participate as approved by the institutional review board at Hartford Hospital (Hartford, Connecticut).
The day before (PRE) the marathon, the subjects provided a medical history and reported their training mileage for the 3 months and 1 week preceding the marathon. The blood pressure at rest and heart rate (Welch Allen 52000 Vital Signs Monitor, Skaneateles Falls, New York) and height and body mass were measured. Venous blood was obtained after a 12-hour fast to measure the total CK, CK myocardial, muscle, and brain isoenzymes (CK-MB, CK-MM, and CK-BB, respectively), myoglobin, hemoglobin, hematocrit, total and high-density lipoprotein cholesterol, and triglycerides. Low-density lipoprotein cholesterol was estimated using the Friedewald equation. Alanine aminotransferase was also measured in this prerace sample. Blood samples were also obtained immediately after (FINISH) the subjects completed the marathon in the main medical tent approximately 100 m from the finish line and the day after the race (within 24 hours of the finish; POST) at a Quest Diagnostics Laboratory. These samples were used to measure the CK, CK isoenzymes, myoglobin, hemoglobin, and hematocrit. Serum was separated from the cells by centrifugation at 5,000 rpm for 10 minutes and stored on dry ice (−80°C). Whole blood was refrigerated. The samples were shipped to Quest Diagnostics, Nichols Institute (Chantilly, Virginia), where all blood analyses were performed.
Physical activity for the 24-hour period before and after the marathon was assessed using a 24-hour physical activity recall (question 8 from the Paffenbarger Physical Activity Questionnaire). The subjects categorized their physical activity by the hours of the day as sedentary, light, moderate, and vigorous activity.
The hematocrit and hemoglobin were measured using a colorimetric assay. Lipid and hepatic panels were performed using a spectrophotometric assay. The CK isoenzymes were measured with electrophoresis, and muscle myoglobin was assessed with the nephelometric assay. Hematocrit and hemoglobin were used to estimate the plasma volume changes, and CK and myoglobin were corrected for the estimated exercise-induced changes in plasma volume, according to the formula of van Beaumont.
Differences in the baseline characteristics between the statin and control groups were assessed using 1-way analysis of variance, with significance set at p <0.05. CK and myoglobin were logarithmically transformed before analysis to normalize their distribution. To determine the effects of statin use on the changes in CK and myoglobin, we used a linear mixed model for repeated measurements with an auto-regressive variance–covariance structure, incorporating time as the within-subjects factor and group (control vs statin) as the between-subjects factor. The subjects were defined as the random factor; all other variables were fixed within the model. The potential categorical factors that could affect the relation between the main effects and outcomes were added into the model to assess significance. The effect of continuous variables was investigated using analysis of covariance. P-values for the mean difference estimates between groups at various points were adjusted using Tukey’s multiple comparison procedure to account for post hoc multiple comparison testing. The repeated measures model was also used to assess the group differences in physical activity before and after the marathon. Pearson correlations and linear regression analysis were used to examine the relations between continuous variables. To investigate the effect of statin potency on the statistical models, the statins were classified by the expected potency of cholesterol reduction according to published dose equivalencies: rosuvastatin 2.5 mg = atorvastatin 5 mg = simvastatin 10 mg = lovastatin 20 mg = pravastatin 20 mg = fluvastatin 40 mg.
Statistical analyses were performed using SAS, version 9.1 (SAS Institute, Cary, North Carolina), and all data expressed as nontransformed values are presented with the group mean ± SD.
Results
The statin and control group subjects were of similar training status and health ( Table 1 ). The control subjects performed more hours of moderate physical activity than did the statin subjects the day after the marathon (3.8 ± 2.4 vs 2.2 ± 1.7 hours; p <0.01), but the other self-reported categories of physical activity did not differ between the groups or before and after the marathon (all p >0.10). The statin users were treated with a variety of statins and statin doses ( Table 2 ). The average potency of statin used by the participants in atorvastatin equivalents was 14.7 mg. Potency was inversely related to the total and low-density lipoprotein cholesterol levels in the statin group (Pearson coefficient −0.55 and −0.48, respectively; both p <0.01). Three statin participants reported using niacin 500 to 1,000 mg. No participant reported consumption of red rice yeast, which is known to affect cholesterol levels.
| Variable | Statin Group (n = 37) | Control Group (n = 43) |
|---|---|---|
| Age (years) | 56 ± 8 | 51 ± 7 |
| Systolic blood pressure at rest (mm Hg) | 140 ± 16 | 137 ± 17 |
| Diastolic blood pressure at rest (mm Hg) | 78 ± 15 | 78 ± 11 |
| Body mass index (kg/m 2 ) | 23.6 ± 2.5 | 23.1 ± 2.9 |
| Low-density lipoprotein cholesterol (mg/dl) | 87 ± 26 | 104 ± 24 ⁎ |
| High-density lipoprotein cholesterol (mg/dl) | 65 ± 14 | 74 ± 21 ⁎ |
| Alanine aminotransferase (U/L) | 26.5 ± 16.1 | 21.6 ± 10.6 |
| Training mileage † (miles/wk) | 37 ± 19 | 40 ± 13 |
| Taper mileage ‡ (miles/wk) | 22 ± 16 | 19 ± 11 |
| Official finishing time (hr:min) | 4:15 ± 0:47 | 3:58 ± 0:41 |
| Blood pressure medication use (n) | 9 | 2 |
| Vitamin/supplement use (n) | 12 | 14 |
⁎ p < 0.05, statin versus control.
† Training mileage = average miles run weekly during training for the Boston Marathon.
‡ Taper mileage = miles run in the week preceding the marathon.
| Drug | Dose (mg) | Patients (n) |
|---|---|---|
| Fluvastatin | 80 | 1 |
| Atorvastatin | 5 | 2 |
| 10 | 3 | |
| 20 | 6 | |
| 80 | 1 | |
| Rosuvastatin | 5 | 1 |
| 10 | 3 | |
| Simvastatin | 10 | 2 |
| 20 | 8 | |
| 40 | 6 | |
| Lovastatin | 20 | 2 |
| Pravastatin | 10 | 2 |
The CK and CK-MB concentrations before and immediately after the marathon were similar in the statin users and controls, but both were higher in the statin users 24 hours after the event ( Figures 1 and 2 ) . Neither myoglobin levels (statin PRE 34.5 ± 4.5, FINISH 781.7 ± 94.2, and POST 182.4 ± 26.8 μg/L vs control PRE 33.8 ± 3.3, FINISH 797.3 ± 99.1, and POST 174.2 ± 74.3 μg/L) nor the percentage of CK as CK-MB (statin PRE 0.1 ± 0.4%, FINISH 0.7 ± 1.2%, and POST 1.2 ± 1.1% vs control PRE 0.0 ± 0.0%, FINISH 0.8 ± 1.2%, and POST 0.9 ± 1.1%) differed between the statin users and controls at any point (both p >0.15 for comparison), although both increased with exercise (p <0.01). CK (but not CK-MB) concentrations in both groups combined were also higher 24 hours after the marathon among those with a finish time of <4 hours versus those with a finish time >4 hours ( Figure 3 ) . However, no combined interaction of statin use and the finish time on the CK response to the marathon was found (p = 0.29). The higher CK values with statin use and faster finishing times persisted (p <0.05) even after controlling for potential covariates, including age, body mass index, miles run during training or the week before the marathon, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and systolic and diastolic blood pressure.
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