Effect of statins on creatine kinase levels before and after a marathon run

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Effect of Statins on Creatine Kinase Levels Before and After
a Marathon Run
Beth A. Parker, PhDa,*, Amanda L. Augeri, MSa, Jeffrey A. Capizzi, MSa, Kevin D. Ballard, PhDb,
Christopher Troyanos, ATCc, Aaron L. Baggish, MDd, Pierre A. D’Hemecourt, MDc, and
Paul D. Thompson, MDa
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 (r2 � 0.13 and r2 � 0.14, respectively; p <0.05) but not in the
controls (r2 � 0.02 and r2 � 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. © 2012 Elsevier Inc.
All rights reserved. (Am J Cardiol 2012;109:282–287)
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Approximately 468,000 persons completed a marathon, a
42-km footrace, in the United States in 2009, a 10% in-
crease from 2008.1 Serious adverse events with marathon
running are rare,2 but such exercise can produce marked
increases in the serum markers of skeletal muscle damage.
The average serum creatine kinase (CK) levels, for exam-
ple, can be �2,000% higher after a marathon.3 Statins can
ncrease resting creatine kinase levels,4 and we have previ-
usly shown increases in CK levels after unaccustomed
xercise in physically untrained subjects treated with lova-
aHenry Low Heart Center, Department of Cardiology, Hartford Hos-
pital, Hartford, Connecticut; bDepartment of Kinesiology, University of
onnecticut, Storrs, Connecticut; cChildren’s Hospital, Boston, Massachu-
etts; and dDivision of Cardiology, Massachusetts General Hospital, Bos-
on, Massachusetts. Manuscript received July 26, 2011; manuscript re-
eived and accepted August 30, 2011
This study was funded by a research grant from Hartford Hospital
Hartford, Connecticut).
Dr. Thompson is a consultant for AstraZenica International, Wilming-
on, Delaware, Merck & Co., Inc., Whitehouse Station, New Jersey, the
chering-Plough Corporation, Kenilworth, New Jersey, Takeda Pharma-
eutical Company, Limited, Deerfield, Illinois, Roche, Inc., Indianapolis,
ndiana, and Genomas, Inc., Hartford, Connecticut and is a member of the
peaker’s bureau for Merck & Co., Inc., Whitehouse Station, New Jersey,
fizer, Inc., Groton, Connecticut, Abbott Laboratories, Abbott Park, Illi-
ois, AstraZenica International, Wilmington, Delaware, and the Schering-
lough Corporation, Kenilworth, New Jersey.
*Corresponding author: Tel: (860) 545-1508; fax: (860) 545-2882.
E-mail address: bparker03@harthosp.org (B.A. Parker).
002-9149/12/$ – see front matter © 2012 Elsevier Inc. All rights reserved.
oi:10.1016/j.amjcard.2011.08.045
tatin.5 Regular physical exercise, and even a single bout of
igorous exercise, protects the skeletal muscle from exer-
ise-induced injury, as measured by the serum CK levels.6
Because both participation in marathons and statin use are
prevalent, we sought to determine whether statin users run-
ning a marathon exhibited greater evidence of muscle dam-
age 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 non-
smokers, 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 non-
steroidal anti-inflammatory drugs that could affect the skel-
etal muscle biomarker levels. The subjects provided written,
informed consent to participate as approved by the institu-
tional review board at Hartford Hospital (Hartford, Con-
necticut).
www.ajconline.org
mailto:bparker03@harthosp.org
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283Miscellaneous/CK Response With Statins and Exercise
The day before (PRE) the marathon, the subjects pro-
vided 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.7 Alanine amino-
ransferase was also measured in this prerace sample. Blood
amples were also obtained immediately after (FINISH) the
ubjects completed the marathon in the main medical tent
pproximately 100 m from the finish line and the day
fter the race (within 24 hours of the finish; POST) at a
uest Diagnostics Laboratory. These samples were used
o measure the CK, CK isoenzymes, myoglobin, hemo-
lobin, and hematocrit. Serum was separated from the
ells by centrifugation at 5,000 rpm for 10 minutes and
tored on dry ice (�80°C). Whole blood was refrigerated.
he samples were shipped to Quest Diagnostics, Nichols
nstitute (Chantilly, Virginia), where all blood analyses
ere performed.
Physical activity for the 24-hour period before and after
he marathon was assessed using a 24-hour physical activity
ecall (question 8 from the Paffenbarger Physical Activity
uestionnaire).8 The subjects categorized their physical ac-
ivity by the hours of the day as sedentary, light, moderate,
nd vigorous activity.
The hematocrit and hemoglobin were measured using a
olorimetric assay. Lipid and hepatic panels were per-
ormed using a spectrophotometric assay. The CK isoen-
ymes were measured with electrophoresis, and muscle
yoglobin was assessed with the nephelometric assay. He-
atocrit and hemoglobin were used to estimate the plasma
olume changes, and CK and myoglobin were corrected for
he estimated exercise-induced changes in plasma volume,
ccording to the formula of van Beaumont.9
Differences in the baseline characteristics between the
statin and control groups were assessed using 1-way anal-
ysis of variance, with significance set at p �0.05. CK and
myoglobin were logarithmically transformed before analy-
sis 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, incorporat-
ing 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 out-
comes were added into the model to assess significance. The
effect of continuous variables was investigated using anal-
ysis of covariance. P-values for the mean difference esti-
mates 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 equiv-
alencies: rosuvastatin 2.5 mg � atorvastatin 5 mg � sim-
vastatin 10 mg � lovastatin 20 mg � pravastatin 20 mg �
fluvastatin 40 mg.10,11
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
Table 1
Subject characteristics
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/m2) 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
aper mileage‡ (miles/wk) 22 � 16 19 � 11
fficial finishing time (hr:min) 4:15 � 0:47 3:58 � 0:41
lood pressure medication use (n) 9 2
itamin/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.
Table 2
Types of statin drugs and doses used by number of participants
Drug Dose (mg) Patients (n)
Fluvastatin 80 1
torvastatin 5 2
10 3
20 6
80 1
osuvastatin 5 1
10 3
imvastatin 10 2
20 8
40 6
ovastatin 20 2
ravastatin 10 2
did the statin subjects the day after the marathon (3.8 � 2.4
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284 The American Journal of Cardiology (www.ajconline.org)
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. Po-
tency 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.
The CK and CK-MB concentrations before and imme-
diately 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
evels (statin PRE 34.5 � 4.5, FINISH 781.7 � 94.2, and
OST 182.4 � 26.8 �g/L vs control PRE 33.8 � 3.3,
FINISH 797.3 � 99.1, and POST 174.2 � 74.3 �g/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%, 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) concentra-
tions 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 con-
trolling for potential covariates, including age, body mass
index, miles run during training or the week before the
marathon, low-density lipoprotein cholesterol, high-den-
sity lipoprotein cholesterol, and systolic and diastolic
blood pressure.
We also examined the relations between the changes in
Figure 1. Group mean � SD of total CK before (Pre), immediately after
(Finish), and 24 hours (Post) after marathon in statin users and controls,
including p value for group-by-time interaction. *Significant change rela-
tive to baseline (pre) at p �0.05 within each group; †significant difference
etween groups at p �0.05.
CK and the baseline characteristics of the 2 groups. Increas-
ing age was positively related to changes in CK immedi-
ately and 24 hours after the marathon in the statin users but
not in the controls (Figure 4). No relation was found be-
tween statin potency and the changes in CK immediately
and 24 hours after exercise (p �0.38). The number of
subjects meeting the clinical definition of a marked CK
elevation (CK �10 times the upper limit of normal12) was
also examined. Nine statin and 8 control group subjects
exhibited CK elevations �10 times the upper limit of nor-
mal 24 hours after exercise; chi-square analysis indicated no
significant difference between the 2 groups (�2 � 0.39; p �
Figure 2. Group mean � SD of CK-MB before (Pre), immediately after
(Finish), and 24 hours (Post) after marathon in statin users and controls,
including p value for group-by-time interaction. *Significant change rela-
tive to baseline (pre) at p �0.05 within each group; †significant difference
etween groups at p �0.05.
Figure 3. Group mean � SD of total CK before (Pre), immediately after
(Finish), and 24 hours (Post) after marathon in runners who finished �4
hours versus �4 hours, including p value for group-by-time interaction. Of
37 statin-using runners and 43 control runners, 17 and 29 finished in �4
hours and 20 and 14 finished in �4 hours, respectively. *Significant
change relative to baseline (pre) at p �0.05 within each group; †significant
ifference between groups at p �0.05.
0.53).
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285Miscellaneous/CK Response With Statins and Exercise
Discussion
Marathon running is associated with marked muscle
damage. The CK levels are on average 2 to 5 times greater
than baseline immediately after completion of a mara-
thon3,13 and 13- to 15-fold greater at 24 hours after the race.
onsiderable interindividual variation exists in the CK re-
ponse, with individual values ranging from �1,000 to
�9,000 U/L.14 This variability in the CK response is
partly attributable to factors affecting performance such
as fitness and training. For example, the CK response 24
hours after the race tends to be higher in faster runners.14
In the present study, we also noted higher CK values,
regardless of statin use, in those completing the event in
�4 versus �4 hours, suggesting more muscle injury in
he faster runners (Figure 3).
In addition, the present study has documented that statins
ugment the increases in CK and CK-MB produced by
arathon running, because statin-using runners exhibited
igher levels of total CK and CK-MB values the day after
he marathon, when the CK level typically peaks,13 com-
ared to control subjects (Figures 1 and 2). These effects
ersisted even after controlling for potential confounding
aseline characteristics. Also, the controlgroup reported
ore hours of moderate physical activity the day after the
arathon; thus, it is unlikely that group differences in phys-
cal activity explain the higher CK and CK-MB values seen
n the statin users. Although the CK-MB values were higher
he day after the race, no differences were found in the
ercentage of total CK from the MB fraction, supporting the
oncept that the MB was skeletal rather than cardiac in
rigin.15
The muscle myoglobin level was not different between
the 2 groups; however, the lack of effect might be attrib-
utable to the faster elimination kinetics of myoglobin
from the systemic circulation.16 Myoglobin, which is
apidly released from injured tissue, reaches an earlier
Figure 4. Relation between changes in CK from day before (Pre) to im
(Post) after the marathon and age in statin users (black squares with sol
line).
eak in plasma and returns to normal values faster than
K. Because the effect of chronic statin therapy on CK
evels was observed 24 hours after the marathon, it is
ossible that the more rapid course of myoglobin release
nd clearance masked an observable difference between
he 2 groups.
Thompson et al17,18 were among the first to note that
xercise during statin therapy might increase the CK levels,
hypothesis later tested in a double-blind, placebo-con-
rolled study of 49 men. The postexercise CK levels were
2% and 77% higher after downhill treadmill walking in
ubjects treated with lovastatin 40 mg daily than in placebo-
reated controls.5 Other studies, however, have failed to
onfirm the greater increases in CK levels after eccentric19
or concentric18 exercise during statin treatment, possibly
wing to the sample size and the use of a crossover design.
t is known, for example, that a single exercise session
rotects the muscle from subsequent injury for the next
everal months; thus, crossover designs could obscure any
ffect of statin treatment.6 The present observation that the
K and CK-MB values were significantly higher in statin
sers after a marathon supports the theory that statin therapy
xacerbates the skeletal muscle damage associated with
rolonged and/or intense exercise.
Sustained muscular contraction during periods of glyco-
en depletion and reduced adenosine triphosphate availabil-
ty result in membrane permeability and fiber damage, per-
itting muscle enzyme efflux20 that is proportional to the
uration and intensity of the exercise.21 Several mecha-
isms exist by which statins could amplify this process.
tatins decrease the serum levels of ubiquinone, a compo-
ent of the mitochondrial electron transport chain, and thus
ight impair mitochondrial oxidative function,22,23 increas-
ing the potential for muscle damage. Statin therapy could
also upregulate skeletal muscle apoptosis24 and alter cal-
cium handling such that calcium leaking from the mitochon-
dria might impair sarcoplasmic reticulum calcium cycling.25
ely after (Finish) the marathon and from day before (Pre) to 24 hours
ession line) versus control group (open squares with dashed regression
mediat
id regr
Animal models suggest that type II glycolytic muscle fibers
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286 The American Journal of Cardiology (www.ajconline.org)
are most vulnerable to statin-associated muscle injury,26
raising the possibility that carbohydrate depletion during a
marathon could make these fibers particularly susceptible to
injury in humans as well.
The CK increases immediately and the day after the
marathon were directly related to age in the statin users but
not in the control subjects (Figure 4). These CK differences
were unlikely to be due to the slightly older age of the statin
users, because no relation has been reported between age
and the marathon CK response among a similar population
of nonstatin-using recreational runners.27 Age increases se-
rum, and ultimately muscle concentrations of statins and,
consequently, is a risk factor for skeletal muscle myop-
athy.12 Therefore, it is plausible that age magnifies the effect
f statins on exercise-associated elevations in CK owing to
he same mechanism by which age increases the risk of
yopathy.
The present study had several limitations. Statin use was
etermined solely by self-report; however, the calculated
tatin potency was inversely associated with the low-density
ipoprotein cholesterol levels, supporting the accuracy of
he subjects’ self-report. The subjects used a variety of
tatins, and most were taking relatively low doses; thus, we
ould not determine whether some statins are more injurious
o the skeletal muscle than others, nor could we evaluate the
uscle injury produced by high doses of powerful statins on
he CK response to a marathon. We also did not qualita-
ively assess the postmarathon pain and muscle soreness and
herefore could not determine whether the elevated CK
evels observed in the statin group resulted in greater post-
ompetition soreness. The control group subjects did per-
orm more hours of moderate physical activity the day after
he marathon, and it is possible there was a deleterious
ffect of the higher CK levels on physical activity in the
tatin users. We did not explore gender differences in the
K response to exercise with statins, an interesting issue
ecause women are less susceptible to exercise-induced
keletal muscle injury but more vulnerable to statin-induced
yopathy.12,28 Finally, we did not assess renal function
before and after the race; thus, an alternative explanation for
our findings could be an effect of statins on CK clearance,
although we are unaware of data supporting this hypothe-
sis.29
The present results have several clinical implications.
Professional athletes are reported to be intolerant of statins
because of muscle complaints.30 The present results suggest
hat increased exercise-induced muscle injury during statin
reatment might contribute to this drug intolerance. The
igher CK values in statin users suggest that statins might
ncrease the risk of important exercise-related rhabdomyol-
sis. Although in the present study, CK elevations �10
imes the upper limit of normal occurred in a similar pro-
ortion of statin and control group subjects, clinicians
hould consider discontinuing statin use for several days
efore endurance events such as a marathon if heat stress or
ther potential exacerbators of rhabdomyolysis might occur.
he latter is particularly important for older runners who
ppear more likely from our study to experience muscle
njury.
cknowledgments: The research assistants were Charles
’Hemecourt, BS, Lindsay Lorson, BS, and William Ro-
an, BS; logistical support was provided by Dave McGil-
ivray, BS, the Boston Athletic Association, Boston, Mas-
achusetts, and Quest Diagnostics, Madison, New Jersey.
1. Marathon Guide Staff. USA marathoning: 2009 overview. Available
at: www.marathonguide.com.
2. Belonje A, Nangrahary M, de Swart H, Umans V. Major adverse
cardiac events during endurance sports. Am J Cardiol 2007;99:849–
851.
3. Kratz A, Lewandrowski KB, Siegel AJ, Chun KY, Flood JG, Van Cott
EM, Lee-Lewandrowski E. Effect of marathon running on hematologic
and biochemical laboratory parameters, including cardiac markers.
Am J Clin Pathol 2002;118:856–863.
4. Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy.
JAMA 2003;289:1681–1690.
5. Thompson PD, Zmuda JM, Domalik LJ, Zimet RJ, Staggers J, Guyton
JR. Lovastatin increases exercise-induced skeletal muscle injury. Me-
tabolism 1997;46:1206–1210.
6. Evans WJ, Meredith CN, Cannon JG, Dinarello CA, Frontera WR,
Hughes VA, Jones BH, Knuttgen HG. Metabolic changes following
eccentric exercise in trained and untrained men. J Appl Physiol 1986;
61:1864–1868.
7. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concen-
tration of low-density lipoprotein cholesterol in plasma, without use of
the preparative ultracentrifuge. Clin Chem 1972;18:499–502.
8. Paffenbarger RS Jr, Wing AL, Hyde RT, Jung DL. Physicalactivity
and incidence of hypertension in college alumni. Am J Epidemiol
1983;117:245–257.
9. Van Beaumont W. Evaluation of hemoconcentration from hematocrit
measurements. J Appl Physiol 1972;32:712–713.
0. Roberts WC. The rule of 5 and the rule of 7 in lipid-lowering by statin
drugs. Am J Cardiol 1997;80:106–107.
1. Miller AE, Hansen LB, Saseen JJ. Switching statin therapy using a
pharmacist-managed therapeutic conversion program versus usual care
conversion among indigent patients. Pharmacotherapy 2008;28:553–561.
2. Pasternak RC, Smith SC Jr, Bairey-Merz CN, Grundy SM, Cleeman
JI, Lenfant C; American College of Cardiology, American Heart As-
sociation, National Heart, Lung and Blood Institute. ACC/AHA/
NHLBI clinical advisory on the use and safety of statins. J Am Coll
Cardiol 2002;40:567–572.
3. Howatson G, McHugh MP, Hill JA, Brouner J, Jewell AP, van Som-
eren KA, Shave RE, Howatson SA. Influence of tart cherry juice on
indices of recovery following marathon running. Scand J Med Sci
Sports 2010;20:843–852.
4. Siegel AJ, Silverman LM, Lopez RE. Creatine kinase elevations in
marathon runners: relationship to training and competition. Yale J Biol
Med 1980;53:275–279.
5. Apple FS, Rogers MA, Casal DC, Sherman WM, Ivy JL. Creatine
kinase-MB isoenzyme adaptations in stressed human skeletal muscle
of marathon runners. J Appl Physiol 1985;59:149–153.
6. Lappalainen H, Tiula E, Uotila L, Mänttäri M. Elimination kinetics of
myoglobin and creatine kinase in rhabdomyolysis: implications for
follow-up. Crit Care Med 2002;30:2212–2215.
7. Thompson PD, Nugent AM, Herbert PN. Increases in creatine kinase
after exercise in patients treated with HMG Co-A reductase inhibitors.
JAMA 1990;264:2992.
8. Thompson PD, Gadaleta PA, Yurgalevitch S, Cullinane E, Herbert PN.
Effects of exercise and lovastatin on serum creatine kinase activity.
Metabolism 1991;40:1333–1336.
9. Reust CS, Curry SC, Guidry JR. Lovastatin use and muscle damage in
healthy volunteers undergoing eccentric muscle exercise. West J Med
1991;154:198–200.
0. Thomson WH, Sweetin JC, Hamilton IJ. ATP and muscle en-
zyme efflux after physical exertion. Clin Chim Acta 1975;59:241–
245.
1. Brancaccio P, Maffulli N, Limongelli FM. Creatine kinase monitoring
in sport medicine. Br Med Bull 2007;81-82:209–230.
2. Wu JS, Buettner C, Smithline H, Ngo LH, Greenman RL. Evaluation
of skeletal muscle during calf exercise by 31-phosphorus magnetic
resonance spectroscopy in patients on statin medications. Muscle
Nerve 2011;43:76–81.
http://www.marathonguide.com
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2
2
2
2
3
287Miscellaneous/CK Response With Statins and Exercise
23. Urso ML, Clarkson PM, Hittel D, Hoffman EP, Thompson PD.
Changes in ubiquitin proteasome pathway gene expression in skeletal
muscle with exercise and statins. Arterioscler Thromb Vasc Biol 2005;
25:2560–2566.
4. Yu JG, Sewright K, Hubal MJ, Liu JX, Schwartz LM, Hoffman EP,
Clarkson PM. Investigation of gene expression in C(2)C(12) myotubes
following simvastatin application and mechanical strain. J Atheroscler
Thromb 2009;16:21–29.
5. Liantonio A, Giannuzzi V, Cippone V, Camerino GM, Pierno S,
Camerino DC. Fluvastatin and atorvastatin affect calcium homeostasis
of rat skeletal muscle fibers in vivo and in vitro by impairing the
sarcoplasmic reticulum/mitochondria Ca2�-release system. J Phar-
macol Exp Ther 2007;321:626–634.
26. Seachrist JL, Loi CM, Evans MG, Criswell KA, Rothwell CE. Roles
of exercise and pharmacokinetics in cerivastatin-induced skeletal mus-
cle toxicity. Toxicol Sci 2005;88:551–561.
7. Jassal DS, Moffat D, Krahn J, Ahmadie R, Fang T, Eschun G, Sharma
S. Cardiac injury markers in non-elite marathon runners. Int J Sports
Med 2009;30:75–79.
8. Evans WJ, Cannon JG. The metabolic effects of exercise-induced
muscle damage. Exerc Sport Sci Rev 1991;19:99–125.
9. Campese VM, Park J. HMG-CoA reductase inhibitors and the kidney.
Kidney Int 2007;71:1215–1222.
0. Sinzinger H, O’Grady J. Professional athletes suffering from familial
hypercholesterolaemia rarely tolerate statin treatment because of mus-
cular problems. Br J Clin Pharmacol 2004;57:525–528.
	Effect of Statins on Creatine Kinase Levels Before and After a Marathon Run
	Methods
	Results
	Discussion
	Acknowledgments
	References