we recently showed that p - selectin , a biomarker greatly associated with coronary disease and inflammation , increased after a marathon .
serious cardiac events have also rarely been associated with marathon running , and increases in such biomarkers of thrombotic and vascular risk such as p - selectin may contribute to this increased cardiac risk .  
hmg coa reductase inhibitors ( statins ) are the most effective medicines for lowering ldl cholesterol and substantially reduce cardiovascular disease mortality .
however , statins evoke many other pleiotropic effects , including anti - inflammatory actions , which could also contribute to their reducing cardiovascular events .
the present study determined whether chronic statin therapy ameliorates the inflammatory response to endurance exercise .
we hypothesized that statin treated runners would exhibit lower p - selectin levels immediately and 24 hours after the marathon than nonstatin using runners .
  thirty seven statin - using athletes ( 29 men and 8 women ) and 43 controls ( 30 men and 13 women ) were recruited through an email sent to all participants registered for the 115th boston athletic association marathon held on april 18 , 2011 .
subjects were recruited if they either had continuously received statin therapy for > 6 months or had not used any lipid - lowering medication .
subjects were nonsmokers , age 35 , and free of known cardiovascular or metabolic disease besides hypercholesterolemia .
subjects were not taking oral contraceptives and/or hormone therapy and agreed to abstain from taking any nonstatin medications for 24 hours before the race that could affect blood biomarkers .
subjects provided written , informed consent to participate as approved by the institutional review board at hartford hospital .
the day before the marathon subjects presented to a room provided by the boston athletic association at the marathon exposition .
subjects provided a medical history and reported their training mileage over the 3 months and week preceding the marathon . resting blood pressure and heart rate (
welch allen 52000 vital signs monitor ; skaneateles falls , ny ) as well as height and body mass were measured .
venous blood was obtained after a 12-hour fast to measure total and high density lipoprotein ( hdl - c ) cholesterol and triglycerides .
low density lipoprotein cholesterol ( ldl - c ) was estimated using the friedewald equation .
plasma was separated from cells by centrifugation at 5000  r.p.m . for 10 minutes and stored on dry ice ( 80c ) .
samples were shipped to quest diagnostics nichols institute , chantilly , va , where blood lipid analyses were performed .
blood was also obtained immediately after the subjects completed the marathon in the main medical tent approximately 100 meters from the finish line and the day after the race ( within 24 hours of the finish ) at the subjects nearest quest diagnostics location .
cryovials obtained remotely were shipped overnight to hartford hospital on dry ice and archived in a 80 freezer .
soluble p - selectin was measured in duplicate using enzyme - linked immunosorbent assays ( r&d systems , minneapolis , minnesota ) ( coefficient of variation 3.6% ) .
for all assays , absorbance was determined on a spectrophotometer ( versamax microplate reader , molecular devices , sunnyvale , california ) , and data were analyzed using associated software ( softmax pro microplate data acquisition and analysis software , version 5.3 , molecular devices , sunnyvale , ca ) .  
differences in baseline characteristics between statin and control groups were assessed with a one - way analysis of variance ( anova ) with significance set at p < 0.05 . to determine the effects of statin use on changes in p - selectin , we used a linear mixed model for repeated measurements with autoregressive variance - covariance structure , incorporating time as the within - subjects factor and group ( control versus statin ) as the between - subjects factor .
subjects were defined as the random factor ; all other variables were fixed within the model .
potential categorical factors that could affect the relation between the main effects and outcomes were added into the model to assess significance , and the effect of continuous variables was investigated using analysis of covariance ( ancova ) .
p values for mean difference estimates between groups at various time points were adjusted using tukey 's multiple comparison procedure to account for post - hoc multiple comparison testing .
pearson correlations and linear regression were used to examine the relationships between continuous variables . to investigate the effect of statin potency in statistical models , statins were classified by 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 [ 6 , 7 ] .
cross - tabulation and chi - squared analyses were performed to examine the frequency distribution of p - selectin among established risk quartiles .
statistical analyses were performed with sas 9.1 ( cary , nc ) , and all data are expressed as nontransformed values are presented in the tables and figures with group means  standard deviation ( sd ) .
statin users were slightly older , had lower ldl - c and hdl - c values ( table 1 ) , and were treated with a variety of statins and statin doses ( table 2 ) .
six different types of statins were normalized for potency using published dose equivalencies [ 6 , 7 ] .
the average potency of statin used by participants in atorvastatin equivalents was 14.7  mg .
potency was inversely related to total and ldl - c in the statin group ( pearson coefficients = 0.37 and 0.36 , resp . , and
both p < 0.05 ) , but not related to p - selectin pre , finish , or post ( p > 0.05 ) .
p - selectin levels prior to the marathon were similar in the statin users and controls and similar to resting levels reported in studies with healthy normal controls   ( table 1 ) .
exercise - induced increases in p - selectin were observed in both groups ; however , the increase in p - selectin immediately after exercise was lower in statin users when controlled for significant covariates bmi , age , and hdl ( figure 1 ) . the increase in p - selectin 24 hours after exercise was also lower in statin users ( figure 1 ) .
there were no significant main effects or interactions among exercise - induced increases in p - selectin , age , or gender .
ldl was positively correlated with p - selectin at finish and post ( p < 0.01 and p < 0.05 , resp . ) , but not at pre ( p = 0.16 ) ( figure 2 ) .  
we also examined the estimated risk of future cardiovascular events using established quartiles according to p - selectin levels measured at finish and post . immediately following the marathon ( finish )
the distribution of runners with a relative risk quartile above the > 4th quartile cut point was significantly higher in controls versus statin using athletes ( 23 control versus 7 statin users ;  = 8.14 ; p < 0.01 ) ( figure 3 ) .
the day following the marathon ( post ) controls tended to have a higher distribution of runners in the 4th quartile when compared to statin users ; however , this trend did not reach statistical significance ( 26 control versus 13 statin users ) ( p = 0.07 ) .
the present study investigated the effect of chronic statin therapy on exercise - associated increases in p - selectin .
we have documented that a marathon run increases p - selectin in both controls and statin using athletes ( figure 1 ) .
these findings are consistent with other studies [ 10 , 11 ] as well as our previously published results from the 2010 boston marathon , in which we observed a similar increase in p - selectin immediately and 24 hours following a marathon in nonstatin using runners .  
importantly , however , the increase in p - selectin was lower in statin users than controls when we adjusted for significant covariates of bmi , age , and hdl . to the best of our knowledge ,
this is the first such study investigating the effects of statin therapy on exercise - associated increases in p - selectin in healthy adults ; however , findings are consistent with data indicating that statins reduce p - selectin in patients with coronary artery disease   and hypercholesterolemia   unrelated to vigorous exercise .  
we have previously noted that the increase in p - selectin immediately following a marathon could increase the risk of a cardiovascular event during the marathon .
have previously shown that the relative risk of future cardiovascular events increases by 27% for each quartile increase in p - selectin .
for example , in our study of boston marathon participants not using statins , twelve runners at finish and 10 runners the day following the marathon had p - selectin values > 45.5  ng / ml ( the second quartile ) , increasing their estimated risk of a cardiovascular event by 27% . in the current study of older runners , the number of runners with p - selectin values exceeding 81.6  ng / ml ( the highest quartile of risk ) immediately following the marathon was significantly higher in controls than in statin using runners ( 23 control versus 7 statin ) ( figure 3 ) .   
the lower levels of p - selectin seen among runners using statins may be due to statins reducing the upregulation of the inflammatory response produced by endurance running [ 14 , 15 ] .
p - selectin , a cell adhesion receptor , is stored within -granules of platelets and weibel - palade bodies of endothelial cells .
cytokine stimulation produces a translocation of p - selectin from the intracellular platelets and endothelial cells to the surface of endothelial cells , which mediates inflammation and platelet aggregation .
inhibition of hmg - coa reductase via statin therapy activates the mevalonate pathway , which initiates downstream isoprenylation and subsequent depletion of cytokines such as interleukin ( il ) and tnf [ 1820 ] .  
we have previously noted that age is positively correlated with p - selectin levels before and after the marathon , possibly contributing to the greater risk of an adverse cv event in older runners .
however , in the present study we did not observe a significant interaction between baseline or exercise - induced increases in p - selectin and age in either group .
this could be due to the older age of the current sample , as other factors including lipid levels , vascular stiffness , bmi   may influence p - selectin levels in older adults .    indeed , independent of statin therapy , ldl was positively correlated with p - selectin immediately after and the day following the marathon ( figure 2 ) , such that runners with the lowest ldl levels also exhibited the lowest postexercise p - selectin values .
platelet - bound oxldl is positively correlated with expression of p - selectin and subsequently platelet aggregation . therefore , in runners who do not achieve low ldl via nonpharmacologic therapies , statin therapy may be a potential therapeutic intervention with which to mitigate the risk of marathon related cardiovascular events .  
statin use was based solely on self - report , but calculated statin potency was inversely associated with ldl cholesterol levels , supporting the accuracy of subject self - reports .
subjects used a variety of statins and doses making it difficult to determine if a dose response effect occurs with low versus high dose statins .
there was not a correlation between potency and p - selectin as we did not recruit based on statin type and dosage and consequently were not powered to detect differences .
we were unable to recruit sufficient numbers of women to explore gender differences in the p - selectin response to exercise with statins .
this would be interesting to explore as male marathon runners have increased incidence of cardiac arrest when compared to women .
the present results are the first to show that exercise - induced inflammation may be attenuated by statin therapy in trained , healthy runners .
these results are promising for runners whose family history and/or disease pathology may place them at greater risk of a cardiac event following exercise . on the other hand
, statins also increase the postexercise increase in creatine kinase suggesting that statin may enhance the muscle damage of exercise .
therefore , clinicians and runners may have to weigh the risks and benefits of using statins prior to an endurance event .
 strenuous endurance exercise increases inflammatory markers and acutely increases cardiovascular risk ; however , statins may mitigate this response . 
 we measured serum levels of p - selectin in 37 runners treated with statins and in 43 nonstatin treated controls running the 2011 boston marathon . 
 venous blood samples were obtained the day before ( pre ) as well as within 1 hour after ( finish ) and 24 hours after ( post ) the race . the increase in p - selectin immediately after exercise was lower in statin users ( pre to finish : 20.5  19.4  ng / ml ) than controls ( pre to finish : 30.9  27.1  ng / ml ; p < 0.001 ) . 
 the increase in p - selectin 24 hours after exercise was also lower in statin users ( pre to post : 21.5  26.6  ng / ml ) than controls ( pre to post : 29.3  31.9  ng / ml ; p < 0.001 ) . 
 furthermore , ldl - c was positively correlated with p - selectin at finish and post ( p < 0.01 and p < 0.05 , resp . ) , irrespective of drug treatment , suggesting that lower levels of ldl - c are associated with a reduced inflammatory response to exercise . 
 we conclude that statins blunt the exercise - induced increase in p - selectin following a marathon and that the inflammatory response to a marathon varies directly with ldl - c levels . 
1. Introduction 
2. Methods
3. Results
4. Discussion 