Jeffrey A. Capizzi

Effect of Statins on Skeletal Muscle Function

Background— Many clinicians believe that statins cause muscle pain, but this has not been observed in clinical trials, and the effect of statins on muscle performance has not been carefully studied. Methods and Results— The Effect of Statins on Skeletal Muscle Function and Performance (STOMP) study assessed symptoms and measured creatine kinase, exercise capacity, and muscle strength before and after atorvastatin 80 mg or placebo was administered for 6 months to 420 healthy, statin-naive subjects. No individual creatine kinase value exceeded 10 times normal, but average creatine kinase increased 20.8±141.1 U/L (P<0.0001) with atorvastatin. There were no significant changes in several measures of muscle strength or exercise capacity with atorvastatin, but more atorvastatin than placebo subjects developed myalgia (19 versus 10; P=0.05). Myalgic subjects on atorvastatin or placebo had decreased muscle strength in 5 of 14 and 4 of 14 variables, respectively (P=0.69). Conclusions— These results indicate that high-dose atorvastatin for 6 months does not decrease average muscle strength or exercise performance in healthy, previously untreated subjects. Nevertheless, this blinded, controlled trial confirms the undocumented impression that statins increase muscle complaints. Atorvastatin also increased average creatine kinase, suggesting that statins produce mild muscle injury even among asymptomatic subjects. This increase in creatine kinase should prompt studies examining the effects of more prolonged, high-dose statin treatment on muscular performance. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00609063.

Effect of Statins on Creatine Kinase Levels Before and After a Marathon Run

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.

25(OH) Vitamin D is Associated with Greater Muscle Strength in Healthy Men and Women

PURPOSE The purpose of the study was to examine the relation between serum 25-hydroxy vitamin D (25(OH)D) levels and muscle strength in 419 healthy men and women over a broad age range (20-76 yr). METHODS Isometric and isokinetic strength of the arms and legs was measured using computerized dynamometry, and its relation to vitamin D was tested in multivariate models controlling for age, gender, resting HR, systolic blood pressure, diastolic blood pressure, body mass index, maximal oxygen uptake (VO(2max)), physical activity counts, and season of vitamin D measurement. RESULTS Vitamin D was significantly associated with arm and leg muscle strength when controlling for age and gender. When controlling for other covariates listed previously, vitamin D remained directly related to both isometric and isokinetic arm strength but only to isometric leg strength. CONCLUSION These data suggest that there may be a differential effect of vitamin D on upper and lower body strength. The mechanism for this difference remains unclear but could be related to differences in androgenic effects or to differences in vitamin D receptor expression. Our study supports a direct relation between vitamin D and muscle strength and suggests that vitamin D supplementation be evaluated to determine whether it is an effective therapy to preserve muscle strength in adults.

Influence of chronic exercise on carotid atherosclerosis in marathon runners

Objectives The effect of habitual, high-intensity exercise training on the progression of atherosclerosis is unclear. We assessed indices of vascular health (central systolic blood pressure (SBP) and arterial stiffness as well as carotid intima-medial thickness (cIMT)) in addition to cardiovascular risk factors of trained runners versus their untrained spouses or partners to evaluate the impact of exercise on the development of carotid atherosclerosis. Setting field study at Boston Marathon. Participants 42 qualifiers (mean age±SD: 46±13 years, 21 women) for the 2012 Boston Marathon and their sedentary domestic controls (46±12 years, n=21 women). Outcomes We measured medical and running history, vital signs, anthropometrics, blood lipids, C reactive protein (CRP), 10 years Framingham risk, central arterial stiffness and SBP and cIMT. Results Multiple cardiovascular risk factors, including CRP, non-high-density lipoprotein cholesterol, triglycerides, heart rate, body weight and body mass index (all p<0.05), were reduced in the runners. The left and right cIMT, as well as central SBP, were not different between the two groups (all p>0.31) and were associated with age (all r≥0.41; p<0.01) and Framingham risk score (all r≥0.44; p<0.01) independent of exercise group (all p>0.08 for interactions). The amplification of the central pressure waveform (augmentation pressure at heart rate 75 bpm) was also not different between the two groups (p=0.07) but was related to age (p<0.01) and group (p=0.02) in a multiple linear regression model. Conclusions Habitual endurance exercise improves the cardiovascular risk profile, but does not reduce the magnitude of carotid atherosclerosis associated with age and cardiovascular risk factors.

Increases in creatine kinase with atorvastatin treatment are not associated with decreases in muscular performance

BACKGROUND The present study examined if increases in creatine kinase (CK) levels during high-dose atorvastatin treatment are associated with changes in skeletal muscle function and symptoms. METHODS The Effect of Statins on Muscle Performance study (STOMP) investigated the effects of atorvastatin 80 mg daily for 6 months on muscle performance, exercise capacity, and the incidence of statin-associated muscle complaints in healthy adults. RESULTS CK levels increased with atorvastatin (n = 202) from 132.3 ± 120.9 U/L (mean ± SD) at baseline to 159.7 ± 170.4 and 153.1 ± 139.4 U/L at 3 and 6 months, respectively (P ≤ 0.002 for both). Changes in CK with atorvastatin treatment were not associated with changes in muscle function or the incidence of myalgia. More subjects on atorvastatin (n = 24) compared to placebo (n = 12 of 217) doubled their CK level at 6 months (P = 0.02). No differences in muscle function or physical activity were observed between atorvastatin-treated subjects who did or did not double their CK. CONCLUSIONS Results of the present investigation extend the findings of STOMP by demonstrating that greater increases in CK levels with high-dose atorvastatin treatment did not deleteriously impact skeletal muscle function or predict skeletal muscle complaints. This study was registered at ClinicalTrials.gov (NCT00609063).

Effect of air travel on exercise-induced coagulatory and fibrinolytic activation in marathon runners.

Objective:Air travel and exercise change hemostatic parameters. This study investigated the effect of air travel on exercise-induced coagulation and fibrinolysis in endurance athletes. Design:A prospective longitudinal study. Setting:The 114th Boston Marathon (April 19, 2010). Participants:Forty-one adults were divided into travel (T: 23 participants, living >4-hour plane flight from Boston) and nontravel (C: 18 participants, living <2-hour car trip from Boston) groups. Independent Variables:Age, anthropometrics, vital signs, training mileage, and finishing time were collected. Main Outcome Measures:Subjects provided venous blood samples the day before (PRE), immediately after (FINISH), and the day following the marathon after returning home (POST). Blood was analyzed for thrombin–antithrombin complex (TAT), tissue plasminogen activator (t-PA), hematocrit (Hct), and the presence of Factor V Leiden R506Q mutation. Results:Thrombin–antithrombin complex increased more in T subjects in PRE to FINISH samples (5.0 ± 4.0 to 12.9 ± 15.6 μg/L) than in C subjects (4.0 ± 1.2 to 6.1 ± 1.2 μg/L; P = 0.02 for comparison). The t-PA increased in both the T (5.4 ± 2.3 to 25.1 ± 12.2 ng/mL) and C (5.6 ± 2.0 to 27.7 ± 11.3 ng/mL) groups in PRE to FINISH samples, and this response did not differ between groups (P = 0.23 for comparison). Both groups exhibited similar t-PA and TAT values at POST that were not different than PRE (all P > 0.35). Age was related to the FINISH TAT values in T (r2 = 0.19; P = 0.04) but not in C (r2 = 0.03; P = 0.53) subjects. Conclusions:Results suggest that the combination of air travel and marathon running induces an acute hypercoaguable state; this hemostatic imbalance is exaggerated with increasing age.

Validity and Reliability of Question 8 of the Paffenbarger Physical Activity Questionnaire Among Healthy Adults

BACKGROUND Little information exists regarding the psychometric properties of question 8 (Q8) of the Paffenbarger Physical Activity Questionnaire (PPAQ) to assess exercise. Thus, we conducted 2 studies to assess the validity and test-retest reliability of Q8 among adults. METHODS Study 1 participants (n = 419) were 44.1 ± 16.1 years of age. Validity was determined by comparing self-reported hr·d-1 in sedentary, light, moderate, and vigorous intensity physical activity (PA) and MET-hr·wk-1 on Q8 at baseline to accelerometer and health/fitness measurements using Spearman rank-order correlations. Study 2 participants (n = 217) were 44.7 ± 16.3 years of age and completed Q8 at baseline, 3 months, and 6 months. Test-retest reliability was determined using repeated measures analysis of covariance, intraclass correlations (ICCs), and standard error of the measurement (SEM). RESULTS Q8 displayed good criterion validity compared with accelerometer measurements (r = .102 to .200, P < .05) and predictive validity compared with health/fitness measurements (r = -.272 to .203, P < .05). No differences were observed in self-reported hr·d-1 in any of the PA categories at baseline, 3 months, and 6 months (ICC: 0.49 to 0.68; SEM: 1.0 to 2.0; P > .05), indicating good reliability. CONCLUSION Q8 demonstrates adequate criterion validity, acceptable predictive validity, and satisfactory test-retest reliability and can be used in conjunction with other components of the PPAQ to provide a complete representation of exercise.

The Interactive Effects of Metabolic Syndrome, Blood Pressure, and Mental Health in Worksite Employees

Abstract Background: Cardiovascular disease (CVD), CVD-related conditions, and mental health disorders are prevalent in the US workforce. We examined associations between metabolic syndrome (METS), blood pressure (BP), and mental health indicators in 1813 employees (25.4% women; 74.6% men) from a large manufacturing firm. Methods: Employees participated in a health screen. Biometric measures were body mass index, waist circumference, BP, and fingerstick determinations of blood lipid-lipoproteins and glucose. Mental health was assessed with 5 self-reported questions regarding anger, depression, anxiety, and family and work stress. Multivariate analysis of covariance tested for differences in BP and mental health indicators in employees (370 employees with METS, and 1443 employees without). Results: Participants were primarily middle-aged (44.8 ± 0.3 years), overweight (27.9 ± 0.1 kg/m2) men (n = 1352) and women (n = 461) with a resting BP of 122.5 ± 0.3 mm Hg and 79.8 ± 0.2 mm Hg, respectively. Diastolic BP (DBP) was found to be 5 mm Hg higher in men with METS compared with men who did not have METS. When questioned, men with higher DBP stated that they often experienced anxiety (n = 39; 91.0 ± 2 mm Hg) compared with men who reported they rarely experienced anxiety (n = 112; 86.2 ± 1.9 mm Hg) (P = 0.020). Similarly, systolic BP (SBP) tended to be 4 mm Hg higher in men with METS who stated they often experienced anxiety (n = 39; 138.9 ± 2 mm Hg) compared with men who reported they rarely experienced anxiety (n = 112; 134.5 ± 1.2 mm Hg) (P = 0.119). Diastolic BP tended to be 2 mm Hg higher among men with METS who stated they often experienced anger (n = 117; 89.4 ± 0.9 mm Hg) compared with those who indicated they rarely experienced anger (n = 157; 87.3 ± 0.8 mm Hg) (P = 0.086), and DBP was 3 mm Hg higher in men with METS who reported overwhelming work stress (n = 83; 89.7 ± 1.1 mm Hg) compared with those reporting little work stress (n = 79; 86.6 ± 1.2 mm Hg) (P = 0.176). In contrast, no associations were found between BP and mental health in men without METS, and in women, regardless of the presence or absence of METS (P > 0.05). Conclusions: Men with METS who reported higher levels of anxiety, anger, and work stress had higher BP than men without METS, who also reported lower levels of these mental health indicators. The METS appeared to adversely interact with BP and mental health in men at this worksite. Our findings suggest worksite health promotion programs can improve the cardiometabolic and mental health profile of US employees.

The Effect of Atorvastatin on Habitual Physical Activity among Healthy Adults

PURPOSE Statin therapy can result in muscle pain, cramps, and weakness that may limit physical activity, although reports are mixed. We conducted a randomized control trial to examine the effect of atorvastatin on habitual physical activity levels in a large sample of healthy adults. METHODS Participants (n = 418) were statin-naive adults (44.0 ± 16.1 yr (mean ± SD)) who were randomized and double-blinded to 80 mg · d(-1) of atorvastatin or placebo for 6 months. Accelerometers were worn for 96 h before and after drug treatment. Repeated-measures analysis tested physical activity levels after versus those before drug treatment among groups with age and VO2max as covariates. RESULTS In the total sample, sedentary behavior increased (19.5 ± 5.1 min · d(-1)), whereas light-intensity (9.1 ± 3.0 min · d(-1)) and moderate-intensity (9.7 ± 2.8 min · d(-1)) physical activity decreased, as did total activity counts (17.8 ± 6.3 d × 10(-3)) over 6 months (P < 0.01), with no differences between groups. The atorvastatin group increased sedentary behavior (19.8 ± 7.4 min · d(-1)) and decreased light-intensity (10.7 ± 4.3 min · d(-1)) and moderate-intensity (8.5 ± 4.0 min · d(-1)) physical activity (P < 0.05). On the other hand, the placebo group increased sedentary behavior (19.2 ± 7.1 min · d(-1)) and decreased moderate-intensity (11.0 ± 3.8 min · d(-1)) and total physical activity counts (-23.8 ± 8.8 × 10(-3) d(-1)) (P < 0.05). CONCLUSIONS Time being sedentary increased and physical activity levels decreased in the total sample over 6 months of drug treatment, independent of group assignment. Our results suggest that statins do not influence physical activity levels any differently from placebo, and the lack of inclusion of a placebo condition may provide insight into inconsistencies in the literature.

Atorvastatin increases exercise leg blood flow in healthy adults.

OBJECTIVES We sought to examine the effect of atorvastatin therapy on exercise leg blood flow in healthy middle-aged and older-men and women. BACKGROUND The vasodilatory response to exercise decreases in humans with aging and disease and this reduction may contribute to reduced exercise capacity. METHODS We used a double-blind, randomly assigned, placebo-controlled protocol to assess the effect of atorvastatin treatment on exercising leg hemodynamics. We measured femoral artery blood flow (FBF) using Doppler ultrasound and calculated femoral vascular conductance (FVC) from brachial mean arterial pressure (MAP) before and during single knee-extensor exercise in healthy adults (ages 40-71) before (PRE) and after (POST) 6 months of 80 mg atorvastatin (A: 14 men, 16 women) or placebo (P: 14 men, 22 women) treatment. FBF and FVC were normalized to exercise power output and estimated quadriceps muscle mass. RESULTS Atorvastatin reduced LDL cholesterol by approximately 50%, but not in the placebo group (p < 0.01). Atorvastatin also increased exercise FBF from 44.2 ± 19.0 to 51.4 ± 22.0 mL/min/W/kg muscle whereas FBF in the placebo group was unchanged (40.1 ± 16.0 vs. 39.5 ± 16.1) (p < 0.01). FVC also increased with atorvastatin from 0.5 ± 0.2 to 0.6 ± 0.2 mL/min/mmHg/W/kg muscle, but not in the placebo subjects (P: 0.4 ± 0.2 vs. 0.4 ± 0.2) (p < 0.01). CONCLUSIONS High-dose atorvastatin augments exercising leg hyperemia. Statins may mitigate reductions in the exercise vasodilatory response in humans that are associated with aging and disease.