Impact of Statin Therapy on Adaptations to Aerobic Exercise
Phase: PHASE4
Conditions: Cardiovascular Diseases
Sponsor: University of Kansas Medical Center

 
 
 
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University of Kansas Medical Center  
RESEARCH PROTOCOL INVOLVING HUMAN SUBJECTS  
 
Version date: 11/15/17 
Principal Investigator: John Thyfault 
Study Title: Impact of statin therapy on adaptations to aerobic exercise 
Co- Investigator(s): Sandra Billinger, Jianghua He  
 
 
I. 
Purpose, Background and Rationale 
A. Abstract 
More than 40 million Americans are currently taking statins for the treatment or prevention of 
hyperlipidemia and cardiovascular disease (CVD). Based on the new usage guidelines from the 
American College of Cardiology and the American Heart Association (ACC/AHA) (2), that number is 
expected to increase to over 60 million (3), reflecting the growing sentiment for more wide-spread use 
of statins, even in otherwise asymptomatic patients. Although generally well-tolerated, statin therapy is 
not without risks. The most common reported side effects include mild to moderate muscle weakness, 
fatigue and/or pain, the incidence of which increase as a function of both dose and duration of statin 
use (4, 5). Statins also increase the risk of developing more serious metabolic conditions, including 
insulin resistance and type 2 diabetes (6-9). The underlying mechanism(s) for these complications is 
unknown. In recent years however, evidence has been mounting from both cell culture and animal 
models that statins interfere with mitochondrial function in muscle (10-12). In the present application, 
we provide data from both ex vivo and in vivo preliminary studies in humans suggesting that statins 
induce progressive and quite striking reductions in skeletal muscle mitochondrial respiratory function 
and blunt adaptations to exercise. The overall aim of the study is to examine whether statin treatments 
differentially blunt the mitochondrial, metabolic, and cardiorespiratory adaptations to aerobic exercise 
training. Our hypothesis is statin therapy will impair exercise induced adaptations in skeletal muscle 
mitochondria content and function (respiration and transcriptional responses), cardiovascular 
responses, and systemic insulin sensitivity. 
  
B. Background and Significance 
According to the Centers for Disease Control and Prevention, nearly one of every four adults over 40 
years of age is taking a statin – which equates to more than 40 million Americans. This number is 
predicted to increase to over 60 million Americans (3) under the new guidelines released in 2013 by the 
American College of Cardiology and the American Heart Association (ACC/AHA). The new guidelines 
which emphasize prevention of stroke as well as cardiovascular disease (CVD), simplify evaluation by 
dividing patients into two broad risk categories, and feature a risk prediction algorithm (14). The new 
guidelines represent a departure from the 2002 National Cholesterol Education Program Adult 
Treatment Panel III statin therapy recommendations based on LDL-C treatment target levels of <70-
100 mg/dl, depending on risk (15). Although not without controversy (16), the new algorithm 
recommends initiation of statin therapy for primary prevention in patients with a predicted 10-year risk 
of CVD of ≥7.5% and consideration of statin therapy for patients with 10-year risks of between 5-

 
 
 
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Fig 1. Relationship between maximal oxygen uptake and 
age in sedentary, active and endurance trained subjects. 
The figure is adapted from Wilson and Tanaka (1) and 
depicts the potential impact of statin therapy to shift (solid red 
line) or accelerate (dotted red line) the loss of aerobic 
capacity relative to age and therefore morbidity and mortality. 
7.5%. Backed by a recent study spanning six continents showing a small but significant decrease in 
CVD events (17) the new guidelines are expected to lead to a dramatic increase in the use of statins 
world-wide for primary prevention in middle-aged individuals who do not have, but are at risk of 
developing CVD. 
Without question, statin therapy is extremely effective at lowering LDL-C and risk for CVD in high risk 
populations, and, in general, statins are well-tolerated (18). Muscle fatigue, pain and weakness are 
idiopathic but well known potential side effects. Less appreciated is the fact that statins also increase 
the risk of developing insulin resistance/type 2 diabetes (6-9, 19-21) and attenuate the beneficial 
effects of exercise on cardiovascular adaptations and fitness (13). In fact, statins when combined with 
exercise increase the risk and severity of adverse muscle reactions (22-24). This interaction effect is of 
obvious concern given the importance of physical activity in the clinical treatment of patients with type 
2 diabetes and/or CVD. Although the mechanism(s) underlying the side effects of statins is unknown, 
there is evidence that the impact of statins on skeletal muscle may be progressive. In the only direct 
comparative cohort study between patients on statins and matched controls, duration of statin therapy 
(< 10 vs. ≥ 10 months) was found to increase the risk of 
developing muscle-related side effects (5), which is 
consistent with clinical reports of some patients 
experiencing symptoms only after years of statin therapy 
(25). Perhaps most alarming, mounting evidence, 
including preliminary data in this application, indicates 
that statins directly compromise mitochondrial respiratory 
function, providing a potential unifying mechanism for the 
dose- and duration-dependent complications associated 
with statin use. Clinically, because the loss of aerobic 
capacity with age (Fig. 1)(1) is an independent risk factor 
for morbidity and mortality (26,27) a direct inhibition of 
respiratory function induced by statin therapy would be 
expected to shift this relationship (see redline) and hasten 
the decline in aerobic capacity needed to support daily 
living (Fig. 1). This is especially alarming given that the 
greatest increase in statin prescription is predicted to 
occur in adults >60 years of age who already have low 
aerobic capacity(3) and that statin therapy is being widely advocated for younger individuals, meaning 
that lifetime statin use may potentiate aging induced loss of aerobic capacity (28). Thus, while the risk 
for CVD undoubtedly favors statin therapy for many patients, it is imperative to develop a better 
understanding of the mechanism(s) underlying the effect of statins on muscle biology to better define 
the risk – benefit ratio for all patients. 
The widespread use of statins combined with the potential for more aggressive use of high intensity 
statin therapy emphasizes the urgency and importance of this research topic to the medical 
community. Importantly, we are studying one of the most widely prescribed and utilized statins, 
atorvastatin (trade name “Lipitor”) (29) making the outcomes applicable to a large number of statin 
users. In addition, high dose (80 mg/day) atorvastatin is widely employed as the “go to” dose based on 
data from three clinical trials showing the largest effect in terms of lowering of CVD risk (30-32). This 
will immediately help physicians and patients make better-informed decisions, thereby improving 
clinical practice in the treatment of CVD and other disorders of metabolism. 

 
 
 
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C. Rationale and Preliminary Data 
Statins are a first line of treatment for patients at risk for the metabolic syndrome and CVD 
because they lower lipids (LDL-C and TG) and reduce CVD. Although, statins undoubtedly reduce 
CVD, they have been shown to increase both insulin resistance (8, 9, 20, 21) and rates of type 2 
diabetes development in large cohort studies (6, 7, 19). Importantly, the mechanism(s) linking 
statins to insulin resistance and type 2 diabetes remain unknown. Statin induced mitochondrial 
dysfunction in skeletal muscle is one of the suggested mechanism(s) for statin induced insulin 
resistance, but this has not been directly tested. 
Although statins provide a powerful 20-40% reduction in relative risk for CVD (19, 85-87), there 
is still room for improvement through the use of potent lifestyle therapies like exercise training. 
At risk patients are commonly encouraged to start a regular aerobic exercise program, that can 
also lower LDL-C and TG, and unlike statins, is a proven efficacious treatment to improve 
insulin sensitivity and protect against type 2 diabetes (88, 89). The ability of exercise to 
increase skeletal muscle mitochondrial content and function is believed to play an important 
role in improving skeletal muscle insulin sensitivity. Exercise also increases cardiorespiratory 
fitness (VO2peak), which is a critical adaptation because low fitness is a powerful independent 
risk factor for CVD, type 2 diabetes, and overall mortality (26, 27, 90-92). In fact, mid-life fitness 
is an excellent prognosticator of susceptibility for chronic disease conditions later in life (93). A 
recent study implicated statin therapy in reducing physical activity levels by a significant amount 
in free living individuals (94). Importantly, another trial found that alterations in physical activity 
(measured by pedometers) significantly impacted CVD risk in at risk patients regardless of 
pharmacotherapy treatment suggesting that increasing or maintaining physical activity 
throughout the lifespan is paramount for CVD protection (95). In summary, these findings 
suggest that the most complete treatment for patients at risk for CVD would combine both statin 
and exercise therapy in addition to maintenance of moderate to high daily physical activity. 
 
Although many clinical 
reviews propose harmful 
interactions with exercise 
and statins, until a recent 
report from our lab, there 
were no carefully controlled 
studies. We published a trial 
comparing the effects of 12 
weeks of exercise vs. 
exercise + statin therapy (40 mg/day simvastatin) in previously sedentary obese participants with 2/5 
metabolic syndrome risk factors (13). Our results showed that statins blocked both exercise induced 
increases in whole body cardiorespiratory fitness and increases in skeletal muscle mitochondrial 
content. As shown in Table 1, the exercise only group experienced a 9%  
increase in cardiorespiratory fitness (VO2peak) and a 13% increase in mitochondrial content (measured 
by muscle citrate synthase activity), while the statin plus exercise group had 1%, and -4% changes, 
respectively. We also now have preliminary data in a subset of subjects (n=15) that centrally mediated 
cardiovascular effects were blunted by statin therapy. Exercise training lowered resting heart rate as 
expected in the exercise only group (Pre: 67±1.6 vs. Post: 64±1.7; P<0.05), but did not lower heart 
rate in the exercise + statin group (Pre: 64±2.0 vs. Post: 65±2.5). Importantly, statin induced blunting 
Table 1 
Exercise Only (n=19) 
Statins + Exercise (n=18) 
 
Pre 
Post 
%∆ 
Pre 
Post 
%∆ 
VO2peak (ml/kg/min) 
 
26.9±1.9 
29.5±2.3 
↑9.5% 
26.1±1.4 
26.5±1.3 
↑2 
Citrate Syn (nmol/min/ug) 
100.4±6.5 
113.6±4.3 
↑13% 
111.0±5 
106.0±5.3 
↓-4.5% 

 
 
 
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of exercise adaptations occurred uniformly in all subjects, and did not just manifest in those with statin 
induced myopathies (no myopathies reported). 
We posit that statin induced impairments in mitochondrial function play a primary role in mitigating 
exercise training responses; however, this hypothesis needs further testing. The next step is to 
determine if statins modify mitochondrial adaptations including respiratory kinetics, H202 emission, and 
transcriptional factors that control mitochondrial biogenesis, providing greater mechanistic insight of 
the potential negative interaction between exercise and statin therapy. Another factor that needs to be 
explored is if a lower dose of statin therapy will not block or mitigate exercise adaptations. Physicians 
reportedly lower the dose of statins for individuals who complain of problems with exercise but this 
approach has not been experimentally tested. In summary, the goals this project are to build upon our 
previously published data to determine if atorvastatin, now the most commonly prescribed statin, 
impairs exercise induced adaptations in skeletal muscle mitochondria content and function (respiration 
and transcriptional responses), cardiovascular responses, and systemic insulin sensitivity. An additional 
goal is to determine if low dose atorvastatin (20 mg/day) does not block these exercise training 
adaptations, an outcome that would provide physicians a new treatment option for patients who want 
to exercise and/or increase daily physical activity but also require statin therapy. 
 
II. 
Research Plan and Design 
 
A. Study Objectives: The overall aim of the study is to determine whether low or high intensity 
statin treatments differentially blunt the mitochondrial, metabolic, and cardiorespiratory 
adaptations to aerobic exercise training.  
a. Primary Objective:  
i. Changes in Cardiorespiratory fitness (VO2peak): Subjects will be tested for 
VO2peak at baseline and post training using a Bruce protocol on a treadmill as 
previously performed (13, 97). Relative (ml/kg-1/min-1) and absolute (L/min-1) 
VO2peak and treadmill time to exhaustion will be used as determinants of fitness 
while additional measures of respiratory quotient (RQ) and heart rate at each 
stage of the GXT, and heart rate recovery and excess post oxygen consumption 
following the test will also be measured as determinants of exercise training 
adaptations. Blood CK levels will be assessed 30 minutes following the cessation 
of exercise and also 24 hour later. In addition, sub-maximal exercise (60% HRR) 
measures of heart rate, RQ, and O2 consumption will also be determined during 
exercise training sessions occurring during the first week and the last week of 
training.  
b. Secondary Objectives:  
i. Mitochondrial Responses in Skeletal Muscle: Multiple aspects of mitochondrial 
function (basal and ADP-stimulated respiratory kinetics under multiple substrate 
combinations, H2O2 production and emitting potential) will be assessed in 
duplicate on permeabilized fiber bundles from freshly obtained muscle biopsy 
samples as previously described (61-64). Fibers are then freeze dried for 
determination of citrate synthase activity (index of mitochondrial content). Frozen 
muscle tissue will also be analyzed for electron transport complex activity, content 
(Western blot using complex I through V antibody cocktail) and cellular redox 
state (GSH/GSSG, thioredoxinred/thioredoxinox) as previously described (63).Of 
the remaining approximate ≥90 mg of muscle biopsy tissue, a small portion (<5 

 
 
 
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mg) will be prepped for electron microscopy for future analysis of morphology 
(mitochondrial size, content, ragged muscle fiber analysis) (66). Remaining 
muscle will be frozen for later analysis of intracellular atorvastatin concentration 
(both the acid and lactone forms) (67), ubiquinone (co-enzyme Q10) (68, 69), 
and potential future gene array, metabolomics, or proteomics analysis. An in-vivo 
assessment of mitochondrial function using NIRS will determine muscle oxygen 
consumption (mVO2) and the recovery kinetics will be determined during a series 
of repeated arterial occlusions following maximal knee extension. The mVO2 data 
are fit to a mono-exponential function to calculate the rate constant, which is 
directly related to the mitochondrial respiratory capacity. (46). The protein and 
mRNA for key transcriptional factors controlling mitochondrial biogenesis and 
function will also be measured (PGC-1α, NRF-1, NRF-2, mTFA) in all subjects as 
done previously (98, 99). In addition, muscle will be frozen in OCT to examine if 
there are altered fiber type changes, and or other important markers including 
apoptosis (TUNEL staining). 
ii. Body Composition, Physical Function, Pain Assessments, and Physical Activity:. 
DEXA will measure bone mineral content (BMC), bone mineral density (BMD) and 
body composition (fat mass, fat-free mass, and percent body fat). Pressure 
thresholds will be determined using an algometer during rest and after exercise.  
Current and usual whole body muscle pain while restingusing 0-10 numeric scale. 
Steps, physical activity and sedentary time will be determined over a 5-day period 
using pedometers and accelerometers. (BodyMedia Sensewear). 
iii. Fasting Blood Draw: Glucose, insulin, total cholesterol, HDL-C, LDL-C, and 
triglycerides, CK, creatinine and ALT will be measured in fasting blood samples. 
iv. Insulin Sensitivity: Glucose and insulin, and insulin sensitivity will be calculated 
using a minimal model program following the IVGTT. 
v. Cardiovascular Function: Heart rate ECG  will be measured under resting and 
maximal exercise conditions.  
B. Study Type and Design: This study is a longitudinal, repeated measures, double-blinded 
design with subjects randomly assigned to placebo, low (20 mg/d) or high (80 mg/d) 
atorvastatin therapy during a 12-week aerobic exercise training protocol. We expect to screen 
approximately 150 participants to enroll (randomize) a maximum of 80 participants. The overall 
goal is to have 60 participants complete all study procedures (20 in each group).   Repeated 
measures design allows each subject to serve as their own control. Placebo groups are included 
to account for potential changes in muscle mitochondrial function independent of statin therapy 
over the 1 year dose-response. 
C. Sample size, statistical methods, and power calculation: The randomization for study 
drugs will be carried out by the biostatistician using a computer-based random number 
generator at a 1:1:1 allocation. Sample size for the study is powered on the powered on the 
basis of detecting a difference in VO2peak between the EX+Plac group and the EX+Atorva80 
group as well as between the EX+Atorva20 group and the EX+Atorva80 group at 12 weeks 
post-treatment. In our previously published study(13) (Table 2) the EX only group had a mean 
2.6 ml/kg/min increase in VO2peak following 12 weeks of training while the EX+Statin group 
only had a 0.4 ml/kg/min increase in VO2peak. The estimated effect size of between group 
differences is 0.9 (Cohen’s d). The increase of VO2peak in the EX+Atorva20 group is expected 

 
 
 
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to be similar to that of EX+Plac group. A sample size of 35 per group provides 80% of power of 
detecting an effect size of 0.75 for a two-sided, two-sample t-test at 0.025 levels. Here, we use 
0.025 for each group comparison to maintain the overall type I error rate at 0.05 level using 
Bonferroni correction. Assuming variances similar to what was observed in the pilot study, this 
study is powered to detect a difference of 1.53 ml/kg/min VO2peak between groups. These 
power calculations led to a desired final sample size of 105 (35/group). We plan an enrollment 
of 120 (40/group) subjects to account for 10% dropout rate. The subject enrollment will be split 
equally between the two sites. As an exploratory analysis, the mean difference of VO2peak (EX+ 
Atorva20- EX+ placebo) and its 95% confidence interval (CI) will be estimated. If the lower 
bound of the 95% confidence interval is greater than -0.8 ml/kg/min, EX+ Atorva20 will be 
considered non-inferior to EX+ placebo. 
 
D. Subject Criteria 
a. Inclusion criteria/Exclusion criteria: 
i. Inclusion Criteria 
• 
Ages 35–60 years 
• 
BMI between 30-39 kg▪m2  
• 
Sedentary (less than 30 min of physical activity/week during last 6 months)  
• 
Weight stable (no more than 5% change in body weight the previous 3 months)  
• 
>5% risk for a cardiovascular event in the next 10 years according to the 
2013 American College of Cardiology/American Heart Association risk 
calculator and/or 2 out of 5 metabolic syndrome risk factors(Triglycerides ≥ 
150 mg/dL; HDL ≤ 40 mg/dL; Glucose ≥ 100mg/dL; Waist Circumference ≥ 
102cm for males, 88cm for females; Blood pressure: ≥ 130mmHg systolic 
and/or 85mmHg diastolic or being treated for hypertension). 
• 
Stable doses of medications for 90 days 
• 
Willing to stop all NSAIDs and aspirin for 7 days prior to muscle biopsy   
• 
 
ii. Exclusion Criteria 
• 
Smoking  
• 
Previous use of  statins  
• 
Use of other medications or supplements that affect lipid profiles or body 
weight in the last 6 months  
o 
e.g., fibric acids, bile acid sequestrants, nicotinic acids, fish oil  
• 
Diagnosis of chronic diseases including CVD, diabetes, other metabolic 
diseases (e.g., thyroid), cancer, HIV, or acquired immunodeficiency syndrome 
• 
History of abnormal bleeding problems 
• 
Currently taking (within the last 10 days) anti-platelet medication (Plavix), 
Warfarin, and other anti-coagulants (eliquis, pradaxa, and xarelto) 
medications. 
• 
>2 fold upper normal limit (UNL) for ALT or creatinine  
• 
Women who are pregnant or breastfeeding  
• 
Individuals with polymorphisms (SLCO1B1) known to be associated with 
susceptibility for statin induced myopathies (tested at screening)  
• 
Currently enrolled in another research study 

 
 
 
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b. Withdrawal/Termination criteria: Subjects are free to abstain from taking their 
statins and leave the study at any time. We will test both muscle enzymes (creatine 
kinase) and liver enzymes (ALT) to determine if statins are causing either muscle 
myopathies or liver injury. This testing will occur at baseline and at 1 month into taking 
statins. If enzymes are elevated, the subject will be taken out of the study for their own 
health. 
 
E. Specific methods and techniques  
This study will require approximately 13 total study visits plus exercising 5 times per week. The total 
time commitment of study visits is approximately 30 hours over the 12 weeks of study participation. 
 
 
 
 
 
a. Testing Procedure  
i. Telephone screen: A telephone screen will be used to collect health history, 
concurrent medications, and physical activity level of potential participants prior to 
in-person screening.  

 
 
 
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ii. Blood draw: A screening blood draw will be used to determine presence of genetic 
markers associated with increased risk of myopathy from statin, creatine kinase 
(CK), kidney function (GFR) and liver enzymes (ALT). CK, GFR and ALT will be 
used to detect abnormal muscle, kidney or liver function prior to enrollment. A 
blood draw will be repeated at 1 month to measure for myopathy, and changes in 
liver and kidney function from statin use.   
iii. Intravenous glucose tolerance test (IVGTT): The subject will arrive following an 
overnight fast (10-12 hrs). Upon arrival, anthropometrics and vital signs will be 
measured. A catheter will be placed in one arm for blood draws. A fasting blood 
draw (~14-16mls) will be used to determine blood glucose, insulin, total 
cholesterol, HDL-C, LDL-C, triglycerides. Creatine kinase (CK) and liver enzymes 
(ALT) will be tested at 6 and 12 months during IVGTT.. CK and ALT will be used to 
detect abnormal myopathy, and changes in liver function from statin use for 
participant safety. Following the baseline draw glucose (50%) will be injected at a 
dose of 0.3 g/kg. Insulin will be mixed with the participant’s blood for injection. 
Blood (5ml) and insulin (1.25 ml) will be injected into a 250 ml bag of sterile saline 
and mixed thoroughly. A dose of 0.025 U/kg body mass will be administered at 
minute 20. These mixing procedures have been safely preformed at the CTSU for a 
recent study (INFORM; HSC#13453).. Serial blood samples (25 total) will be 
obtained from the other arm at minutes 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 19, 22, 25, 
30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, and 180. Plasma will be frozen at -
80°C for later determination of glucose and insulin, and insulin sensitivity will be 
calculated using a minimal model program (77). A total of approximately 622 ml of 
blood will be collect over the 12 month intervention. After analysis for current 
project is complete any remaining blood samples will be stored indefinitely for 
future research. Fasting blood draw will be repeated at , 4 and 12 weeks. The 
IVGTT will be repeated at week12. 
iv. Muscle biopsy: After an overnight fast, the participant will complete a survey to 
confirm the absence of bleeding disorders, and avoidance of NSAIDs and aspirins 
for 7 days prior to biopsy. Participants will then lie on a table in a supine position. 
A location on the mid-thigh will be identified. The area will be properly shaved and 
then thoroughly cleaned using sterile techniques (alcohol and iodine). A sterile 
drape is then placed over the leg with the biopsy site showing through a 
fenestration in the center of the drape. A numbing agent will be lightly sprayed 
onto the biopsy location (ethyl chloride) immediately before the skin, adipose, and 
muscle fascia is anesthetized with lidocaine (1-2% HCL). After allowing 1-2 
minutes for the site to become numb the skin and fascia is incised with a sterile 
scalpel (#11). The Bergstrom needle (5mm) is then placed through the incision 
into the vastus lateralis muscle. Suction is applied to the proximal port of the 
needle, and the tissue is cut rapidly with the internal portion of the needle, and 
the entire needle is removed from the incision. Sterile gauze is placed on the 
incision site and pressure is applied with an ice pack for ~5 minutes. The site is 
then closed with a steri-strip and band-aid. Sterile gauze is then applied on top of 
the band-aid and pressure is applied by wrapping coban around the thigh. 
Approximately 100-200 mg of skeletal muscle will be collected during each biopsy 
in one pass. In the case where less muscle is harvested per pass, one more 
additional pass will be taken with the participants consent. The tissue collected is 

 
 
 
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dissected free of connective tissue and separated for mitochondrial function 
studies or frozen in liquid nitrogen for subsequent biochemical analyses as done 
previously (13, 61). After analysis for current project is complete any remaining 
muscle samples will be stored indefinitely for future research. Muscle biopsies will 
be repeated at 4 weeks and 12 weeks. Dr. Thyfault has performed over 300 
skeletal muscle biopsies without incidence since starting his independent lab in 
2005.See appendix for letter from IRB Director (Michele Kennett) at Dr. Thyfault’s 
previous institution (MU) stating his record for conducting muscle biopsies and a 
letter of support for the procedure from Dr. Jeff Burns, the Director of the CTSU. 
Additionally, Neurologists who study various muscle diseases regularly perform the 
technique at KUMC.  Muscle biopsies will be repeated at 4  and 12 weeks. 
v. Near InfraRed Spectroscopy (NIRS): Muscle mitochondrial functional capacity will 
be measured non-invasively using a NIRS technique developed by Dr. Terence 
Ryan, a member of the research team at ECU (46). Participants will perform 
submaximal knee extension exercise to increase muscle oxygen consumption 
(mVO2) and the recovery kinetics is determined during a series of repeated 
arterial occlusions. The mVO2 data are fit to a mono-exponential function to 
calculate the rate constant, which is directly related to the mitochondrial 
respiratory capacity. NIRS will be repeated at week 12.  
vi. Pain Assessment: Pressure pain threshold will be objectively assessed by a 
computerized algometer at rest and after exercise (73). In addition, we will ask 
participants to rate their current and usual whole body muscle pain while resting 
and moving using 0-10 numeric scales (0 = no pain, 10 = most intense pain 
imaginable) at different time points. We will ask the participants to rate the 
highest pain felt immediately and for up to 30 minutes after each maximal 
exercise test, as well as 24 hours later. Pain assessments will be repeated at week 
12. 
vii. Muscular Strength Assessment: Knee isometric strength will be assessed using a 
Biodex dynamometer.  Participants will be seated in a specialized chair and leg 
will be strapped to the dynamometer arm.  Participants will also be secured to the 
chair to ensure isolation of the knee joint. Trained staff will instruct participants 
on how to gradually develop force in one second. Following 3 practice trials of 
submaximal contraction of both flexion and extension, participants will be asked 
to alternate between maximal flexion and extension with 60 seconds rest between 
contractions. There will be 3 trials of flexions and extension on both legs. Muscular 
strength assessments will be repeated at 1, 6, and 12 months       
 
viii. Physical Performance Assessment: A series of physical performance 
measurements will be performed to access balance, gait speed, and strength (74). 
The physical performance will be repeated at week 12. 
ix. Body Composition: Participants will be evaluated with dual energy x-ray 
absorptiometry (DEXA, Lunar Prodigy, version 11.2068, Madison, WI) to 
determine fat-free mass, fat mass and percent body fat at. DEXA uses very low X-
ray doses (0.02mREM) to detect changes in body composition. DEXA body 
composition will be repeated at week 12.  
x. Exercise Testing: Whole body steady state submaximal O2 consumption will be 
determined during a standard 6 min treadmill test (2.5 mph) to determine VO2 
cost. Subjects will then complete a ramped treadmill test (Bruce protocol) to 
determine cardiorespiratory fitness (VO2 peak) and peak heart rate as previously 

 
 
 
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described (13). We will also investigate post exercise oxygen consumption and 
heart rate at 60, 90, 120, and 300 seconds after cessation of the max test to 
determine if exercise recovery is impacted by statins. Blood will be sampled for 
measurement of CK 20-30 minutes following the maximal exercise to assess 
potential muscle damage. Exercise testing will be repeated at week 12. 
xi. Cardiovascular Function: These measures include both heart rate and stroke 
volume performed under both resting and sub-maximal exercise conditions 
(performed on separate days). Stroke volume will be estimated by finometer 
placed on finger (80). Cardiovascular function will be repeated at week 12. 
xii. Physical Activity Monitoring: Physical activity levels and sedentary time will be 
assessed by pedometers and accelerometers (BodyMedia Sensewear) (75, 76) for 
5 day periods. Physical activity monitoring will be repeated at week 12. 
xiii. Stain Therapy Intervention: Once participants have successful completed baseline 
testing, the participant will be randomly assigned to 1 of 3 groups (1:1:1 ratio). 
Statins will be prescribed as a placebo or at a dosage of 20 or 80 mg/day 
(atorvastatin; Lipitor) by the study physician at KUMC,  Dr. John Miles, MD. 
Subjects and research team will be blinded to the type and dose of statin. 
Statins will be dispensed by the KUMC Investigational Pharmacy at regular 
intervals during the participant’s enrollment in the study. The study physician will 
provide care for any problems associated with the statin treatment after un-
blinding by the chair of the Data Safety Monitoring Board, Dr. Russell 
Swerdlow. All doses fall within the norms of recent recommendations and are 
given chronically (2) 
xiv. Aerobic Exercise Intervention:  Exercise training will be performed as done 
previously (13) and will consist of brisk walking and/or slow jogging on a treadmill 
5 d each week at approximately 65-75% of each subject’s VO2peak, 45 
min/session, at an energy expenditure of 1800-2000 kcal/wk, for 12 weeks.  The 
exercise training will follow a three-stage progression: 1. wk 1=30 min, 3 d/wk, 
60% VO2max; 2. wk 2=30 min, 5 d/wk, 60% VO2max; and 3. wk 3-12=45 min, 
5 d/wk, 60-75% VO2peak. Exercise intensity for each session will be monitored 
using heart rate monitors every 5 minutes and at least four exercise sessions per 
week will be supervised within KUMC exercise facilities. 
 

 
 
 
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F. Risk/benefit assessment:  
a. Potential risks: 
i. Exercise: Some risks are associated with the exercise testing used to assess 
maximal aerobic capacity. Cardiovascular events during maximal exercise and in 
recovery are possible but rare in this population (1). However, these risks could 
be serious. Therefore, initial screening by maximal stress test will be performed in 
a clinical setting under the direction of a medical monitor (medical monitor only 
supervises the graded exercise test). Muscle soreness and strain are possible with 
exercise testing and training, but these are not a serious risk. The maximal 
aerobic capacity test represents greater risk of cardiovascular events than the 
training exercise because of the increased intensity of the exercise. However, 
events are extremely rare, and subjects will be screened for risk of cardiovascular 
disease and symptoms. Emergency equipment, including defibrillator, and 
ambulance plan are available for all subjects. Exercise training will be monitored 
by trained study staff to reduce risk. 
ii. Statins: Statin therapy is associated with muscle issues that range from more 
minor issues of muscle pain, cramping and fatigue, to myopathies, to the very 
severe issues of rhabdomyalgia, although this is rare. Statins are the most 
prescribed drug in the world. Statins are also associated with headaches, nausea, 
and constipation. Statins are also not well tolerated by athletes suggesting that 
exercise may worsen the effects of statins on skeletal muscle. Thus, there is the 
potential that participants in our study may have adverse effects while taking 
statins. A recent trial conducted by our consultant, Dr. Paul Thompson, utilized 80 
mg/day of atorvastatin and found that ~15% of participants experienced pain and 
weakness (2). atorvastatin 80 mg is an increasingly common dose because three 
large clinical trials, REVERSAL (atorva 80 v. prava 40, n=502) (3), PROVE IT 
(atorva 80 v. prava 40, n=4,162) (4), and TNT (atorva 80 v. prava 10, n=10,001) 
(5) demonstrated reduced atherosclerosis and cardiac events with atorvastatin 80 
mg. These studies were done in CAD patients, a group on multiple other 
medications and likely to be at higher risk for side effects than our healthy 
subjects. Nevertheless, side effects were rare. Liver function test (>3 times upper 
normal limits [UNL]) and creatinine kinase (CK) elevations (> 10 UNL) occurred in 
only 1-3.3% of patients treated with atorvastatin 80 mg for up to 24 months, 
respectively. These side effects should be even more rare given that we will pre-
screen and exclude individuals with polymorphisms (GATM and SLC01B1) that 
increase risk for myopathy. We will test both muscle enzymes (creatine kinase) 
and liver enzymes (ALT) to determine if statins are causing either muscle 
myopathies or liver injury. This testing will occur at baseline and at 1 month into 
taking statins. If enzymes are elevated, the subject will be taken out of the study 
for their own health. Finally, study physicians at KUMC who commonly prescribe 
statins and deal with patients who experience statin induced problems will provide 
medical coverage for our studies. Subjects are free to abstain from taking their 
statins and leave the study at any time. Importantly, most individuals report that 

 
 
 
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statin induced complications go away very quickly after stopping the therapy. 
Subjects who are discontinued from the study for a medical reason judged to be 
appropriate by the study doctors will receive the same reimbursement as if they 
completed the study to avoid the possibility that a subject would “soldier on” 
simply for the reimbursement. 
iii. Muscle Biopsies: Acute issues of muscle tightness, soreness, and bruising can be 
associated with muscle biopsies. More severe problems include the risk of 
infection. To avoid these issues the biopsy procedures are conducted with sterile 
techniques under medical supervision. Moreover, the subjects are given detailed 
instructions including how to take care of the incision site and who to contact 
should anything seem abnormal. 
iv. IVGTT Catheter Placement and Venipuncture: Their risk is very minimal. However, 
certain risks including discomfort, blood clot, minor bleeding, bruising, infection, 
and redness can occur. Aseptic techniques will be used to minimize such risks. 
Risks of bruising and minor pain can occur with venous phlebotomy. Venous 
catheter placements can rarely cause bleeding, bruising, soreness, and infection. 
Risk of bleeding after removal of the line also is possible. Infusion of glucose or 
insulin may cause the subject to feel nauseous or flushed. Drinks and snacks will 
be available for the subjects at the completion of the IVGTT should they have low 
blood sugar or feel nauseous. 
v. DEXA: The DEXA scan may make participants slightly uncomfortable because you 
have to hold very still. This research study involves exposure to radiation equal to 
approximately the level of radiation that most Americans receive in about 2 days 
from background radiation, such as naturally occurring radioactivity in the soil and 
air. The risk from radiation exposures of this magnitude is too small to be 
measured directly and is considered to be very low when compared with other 
everyday risks. 
b. Potential Benefits: All subjects will gain health information about themselves. At the 
end of the study, results collected will be shared with the subject in face-to-face 
meetings. Moreover, although we are studying the impact of statins on muscle health, 
statins overall do have a strong track record of lowering blood lipids and in most trials 
lowering cardiovascular risk. Moreover, the health information gained throughout the 
study will aid the subjects in making future medical decisions with their physicians in 
relation to cardiovascular and diabetes risk. The aerobic exercise intervention will 
represent a stimulus for the beginning of a permanent improvement in lifestyle and a 
dramatic reduction in risk of cardiovascular disease. 
In summary, the benefits to the subjects are substantial, and the information detailing 
the impact of statins on mitochondrial, metabolic, and cardiovascular function have the 
promise of helping millions of patients and physicians evaluate the risk to benefit ratio of 
statin therapy. There are risks associated with the study, but the experience and medical 
expertise of the research team should keep these at a minimum, and our track record 
with exercise and diet research indicates that this diligence has been effective. 

 
 
 
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G. Location where study will be performed: All portions of the study will occur at KUMC.  
H. Collaboration: This is a Multi-PI application from Drs. John Thyfault and Darrell Neufer from 
the University of Kansas Medical Center and East Carolina University, respectively. Both 
investigators have been conducting research on statins for several years. The project was 
born out of a common desire to combine their individual expertise to investigate the 
mechanisms underlying skeletal muscle complications associated with statin therapy in a 
repeated measures, longitudinal design. Due to the scope of the design (i.e., number of 
subjects, duration) and complexities of the primary outcome measures, it was felt a multi-PI, 
multi-institutional approach represented the most efficient and statistically valid means of 
completing the project and thereby making truly sustained impact of the field. Each 
investigator has trained at/frequently visited the other institute and is quite familiar with the 
research environments. Standard operating procedures will be developed for all common 
testing and primary outcome measurements, and each investigator and their key personnel 
will visit the other institute prior to commencing the study to conduct trial runs to insure 
continuity. The PIs will share responsibility for fiscal and research management. Using the 
multi-PI approach with two investigators with translational research experience and 
complimentary analytical expertise dramatically increases the power of the study and the 
likelihood of successfully completing the proposed aims. 
I. Single IRB Review for a Multi-site study: NA 
 
J. Personnel who will conduct the study, including: 
1. Indicate, by title, who will be present during study procedure(s): PI, Study Coordinator 
2. Primary responsibility for the following activities, for example:  
a. Determining eligibility: PI, Study Coordinator  
b. Obtaining informed consent: PI, Study Coordinator  
c. Providing on-going information to the study sponsor and the IRB: PI, Study 
Coordinator 
d. Maintaining participant's research records: PI, Study Coordinator 
e. Completing physical examination: PI, CTSU Nurse 
f. Taking vital signs, height, weight: CTSU Nurses  
g. Drawing / collecting laboratory specimens: CTSU Nurses 
h. Performing / conducting tests, procedures, interventions, questionnaires: PI, 
Study Coordinator 
i. Completing study data forms: Study Coordinator 
j. Managing study database: PI 
 
K. Assessment of Subject Safety and Development of a Data and Safety Monitoring 
Plan 

 
 
 
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a. Key personnel: John P. Thyfault, PhD, Sandy Billinger, PhD, Darrell Neufer, PhD, John 
Miles, MD, study physician at KUMC and Bruce Ferguson, MD, study physician at ECU. 
b. Plan for safety monitoring and review: Dr. Megan Baumgardner will serve as the 
Chair of the Data Safety Monitoring Board and will convene every 6 months with the 
other members, Drs. Nicol and LeMaster to make decisions on safety of the participants. 
Enrollment data will also be reviewed twice a year by the DSMB. In addition, data will be 
reviewed on a yearly basis with the biostatistician, Dr. He to determine if the studies 
should be shortened do to either no measured effect or due to effects that are greater 
than what power calculations indicated. If problems occur with participants, blinded study 
staff will alert Dr. Baumgardner.  Dr. Baumgardner will have access to dose and type of 
statin and will consult the study physicians/cardiologist to make a decision on whether 
the subject should be removed from the study for safety concerns. The PI and other key 
personnel will be examining research data on a subject to subject basis to ensure it is 
accurate and to address any potential problems that may arise with the protocols. In 
addition, Drs. Neufer and Thyfault will discuss data at least once per month through in 
person meetings or by phone to ensure that data collection is occurring in a consistent 
manner at both locations.Plan for adverse event reporting: Adverse events will be 
defined as any untoward medical occurrence in study participants or others immediately 
involved in the performance of the protocol, which does not necessarily have a causal 
relationship with the study treatment, but results in a change in intervention, daily 
function, hospitalization or rated category 3 or above using the National Cancer Institute 
Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Expected events such as 
slight muscle soreness consistent with statin therapy, or those consistent with a 
participant’s prior medical history not sufficient to alter the intervention will not be 
considered an AE. Staff involved in performance of the protocol (e.g. coordinators) will 
continually monitor participants for adverse events throughout the intervention, and 
study staff will assess adverse events at every testing visit as well as during regularly 
scheduled telephone assessments with all randomized participants.  
If study staff, tester, or participant reports adverse events or complaints, relevant 
information will be collected and documented. The participant will be evaluated by the 
unblinded investigator identified in the protocol. The investigator will determine the 
severity (according to the CTCAE) and relatedness of the AE to the intervention. The 
investigator will identify adverse events of clinical concern, those that may require 
further workup, or suggest that additional participation in the intervention might be a 
safety risk. These AEs will first be discussed with the participant and then communicated 
to the study staff or providers with participant’s consent and as appropriate. Serious 
adverse events directly related to study intervention will be reported immediately to the 
IRB. Any adverse event rate over 30% in 12 mo will be reported to the NIH.  
 
 
III. 
Subject Participation 
 
A. Recruitment: 
a. Subjects will be recruited from the KUMC campus, from hospitals and clinics associated 
with KUMC and metro-Kansas City, Kansas and Missouri areas. Recruiting will occur 
through physicians and clinics and through advertisements in emails, flyers, newspaper 

 
 
 
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ads, radio spots, etc. Interested subjects will call or email and undergo initial phone 
screening, conducted by trained study staff, to see if they qualify. Should they meet the 
initial qualifications, they will come to the lab for an informed consent meeting with the 
PI, research coordinator, or other study staff. They will then be provided with an 
informed consent that is fully approved by the IRB at KUMC to review prior to the in-
person meeting. Subjects who are interested in taking part in the study will be asked to 
sign the informed consent in the presence of a witness. Participants will have adequate 
opportunity to review the informed consent and to ask any questions they may have 
about the research protocol, compensation, risks, and benefits of taking part in the 
study. 
b. The targeted/ planned distribution of subjects by sex/gender and racial/ethnic groups for 
the proposed study or protocol will follow the local demographics. The Kansas City area 
has a population that is comprised of 13 % African American, 2% Asian, 5% Hispanic, 
and 80% Caucasian. It is anticipated that the study population at KUMC will have much 
the same racial and ethnic make-up. Statistical comparisons among minorities or 
between minority and Caucasian groups are not aims of the current study. We fully 
intend to enroll every eligible minority individual in these studies. Ample pools of all 
targeted populations exist. 
 
c. Selection criteria: Only premenopausal women will be included in this study because of 
the possible complications that hormone replacement therapy may have upon findings. It 
is anticipated that women will comprise approximately 50% of the study subjects. It is 
also anticipated that gender will not be a significant factor in the response to exercise 
training or statin therapy, and hence, it is anticipated that the data from both genders 
will be compiled and analyzed as a group. 
 
d. Exclusions: No minority groups will be excluded. 
 
e. Outreach: The subject pool will be limited to the greater Kansas City (MO and KS) area. 
Subject will need to make regular visits to the laboratories, and thus, subjects will only 
be recruited who are within the county region and can regularly make appointments. 
 
B. Screening Interview/questionnaire: NA 
 
C. Informed consent process and timing of obtaining of consent: Should the participant 
meet the initial qualifications, they will come to the lab for an informed consent meeting with 
the PI, research coordinator, or other study staff. They will be provided with an informed 
consent that is fully approved by the IRB at KUMC to review prior to the in-person meeting. 
Subjects who are interested in taking part in the study will be asked to sign the informed 
consent in the presence of a witness. Participants will have adequate opportunity to review 
the informed consent and to ask any questions they may have about the research protocol, 
compensation, risks, and benefits of taking part in the study. 
D. Alternatives to Participation: NA 
 

 
 
 
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E. Costs to Subjects: There is no cost to subjects for participation in this study. 
 
F. How new information will be conveyed to the study subject and how it will be 
documented: New information about risks associated with involvement in the study will be 
disseminated but no other information will be disclosed. 
 
G. Payment, including a prorated plan for payment: Participants will receive a one-time 
compensation of $400 for completing all study visits. If participation ends early, participants will 
receive $75 for each study visit excluding screening. They will be given a ClinCard, which works 
like a debit card. After completion of the study, payment will be added to the card by computer. 
The money will be available within 1 business day. Participants can use the ClinCard at an ATM 
or at a store. Study staff will collect their name, address, and social security number to allow 
them to set the participant up in the ClinCard system through the KUMC Research Institute. 
Study payments are taxable income. A form 1099 will be sent to the subject and the Internal 
Revenue Service if your payments are $600 or more in a calendar year. The subjects’ personal 
information will be kept on a secure computer. It will be removed from the computer after the 
study is over and the money on the card has been used. The information will not be shared with 
other businesses. It will be kept confidential. 
 
H. Payment for a research-related injury: We will include the following text in the consent 
form: “All forms of medical findings, whether routine or experimental, involve some risk of 
injury. In spite of all safety measures, you might develop medical problems from 
participating in this study. You must report any suspected illness or injury to the study 
coordinator immediately. If such problems occur, you will be provided with emergency 
medical treatment and the investigator will assist you in getting proper follow-up medical 
treatment. Neither the investigator nor the sponsor will provide compensation for research-
related injuries. Payment of lost wages, disability or discomfort is not available. You do not 
give up any of your rights by signing this form.”  
 
IV. 
Data Collection and Protection 
A. Data Management and Security: All identifiable files, data, and tissue will be coded and 
stored in secure locations. These data include: study progression, subject numbers, percent 
completion, data quality, subject retention, adverse events, etc. 
The PIs at both KUMC and ECU will be responsible for the quality of the data and will 
supervise the data acquisition with the help of study coordinators. All data will be coded for 
confidentiality, and only the PI, study coordinator, and study statistician will have access to 
the code. The results of each test on each subject will be screened by the study coordinator 
prior to entering on the spreadsheet. This is standard practice in our laboratories. Hard 
copies are kept in dedicated locked cabinets. Coded data files will be sent to the study 
statistician for statistical analyses. These analyses will be sent to the PI and study 
coordinator for dissemination to appropriate co-Is. At the end of participation in the study, 
each subject will receive a personal data summary of their test results. The study 
coordinator or a study investigator will discuss the results with the subject. 
After 1 year, the PI’s including the biostatistician, Dr. Jianghua He will be un-blinded but the 
study staff will remain blinded, so that the important research findings can begin to be 

 
 
 
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delineated. This will also allow for Dr. He to being to examine if the trial is finding more or 
less significant effects for outcome measures.  
 
B. Sample / Specimen Collection: All subjects will be assigned a data code. Blood and tissue 
samples will be labeled with the participant’s data code and stored in a locked freezer. Blood 
and tissue samples will be stored indefinitely following completion of current project for 
future research.  
 
C. Tissue Banking Considerations: Following completion of the current project, remaining 
blood and tissue samples will remain in locked freezer indefinitely. Samples will only be used 
by investigators of the current project, both KUMC and ECU, when a new biomarkers or 
techniques of interest emerge.  
 
D. Procedures to protect subject confidentiality: Risks to confidentiality are reduced by 
assigning all subjects to a data code. Folders are stored in locked file cabinets, and only the 
PI and study coordinator have access to the locked files. Individual names or initials are not 
used in any discussions or publications of the data. 
 
E. Quality Assurance / Monitoring: Data will be reviewed twice a year by the Board Chair. 
In addition, data will be reviewed on a yearly basis with the biostatistician, Dr. He to 
determine if the studies should be shortened do to either no measured effect or due to 
effects that are greater than what power calculations indicated. The PI and other key 
personnel will be examining research data on a subject to subject basis to ensure it is 
accurate and to address any potential problems that may arise with the protocols. In 
addition, Drs. Neufer and Thyfault will discuss data at least once per month through in 
person meetings or by phone to ensure that data collection is occurring in a consistent 
manner at both locations. 
 
 
V. 
Data Analysis and Reporting 
 
A. Statistical and Data Analysis: This project is a two-factor study. One factor is treatment 
group (between subjects) and a second factor is time of data collection (0, 1, 6, and 12 
months) (within subject). The data analysis will be carried out for the primary outcome 
variable of cardiorespiratory fitness, in addition to other outcome variables (muscle 
mitochondrial change, and insulin sensitivity, etc.). For each measure, its baseline measure 
and age will be added as covariates to adjust for the individual difference at baseline. Two-
way interaction between treatment and time will be added in the model for testing if the 
outcome changes differently between groups over time. Additional variables, such as 
demographics, BMI, physical activity, etc. may also be included as covariates. If the test of 
trend difference is significant, then the comparison at each time point will also be considered 
to identify when the difference between groups reaches the maximum. Least Square Means 
will be used for the aforementioned comparisons. The statistical analysis will be performed 
with mixed procedure in STATA 13.1 (StataCorp LP, College Station, TX). Mixed model does 

 
 
 
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not require complete data for a longitudinal study. Residual analyses will be conducted and 
efforts to address those will be made, including appropriate transformations. 
 
B. Expected Outcomes: The EX+Plac group and EX+Atorva20 groups will have a significant 
increase in VO2peak, stroke volume, and a lowering of resting heart rate, common 
responses to exercise training. Measures of mitochondrial content (citrate synthase) and 
function (in-vivo NIRS, and ex-vivo respiration) will improve following the intervention, and 
will be preceded by increases in transcription factors (PGC-1α, NRF-1, NRF-2, mTFA) known 
to control mitochondrial biogenesis measured at 1 month. Insulin sensitivity will also 
improve in the EX+Plac and Ex+Atorva20 groups. In contrast, the EX+Atorva80 group will 
display diminished mitochondrial and cardiorespiratory adaptations because of compromised 
respiratory capacity and disturbances in redox balance in skeletal muscle. This may occur 
due to a blunted exercise induced increase in PGC-1α which is known to up regulate anti-
ROS defense enzymes (101). Other cardiovascular adaptations may not improve in the 
EX+Atorva80 group, which could be due to impaired mitochondria oxygen consumption. We 
expect measures of pain and function to be triggered by the combination of exercise and 
Atorva80 treatment. These findings would indicate that higher dose atorvastatin impair 
exercise adaptations and that physicians should consider prescribing lower dose atorvastatin 
to patients who plan to utilize exercise training to lower cardiovascular risk. If these findings 
occur we will have remaining tissues to examine further mechanisms including if these 
findings are associated with reduced cellular ubiquinone levels, and altered balance between 
pathways controlling autophagy and apoptosis (Bcl-2 and Bax). These can be further 
supported by immunoflourescent examination of muscle fiber type changes and 
quantification of apoptosis by TUNEL staining. Given that a rodent study showed atorvastatin 
therapy blocked exercise induced increases in Glut4 mRNA and glycogen content (102), and 
that mitochondrial adaptations are critical for improved insulin sensitivity, we expect the 
EX+Atorva group will also display impaired improvements in insulin sensitivity. 
 
C. Study results to participants: At the end of participation in the study, each subject will 
receive a personal data summary of their test results. The study coordinator or a study 
investigator will discuss the results with the subject. Results to be shared include: Body 
composition, exercise testing results, lipid profile, liver function (ALT), and glucose and 
insulin results from IVGTT, and summary of physical activity levels.  
 
D. Publication Plan: We will publish all data derived from this award in a timely fashion and to 
make those data freely available to the general research community whenever possible. All 
genomic data will be made publicly available through NCBI’s Gene Expression Omnibus 
(GEO), and all publications that result from this work will be deposited in PubMed Central 
(PMC). 
 
VI. 
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