Clinical trial NCT02530996
Conditions: Rheumatologic Disease
Sponsor: VA Office of Research and Development
Start date: 2016-01-01; Completion date: 2019-12-31
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Systemic sclerosis (SSc; scleroderma) is a multi-organ systemic disease characterized by activation of immune cells, which results in vascular dysfunction (vasculopathy) and subsequent scarring (fibrosis). SSc has a higher than expect prevalence in the US military. On a national level there are 5,766 SSc patients (ICD-9 710.1) presently cared for in the Veterans Health Administration (VHA). While there is no cure for SSc, studies of therapeutics that can help slow disease progression are valuable to our Veterans. This proposal addresses the solicitation for projects with attention to SSc requested by President Obama after reviewing potential contamination of water at Camp Lejeune. This proposal is a patient-centered outreach for our Veterans with SSc to inform and prevent catastrophic endstage vascular abnormalities, including digital ulcers, pulmonary arterial hypertension (PAH) and scleroderma renal crisis in SSc. The study proposes a novel application of a therapeutic for this disease. A better understanding of the initiating insult and natural progression of SSc vasculopathy is needed in order to develop therapeutics with a goal of curing/treating the underlying disease. This project has the potential to impact not only Veterans with SSc, but also those with vascular abnormalities including digital ulcers, PAH, and renal crisis. This proposal represents a potential major therapeutic advance for our Veterans with SSc.

Detailed description:
Although SSc is heterogeneous in the extent of organ involvement and prognosis, it is accepted that all SSc cases have a progressive and usually devastating course. Since vasculopathy precedes fibrosis in this disease, a focus on understanding its natural history and preventative measures for vascular dysfunction has profound implications. This pilot work suggests that measurement of endothelial dysfunction with flow mediated dilatation (FMD) holds promise as novel method to assess disease progression as well as the therapeutic efficacy of the pharmacologic compound tetrahydrobiopterin (BH4) in SSc. The investigators believe that BH4, which targets the endothelium, has great promise to reduce SSc-related tissue hypoxia, end organ damage, and potentially may impact underlying disease progression. The first aim will adopt an integrative approach and validate a novel, non-invasive technique, FMD to define vasculopathy in SSc. The second aim and third aim (which is reported in this PRS report) will examine if BH4 is effective in ameliorating vascular dysfunction in patients with SSc and determine the role of oxidative stress in BH4-mediated improvements in vascular function in patients with SSc. The overarching goal of these aims is to improve vasculopathy detection and management in Veterans with SSc.

Arms: arm 1: Six SSc received oral placebo 10 mg/kg and had flow mediated dilatation measured. After a five day washout they crossed over to oral BH4 10 mg/kg and had flow mediated dilatation measured. Blood samples were obtained from these SSc patients and assessed for oxidative stress. arm 2: Six SSc received oral BH4 10 mg/kg and had flow mediated dilatation measured. After a five day washout they crossed over to oral placebo 10 mg/kg and had flow mediated dilatation measured. Blood samples were obtained from these SSc patients and assessed for oxidative stress.
Interventions: intervention 1: BH4 intervention 2: Vasculopathy assessment intervention 3: Placebo
Intervention descriptions: intervention 1: BH4 10 mg/kg/day given once to a total of 12 SSc patients intervention 2: Non-invasive technique, flow mediated dilatation (FMD) to define vasculopathy in SSc. intervention 3: On the experimental days, patients reported to the laboratory after having consumed a standardized breakfast and oral BH4 (10mg/kg) or placebo five hours prior to their arrival. All measurements were taken at the same time of day to eliminate any diurnal effects. All participants abstained from alcohol, caffeine, and exercise for ≥12 hours prior to the study. Additionally, vasodilatory medications were discontinued 12 hours prior to study visit. In premenopausal women, measurements were performed during the early follicular phase of the menstrual cycle. All measurements were made under quiet, comfortable, ambient (\~22°C) laboratory conditions.

Protocol documents:
SAP_002.pdf: 
Statistical analysis 
Power calculations were performed using G*Power computer software version 3. The 
α-level used for power analysis was set at 0.05. Sample-size calculations were based on the 
number of patients needed to detect significant differences in FMD between placebo and 
BH4 (20, 21). With 12 patients/group we had >95% power to detect differences in FMD 
between placebo and BH4. Statistics were performed using SPSS software (IBM, Chicago, 
IL). Paired t-tests were used to identify significant changes in measured variables between 
placebo and BH4. To determine if an effect of visit order was present, the difference in BH4 
vs. placebo was calculated and patients were separated into groups based on order of 
conditions. Unpaired t-tests were used to identify significant changes in measured variables 
between ordered groups. Statistical significance was set at P<0.05 for all analyses. Data are 
presented as mean±SEM. 
Study: IMMA-006-14F
NCT02530996
Systemic Sclerosis (SSc) Vasculopathy: Improved Clinical Monitoring and Treatment 
4/19/2016

Prot_001.pdf: 
 
1
Protocol Summary 
Version 9: March 2015 
 
“Vascular and Autonomic Maladaptations in Patients with Vascular Dysfunction”. 
 
Principal Investigator: 
Russell S. Richardson, Ph.D., Professor of Medicine 
Department of Medicine, Division of Geriatrics 
University of Utah and GRECC. 
 George E. Whalen VA Medical Center 
500 Foothill Drive, Salt Lake City, UT 84148 
(760) 207-4570 
(801) 584-5640 (fax) 
r.richardson@hsc.utah.edu 
 
Co-Investigators: 
Josef Stehlik M.D., MPH 
Department of Medicine, Cardiology, University of Utah 
Cardiovascular Center, University Hospital 
50 North Medical Drive, Salt Lake City, UT 84132 
(801) 585-5122; Josef.Stehlik@hsc.utah.edu 
 
Mark A. Supiano, M.D. 
Department of Medicine, Division of Geriatrics, University of Utah and GRECC. 
 George E. Whalen VA Medical Center 
500 Foothill Drive, Salt Lake City, UT 84148 
 (801) 587-9103; mark.supiano@hsc.utah.edu 
 
Phillip Kithas, M.D. 
Department of Medicine, Internal Medicine 
George E. Whalen VA Medical Center 
500 Foothill Drive, Salt Lake City, UT 84148 
(801) 587-1565 ext. 2657 
 
Jose N. Nativi Nicolau, M.D. 
Department of Medicine, Cardiology, University of Utah 
Cardiovascular Center, University Hospital 
50 North Medical Drive, Salt Lake City, UT 84132 
(801) 339-1147; jose.nativi@hsc.utah.edu 
 
 
David Morgan, M.D. 
30 N 1900 E RM 3C444, SLC, UT 84132-2101 
801-581-6393 
david.morgan@hsc.utah.edu 
 
Amber Bledsoe, M.D. 
30 N. 1900 E RM 3C444, SLC, UT 84132-2101 
801-581-6393 
Amber.bledsoe@hsc.utah.edu 
 
 


 
2
Van Reese, M.S.  
VA Medical Center Bldg 2, 500 Foothill Drive, SLC UT 84148 
582-1565 ext. 4335; Van.reese@hsc.utah.edu 
 
Markus Amann, Ph.D. 
VA Medical Center Bldg 2, 500 Foothill Drive, SLC UT 84148 
582-1565 ext. 4335; markus.amann@utah.edu 
 
Joel D. Trinity, Ph.D. 
VA Medical Center Bldg 2, 500 Foothill Drive, SLC UT 84148 
582-1565 ext. 4335; joeltrinity@mail.utexas.edu 
 
D. Walter Wray, Ph.D. 
Department of Medicine, Division of Geriatrics, University of Utah and GRECC 
 George E. Whalen VA Medical Center 
500 Foothill Drive, Salt Lake City, UT 84148 
(858) 534-6967   
walter.wray@hsc.utah.edu 
 
Melissa A. H. Witman, Ph.D. 
VA Medical Center Bldg 2, 500 Foothill Drive, SLC UT 84148 
582-1565 ext. 4313 
melissa.hayman@utah.edu 
 
Ryan Garten, Ph.D. 
VA Medical Center Bldg 2, 500 Foothill Drive, SLC UT 84148 
582-1565 ext. 4313 
Rsgarten@gmail.com 
 
Jon Groot, B.S. 
VA Medical Center Bldg 2, 500 Foothill Drive, SLC UT 84148 
582-1565 ext. 4313 
wadodude@hotmail.com 
 
Matt Rossman, B.S. 
VA Medical Center Bldg 2, 500 Foothill Drive, SLC UT 84148 
582-1565 ext. 4313 
Matt.Rossman@utah.edu 
 
Song Young Park, B.S. 
VA Medical Center Bldg 2, 500 Foothill Drive, SLC UT 84148 
582-1565 ext. 4313 
Song.Park@utah.edu 
 
Jayson Gifford, B.S. 
VA Medical Center Bldg 2, 500 Foothill Drive, SLC UT 84148 
582-1565 ext. 4313 
jayson.gifford@utah.edu 
 
 
 
 


 
3
Maydeen Ogara, A.S., CRA, AGTS (Clinical Research Coordinator) 
VA Medical Center Bldg 2, 500 Foothill Drive, SLC UT 84148 
582-1565 ext. 1495 
maydeen.ogara@hsc.utah.edu 
 
Simran Sidhu, Ph.D. 
VA Medical Center Bldg. 2, 500 Foothill Drive, SLC UT 84148 
(801)582-1565 ext. 4313 
Simran.Sidhu@utah.edu 
 
Joshua Weavil, M.S. 
VA Medical Center Bldg. 2, 500 Foothill Drive, SLC UT 84148 
(801)582-1565 ext. 4313 
j.weavil@utah.edu 
 
Ashley Nelson, M.D. 
VA Medical Center Bldg. 2, 500 Foothill Drive, SLC UT 84148 
(801)582-1565 ext. 4313 
Ash.Nelson@hsc.utah.edu 
 
Tyler Mangum, B.S. 
VA Medical Center Bldg 2, 500 Foothill Drive, SLC UT 84148 
582-1565 ext. 4313 
T.mangum@utah.edu 
 
Josh Lee, Ph. D. 
VA Medical Center Bldg 2, 500 Foothill Drive, SLC UT 84148 
801-584-5658 
J.F.Lee@utah.edu 
 
Heather Clifton, Ph. D. 
VA Medical Center Bldg. 2, 500 Foothill Drive, SLC UT 84148 
582-1565 ext. 1949 
heather.clifton@utah.edu 
 
Daniel Machin, Ph. D. 
Internal Medicine 
VA Medical Center Bldg. 2, 500 Foothill Drive, SLC UT 84148 
801-582-1565 Ext. 4334 
d.machin@utah.edu 
 
 
Tracy Frech, M.D. 
Rheumatology 
4B200 School of Medicine, 30 N. 1900 E. 
Salt Lake City, UT  84132 
801-548-4837 
Tracy.Frech@hsc.utah.edu 
 
 
 
 


 
4
Mark Sievert, M.D.  
School of Medicine, 50 N. Medical Drive 
Salt Lake City, UT  84132 
608-215-2310 
Mark.sievert@hsc.utah.edu 
 
Anthony Donato, M.S. Ph.D. 
Geriatrics, VAMC 500 Foothill Drive 
Building 2, Room 1D30 
Salt Lake City, UT  84148 
801-582-1565 Ext 4237 
Tony.donato@utah.edu 
 
 
 
 
 
 
 


 
5
BACKGROUND AND INTRODUCTION: 
 
 
Heart failure (HF) is a serious condition where the heart is unable to fill or pump 
blood efficiently throughout the body in order to meet the body’s needs.  Typically, the 
heart becomes weakened as a result of progressive coronary artery disease or 
hypertension.  There are several different types of HF, including chronic and acute heart 
failure.  Common symptoms seen in patients with HF are fatigue, weakness, rapid or 
irregular heartbeat, dyspnea, persistent cough or wheezing, lack of appetite, and chronic 
or acute swelling of feet, ankles, legs, or abdomen.  HF most often effects older 
individuals that have one or more of the following risk factors: high blood pressure, 
coronary artery disease, myocardial infarction, irregular heartbeats, diabetes, congenital 
heart defects, sleep apnea, certain viruses, alcohol use, or some kidney conditions. 
There is no cure for HF and in the most severe stage; heart transplantation (HTx) is 
usually the best option. 
  
One of the primary criteria in diagnosis and severity of HF is the response to a 6-
min walk test, emphasizing the clear detrimental effect of this disease on the capacity for 
physical activity. Surprisingly, it is now well established that this cannot be attributed to a 
cardiac limitation, but rather is related to peripheral adaptations characteristic of the 
disease. Together, several recent studies have advanced the “muscle hypothesis”, 
which proposes that disease-related changes in ergoreceptor (metaboreceptor and 
mechanoreceptor) sensitivity in skeletal muscle collectively result in elevated muscle 
afferent activity that in turn further elevates sympathetic nerve activity (SNA) [1]. While 
the mechanism responsible for the adaptation is poorly understood, there is new 
evidence from animal studies that skeletal muscle oxidative stress may contribute to 
heightened ergoreceptor sensitivity [2]. Nonetheless, relative importance of metabolic 
versus mechanical receptors to this maladaptive process remains somewhat uncertain.  
As HF progresses, poor contractile function and the subsequent reduction in 
arterial blood pressure is corrected by the carotid and pulmonary baroreflexes. There is 
evidence both for [3] and against [4] disease-related changes in carotid baroreflex 
control of heart rate (vagus nerve) and of muscle sympathetic nerve activity (MSNA) in 
HF, by mechanisms which remain poorly understood. The arterial baroreflex typically 
buffers the muscle metaboreflex by limiting peripheral vasodilation, but in HF the loss of 
baroreflex sensitivity could contribute to the apparent metaborefelx sensitivity simply 
through decreased buffering capacity [5]. To our knowledge, the combined effects of 
altered baroreflex, chemoreflex, and mechanoreflex responses in HF have not been 
systematically studied in humans. 
Heightened SNA has been identified as a primary predictor of mortality in HF [6]. 
The consequence of this well described sympathoexcitation during exercise in HF 
patients may be a level of vasoconstriction in the exercising muscle that cannot be 
overcome, i.e. an impaired “functional sympatholysis”. However, to date, no attempt has 
been made to evaluate disease-related changes in alpha adrenergic sensitivity in this 
cohort. Further, if this disease does in fact infer a level of vasoconstriction that is 
restraining muscle blood flow during exercise, interventions that may limit this 
maladaptive process are of clear interest. One such intervention is exercise training, 
which reduces SNA in many experimental models of HF [7, 8]. Recent studies in HF 
patients have supported earlier animal work, demonstrating the ability of aerobic 
exercise training to restore SNA to that of young healthy controls [9]. To date, very little 
is known regarding the mechanism(s) and time course for the well-documented training-
induced improvements in SNA  
 
Vascular dysfunction has been documented in patients with HF [10], which 
includes the inability of vessels to respond to physiological stimuli such as increased 
blood flow and endothelium-dependent vasodilation [11]. Heart transplantation (HTx) 


 
6
results in a denervated heart. As a result the changes in cardiac output and heart rate 
normally triggered by changes in the sympathetic and parasympathetic tone are 
abolished or blunted.  
There has been increasing interest in vascular function as the health and 
elasticity of major arteries is a risk factor for various types of cardiovascular disease and 
has been suggested to “naturally” deteriorate with age.  In addition, there has also been 
increasing interest in isolating the physiological and mechanical contributors to the blood 
flow response, especially during exercise (exercise hyperaemia).  The examination of 
vascular function in patients with HF and following HTx maybe important with regards to 
the prevalence of cardiovascular disease in these populations. While the abnormal 
hemodynamic responses common in HF and HTx patients compared with healthy 
individuals may help to further explain the mechanisms behind vessel vasodilation and 
changes in blood flow at the onset of exercise. 
 
Oxidative stress is determined by the level of free radicals and the body’s 
antioxidant capacity.  High levels of vascular free radicals have been associated with 
many chronic diseases including heart failure, hypertension, atherosclerosis, diabetes, 
and the normal aging process [12].  With the presence of heart failure and the invasive 
nature of a heart transplantation it seems reasonable that ingesting an exogenous 
antioxidant cocktail (vitamins C, E, and alpha lipoic acid), used with efficacy by our group 
in the past [13-17], may decrease circulating levels of free radicals and may actually 
improve vascular function but the exact effects and potential mechanisms of action in 
this population are unknown. 
One mechanism by which the antioxidant cocktail improves vascular function, 
may be through preventing oxidation of tetrahydrobiopterin (BH4), a critical co-factor for 
the endothelial nitric oxide synthase enzyme, allowing greater NO bioavailability and less 
oxidative stress production [18]. Some suggest that loss of BH4 may be one of the 
precipitating factors inducing free radical production [19], and acute administration of 
BH4 alone has been demonstrated to improve vascular function in aged [20] and those 
with HF [21]. Although, evidence from the in vitro literature indicates there is a strong 
potential for synergy between BH4 and antioxidants [22], this has yet to be tested in 
humans if BH4, antioxidants, or BH4 + antioxidants are capable of improving vascular 
function in HF patients and age matched controls over placebo. 
 
  
OBJECTIVES: 
The objectives of this study are to provide greater insight into changes in muscle and 
cardiovascular function and exercise-induced hyperaemia associated with congestive 
heart failure (HF) and post-heart transplantation (HTx). 
 
 
Specific Aim 1: 
To examine vascular function and the subsequent exercise-induced hyperaemia in both 
healthy controls and patients having congestive heart failure and post-cardiac transplant. 
 
Hypothesis: There will be progressively reduced vascular function from the time of HTx 
through 10 years post-HTx. 
 
Hypothesis: HTx patients we will not see an increase in cardiac output with the initiation 
of passive exercise. 
 
Hypothesis: With the isolated limb passive movement model exercise induced 
hyperaemia will be significantly attenuated in the HTx patients and little to no 
hyperaemia will occur in the non-moving control leg. 


 
7
Hypothesis: The antioxidant cocktail will attenuate circulating levels of free radicals and 
may improve vascular function, both as assessed by flow-mediated vasodilation (FMD) 
and the passive movement protocol, but will be further improved with co-ingestion of 
BH4, over placebo, antioxidants, or BH4 alone. 
 
Specific Aim 2:  
To determine the extent to which muscle ergoreceptor (mechanoreceptor and 
metaboreceptor) and arterial baroreflex dysfunction is present in HF, to evaluate the 
interaction of these reflexes, and to identify which cardiovascular parameters are most 
affected by potential ergoreceptor and baroreceptor adaptations. 
 
Hypothesis: HF patients will exhibit greater mechanoreceptor and metaboreceptor 
sensitivity than age-matched controls, while carotid baroreflex sensitivity will be blunted 
in HF. This heightened ergoreceptor sensitivity in HF is due, in part, to blunted baroreflex 
sensitivity.     
 
Hypothesis: A reduction in oxidative stress, induced by either acute or chronic ingestion 
of the antioxidant cocktail, will reduce mechanoreceptor and metaboreceptor sensitivity 
in HF patients and not age-matched controls.  
 
Hypothesis: Chronic ingestion of and antioxidant cocktail, combined with the eNOS 
cofactor tetrahydrobiopterin (BH4), will reduce mechanoreceptor and metaboreceptor 
sensitivity in HF patients and not age-matched controls. 
 
Specific Aim 3:  
To determine whether exercise training can alter muscle ergoreceptor and carotid 
baroreceptor sensitivity in HF patients, and to characterize the time course for 
ergoreceptor- and baroreceptor-related changes.   
 
Hypothesis: Exercise training will reduce muscle ergoreceptor sensitivity and increase 
carotid baroreflex sensitivity if HF but not age-matched controls.         
 
Specific Aim 4: 
To determine the degree to which elevated SNS activity in expressed in the exercising 
muscle at rest and during aerobic exercise. 
 
Hypothesis: HF patients will exhibit a sustained response to infused adrenergic drugs 
during exercise compared to healthy controls, demonstrating “impaired functional 
sympatholysis” in the cohort. 
 
 
PARTICIPANT SELECTION CRITERIA: 
 
Inclusion criteria: 
 
Patients treated for heart failure (NYHA class I, II, or III) 
 
Patients who have undergone heart transplantation (HTx) 
 
Patients with Hypertension (HTN) 
 
Patients with Chronic Obstructive Pulmonary Disorder (COPD) 
 
Patients with Scleroderma 
 
Healthy controls of all ages 
 
 


 
8
Exclusion criteria: 
 
Age less than 18 years 
 
Patients unwilling or unable to give consent 
 
Subjects in whom the study procedures would not be recommended for medical 
reasons. This determination will be made by Dr. Stehlik, the physician directly 
responsible for the patient’s care. 
 
It is anticipated that patients who are currently hospitalized would not participate until 
released to outpatient care. 
 
NYHA class IV heart failure patients. 
 
Women who are pregnant.  
 
 
DESIGN: 
Procedures that are part of this study are strictly research-related and are not 
considered standard of care. This is a cross-sectional and short-term longitudinal study. 
Patients may be eligible to participate in the study several times (e.g. participation before 
and after transplant, participation at different time intervals after heart transplantation, 
participation in a training protocol), but are not required to do so. Patients may enroll in 
protocols 2, 3, or 4 any time after completion of protocol 1. However, after completing 
protocol 2, 3, or 4, patients must wait two months before enrolling in an additional 
protocol. Patients may also participate in protocol 3 (pre-training) or protocol 4 without 
agreeing to the exercise training portion of the study. The study procedures will include 
multiple visits to the laboratory in a fasted and rested state, as outlined below. 
Comparisons will be made between the healthy controls, HF, and HTx patients.   
 
STUDY PROCEDURES: 
The protocols that patients may choose to participate are outlined on the diagram below; 
   
 
 
 
 


 
9
STUDY PROCEDURES (continued): An overview of each visit to the laboratory, 
including chronology of each protocol, is listed on the following pages. This is followed 
by separate headings that provide details for the underlined techniques and 
measurements identified in each protocol, listed alphabetically. 
 
Preliminary Day 
A signed consent form will be obtained prior to any research procedures. Upon arrival to 
the lab (VA Bldg. 2, Room 1D21), a screening questionnaire will be filled out that will 
include questions concerning risks such as: age, family health history, smoking, 
hypertension, hypercholesterolemia, sleep-related breathing disorders, physical activity 
and allergies (iodine, latex, drugs, etc). A venous blood sample (4 ml) will be drawn from 
which a Metabolic Panel, Complete Blood Count (CBC), and a Lipid Panel will be 
assessed. Women of childbearing age will provide a urine sample for pregnancy testing, 
and will provide information concerning method of birth control. 
Following health history and blood sample, all subjects may be asked to perform 
several tasks to assess cognitive abilities and fitness levels and to wear a pedometer for 
a week, which will measure activity levels. All subjects will complete a series of exercise 
tests. Subjects will complete one or more of the following: a graded exercise test to 
volitional exhaustion (bike or treadmill, < 15 min), maximal handgrip test (1 min), 
maximal leg extension test (< 15 min), and maximal plantar flexion test (< 15 min). 
Sufficient recovery will be allowed between tests, an ECG will be assessed at all times. 
The PI will be present for all exercise tests, and a physician will be immediately available 
if needed.  
The handgrip, leg extension and plantar flexion graded exercise tests are 
considered low cardiovascular risk tests due to the recruitment of an isolated small 
muscle mass that results in minor cardiovascular stress. For all subjects these exercise 
tests will be conducted in the presence of the PI. In addition, a board certified physician 
(Dr. Kithas or Supiano) will be immediately available if needed.  
For the graded test to volitional exhaustion, exercise will be completed under 
physician supervision, and the subject will be monitored by an  ECG throughout the 
exercise test. Any abnormal ECG responses during the exercise test (overt arrhythmia, 
severe [3 mm] ST segment depression, elevated [1mm] ST segment in non-Q wave 
lead, frequent extra-ventricular systoles) or adverse responses such as chest pain, leg 
pain, or unsteadiness will serve as criteria to stop the test, in accordance with American 
Heart Association guidelines. Questionable findings will be referred to a cardiologist for 
inspection/diagnosis prior to further involvement in the protocol.  
 
PROTOCOL 1 (Acute Supplementation, 4 visits): 
 
On four separate visits, patients will take one of the following: placebo, antioxidants, BH4 
(10mg/kg), or BH4 + antioxidants, 2 hours prior to arrival in the lab in a balanced, double-
blind fashion. A member of the investigative team will provide these pills to subjects in 
bags labeled “A”, “B”, “C”, or “D” during the preliminary visit described above. These four 
visits will take place at least 48 hrs. apart, but are expected to be completed within 2 
weeks.Protocol 1 procedures: Subjects will report to the laboratory (VA bldg. 2 room 
1D21) at 0800 in a fasted state, having abstained from caffeine and exercise for the past 
12 hours. Upon arriving in the lab a venous blood sample (4 ml) will be drawn from 
which measures of oxidative stress and antioxidant capacity will be assessed. Following 
the blood sample, all subjects will have their height, weight, skin fold thickness and 
resting arterial blood pressure (ABP) recorded. Women of childbearing age will be asked 
to submit to a urine pregnancy test provided by the research site. Next, arterial stiffness 
measures will be completed. After lying quietly for an additional 20 minutes, the subject 


 
10
will undergo the flow mediated vasodilation (FMD) test in their arm (brachial artery). 
Nitroglycerin (NTG) will then be administered to evaluate endothelium-independent 
vasodilation. Two 
oral 
nitroglycerin 
tablets 
(0.8mg) 
will 
be 
administered 
sublinguilly.  Measurements will be made for 5 minutes.  Subjects will then rest 20-min to 
allow drug washout and restoration of steady-state hemodynamics. Following NTG, limb 
blood flow will be measured during four exercise protocols that utilize a single arm and 
single leg. First, the arm and leg will be passively moved through a normal range of 
motion (the participant will stay relaxed and try not to engage their muscles). Qualified 
personnel of the Vascular Laboratory will be supporting and moving the arm or leg for 
the participant. Next, an active exercise test will be performed, which requires that the 
participants give maximum effort for either the arm or leg by moving that appendage 
through a normal range of motion against some resistance. The arm or leg will be the 
only part of the body moving or producing any effort.  
 
PROTOCOL 2 (Chronic Supplementation, 7 visits): 
 
For this protocol, patients will be divided into four groups taking one of the following: (1) 
placebo, (2) antioxidants, (3) BH4 (10mg/kg), or (4) BH4 + antioxidants, one time daily for 
30 days. A member of the investigative team will provide these pills to subjects in bags 
labeled “A”, “B”, “C”, or “D” during the preliminary visit described above. Assignment to 
group will be balanced and both investigator and subject will be blinded to the group. 
Compliance for pill consumption will be monitored by an online database to which 
subjects will log in each day or a phone call if internet access is not available. 
 
Day 0: Subjects will report to the laboratory (VA bldg. 2 room 1D21) at 0800 in a fasted 
state, having abstained from caffeine and exercise for the past 12 hours. Upon arrival, 
women of childbearing age will submit toa urine pregnancy test, provided by the site, as 
part of the preliminary study process. Catheters will be placed in the arm (brachial artery 
and vein) or leg (common femoral artery and femoral vein) by a licensed physician using 
standard 
sterile 
technique. 
After 
instrumentation, 
an 
Arterial 
Elasticity 
Measurements/Pulse Contour Analysis (PCA) test will be performed immediately 
followed by a flow mediated vasodilation (FMD) test in the arm (brachial artery) or leg 
(popliteal artery). Following the FMD test, a muscle biopsy will be taken from the vastus 
lateralis of one leg. Next, two microelectrodes will be placed in the contralateral leg 
(popliteal fossa) for direct recording of muscle sympathetic nerve activity (MSNA). 
Subjects will rest for approximately 10 minutes, followed by resting measurements of 
arterial blood pressure (ABP), heart rate (HR), limb blood flow (LBF) (ultrasound 
Doppler), muscle sympathetic nerve activity (MSNA), and collection of resting blood 
samples.  
After resting measurements, baroreflex sensitivity will be assessed using both 
pharmacologic and direct techniques. Using the modified oxford technique, a series of 
I.V. pressor and depressor bolus drug infusions will be administered, and changes in 
ABP, HR, LBF and MSNA will be measured. After a 15-min recovery, carotid baroreflex 
sensitivity will be assessed directly using a neck chamber that provides localized 
distension or compression of the carotid artery, provoking small changes in carotid sinus 
pressure. This neck pressure/neck suction (NP/NS) technique will alter afferent carotid 
baroreflex activity, and again changes in ABP, HR, LBF, and MSNA will be measured. 
This will be followed by an additional 15-min recovery for return to a hemodynamic 
steady-state. 
Following baroreflex testing, muscle ergoreceptor sensitivity will be determined. 
Muscle mechanoreceptor sensitivity will be determined during 3-min of passive leg 
movement. This will be followed by muscle metaboreceptor sensitivity testing in both the 


 
11
arm and leg utilizing post-exercise circulatory occlusion (PECO). Three levels of arm 
(handgrip exercise) and leg (knee-extensor exercise) will be performed at 20, 40, and 
60% of maximal effort (3-min bout), with 2-min of PECO at the cessation of each 
exercise bout. During each of these exercise bouts, ABP, HR, LBF, and MSNA will be 
measured, and blood samples will be taken at each exercise intensity for blood gas 
analysis, and to assess the balance between antioxidants and oxidative stress across 
the leg.   
After a 15-min recovery, the PECO protocol described above will again be 
performed with superimposed carotid baroreflex testing (modified oxford technique) to 
assess potential metaboreceptor-baroreceptor interaction. 1-2 doses of both PE and 
SNP will be administered during the post-exercise cuff occlusion depending on the rate 
of blood pressure change during drug infusion. 
 
Days 10, 20, 30, 33 and 37: Following the baseline visits, subject will Patients will return 
to the lab five times after enrolling in the 30-day supplementation: days 10, 20, and 30, 
and two visits following discontinuation of the supplementation (days 33 and 37).  
 
On Day 30, subjects will repeat the “Day 0” protocol outlined above.  
 
Days 10, 20, 33, and 37 are non-invasive study days, with the following protocol;  
Subjects will report to the laboratory (VA bldg. 2 room 1D21) at 0800 in a fasted state, 
having abstained from caffeine and exercise for the past 12 hours. Upon arriving in the 
lab a venous blood sample (4 ml) will be drawn from which measures of oxidative stress 
and antioxidant capacity will be assessed. Following the blood sample, all subjects will 
have their height, weight, skin fold thickness and resting arterial blood pressure (ABP) 
recorded. Women of childbearing age will take a urine pregnancy test. Next, arterial 
stiffness measures will be completed. After lying quietly for an additional 20 minutes, the 
subject will undergo the flow mediated vasodilation (FMD) test in their arm (brachial 
artery). Following the FMD test, limb blood flow will be measured during four exercise 
protocols that utilize a single arm and single leg. First, the arm and leg will be passively 
moved through a normal range of motion (the participant will stay relaxed and try not to 
engage their muscles). Qualified personnel of the Vascular Laboratory will be supporting 
and moving the arm or leg for the participant. Next, an active exercise test will be 
performed, which requires that the participants give maximum effort for either the arm or 
leg by moving that appendage through a normal range of motion against some 
resistance. The arm or leg will be the only part of the body moving or producing any 
effort.  
 
 
PROTOCOL 3  
Pre-Training Protocol: 
Subjects will report to the laboratory (VA bldg. 2 room 1D21) at 0800 in a fasted state, 
having abstained from caffeine and exercise for the past 12 hours, and catheters will be 
placed in the arm (brachial artery and vein) or leg (common femoral artery and femoral 
vein) by a licensed physician using standard sterile technique. After instrumentation, an 
Arterial Elasticity Measurements/Pulse Contour Analysis (PCA) test will be performed, 
immediately followed by a flow mediated vasodilation (FMD) test in the arm (brachial 
artery) or leg (popliteal artery). Next, two microelectrodes will be placed in the 
contralateral leg (popliteal fossa) for direct recording of muscle sympathetic nerve 
activity (MSNA). Subjects will rest for approximately 10 minutes, followed by resting 
measurements of arterial blood pressure (ABP), heart rate (HR), limb blood flow (LBF) 


 
12
(ultrasound Doppler), muscle sympathetic nerve activity (MSNA), and collection of 
resting blood samples.  
After resting measurements, baroreflex sensitivity will be assessed using both 
pharmacologic and direct techniques. Using the modified oxford technique, a series of 
I.V. pressor and depressor bolus drug infusions will be administered, and changes in 
ABP, HR, LBF and MSNA will be measured. After a 15-min recovery, carotid baroreflex 
sensitivity will be assessed directly using a neck chamber that provides localized 
distension or compression of the carotid artery, provoking small changes in carotid sinus 
pressure. This neck pressure/neck suction (NP/NS) technique will alter afferent carotid 
baroreflex activity, and again changes in ABP, HR, LBF, and MSNA will be measured. 
This will be followed by an additional 15-min recovery for return to a hemodynamic 
steady-state. 
Following baroreflex testing, muscle ergoreceptor sensitivity will be determined. 
Muscle mechanoreceptor sensitivity will be determined during 3-min of passive leg 
movement. This will be followed by muscle metaboreceptor sensitivity testing in both the 
arm and leg utilizing post-exercise circulatory occlusion (PECO). Three levels of arm 
(handgrip exercise) and leg (knee-extensor exercise) will be performed at 20, 40, and 
60% of maximal effort (3-min bout), with 2-min of PECO at the cessation of each 
exercise bout. During each of these exercise bouts, ABP, HR, LBF, and MSNA will be 
measured, and blood samples will be taken (at each exercise intensity) for blood gas 
analysis and to assess the balance between antioxidants and oxidative stress across the 
leg.   
After a 15-min recovery, the PECO protocol described above will again be 
performed with superimposed carotid baroreflex testing (modified oxford technique) to 
assess potential metaboreceptor-baroreceptor interaction. 1-2 doses of both PE and 
SNP will be administered during the post-exercise cuff occlusion depending on the rate 
of blood pressure change during drug infusion. 
 
Exercise Training (12 weeks): 
Patients who agree to participate in the training portion of the study will report to the 
laboratory (VA Building 2 room 1D23) for 12 consecutive weeks (2-3 days per week, 1-2 
hours per visit) for supervised exercise training. Small muscle mass exercise will be 
performed so that high intensity training can be carried out without reaching 
cardiopulmonary limits to O2 transport, which is of critical importance when studying HF 
patients. Single-leg training will thus be utilized, using the knee-extensor exercise 
paradigm described below. Exercise intensity will be customized to the ability of each 
patient, and will be increased as tolerated every two weeks by re-assessing maximal 
power output in a conventional incremental test, to gain the greatest effect. A member of 
the research team will supervise all training sessions, and a physician will be 
immediately available if needed. Drs. Wray and Richardson have extensive experience 
with this exercise training protocol, including studies in the elderly, COPD and HF 
patients [13, 14, 23-33].     
 
 
 
Intra-training and Post-training Protocol (weeks 2, 4, 6, 8, 10, and 12): 
Patients will undergo bi-weekly assessment arterial elasticity, flow mediated vasodilation 
(FMD), muscle ergoreceptor sensitivity, and baroreflex sensitivity to track training-related 
improvements in muscle and cardiovascular parameters. The sequence and 
instrumentation will be identical to the pre-training protocol described above, with the 
following two exceptions; MSNA measurements will be made only at weeks 4, 8, and 12, 
and femoral catheters will be placed only at weeks 6 and 12. For experimental days that 


 
13
do not include femoral arterial and venous catheters, the antecubital vein will be 
catheterized. 
 
PROTOCOL 4 (6-8 hours per visit, 2 visits) 
 
Day 1 (Arm Protocol)  
Resting measurements (4 hours): Upon arrival to the lab, catheters will be placed in 
the non-dominant arm (brachial artery and basilica or cephalic vein) by a licensed 
physician. Following placement of catheters, intra-arterial infusion of Phenylephrine 
(PE), Dexmedetomidine (DEX), Tyramine (TYR), Phentolamine (PHEN), and Saline 
(control) will be performed in a randomized fashion. During the PHEN infusion, 
propranolol will be co-administered (I.V.) to prevent beta adrenergic tachycardia (control 
subjects only). Each drug infusion will last for approximately 15-min, and 20-min will be 
allotted between each infusion to allow drug washout and restoration of steady-state 
hemodynamic values.  
 
Exercising measurements (4 hours): Subjects will perform five bouts of incremental 
handgrip exercise at three intensities (30%, 45%, and 60% of MVC, four minutes per 
stage). During each exercise bout, either PE, DEX, TYR, PHEN, or Saline (control) will 
be administered in a randomized fashion. During the PHEN infusion, propranolol will be 
co-administered (I.V.) to prevent beta adrenergic tachycardia (control subjects only). For 
PE, DEX, and TYR, exercise will be performed for 3 min to reach steady-state, followed 
by 1-min of drug infusion. For the PHEN trial, drug will be administered continuously 
throughout the exercise protocol and compared to continuous Saline infusion. Each 
exercise bout will last approximately 12 minutes, with 30 minutes rest between exercise 
bouts.  
 
During both rest and exercise, arterial blood pressure, venous blood pressure, heart 
rate, and limb blood flow (ultrasound Doppler) will be measured continuously. An 
independent observer not involved in data collection will watch the electrocardiogram 
(EKG) and blood pressure monitors at all times to track the cardiovascular responses to 
exercise and drug infusions.  
 
Day 2 (Leg Protocol) 
Resting measurements (4 hours): Upon arrival to the lab, catheters will be placed in 
the femoral artery and vein by a licensed physician. Following placement of catheters, 
intra-arterial infusion of Phenylephrine (PE), Dexmedetomidine (DEX), Tyramine (TYR), 
Phentolamine (PHEN), and Saline (control) will be performed in a randomized fashion. 
During the PHEN infusion, propranolol will be co-administered (I.V.) to prevent beta 
adrenergic tachycardia. Each drug infusion will last for approximately 15-min, and 20-
min will be allotted between each infusion to allow drug washout and restoration of 
steady-state hemodynamic values.  
 
Exercising measurements (4 hours): Subjects will perform five bouts of incremental 
knee-extensor (KE) exercise at three intensities (25%, 50%, and 75% of KE max, four 
minutes per stage). During each exercise bout, either PE, DEX, TYR, PHEN, or Saline 
(control) will be administered in a randomized fashion. During the PHEN infusion, 
propranolol will be co-administered (I.V.) to prevent beta adrenergic tachycardia. For PE, 
DEX, and TYR, exercise will be performed for 3 min to reach steady-state, followed by 1-
min of drug infusion. For the PHEN trial, drug will be administered continuously 
throughout the exercise protocol and compared to continuous Saline infusion. Each 


 
14
exercise bout will last approximately 12 minutes, with 30 minutes rest between exercise 
bouts.  
 
During both rest and exercise, arterial blood pressure, venous blood pressure, heart 
rate, and limb blood flow (ultrasound Doppler) will be measured continuously. An 
independent observer not involved in data collection will watch the electrocardiogram 
(EKG) and blood pressure monitors at all times to track the cardiovascular responses to 
exercise and drug infusions.  
 
TECHNIQUES AND MEASUREMENTS 
 
Antioxidant Supplementation: Antioxidant or placebo will be consumed in two doses 
approximately 120 minutes and 90 minutes prior to the other procedures.  The first 
antioxidant dose at 120 minutes prior will include: Vitamin E 200 IU (1 tablet), Vitamin C 
500 mg (1 tablet), and Alpha-lipoic Acid 300 mg (3 tablets).  The second antioxidant 
dose approximately 90 minutes prior will include: Vitamin E 400 IU (water dispersable) (1 
tablet), Vitamin C 500 mg (1 tablet), and Alpha-lipoic Acid 300 mg (3 tablets).  The PI’s 
and Co-I’s have previously utilized this supplementation protocol in studies of both aging 
and disease and a very similar protocol when testing the ability of antioxidant 
supplementation to prevent free radical-mediated damage [14-16, 34-36]. 
 
Arterial Elasticity Measurements/Pulse Contour Analysis (PCA) test: Arterial 
elasticity will be measured using the HDI/Pulsewave™CR-2000 CardioVascular Profiling 
System (Hypertension Diagnostic, Inc., Eagan, Minnesota, USA).  The DO-2020 System 
records and analyzes the blood pressure waveform data from the Arterial PulseWave 
Sensor.  PCA measurements will be obtained in the morning following an overnight fast 
of at least eight hours and prior to engaging in any strenuous physical activity.  Following 
10 minutes of supine rest, large and small artery elasticity indices will be obtained.  A 
blood pressure cuff will be wrapped around the subject’s upper left arm, and a rigid 
plastic wrist stabilizer to minimize movement of the right wrist will be used during the 
PCA test.  With the right forearm in a supinated position, an Arterial PulseWave™Sensor 
will be placed on the skin directly over the radial artery at the point of the strongest 
pulse.  The sensor will be adjusted to the highest relative signal strength, and the large 
and small arterial elasticity measurements will be obtained during 30 seconds of blood 
pressure waveform collections.  In addition, other cardiovascular parameters will be 
recorded during this waveform collection, including pulse rate, systolic blood pressure, 
diastolic blood pressure, systemic vascular resistance, and total vascular impedance.  
Measurement will be obtained and averaged over three consecutive 30-second trials.  
This part of the procedures will last approximately 30 minutes.   
 
Blood sampling: As part of the preliminary screening, a venous blood sample (4 ml) will 
be drawn from all subjects for assessment of overall health (metabolic panel, complete 
blood chemistry, and lipid panel). On the experimental days, arterial and venous blood 
will be collected anaerobically with sterile syringes from the above-mentioned catheters 
at rest and during each exercise level for assessment of metabolic and aerobic status, 
and to test for markers of oxidative stress. For protocol 1, 15 ml of venous blood will be 
obtained. For protocol 2, one sample of arterial (4 ml) and venous (4 ml) blood will be 
taken at rest and during each level of arm and leg exercise. 
 
Catheter placement:  Prior to catheter placement, the subject will first be connected to 
a 3-lead ECG monitor. At each catheter insertion site, local anesthesia with lidocaine will 


 
15
be applied (1% lidocaine; 1.33mg/kg assuming 75 kg body weight, with an upper limit of 
10 ml). Sterile technique will be applied to minimize risk of infection. 1.0 mg of atropine 
will be available in case of sudden vagal reactions. The leg (femoral artery and vein, 
18G Cook Catheter or equivalent) will be cannulated by a qualified and privileged 
physician who will assume responsibility for the placement and removal of these 
catheters. Following catheter removal, wounds will be dressed and the subjects 
educated as to proper care. No subject will be released until hemostasis is clearly 
present.  Follow-up contact with the subject will continue over the following two days. It 
should be noted that the PI and Co-I’s of this proposal have significant experience with 
catheter-related studies [29, 30, 37-46], having coordinated the use and insertion of 
these exact catheters over a hundred times in the last ten years without incidence of 
bleeding, infection or tissue damage. In fact, several subjects have performed multiple 
studies with the PI, indicating the benign nature and positive outcome of the procedures. 
The PI and Co-I’s of this proposal have current University of Utah IRB approval for this 
procedure in elderly (IRB# 00030810) and COPD patients (IRB# 00032404).   
 
Flow-mediated vasodilation (FMD) test: A blood pressure cuff will be placed on the 
upper arm and inflated to >250 mmHg for five minutes to partially occlude the forearm. 
Ultrasound Doppler measurements will be made in the brachial artery to evaluate FMD 
upon cuff release. Dr. Richardson’s laboratory has direct experience with this technique 
[23].  
 
Limb Blood Flow: An ultrasound Doppler system (Logiq 7, GE Medical Systems, 
Milwaukee, Wisconsin, USA) equipped with two linear array transducers operating at an 
imaging frequency of 7-8 MHz and 12-14 MHz will be used for the leg and arm, 
respectively. Vessel diameter will be determined at a perpendicular angle along the 
central axis of the scanned area, where the best spatial resolution is achieved.  The 
brachial artery (BA) of the right arm will be insonated approximately midway between the 
antecubital and axillary regions, medial to the biceps brachii muscle. The blood velocity 
profile will be obtained simultaneously using the same transducers with a Doppler 
frequency of 4.0-5.0 MHz, operated in the high-pulsed repetition frequency mode (2-25 
kHz) with a sample depth of 1.5-3.5 cm  and the probe maintained at an insonation 
angle of 60° or less. Sample volume will be maximized according to vessel size and 
centered, verified by real-time ultrasound visualization of the vessel. Using artery 
diameter and Vmean, blood flow is calculated as: blood flow (ml/min) = Vmean · π · (Vessel 
Diameter/2)2 · 60. At all sample points, arterial diameter and angle-corrected, time-
averaged, and intensity-weighted mean blood velocity (Vmean) values can be calculated 
using commercially available software (Logiq 7). Ultrasound digital images and velocity 
spectra segments of five minutes will be recorded and saved to the GE Logiq 7 hard 
drive for off-line image and waveform analysis. Dr. Richardson’s laboratory has 
extensive experience with this methodology [23, 28, 40, 47, 48]. 
 
Modified Oxford Technique: Carotid baroreflex sensitivity will be determined by 
assessing HR responses to an increase or decrease in arterial blood pressure evoke by 
I.V. phenylephrine (PE) and sodium nitroprusside (SNP), respectively. Drugs will be 
administered sequentially intended to provoke a 10-15 mmHg change in blood pressure 
(PE 100-150 µg; SNP 50-150 µg). These drugs are considered to be investigational by 
the FDA, and thus an investigational new drug (IND) number has been issued to the PI 
(IND#108367). This technique has been utilized extensively in a research setting to 
determine baroreflex sensitivity in HF [49]. 
 


 
16
Muscle biopsy: All biopsies will be taken from the vastus lateralis approximately 3.5 cm 
deep, 15 cm proximal to the knee and slightly distal to the ventral mid-line of the muscle.  
The 5 mm diameter biopsy needle (Bergstrom) is attached to sterile tubing and a syringe 
to apply a negative pressure to assist in the muscle sample collection [50]. Lidocaine 
(2%) will be used as local anesthetic. The muscle samples from each biopsy will be 
immediately frozen in liquid nitrogen and stored at -80oC for future microscopy, EPR 
spectroscopy, molecular and biochemical assays or immersion-fixed in gluteraldehyde 
for EM analysis. With our current technique and experience, utilizing 2-3 passes of the 
needle and double cut, we are able to attain as much as 300-400 mg of muscle which 
will permit the performance of all proposed analyses. The Principal Investigator has 
been involved in over 100 of these procedures with no negative outcomes [31-33, 46, 
51], and currently holds VA credentialing and IRB approval for this procedure in both 
COPD patients and control subjects (IRB#00032404, “Mechanisms of Adaptation to 
Exercise in Health and COPD”). Additionally, in support of this technique, a series of 
subjects recently underwent 5 biopsies each over a period of time, illustrating that the 
biopsy experience is acceptable to the subjects.  
 
Muscle sympathetic nerve activity: Postganglionic muscle sympathetic nerve activity 
(MSNA) will be recorded with standard microneurographic techniques. In the right leg, 
low-voltage (3-4 Volts) stimuli will be applied to the skin behind the knee using a pencil-
shaped electrode. Stimuli will be applied intermittently (i.e. 1 stimulus every 15 seconds) 
for approximately two minutes to map the path of the nerve. This procedure will cause 
light muscle twitching of the foot. Once the nerve path is identified, two very small 
tungsten microelectrodes (1-4 micrometers) will be inserted into the skin. The first 
electrode will be inserted 2-3 cm distal to the nerve map and acts as a reference, and 
the second electrode will be inserted near the fibular head and advanced until it reaches 
the peroneal nerve (1-2 cm). This electrode will be used for recording only. MSNA 
recordings display a pulse-synchronous burst pattern and an increase in burst frequency 
with end-expiratory breath hold and Valsalva maneuver, but with no response to startle 
or skin stroking. These characteristics will be used to determine proper electrode 
placement for the MSNA recordings. One of the co-investigators (Dr. Wray) is trained in 
microneurography and routinely performs this procedure under IRB # 00030810, 
“Vascular Function in Health and Disease”. 
 
Neck Pressure/Neck Suction (NP/NS): Graded levels of pressure and suction will be 
generated by a variable pressure source and delivered through solenoid valves to a 
custom-made neck chamber that encompasses the anterior 2/3 of the neck, creating an 
air-tight seal around the neck. The application of neck pressure (NP) increases pressure 
within the neck chamber that compresses the carotid baroreceptors and causes a 
decrease in carotid sinus transmural pressure, thereby exposing the carotid 
baroreceptors to a mild hypotensive stimulus. Neck suction (NS) stretches the carotid 
baroreceptors and causes an increase in carotid sinus transmural pressure that 
effectively delivers a mild hypertensive stimulus to the carotid baroreceptors. Baroreflex 
sensitivity will be assessed by measuring changes in HR, ABP and MSNA during 2–4 
trials of random ordered single 5 s pulses of NP (+40 and +20 Torr) and NS (-20, -40, -
60, and -80 Torr), or through the rapid pulse train NP/NS protocol (12 consecutive, ECG-
triggered 500 ms pulses of NP and NS ranging from +40 to -80 Torr). Dr. Wray has 
extensive training using the neck collar and NP/NS protocol [52-56].  
 
Non-invasive arterial blood pressure: Systemic arterial blood pressure (ABP) will be 
measured non-invasively on a continuous basis using finger photoplethysmography 
(Finometer, Ohmeda, Madison, WI, USA). The finometer cuff is placed on the middle 


 
17
finger of the right hand and is supported on a modified surgical stand adjusted to 
position the finger cuff at heart level. 
 
Exercise: Passive leg movement will be performed by a member of the research team 
moving the subject’s leg through a normal range of motion (90°- 180°).  
 
Active leg exercise will be performed using a custom-built knee-extensor ergometer with 
the subject moving the leg between 90°- 180°.  
 
Plantar flexion exercises will be performed using an ergometer specifically designed to 
isolate the gastrocnemius and the soleus complex.  
 
Arm exercise will involve rhythmic handgrip using a computer-interfaced dynamometer.   
 
Each of these exercise modalities are small muscle mass and therefore only minimally 
tax the heart and lungs, even at maximal efforts [57].  All exercise testing will be 
completed in the VA Medical Center Building 2 room 1D23. 
 
Post-Exercise Circulatory Occlusion (PECO): To active afferent muscle fibers that are 
sensitive to exercise-induced metabolites, supra-systolic (220-240 mmHg) circulatory 
occlusion of the exercised limb will be applied upon cessation of the 3-min exercise bout. 
This will be achieved through inflation of a modified blood pressure cuff placed on either 
the arm (upper arm, immediately proximal to elbow) or leg (upper thigh) for 2-min. This 
procedure is used routinely in a clinical research setting, including studies involving HF 
[58].  
 
STUDY DRUGS: The overall objective of all drug infusions for this protocol is to achieve 
maximal receptor occupancy in the limb while avoiding spillover of the drug into the 
systemic circulation. All drug doses have been determined using previously published 
ranges, and are calculated per 100 ml (e.g. dl) limb volume. All drug preparation, 
dispensing, and disposal will be handled by the VAMC SLC Inpatient Pharmacy. All 
drugs have been approved by the FDA for use in the manner described herein 
(IND#113,067). 
 
1. Phenylephrine (PE): At rest, PE will be administered in five doubling doses (0.03-
0.06-0.12-0.24-0.48 mcg/dl/min, 2-min per dose) to establish a dose-response for 
PE-induced vasoconstriction. During exercise, PE will be administered at 0.24 
mcg/dl/min, and adjusted for the exercise-induced increase in limb blood flow. 
The method for determining this dose range is based on previously published 
studies [40, 59].    
 
2. Dexmedetomidine (DEX): At rest, DEX will be administered in five doubling 
doses (1.5-3-6-12-24 ng/dl/min, 2-min per dose) to establish a dose-response for 
DEX-induced vasoconstriction. During exercise, DEX will be administered at 6 
ng/dl/min, and adjusted for the exercise-induced increase in limb blood flow. The 
method for determining this dose range is based on previously published studies 
[60, 61]. 
 
3. Tyramine (TYR): At rest, TYR will be administered in five doubling doses (2-4-8-
16-32 mcg/dl/min, 2-min per dose) to establish a dose-response for DEX-induced 
vasoconstriction. During exercise, TYR will be administered at 8 mcg/dl/min, and 


 
18
adjusted for the exercise-induced increase in limb blood flow. The method for 
determining this dose range is based on previously published studies [62-65].    
 
4. Phentolamine (PHEN): At rest, PHEN will be administered in three doubling 
doses (5-10-20 mcg/dl/min) to establish complete alpha adrenergic blockade. 
During exercise, PHEN will be administered at 5 mcg/dl/min, and adjusted for the 
exercise-induced increase in limb blood flow. The method for determining this 
dose range is based on previously published studies [66-70]. 
 
5. Propranalol: At rest and during exercise, propranolol (a non-selective beta 
adrenergic antagonist) will be administered intravenously for 5-min (0.15 mg/kg, 
max 10 mg) prior to PHEN infusion to limit the possibility of beta adrenergic 
tachycardia during PHEN administration. This infusion will be administered only 
in control subjects, as the HF patients all receive beta-blocking drugs as part of 
their optimized pharmacotherapy. 
 
6. Kuvan (BH4): will be administered at a dose of 10 mg/kg body weight. 
 
7. 
Nitroglycerin (NTG): will be administered to evaluate endothelium-independent 
vasodilation in the  arm and leg.  Two oral nitroglycerin tablets (0.8mg) will be 
administered sublinguilly.  Measurements will be made for 5 minutes.  Subjects 
will then rest 20-min to allow drug washout and restoration of steady-state 
hemodynamics. 
 
 
 
 
POTENTIAL RISKS 
Catheter-related risks.  There is also the possibility of fainting, dizziness, and possible 
pain and bruising as a result of catheter insertion. There is a risk of infection, swelling, and 
discomfort at the insertion sites, and a risk that bleeding may occur after catheters 
removal. A clot or excessive bleeding at the puncture site could result in a partial 
blockage of the blood flow to the arm or leg, which in extreme cases could lead to loss of 
the limb. These risks are minimized by careful patient selection, catheter insertion by a 
physician with experience using proper equipment and sterile methods, adequate 
pressure for >30 minutes following catheter removal, and appropriate patient education 
and follow-up. The PI and several CO-I’s named herein have significant cumulative 
experience in this areas, having been involved in several hundred successful catheter-
based studies with no instances of bleeding, infection, femoral vein thrombosis or soft 
tissue damage as a result of the procedures proposed. 
 
Drug Infusion Risks: At higher intra-arterial doses, the risk exists for significant spillover 
of the drug into the systemic circulation resulting in acute changes in arterial blood 
pressure. Thus, during the higher limb blood flow which occurs during exercise, blood 
pressure will be closely monitored, and infusions will be discontinued if acute 
hypertension is observed (>15 mmHg rise in systolic or diastolic pressure). The 
proposed doses for all drugs included in this protocol have been demonstrated to act 
locally, with minimal systemic effects. The PI and CO-I’s on this protocol have extensive 
experience with intra-arterial drug infusions, and routinely perform infusion studies 
identical to those described above in a concurrent IRB-approved project (IRB#30810, 
“Vascular Function in Health & Disease”).    
 


 
19
Phenylephrine (PE): Systemic doses of PE may cause headache, reflex bradycardia, 
excitability, restlessness and rarely arrhythmias, and is contraindicated in patients with 
severe hypertension, ventricular tachycardia, or in patients who are hypersensitive to it 
or to any of the components. If used in conjunction with oxytocic drugs, the pressor 
effect of sympathomimetic pressor amines is potentiated. The obstetrician should be 
warned that some oxytocic drugs may cause severe persistent hypertension and that 
even a rupture of a cerebral blood vessel may occur during the postpartum period. PE 
contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including 
anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain 
susceptible people. The overall prevalence of sulfite sensitivity in the general population 
is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic 
than in nonasthmatic people. Phenylephrine hydrochloride should be employed only with 
extreme caution in elderly patients or in patients with hyperthyroidism, bradycardia, 
partial heart block, myocardial disease or severe arteriosclerosis. The pressor effect of 
sympathomimetic pressor amines is markedly potentiated in patients receiving 
monoamine oxidase inhibitors (MAOI). Therefore, when initiating pressor therapy in 
these patients, the initial dose should be small and used with due caution. The pressor 
response of adrenergic agents may also be potentiated by tricyclic antidepressants. 
 
Dexmedetomidine (DEX): Systemic doses of DEX may cause acute hypotension and 
bradycardia. Because systemic DEX decreases sympathetic nervous system activity, 
hypotension and/or bradycardia may be expected to be more pronounced in patients 
with hypovolemia, diabetes mellitus, or chronic hypertension and in elderly patients. 
There are no published contraindications. 
 
Tyramine (TYR): Systemic doses of TYR may produce acute hypertension and a reflex 
bradycardia. There are no published contraindications. 
 
Phentolamine (PHEN): Systemic doses of PHEN may cause acute and prolonged 
hypotensive episodes, tachycardia, and cardiac arrhythmias. In addition, weakness, 
dizziness, flushing, orthostatic hypotension, nasal stuffiness, nausea, vomiting, and 
diarrhea may occur. Myocardial infarction, cerebrovascular spasm, and cerebrovascular 
occlusion have been reported to occur following the administration of phentolamine, 
usually in association with marked hypotensive episodes. Systemic PHEN administration 
is contraindicated in patients with myocardial infarction, coronary insufficiency, angina, 
or other evidence suggestive of coronary artery disease; hypersensitivity to 
phentolamine or related compounds. 
 
Propranolol: Contraindicated in patients with cardiogenic shock, sinus bradycardia and 
greater than first degree block, bronchial asthma, and in patients with known 
hypersensitivity to the drug. Systemic doses of propranolol may cause bradycardia and 
hypotension.   
 
Nitroglycerin (NTG): is contraindicated in patients with early myocardial infarction, 
severe anemia, increased intracranial pressure, and those with a known hypersensitivity 
to nitroglycerin. Sublingual NTG is also contraindicated in patients who are using a 
phosphodiesterase-5 (PDE-5) inhibitor (e.g., sildenafil citrate, tadalafil, vardenafil 
hydrochloride).  
 
Myocardial ischemia, infarction, arrhythmia, and death during exercise.  This should be 
uncovered in the non-invasive initial testing of each subject, and if found the subject will 
be excluded and referred to his/her physician.  The responses to absolute and relative 


 
20
indications for the termination of an exercise test are variable depending upon the 
finding. However, an incident of ischemia presented as chest pain, shortness of breath, 
acute hypotension (<80/40 mmHg), or abnormal ECG findings (>2-3 mm ST depression 
or appearance of S3 or S4 heart sounds) would result in the immediate termination of 
exercise. The subject would be placed in a supine position, administered oxygen and 
assessed by the on site physician and research staff. If the condition did not improve or 
worsened either 911 or the Code Team would be called dependent upon the location. In 
all cases this occurrence would be documented and the subject would ultimately be 
referred to their physician. Cardiac function will be monitored during all exercise studies 
with an ECG monitor. 
 
Microneurography: The nerve recording procedure occasionally may result in the leg 
muscles feeling tired one or two days after the experiment, a pins-and-needles feeling 
(paresthesia), or a greater sensitivity to touch in the leg.  However, since 1979, 
microneurography has been performed on several thousand subjects in the U.S. and 
abroad without any lasting complications. Dr. Wray has performed microneurography in 
many subjects without persistent complications. Many subjects volunteer repeatedly for 
microneurographic studies, indicative of the benign nature of this technique. 
 
Muscle biospy risks: Using sterile technique and a minimal skin incision (about 1/8”) over 
the anterolateral mid-thigh, the standard needle aspiration method for muscle biopsy has 
not produced bleeding nor infectious complications to date. There is the possibility of a 
small scar the size of the incision (1/8”). No subject is released until hemostasis has 
been secured, and the skin site dressed. Subjects are always carefully instructed in the 
routine prevention of infection and bleeding of biopsy sites. As lidocaine is used as the 
anesthetic there is the risk of toxicity, however the low concentration 0.5% and the use 
of less than 10-15 ml greatly reduces this concern. 
 
Neck Pressure/Neck Suction (NP/NS): There are no reports in the medical literature 
evaluating the risks of NP/NS in either patients or healthy control subjects. However, 
there are over 100 studies indexed in the NLM PubMed database (keyword search 
“neck”; “suction”; “heart rate”) that have used the NP/NS technique safely and 
effectively, with no report of catastrophic events such aortic dissection or stroke. 
Included among these are eight published studies from four independent labs which 
have utilized the technique in heart failure patients [71-78]. The nature of the NP/NS 
technique is somewhat similar to carotid sinus massage, providing some framework for 
risk assessment. Contraindications for carotid sinus massage are the presence of a 
carotid bruit, a known carotid stenosis >50%, and a history of myocardial infarction or 
stroke within the preceding 3 months. These contraindications will serve as exclusion 
criteria for participation in the NP/NS portion of the study, and in these patients, only the 
modified oxford technique will be used to assess baroreflex sensitivity. Further, 
ultrasound Doppler of the carotid artery and physical exam will be performed in all 
patients during the preliminary visit to the laboratory to identify as-yet undiagnosed 
carotid stenoses and bruits, respectively. If any significant plaque is identified during 
these exams, only the modified Oxford test will be performed for assessment of 
baroreflex function.  
 
Pregnancy Risks: The risks for some of the procedures included in protocols 2 and 3 to 
an unborn fetus are not known. Thus, if participant is pregnant, they may not participate 
in these protocols. If participant is not pregnant, but of childbearing age, they must use 
appropriate contraceptives to prevent pregnancy while participating in these protocols. 
Participants will be asked to submit to a urine pregnancy test provided by the research 


 
21
site. Should participants become pregnant while enrolled, they will be withdrawn from 
the study. 
 
Participation in multiple protocols: Each protocol is associated with the risks outlined 
above. However, there is no known accumulative risk associated with participation in 
multiple protocols.   
 
STATISTICAL METHODS, DATA ANALYSIS AND INTERPRETATION: 
 
Protocol 1: The data collected in this study will examine the effects of cardiac 
transplantation on vascular function and exercise hyperaemia. The cross-sectional data 
will be analyzed using student’s t-tests and analysis of variance (ANOVA). A repeated-
measure ANOVA will be performed on all longitudinal data collected. Correlations will be 
performed on all the data. A priori power analysis will be performed, but previous studies 
suggest that approximately 20 subjects per study group will be necessary to achieve 
adequate power with the expected effect size.  
 
Protocols 2, 3 and 4: A total of 80 subjects (40 with heart failure NYHA class I-III and 
40 age-matched controls) will be recruited for the protocols outlined above. With the 
stringent restrictions and pre-screening processes outlined above, we estimate a 6:1 
ratio of those interested in participating to those who are ultimately deemed eligible. 
Further, we estimate a dropout rate of 10%, which may increase for subjects who agree 
to participate in multiple protocols. We have taken these issues of subject recruitment 
and adherence into account in the overall experimental design, such that the protocols 
with the proposed sample size are attainable within the timeline of the proposed project.  
 
The experimental design and statistical analyses have been developed with an 
emphasis upon the focused and well powered testing of the primary hypotheses, but 
guided by the parallel intent to minimize subject burden and study costs. The proposed 
sample size (n = 80) is based upon power analyses of preliminary data for primary 
measurements such as HR, ABP, MSNA, and blood flow. To ensure the recognition of 
even smaller differences than those observed in preliminary data, we will study 40 
subjects per group, resulting in >90% power. Statistical analyses will include 
independent statistics (ANOVA and non-paired t-tests) to examine the differences in the 
cross-sectional comparisons (i.e. HF vs. age-matched controls). Two or three-way 
repeated measures ANOVA will be utilized to identify between group differences in these 
outcome measurements during multiple levels of exercise (i.e. PECO test) and during 
multiple levels of baroreflex stimulation. In addition, each specific aim will routinely utilize 
regression analyses to assist in the interpretation of the data collected. Although some 
multivariate measurements are being made and such an approach will likely require the 
characterization of covariation patterns, our initial approach will be predominantly 
univariate. This design will be aided by the detailed subject screening and subject 
selection which minimizes the number of covariates by, where possible, equally 
distributing variables across groups (e.g. gender, activity level, etc.). However, 
secondary covariate analyses will be performed that determine the role of measured 
variables that are not driven by age or disease state, but do exert an influence upon the 
major dependent variables.  
 
Clinical Records: Patient demographics (DOB, gender, height, weight), past medical 
history, medication use, and results of cardiovascular tests (echocardiogram, 
catheterization, stress test) will be collected. 
 


 
22
The following procedures are in place in the Vascular Laboratory to assure safety 
of research participants: 
1. 
Properly trained personnel will monitor all exercises to ensure they are 
performed correctly. 
2. 
The blood draws will be performed by a certified phlebotomist/registered 
nurse, who is familiar with all disease transmission safeguards and emergency 
procedures, should a problem arise. 
3. 
Blood pressure cuffs will only be inflated to obtain the necessary 
measurements, and will be deflated immediately afterwards. 
4. 
Immediate emergency – call 911, as typically employed at the Salt Lake 
City VA Medical Center that are not covered by the code team from the hospital. 
5. 
A crash cart and defibrillator are maintained in the laboratory. 
 
The following procedures are in place in the Vascular Laboratory to protect 
sensitive subject information: 
1. 
The laboratory is kept locked when there are no lab personnel present. 
2. 
The Logic 7 is turned off when not in use for vascular analyses.  The 
computer is password protected and only the investigators related to this project 
know the password. 
3. 
Hard copies of subject information will be kept in a locked file cabinet in 
Dr. Richardson’s office. Any electronic copies will be kept on a password secured 
computer. 
4. 
Subjects are given copies of their measurements upon request. 
5. 
Each subject will be identified by code numbers.  These numbers will be 
used in a statistical spreadsheet while all statistical analyses are performed.  The 
maximal length of storing this information is 5 years, upon which it will be 
destroyed.  
 
ADMINISTRATIVE RESPONSIBILITIES:  
 
Facilities and Equipment: All protocols will be conducted in the state-of-the-art Human 
Vascular Laboratory at the VA Medical Center, Building B, room 1D23. The laboratory 
measures 600 sq ft in size, and is more than adequate to house these studies. This 
laboratory contains all equipment necessary to complete the proposed work, including: 
Three adjustable hydraulic gurneys; Three ultrasound Doppler system (Logiq 7 and 
Logiq I, GE Medical Systems, Milwaukee, Wisconsin, USA) for determination of limb 
blood flow and vasodilation; A Finger photoplethysmograph (Finometer, Ohmeda, 
Madison, WI, USA) for measurements of arterial blood pressure; A metabolic cart (O2 
consumption) with spirometer (pulmonary function testing); (A 12-lead ECG; A “crash-
cart” and defibrillator; Several custom-built ergometers specifically designed for knee-
extensor, plantar flexion, handgrip, and cycling exercise; and several PC-based work 
stations for data acquisition and analysis. All research records and collected samples will 
be housed in a locked structure in this laboratory.  
 
Recruitment: All cardiac transplant subjects in this study will be volunteers recruited 
through the VA hospital and University of Utah Cardiac Transplant Program, though 
printed advertisement or physician referral. In the case of physician referral, patients 
who are deemed eligible for the study will be referred to the study coordinator to gather  
further information – the physician will not provide patients with a detailed description of 
the study. The healthy control subjects will be recruited by printed advertisement, 
physician referral, and word of mouth around the VA hospital and the University of Utah.  
 


 
23
Subject payment will be as follows: 
 
Preliminary Day: Subjects will be paid $20 upon completion.   
 
Protocol 1: Subjects will be paid $100 upon completion of the four visits, $15/hr pro-rate.  
 
Protocol 2: Subjects will be paid $300 ($15/hr pro-rate) upon completion of the chronic 
supplementation regimen. 
 
Protocol 3: Subjects may choose to participate only in the pre-training portion of the 
study, or enroll in the exercise training program.  
 
Subjects who do not enroll in the exercise training portion of the protocol will 
receive a total of $100 upon completion of the “pre-training” visit, $15/hr pro-rate. 
 
Subjects who enroll in the exercise training portion of the protocol will be paid 
$500 ($15/hr. pro-rate) upon completion of the exercise training  
 
Protocol 4: Subjects will be paid $150 per visit, two visits required.  
 
Data Safety & Monitoring: 
 
Although there are risks associated with the proposed studies, these risks are 
considered minimal. Nonetheless, in the interest of participant safety and to ensure 
compliance with IRB and FDA regulations, we propose the implementation of a data 
safety and monitoring group. Four members of the Utah Vascular Research Lab faculty 
(Drs. Richardson, Amann, Trinity and Wray), Mark Supiano, M.D., Micah Drummond, 
Ph.D., Alan Light, Ph.D., Jacob Jessop, D.O. and Dorothea Rosenberger, M.D. will 
make up the monitoring group, all of whom are affiliated with research at the University 
of Utah and the SLC VA. These members will meet on a quarterly basis, and, in the 
interim, the board will convene in response to any adverse events or unanticipated 
problems associated with the proposed studies.  
In order to meet the regulatory requirements of 21 CFR 312.56 regarding 
monitoring for compliance with federal regulations, thereby ensuring data quality and 
that the rights, safety and welfare of study subjects are adequately protected, this study 
will include a provision for internal monitoring by an independent qualified reviewer. The 
PI will identify a qualified reviewer and present the name of the proposed reviewer to the 
DSMB for approval. The reviewer will monitor all aspects of the study for compliance 
with federal regulations and Good Clinical Practices after the first three (3) subjects have 
been enrolled.  
The reviewer will provide a written summary of findings which will be presented 
to the DSMB at the next meeting. Corrective actions indicated will be followed by the 
DSMB at subsequent meetings and documented in the minutes. If indicated, the DSMB 
will require additional monitoring. Also, if indicated, any protocol deviations or violations 
will be reported the IRB with appropriate corrective action described and a preventative 
action plan outlined to avoid recurrence.  
If follow-up monitoring is not indicated, there will be a final monitoring visit after 
the last subject has been enrolled but prior to study close-out. As above, a written 
summary of findings will be provided to the DSMB for any appropriate action prior to 
DSMB authorization of study closure. This final monitoring report will be provided to the 
IRB as part of the Final Report in ERICA. 
 
All subjects participate on a strictly voluntary basis, and thus any protocol may be 
stopped at any time and for any reason at the subject’s request. Additional criteria to 


 
24
discontinue a protocol will be any evidence that the subject’s health is at risk, as 
identified by a member of the investigative team. Subject safety is at the forefront of all 
studies, and for this reason all investigators are trained to identify overt (i.e. abnormal 
ECG patterns, acute change in blood pressure, etc.) and more subtle (i.e. skin pallor or 
redness, changes in subject demeanor, etc.) signs that a subject may be adversely 
affected by the experimental interventions. Adverse events and unanticipated problems 
are broadly defined as any instance of a medical complication arising from catheter 
insertion (i.e. excessive bleeding and swelling at insertion site) or drug infusion (i.e. 
acute hypertension, bradycardia, etc.) as listed under the “potential risks” section below.  
In the instance of an adverse event, the protocol will be discontinued and the 
study will be temporarily suspended while DSMB members will review the cause of the 
event. When appropriate, unanticipated adverse events will be reported within 10 
working days, in accordance with the University of Utah IRB Reporting Policy.  
 
 
IND Regulations for Data Safety & Monitoring: 
As a sponsor of an IND, we are additionally responsible for reporting protocol deviations, 
violations, and adverse events to the FDA, which will be implemented in compliance with 
the Code of Federal Regulation (21CFR312.32, b – e), as follows; 
(b) Review of safety information. The sponsor shall promptly review all information 
relevant to the safety of the drug obtained or otherwise received by the sponsor from any 
source, foreign or domestic, including information derived from any clinical or 
epidemiological investigations, animal investigations, commercial marketing experience, 
reports in the scientific literature, and unpublished scientific papers, as well as reports 
from foreign regulatory authorities that have not already been previously reported to the 
agency by the sponsor. 
(c) IND safety reports --(1)Written reports --(i) The sponsor shall notify FDA and all 
participating investigators in a written IND safety report of: 
(A) Any adverse experience associated with the use of the drug that is both 
serious and unexpected; or 
(B) Any finding from tests in laboratory animals that suggests a significant risk for 
human 
subjects 
including 
reports 
of 
mutagenicity, 
teratogenicity, 
or 
carcinogenicity. Each notification shall be made as soon as possible and in no 
event later than 15 calendar days after the sponsor's initial receipt of the 
information. Each written notification may be submitted on FDA Form 3500A or in 
a narrative format (foreign events may be submitted either on an FDA Form 
3500A or, if preferred, on a CIOMS I form; reports from animal or epidemiological 
studies shall be submitted in a narrative format) and shall bear prominent 
identification of its contents, i.e. , "IND Safety Report." Each written notification to 
FDA shall be transmitted to the FDA new drug review division in the Center for 
Drug Evaluation and Research or the product review division in the Center for 
Biologics Evaluation and Research that has responsibility for review of the IND. If 
FDA determines that additional data are needed, the agency may require further 
data to be submitted. 
(ii) In each written IND safety report, the sponsor shall identify all safety 
reports previously filed with the IND concerning a similar adverse 


 
25
experience, and shall analyze the significance of the adverse experience 
in light of the previous, similar reports. 
(2)Telephone and facsimile transmission safety reports. The 
sponsor shall also notify FDA by telephone or by facsimile 
transmission 
of 
any 
unexpected 
fatal 
or 
life-threatening 
experience associated with the use of the drug as soon as 
possible but in no event later than 7 calendar days after the 
sponsor's initial receipt of the information. Each telephone call or 
facsimile transmission to FDA shall be transmitted to the FDA new 
drug review division in the Center for Drug Evaluation and 
Research or the product review division in the Center for Biologics 
Evaluation and Research that has responsibility for review of the 
IND. 
(3)Reporting format or frequency. FDA may request a sponsor to 
submit IND safety reports in a format or at a frequency different 
than that required under this paragraph. The sponsor may also 
propose and adopt a different reporting format or frequency if the 
change is agreed to in advance by the director of the new drug 
review division in the Center for Drug Evaluation and Research or 
the director of the products review division in the Center for 
Biologics Evaluation and Research which is responsible for review 
of the IND. 
(4) A sponsor of a clinical study of a marketed drug is not required 
to make a safety report for any adverse experience associated 
with use of the drug that is not from the clinical study itself. 
(d) Followup. 
(1) The sponsor shall promptly investigate all safety information received by it. 
(2) Followup information to a safety report shall be submitted as soon as the 
relevant information is available. 
(3) If the results of a sponsor's investigation show that an adverse drug 
experience not initially determined to be reportable under paragraph (c) of this 
section is so reportable, the sponsor shall report such experience in a written 
safety report as soon as possible, but in no event later than 15 calendar days 
after the determination is made. 
(4) Results of a sponsor's investigation of other safety information shall be 
submitted, as appropriate, in an information amendment or annual report. 
(e) Disclaimer. A safety report or other information submitted by a sponsor under this 
part (and any release by FDA of that report or information) does not necessarily reflect a 
conclusion by the sponsor or FDA that the report or information constitutes an admission 
that the drug caused or contributed to an adverse experience. A sponsor need not admit, 
and may deny, that the report or information submitted by the sponsor constitutes an 
admission that the drug caused or contributed to an adverse experience. 


 
26
We are also required by the FDA to provide annual reports, in accordance with  
21CFR312.33, as follows; 
A sponsor shall within 60 days of the anniversary date that the IND went into effect, 
submit a brief report of the progress of the investigation that includes: 
(a)Individual study information. A brief summary of the status of each study in progress 
and each study completed during the previous year. The summary is required to include 
the following information for each study: 
(1) The title of the study (with any appropriate study identifiers such as protocol number), 
its purpose, a brief statement identifying the patient population, and a statement as to 
whether the study is completed. 
(2) The total number of subjects initially planned for inclusion in the study; the number 
entered into the study to date, tabulated by age group, gender, and race; the number 
whose participation in the study was completed as planned; and the number who 
dropped out of the study for any reason. 
(3) If the study has been completed, or if interim results are known, a brief description of 
any available study results. 
(b)Summary information. Information obtained during the previous year's clinical and 
nonclinical investigations, including: 
(1) A narrative or tabular summary showing the most frequent and most serious adverse 
experiences by body system. 
(2) A summary of all IND safety reports submitted during the past year. 
(3) A list of subjects who died during participation in the investigation, with the cause of 
death for each subject. 
(4) A list of subjects who dropped out during the course of the investigation in 
association with any adverse experience, whether or not thought to be drug related. 
(5) A brief description of what, if anything, was obtained that is pertinent to an 
understanding of the drug's actions, including, for example, information about dose 
response, information from controlled trials, and information about bioavailability. 
(6) A list of the preclinical studies (including animal studies) completed or in progress 
during the past year and a summary of the major preclinical findings. 
(7) A summary of any significant manufacturing or microbiological changes made during 
the past year. 
(c) A description of the general investigational plan for the coming year to replace that 
submitted 1 year earlier. The general investigational plan shall contain the information 
required under 312.23(a)(3)(iv). 


 
27
(d) If the investigator brochure has been revised, a description of the revision and a copy 
of the new brochure. 
(e) A description of any significant Phase 1 protocol modifications made during the 
previous year and not previously reported to the IND in a protocol amendment. 
(f) A brief summary of significant foreign marketing developments with the drug during 
the past year, such as approval of marketing in any country or withdrawal or suspension 
from marketing in any country. 
(g) If desired by the sponsor, a log of any outstanding business with respect to the IND 
for which the sponsor requests or expects a reply, comment, or meeting 
 
Control of Investigational Drugs: The VA Pharmacy will order, store, and dispense 
Phenylephrine Hydrochloride USP and Sodium Nitroprusside USP. The investigative 
team will administer and dispose of the drugs, which will be documented according to 
FDA guidelines. 
  


 
28
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sensitivity on peripheral hemodynamics. Hypertension, 2008. 51(6): p. 
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Wray, D.W., S.K. Nishiyama, A.J. Donato, M. Sander, P.D. Wagner, and 
R.S. Richardson, Endothelin-1-mediated vasoconstriction at rest and 
during dynamic exercise in healthy humans. American journal of 
physiology. Heart and circulatory physiology, 2007. 293(4): p. H2550-6. 
40. 
Wray, D.W., P.J. Fadel, M.L. Smith, P. Raven, and M. Sander, Inhibition of 
alpha-adrenergic vasoconstriction in exercising human thigh muscles. J 
Physiol, 2004. 555(Pt 2): p. 545-63. 
41. 
Hogikyan, R.V., J.J. Wald, E.L. Feldman, D.A. Greene, J.B. Halter, and 
M.A. Supiano, Acute effects of adrenergic-mediated ischemia on nerve 
conduction in subjects with type 2 diabetes. Metabolism, 1999. 48(4): p. 
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42. 
Hogikyan, R.V. and M.A. Supiano, Homologous upregulation of human 
arterial alpha-adrenergic responses by guanadrel. J Clin Invest, 1993. 
91(4): p. 1429-35. 
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Hogikyan, R.V., A.T. Galecki, J.B. Halter, and M.A. Supiano, Heightened 
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Barden, J., L. Lawrenson, J.G. Poole, J. Kim, D.W. Wray, D.M. Bailey, and 
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trained human skeletal muscle. Am J Physiol Heart Circ Physiol, 2007. 
292(5): p. H2491-7. 
45. 
Richardson, R.S., B. Grassi, T.P. Gavin, L.J. Haseler, K. Tagore, J. Roca, 
and P.D. Wagner, Evidence of O2 supply-dependent VO2 max in the 
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Richardson, R.S., B.T. Leek, T.P. Gavin, L.J. Haseler, S.R. Mudaliar, R. 
Henry, O. Mathieu-Costello, and P.D. Wagner, Reduced mechanical 
efficiency in chronic obstructive pulmonary disease but normal peak VO2 
with small muscle mass exercise. Am J Respir Crit Care Med, 2004. 
169(1): p. 89-96. 
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Wray, D.W., A.J. Donato, A. Uberoi, J.P. Merlone, and R.S. Richardson, 
Onset exercise hyperaemia in humans: partitioning the contributors. J 
Physiol, 2005. 565(Pt 3): p. 1053-60. 
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Baily, R.G. and L.I. Sinoway, Insight into human baroreceptor function 
using multiple indices of neural activity. Heart Fail, 1990. 6(1): p. 33-41. 
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Hennessey, J.V., J.A. Chromiak, S. DellaVentura, J. Guertin, and D.B. 
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Bailey, D.M., L. Lawrenson, J. McEneny, I.S. Young, P.E. James, S.K. 
Jackson, R.R. Henry, O. Mathieu-Costello, J.M. McCord, and R.S. 
Richardson, Electron paramagnetic spectroscopic evidence of exercise-
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vasoconstriction following alpha-2 adrenergic receptor blockade in 
humans. Autonomic neuroscience : basic & clinical, 2008. 138(1-2): p. 
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M.L. Smith, Dynamic carotid baroreflex control of the peripheral circulation 
during exercise in humans. J Physiol, 2004. 559(Pt 2): p. 675-84. 
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Ogoh, S., S. Volianitis, P. Nissen, D.W. Wray, N.H. Secher, and P.B. 
Raven, Carotid baroreflex responsiveness to head-up tilt-induced central 
hypovolaemia: effect of aerobic fitness. J Physiol, 2003. 551(Pt 2): p. 601-
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and P.B. Raven, Carotid baroreflex control of leg vascular conductance at 
rest and during exercise. J Appl Physiol, 2003. 94(2): p. 542-8. 
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Fadel, P.J., M. Stromstad, D.W. Wray, S.A. Smith, P.B. Raven, and N.H. 
Secher, New insights into differential baroreflex control of heart rate in 
humans. Am J Physiol Heart Circ Physiol, 2003. 284(2): p. H735-43. 
57. 
Lawrenson, L., J.G. Poole, J. Kim, C. Brown, and R.S. Richardson, 
Vascular and metabolic response to isolated small muscle mass exercise: 
effect of age. American Journal of Physiology and Heart Circulatory 
Physiology, 2003. 285: p. H1023-31. 
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Scott, A.C., D.P. Francis, A.J. Coats, and M.F. Piepoli, Reproducibility of 
the measurement of the muscle ergoreflex activity in chronic heart failure. 
Eur J Heart Fail, 2003. 5(4): p. 453-61. 
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Wray, D.W., S.K. Nishiyama, and R.S. Richardson, Role of {alpha}1-
adrenergic vasoconstriction in the regulation of skeletal muscle blood flow 
with advancing age. Am J Physiol Heart Circ Physiol, 2009. 296(2): p. 
H497-504. 
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Masuki, S., J.H. Eisenach, F.A. Dinenno, and M.J. Joyner, Reduced 
forearm alpha1-adrenergic vasoconstriction is associated with enhanced 
heart rate fluctuations in humans. Journal of applied physiology, 2006. 
100(3): p. 792-9. 
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Masuki, S., F.A. Dinenno, M.J. Joyner, and J.H. Eisenach, Selective 
alpha2-adrenergic properties of dexmedetomidine over clonidine in the 
human forearm. Journal of applied physiology, 2005. 99(2): p. 587-92. 
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Dinenno, F.A., N.M. Dietz, and M.J. Joyner, Aging and Forearm 
Postjunctional {alpha}-Adrenergic Vasoconstriction in Healthy Men. 
Circulation, 2002. 106(11): p. 1349-1354. 
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Dinenno, F.A., S. Masuki, and M.J. Joyner, Impaired modulation of 
sympathetic alpha-adrenergic vasoconstriction in contracting forearm 
muscle of ageing men. J Physiol, 2005. 567(Pt 1): p. 311-21. 
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Eisenach, J.H., E.S. Clark, N. Charkoudian, F.A. Dinenno, J.L.D. Atkinson, 
R.D. Fealey, N.M. Dietz, and M.J. Joyner, Effects of chronic 
sympathectomy on vascular function in the human forearm. J Appl 
Physiol, 2002. 92(5): p. 2019-2025. 
65. 
Rosenmeier, J.B., S.J. Fritzlar, F.A. Dinenno, and M.J. Joyner, Exogenous 
NO administration and {alpha}-adrenergic vasoconstriction in human 
limbs. J Appl Physiol, 2003. 95(6): p. 2370-2374. 


 
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Sex differences in alpha-adrenergic support of blood pressure. Clinical 
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Society, 2010. 20(4): p. 271-5. 
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Casey, D.P., B.D. Madery, T.L. Pike, J.H. Eisenach, N.M. Dietz, M.J. 
Joyner, and B.W. Wilkins, Adenosine receptor antagonist and augmented 
vasodilation during hypoxic exercise. Journal of applied physiology, 2009. 
107(4): p. 1128-37. 
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Wilkins, B.W., T.L. Pike, E.A. Martin, T.B. Curry, M.L. Ceridon, and M.J. 
Joyner, Exercise intensity-dependent contribution of beta-adrenergic 
receptor-mediated vasodilatation in hypoxic humans. The Journal of 
physiology, 2008. 586(4): p. 1195-205. 
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alpha-adrenoceptors and basal limb vascular tone in healthy men. The 
Journal of physiology, 2002. 540(Pt 3): p. 1103-10. 
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Cooper, V.L. and R. Hainsworth, Effects of head-up tilting on baroreceptor 
control in subjects with different tolerances to orthostatic stress. Clin Sci 
(Lond), 2002. 103(3): p. 221-6. 
72. 
Creager, M.A. and S.J. Creager, Arterial baroreflex regulation of blood 
pressure in patients with congestive heart failure. J Am Coll Cardiol, 1994. 
23(2): p. 401-5. 
73. 
Osterziel, K.J., R. Dietz, W. Schmid, K. Mikulaschek, J. Manthey, and W. 
Kubler, ACE inhibition improves vagal reactivity in patients with heart 
failure. Am Heart J, 1990. 120(5): p. 1120-9. 
74. 
Osterziel, K.J., N. Rohrig, R. Dietz, J. Manthey, J. Hecht, and W. Kubler, 
Influence of captopril on the arterial baroreceptor reflex in patients with 
heart failure. Eur Heart J, 1988. 9(10): p. 1137-45. 
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Signorini, P. Castiglioni, A. Azzellino, G. Mancia, and A.U. Ferrari, 
Enhanced baroreceptor control of the cardiovascular system by 
polyunsaturated Fatty acids in heart failure patients. J Am Coll Cardiol, 
2006. 48(8): p. 1600-6. 
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Bianchini, L. Tavazzi, and L. Bernardi, Physiology and pathophysiology of 
heart rate and blood pressure variability in humans: is power spectral 
analysis largely an index of baroreflex gain? Clin Sci (Lond), 1995. 88(1): 
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77. 
Sopher, S.M., M.L. Smith, D.L. Eckberg, J.M. Fritsch, and M.E. Dibner-
Dunlap, Autonomic pathophysiology in heart failure: carotid baroreceptor-
cardiac reflexes. Am J Physiol, 1990. 259(3 Pt 2): p. H689-96. 
78. 
Vogt, A., C. Unterberg, and H. Kreuzer, Acute effects of the new 
angiotensin converting enzyme inhibitor ramipril on hemodynamics and 
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1987. 59(10): p. 149D-154D. 
 

ICF_003.pdf: 
Tracy Frech, M.D. 
 
Page 1 of 13 
Systemic sclerosis (SSc) vasculopathy: Improved clinical monitoring and treatment 
Version date: 10 July 2020  
FOOTER FOR IRB USE ONLY 
Version: K0218 
 
 
University of Utah 
Institutional Review Board 
Approved 8/16/2020 
Expires 8/15/2021 
IRB_00038705 
 
Consent and Authorization Document 
 
Title: 
Systemic sclerosis (SSc) vasculopathy: Improved clinical monitoring and 
treatment 
Investigator: 
 
Tracy Frech, MD 
 
 
 
University of Utah, Division of Rheumatology 
 
 
 
(801) 581-4333 
 
BACKGROUND 
You are being invited to take part in a research study. Before you decide it is important for you to 
understand why the research is being done and what it will involve. Please take time to read the 
following information carefully and discuss it with friends and relatives if you wish. Ask us if there is 
anything that is not clear or if you would like more information. Take time to decide whether or not you 
want to volunteer to take part in this research study.  
 
This study is being done to try to find out the causes of systemic sclerosis which is an autoimmune 
condition associated with changes to blood vessels (vasculopathy) and abnormal scarring (fibrosis) of 
skin, lungs, heart, gastrointestinal tract, and kidneys.  We want to determine if there is a gene 
responsible for this disease, and we are interested in finding “biomarkers” that will help doctors predict 
who is at risk for developing lung, kidney, and gastrointestinal vasculopathy and fibrosis manifestations 
of this disease, and how best to treat them.  A biomarker is a biochemical characteristic that can be used 
to measure the progress of disease or the effects of treatment. 
 
A gene carries a code which is present in every cell in your body.  The code tells the body how to do its 
work.  If this code on your genes has any errors, known as mutations, then your body may get a disease.  
This mutation can sometimes be passed from one generation to the next and cause disease in many 
members of your family.  We want to find out if there is a mutation in any of your genes which may be 
responsible for this disease which seems to run in your family.  
 
We are asking you to consider taking part in this study because your physician has diagnosed you or 
your family member with systemic sclerosis.  We hope that this study will allow us to understand this 
disease better and might someday lead to the treatment of it.   
 
This study is supported by Merit Award from the United States (U.S.) Department of Veterans Affairs 
Clinical Science R&D (CSRD) Service. 
 
STUDY DESIGN 
This is an observational study of patients diagnosed by a rheumatologist with systemic sclerosis (SSc).  
An observational study is one in which individuals are observed and/or certain outcomes are measured 
but no treatment is given.  To be eligible to participate, there are certain entry requirements that must 
be met. Your rheumatologist will assess you to determine whether you meet the entry requirements 
and it is appropriate for you to participate. If you qualify and decide to participate in this study, your 


Tracy Frech, M.D. 
 
Page 2 of 13 
Systemic sclerosis (SSc) vasculopathy: Improved clinical monitoring and treatment 
Version date: 10 July 2020  
FOOTER FOR IRB USE ONLY 
Version: K0218 
 
 
University of Utah 
Institutional Review Board 
Approved 8/16/2020 
Expires 8/15/2021 
IRB_00038705 
 
participation may last about 10 years. This is a long-term study because changes and outcomes of this 
disease evolve over time.  
 
During this research study, we will only collect and store information from procedures and assessments 
if they are performed as part of your standard of care and during your routine medical care visits.  We 
will also gather information from research-related questionnaires you complete and we may collect 
research-related blood and tissue samples.  Study visits will take approximately 1.5-2 hours and every 
effort will be made to have your study visits coincide with your regularly scheduled routine 
rheumatology care visits. 
 
STUDY PROCEDURES 
Baseline and Follow-Up Visits 
No study-related procedures will be performed until you have signed this consent form and agree to 
take part in this study.   
 
Baseline Visit 
This Baseline Visit will be scheduled to coincide with one of your routine care visits.  During this Baseline 
Visit the following procedures may be performed and you will be asked to: 
 Provide your complete medical history, family medical history and review your past and current 
medications. This information will be obtained from your medical records and questions answered 
by you. Examples of the types of records we may review include but are not limited to routine 
echocardiograms, pulmonary function tests, upper and lower endoscopy reports, pathology reports, 
questionnaires, blood work (such as chemistries), stool studies, radiographic images, diet or 
symptom diaries, and urine analyses.  We would normally collect this information during a routine 
care visit; 
 Have a physical exam with height, weight, and your vital signs measured (such as blood pressure, 
heart rate, etc).  These procedures are routine and normally performed during a routine care visit; 
 Provide routine blood and urine samples that will be tested for clinical assessment and disease 
activity.  These samples are normally collected for routine care; 
 We may collect research-related blood samples including a DNA blood sample.  The DNA sample will 
only be collected one time during the course of this study. If a DNA blood sample is not collected at 
the baseline visit, it will be obtained at the next available follow up visit. These samples will be 
collected for study-related purposes, and would not be collected for routine care.  These samples 
are in addition to the samples collected for disease activity.  No more than 5 tablespoons of blood 
(includes blood drawn for routine and study-related purposes) will be collected for this visit; 
 We may collect a skin biopsy. Biopsy specimens may provide key information about the causes of 
scleroderma. Family members and friends that agree to take part in this study, as part of the control 
group, may also be asked to provide a skin biopsy to use as a comparison to affected skin. You 
would not have this skin biopsy procedure as part of your routine care and this would be performed 
for study purposes only.  Dr. Frech will collect two 3-4 millimeter biopsies using a punch biopsy 
instrument;  
 Complete several questionnaires that will ask you to assess the impact of scleroderma on your quality of 
life and your physical and mental health. This will take about 20 minutes to complete. You will be asked 


Tracy Frech, M.D. 
 
Page 3 of 13 
Systemic sclerosis (SSc) vasculopathy: Improved clinical monitoring and treatment 
Version date: 10 July 2020  
FOOTER FOR IRB USE ONLY 
Version: K0218 
 
 
University of Utah 
Institutional Review Board 
Approved 8/16/2020 
Expires 8/15/2021 
IRB_00038705 
 
to complete these questionnaires for the study.  You would not normally be asked to complete 
questionnaires during a routine care visit; 
 Have other tests that may be ordered by your doctor for your routine care. 
 
Follow-Up Visits 
You will be asked to return for your first follow-up visit six months after the Baseline Visit, and then for a 
follow-up visit every six months thereafter for the duration of the study. Every effort will be made to 
have follow-up visits coincide with your routine Rheumatology care visits. 
 
During the Follow-Up Visit the following procedures may be performed and you will be asked to: 
 Review your health and medication (s) for changes since your last visit. We would normally collect 
this information during a routine care visit; 
 Have a physical exam with height, weight, and your vital signs measured (such as blood pressure, 
heart rate, etc).  These procedures are routine and normally performed during a routine care visit; 
 Provide routine blood and urine samples that will be tested for clinical assessment and disease 
activity.  These samples are normally collected for routine care; 
 We may collect research-related blood samples. These samples will be collected for study-related 
purposes, and would not be collected for routine care.  These samples are in addition to the 
samples collected for disease activity.  No more than 2-4 tablespoons of blood (includes blood 
drawn for routine and study-related purposes) will be collected per visit; 
 We may collect a skin biopsy. Biopsy specimens may provide key information about the causes of 
scleroderma and may be collected up to three more times during your study participation. You 
would not have this skin biopsy procedure as part of your routine care and this would be performed 
for study purposes only.  Dr. Frech will collect two 3-4 millimeter biopsies using a punch biopsy 
instrument.  
 Complete several questionnaires that will ask you to assess the impact of scleroderma on your quality of 
life and your physical and mental health. This will take about 20 minutes to complete. You will be asked 
to complete these questionnaires for the study.  You would not normally be asked to complete 
questionnaires during a routine care visit; 
 Have other tests that may be ordered by your doctor for your routine care. 
 
Questionnaires 
You will be asked to complete questionnaires in-person at every study related visit as described above. If 
you would like to complete them electronically, you will have the option to provide the research staff 
with your email address. The electronic version of the questionnaires are identical to the paper version 
but will be made available through a link provided in an email and will allow you access to a study portal 
called “REDCap” from your smart phone, mobile device or computer. If you are not able to (or do not 
want to) complete the questionnaires electronically, you will be asked to complete them on paper which 
will be provided to you by the study team during your clinic visit. You may switch between completing 
the questionnaires using the study portal or the paper version. 
 
If you use the study portal to complete the questionnaires electronically, the email you receive will 
provide instructions on how to utilize the portal. The email address you provide to the study team will 


Tracy Frech, M.D. 
 
Page 4 of 13 
Systemic sclerosis (SSc) vasculopathy: Improved clinical monitoring and treatment 
Version date: 10 July 2020  
FOOTER FOR IRB USE ONLY 
Version: K0218 
 
 
University of Utah 
Institutional Review Board 
Approved 8/16/2020 
Expires 8/15/2021 
IRB_00038705 
 
be used solely for the purpose of sending a link and instructions. It will not be shared or disclosed in any 
other matter. Additionally, standard data rates that apply will be your responsibility.  
 
Other Assessments 
Other examinations that may be performed at both baseline and follow-up visits include peripheral 
nerve testing and a nailfold capillary exam. The nailfold capillary exam is a simple and non-invasive test 
that uses a special microscope to look at the capillaries along the nailbed. This test can help determine 
any vascular changes or abnormalities associated with Raynaud’s phenomenon and/or SSc. The 
peripheral nerve test is also a simple and non-invasive exam that assesses specific nerves and senses by 
placing the tip of a tuning fork on to certain extremities such as your toes and legs to see if you can 
sense vibrations.  
 
We would like to measure blood flow in patients with SSc and their family members. Blood flow will be 
measured with an ultrasound machine. This is a non-invasive procedure. A blood pressure cuff will be 
wrapped around your forearm or around your lower leg. Gel will be applied on the area of the arm or 
leg that will be used for measuring blood flow. The blood pressure cuff will be inflated to 250 mmHg, the 
upper end of the normal inflation range, for five minutes to stop blood flow of the artery that will be 
examined for change in diameter upon cuff deflation using the ultrasound machine. This procedure is 
referred to as the measurement of flow-mediated vasodilation (FMD). Since obstructing the blood flow 
for five minutes may be painful for some individuals it should be noted that if you wish to stop this test 
at any point during the measurement the research personnel will do so. This assessment will take about 
30 minutes and will be performed at every study visit.  
 
Another blood flow measurement may be done by taking an image of the vessels under your tongue 
(sublingual) using a specific type of camera called a Laser Speckle Imaging (LSI) device. You will be asked 
to hold your mouth open wide and place the tip of your tongue on the roof of your mouth for a couple 
of minutes while your doctor captures images of the blood vessels under your tongue. This procedure is 
non-invasive and will take approximately 5 minutes.  
 
If you undergo any assessments, procedures, or treatment as part of your routine care for digital ulcers 
and/or hand contractures, we ask that we be allowed to obtain records and information related to this 
care and use the data as part of this study to learn more about vasculopathy and fibrosis.  
 
As part of your routine gastrointestinal (GI) care, your gastroenterologist may perform a biopsy in your 
GI tract.  If you have a GI biopsy performed for your routine care, we ask that we be allowed to collect, 
study and store a portion of the GI biopsy specimen(s). You may also be asked to provide an optional 
stool sample. We will also study these biopsy specimens to learn about vasculopathy and fibrosis. 
 
Your information will be provided to the Utah Population Database (UPDB) for linkage into pedigrees 
and merged with other genetic studies by the same investigators who are studying scarring lung 
diseases, and other conditions associated with scleroderma or vasculopathy This is because we think 
there is a possibility that the same genes may be involved in scleroderma as with these other diseases. 
 


Tracy Frech, M.D. 
 
Page 5 of 13 
Systemic sclerosis (SSc) vasculopathy: Improved clinical monitoring and treatment 
Version date: 10 July 2020  
FOOTER FOR IRB USE ONLY 
Version: K0218 
 
 
University of Utah 
Institutional Review Board 
Approved 8/16/2020 
Expires 8/15/2021 
IRB_00038705 
 
The genetic and clinical results will only be available to the investigators conducting the research.  You 
will not receive the results of the genetic tests unless the skin biopsy results could impact your 
treatment course, in which case the study doctor may decide to review the skin biopsy results with you. 
 
TISSUE BANKING 
As part of this study, we would like to put some of your blood and biopsy specimen(s) in a tissue 
bank so that other researchers can use it in the future.  Future research about systemic sclerosis 
may be done on your blood and biopsy specimen(s), which may help us learn more about the 
disease.  Your blood and biopsy specimen(s) will be stored in a lab here at the University of Utah 
Medical Center.  The samples may be shared with other researchers at the local institution (i.e. 
University of Utah, Primary Children’s Medical Center, VA SLCHCS) and at other institutions (i.e. the 
National Institutes of Health).  
 
A cell line may be made from your blood to provide a renewable supply of DNA and other cell 
components for research. A cell line is a frozen sample of specially processed white cells from your 
blood that allows us to grow more white cells and obtain more DNA and other cell components, 
e.g., RNA and proteins, from them as needed for future research projects.  If you do not want your 
sample to be used to create an immortalized cell line and you do not want your blood to be saved 
for future research, you should not participate in this study. 
 
No matter what you decide to do, your decision will not affect your medical care.  
 
If you give permission for your sample(s) to be saved for future research by the University of Utah or 
its research partners, the Institutional Review Board may review and approve each new project. The 
Institutional Review Board may require that you be contacted for your permission prior to the use 
of the sample(s) in a new project if it determines new consent is required for your protection. 
 
Tissue or blood samples obtained from you in this research may help in the development of a 
commercial product by the University of Utah or its research partners.  There are no plans to 
provide financial compensation to you should this occur. Your sample will be coded so that your 
name is not on the sample.  Dr. Frech and the University of Utah will keep your name in a separate 
place so that we can link your sample back to you later if we need to. You can have your blood 
sample removed from this tissue bank later.  You will need to contact Dr. Frech at (801) 581-7724. 
The future results or findings will not be given back to you.    
 
RISKS 
Risks of drawing your blood include bruising, bleeding, and some mild discomfort. You may experience 
light-headedness or feeling faint at the time of blood sampling.  If you feel dizzy you will be instructed to 
lie down for a few minutes to avoid hurting yourself if you fall.  Infection at the site of the blood 
sampling could occur and would be uncommon. 
  
Risks and discomforts of skin biopsies include an allergic reaction to the local anesthetic used to reduce 
any discomfort you might experience during the procedure.  After the skin is numb, there should be 
little if any discomfort during the procedure.  Some slight bleeding, bruising, tenderness, or pain may be 


Tracy Frech, M.D. 
 
Page 6 of 13 
Systemic sclerosis (SSc) vasculopathy: Improved clinical monitoring and treatment 
Version date: 10 July 2020  
FOOTER FOR IRB USE ONLY 
Version: K0218 
 
 
University of Utah 
Institutional Review Board 
Approved 8/16/2020 
Expires 8/15/2021 
IRB_00038705 
 
experienced after the procedure has been completed.  Infection or scarring at the site of the punch 
biopsy could occur. 
 
There is no physical risk to answering questions or completing the questionnaires. The medical interview 
and questionnaires used are not expected to be psychologically harmful or stressful. 
 
UNFORESEEABLE RISKS 
Participation in the study may involve risks that are currently unforeseeable. You will be notified 
immediately of any new significant findings discovered during the course of the research that may affect 
your willingness to continue in the study.  
 
BENEFITS 
There are no direct medical benefits to you from your taking part in this study.  We hope that the 
information we obtain from this study will help us give better treatment to patients with systemic 
sclerosis in the future.  It is important to note that we will not report any of your specific genetic 
information directly back to you and your family. 
 
ALTERNATIVE PROCEDURES 
You may choose not to participate in this study.  You will receive the same standard of care whether you 
are in this study or not.  Your medical care and benefits will not be affected if you choose not to take 
part in this study. 
 
PERSON TO CONTACT 
If you have questions, complaints or concerns about this study, you can contact Dr. Frech at 581-7724.   
If you think you may have been injured from being in this study, please call Dr. Tracy Frech at (801) 581-
4333. If you are calling outside of regular office hours, a rheumatologist is available 24 hours a day.  The 
on-call rheumatologist can be reached by calling the hospital operator at (801) 581-2121. 
 
Institutional Review Board: Contact the Institutional Review Board (IRB) if you have questions regarding 
your rights as a research participant. Also, contact the IRB if you have questions, complaints or concerns 
which you do not feel you can discuss with the investigator. The University of Utah IRB may be reached 
by phone at (801) 581-3655 or by e-mail at irb@hsc.utah.edu.   
 
Research Participant Advocate:  You may also contact the Research Participant Advocate (RPA) by 
phone at (801) 581-3803 or by email at participant.advocate@hsc.utah.edu.  
 
RESEARCH-RELATED INJURY 
If you are injured from being in this study, medical care is available to you at the University of Utah as it 
is to all sick or injured people. The University of Utah has not set aside any money to pay the costs for 
such care. The University will work with you to address costs from injuries. Costs would be charged to 
you or your insurance company (if you have insurance), to the study sponsor or other third party (if 
applicable), to the extent those parties are responsible for paying for medical care you receive. Since 
this is a research study, some health insurance plans may not pay for the costs. By signing this consent 


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form you are not giving up your right to pursue legal action against any parties involved with this 
research. 
 
The University of Utah is a part of the government. If you are injured in this study, and want to sue the 
University or the doctors, nurses, students, or other people who work for the University, special laws 
may apply. The Governmental Immunity Act of Utah is a law that controls when a person needs to bring 
a claim against the government, and limits the amount of money a person may recover. See sections 
63G -7-101 to -904 of the Utah Code. 
 
VOLUNTARY PARTICIPATION 
It is up to you to decide whether or not to take part in this study. If you decide to take part you are still 
free to withdraw at any time and without giving a reason. Refusal to participate or the decision to 
withdraw from this study will involve no penalty or loss of benefits to which you are otherwise entitled. 
If you don’t take part, you can still receive all standard care that is available to you. This will not affect 
the relationship you have with your doctor or other staff, nor decrease the standard of care that you 
receive as a patient. 
 
OPTIONAL SUB-STUDY 
Whole Genome or Exome Sequencing: 
In addition to standard genetic tests, we may want to perform whole genome or whole exome sequencing 
of your DNA, and DNA from other members of your family if they are willing to provide DNA.  Since this is 
a special test, we are asking you separately if you are willing to participate in this part of the study.  Your 
decision to participate in this optional study is entirely voluntary. You may refuse this additional research 
and still participate in the main portion of the trial. If you refuse to participate in this additional research, 
or if you decide to withdraw at any time later on, you will not experience any penalty or loss of any benefits 
to which you are otherwise entitled. 
 
Traditional genetic tests look for misspellings in a small number of genes at specific places on your 
genome. Usually these places have already been identified as being associated with a particular disease 
or condition, such as SSc, lupus or other autoimmune diseases.  However, if we want to find additional 
genes or areas between genes that are associated with disease, we need to perform whole genome 
sequencing.  Whole genome sequencing determines your entire genetic code (called your genome).  The 
information that we gather from these tests could help us identify other regions of DNA that could be 
contributing to your disease. 
 
Whole genome sequencing (also known as full genome sequencing) is a test that determines your entire 
genetic code, called your genome. Every cell in your body contains this code spelled out in your DNA, 
designated by the letters A, T, C, and G. All people have very similar genomes – about 99.6 percent 
identical – consisting of approximately six billion letters. However, everyone is unique and between any 
two people there could be approximately 24 million places where the spelling is different. The genomes 
of related family members are usually more similar than the genomes of unrelated people. By looking at 
your genome and comparing it to the genomes of other family members without disease, we may be 
able to identify places where your genomes don’t match-up. These newly-identified places could be 
associated with your disease. This information will allow us to focus on areas of your genome that are 


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good candidates for more investigation. These areas may become the next newly-identified genes 
associated with your disease.  
 
Instead of whole genome sequencing, we may ask you and your family members to volunteer for whole 
exome sequencing. Your genome consists of genes, which include short segments of DNA that encode 
exons that code for proteins, and many long segments of DNA that do not contain genes. Scientists use 
the term 'exome' to represent all of the exons, or protein-coding regions, of the genome. Whole exome 
sequencing is similar to whole genome sequencing in that it looks at the entire genome, but whole exome 
sequencing only records the gene regions of the genome. 
 
We may not sequence your genome/exome immediately, but instead may do this at some point in the 
future as needed. In most cases, if we do perform this test it will be done within a few years of obtaining 
the sample. However, in some cases there may be a longer period of time before sequencing is performed. 
Your samples will be stored for an indefinite period of time.  
 
Other Considerations for Whole Genome/Exome Sequencing: 
1) Genetics is a fast moving field and new findings for a wide range of diseases are announced every day.  
By sequencing your entire genome or exome, we may discover misspellings in genes not currently 
recognized as being associated with SSc or inflammation.  These are called incidental or secondary 
findings.  Since we are looking exclusively for genome regions associated with inflammation and SSc, we 
will not intentionally look for incidental misspellings and will generally not inform you of any that we find.  
However, in cases where we happen to find specific gene variants that we think are urgently important to 
your health, we will inform you.  We expect this type of situation to be very uncommon. 
 
We will periodically recheck your genome or exome sequence as new information related to SSc and 
inflammation becomes available and may report our findings back to you.  For either incidental or disease-
related findings, you will be given a choice to learn or not to learn the information.  We may not find 
changes in your genes for many months or even years because of the amount of time it takes to complete 
our genetic studies. 
 
2) Your genome or exome sequence contains a very large amount of data, which will be stored in a 
centralized database maintained by the National Institutes of Health (NIH) according to NIH guidelines. 
This database could be created specifically for this study or may be part of a large, previously-established 
NIH database. In addition to your genome or exome sequence data, clinical information about you – such 
as your disease history, your symptoms, laboratory test results, and general statistical information about 
you (for example, your age, sex, and ethnicity) – may also be included in the database.  Your data will be 
assigned an identifier number and any personal information that could connect you to your data (such as 
your name, address, or date of birth) will be removed from the database.  Any of your personally 
identifiable information collected for the study will be kept by study investigators, in files separate from 
the database.  The study investigators will be the only ones with access to your personal information and 
who could connect you to your database identifier number.  In addition, only medical scientists with 
legitimate research interests will be allowed access to your data for analysis purposes. Most of these 
medical scientists will be investigating conditions related to SSc and inflammation.  However, your data 
could be made available to medical scientists pursuing research unrelated to these conditions.  The 


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systems holding your data and personal information have extensive safeguards to prevent unauthorized 
access.  But even with the best safeguards, there is always the possibility of a breach of security in the 
database and the possibility that someone could deduce your identity by comparing your DNA sequence 
data in the database to DNA sequence information they may have obtained from you.  Also, your data 
and personal information could be released to authorities in response to a legal subpoena.  If at any time 
you would like us to remove your sequence data and/or clinical information from the database, please let 
us know in writing and we will remove your data from the database. You must give your revocation in 
person to the Principal Investigator or the Principal Investigator’s staff, or mail it to Tracy Frech, MD, 30 
North 1900 East, 4B200 SOM, SLC, UT 84132.   However, we will not be able to remove your patient 
records from the research study or retract analyses or publications that used your data prior to your 
written request. 
 
If you give permission for your sample(s) to be saved for future research by the University of Utah 
Hospital and Clinics and/or the National Institutes of Health, the Institutional Review Board may review 
and approve each new project. The Institutional Review Board may require that you be contacted for 
your permission prior to the use of the sample(s) in a new project if it determines new consent is 
required for your protection.  
 
If you do not want your samples and clinical information stored for an indefinite period of time in the NIH 
centralized database for use in research related to SSc and other health problems, you should not 
participate in this optional study.  
 
Risks and Discomfort:  
The risks and discomforts of genetic testing in this study include the following: 
 
1) The risk of diagnosing a genetic condition unrelated to SSc and inflammation.  Should we uncover 
incidental or secondary genetic findings that are of significant importance to your health now, or in the 
future, and if you have indicated that you wish to learn about this information, then we will inform you.   
In whole exome or whole genome sequencing, we will obtain sequence data on many genes that are not 
known to have a role in SSc.  For the purposes of this study, we intend to focus our analyses on those 
genes likely to have a role in SSc, but it remains possible that we will unintentionally find possible 
sequence variants that cause genetic disorders not related to the autoimmune diseases.  For any such 
case, it will be highly unlikely that our laboratory will be certified to return such information back to you 
or your physician.  Although we will not make a systematic effort to identify all such possible deleterious 
mutations, if any do come to our attention and appear to be urgently important to your health, we will 
report this information to your study physician.  Confirmation by a certified laboratory would be 
necessary before your physician could contact you with any results.  Confirmation and further 
evaluation of any genetic results, genetic counseling, and any treatment that is required, will need to be 
done by your health care providers. 
 
2) The unwanted possibility of discovering that parental relationships in a family are not true genetic 
relationships.  In these cases, we will not perform any tests to determine explicit genetic relationships and 
may decide not to inform you and/or your family members of the unproven possibility of false genetic 


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relationships.  Due to the possibility of mistaken family relationships, we may also decide not to include 
you and/or your family members' data in the research study. 
 
3) The possibility that people outside of the study may gain access to your personal information.  The 
study has extensive safeguards in place to prevent this from happening.  If we become aware that your 
personal information has been compromised, we will inform you as soon as possible. 
A Federal law, called the Genetic Information Nondiscrimination Act (GINA), generally makes it illegal for 
health insurance companies, group health plans, and most employers to discriminate against you based 
on your genetic information.  According to this law, health insurance companies or group health plans (as 
of May 21, 2010) cannot request your genetic information or use it to make decisions about your eligibility 
or premiums; and employers cannot use it in deciding to hire, promote, or fire you, or in setting the terms 
of your employment (as of Nov 21, 2009).   
The following link contains details on this policy: 
http://www.genome.gov/Pages/PolicyEthics/GeneticDiscrimination/GINAInfoDoc.pdf.  You may ask your 
research team for additional information or a copy of The Genetic Information Discrimination Act of 2008 
informational document.  
 
Be aware that this Federal law does not protect you against genetic discrimination by companies that 
sell life insurance, disability insurance, or long-term care insurance. 
 
Because we are asking your permission to collect, code, and store your blood sample for DNA, RNA and 
protein analysis, please read each sentence below, think about your choice, and mark “YES” or “NO”. No 
matter what you decide to do, your decision will not affect your medical care or your participation in 
the main portion of the study. 
 
1. May the University of Utah and its research partners, including the National Institutes of Health, 
collect, code and store your blood sample(s) and clinical information for use in research, including 
DNA, RNA and protein analysis related to SSc and other health problems? (Your name and other 
identifying information will not be kept with your samples). 
□ YES  
I agree to participate in this optional portion of the study and my sample(s) and 
clinical information may be stored and used for DNA, RNA and protein analysis for 
research purposes. 
 
□ NO  
I do not want to participate in this optional portion of the study. I do not give 
permission to have additional samples of blood drawn for DNA, RNA, and protein 
analysis. (If you choose this option, you will not participate in the tissue bank sub-
study.  This will not affect your participation in the main portion of the study.) 
 
2. May the University of Utah and its research partners, including the National Institutes of Health, 
retain your blood sample(s) and clinical information after the end of this research project for use in 
future research, including DNA, RNA and protein analysis related to SSc and other health problems? 
(Your name and other identifying information will not be kept with your samples). 


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□ YES  
I agree to participate in this optional portion of the study and my sample(s) and 
clinical information may be retained and used for DNA, RNA and protein analysis 
for future research. 
□ NO  
I do not want to participate in this optional portion of the study. I do not give 
permission to have additional samples of blood drawn for DNA, RNA, and protein 
analysis. (If you choose this option, you will not participate in the tissue bank sub-
study.  This will not affect your participation in the main portion of the study.) 
 
3. The University of Utah and its research partners, including the National Institutes of Health, will not 
provide the results of genetic testing to you or your physician.  An exception would be made if the 
results from the genetic testing reveal information of urgent clinical significance to your health or 
your family members. This information would be provided to your physician who would then contact 
you to discuss the results and provide any necessary counseling or treatment if required. Please mark 
one of the boxes below to tell us if you would like this information provided to you should it become 
available.  
 
□ YES  
I give permission for my physician and me to be informed of any results obtained 
from the genetic testing performed as part of this optional study if they are 
clinically significant and would have an urgent direct effect on my health or the 
health of my family member(s). 
 
□ NO  
I do not want to be notified of any results obtained from the genetic testing 
performed as part of this optional study.  
 
COSTS AND COMPENSATION TO PARTICIPANTS 
There are no costs or compensation to you for taking part in this study.  Any additional studies that are 
done on you that are not already a part of your medical evaluation by your doctor will be paid for 
through the study and not billed to your insurance.    
 
NUMBER OF PARTICIPANTS 
We anticipate enrolling up to 500 patients from the University of Utah, 50 patients from the George E. 
Wahlen VA in Salt Lake City, and 300 family members living in or near Utah. 
 
AUTHORIZATION FOR USE OF YOUR PROTECTED HEALTH INFORMATION  
Signing this document means you allow us, the researchers in this study, and others working with us to 
use some information about your health for this research study. 
 
This is the information we will use and include in our research records:  
A. Name 
A. Address 
B. Telephone Number 


Tracy Frech, M.D. 
 
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C. Birth Date 
D. Family medical History 
E. Current and past medicines or treatments 
F. Past medical history 
G. Results of laboratory, radiographic, cardiac function, pulmonary function, gastrointestinal 
function, or pathologic tests 
H. Results of physical exam or other routine exams 
I. 
Results of outside previous physical evaluations 
 
J. All tests and procedures that will be done in the study 
 
In addition to your protected health information located at the University of Utah, we may want to 
request the above test results previously performed at another institution.  If we should need this 
information, we will have you sign a separate consent called a “Medical Release of Information”. 
 
How we will protect and share your information: 
 
We will do everything we can to keep your information private but we cannot guarantee this. 
Study information will be kept in a secured manner and electronic records will be password 
protected. Study information may be stored with other information in your medical record. 
Other doctors, nurses, and third parties (like insurance companies) may be able to see this 
information as part of the regular treatment, payment, and health care operations of the 
hospital. We may also need to disclose information if required by law. 
 
 
In order to conduct this study and make sure it is conducted as described in this form, the 
research records may be used and reviewed by others who are working with us on this research: 
o Members of the research team and University of Utah Health Sciences Center; 
o 
The University of Utah Institutional Review Board (IRB), who reviews research involving 
people to make sure the study protects your rights; 
o The Utah Population Database (UPDB): The UPDB is a University of Utah research 
resource and is an extensive research database of demographic information linked to 
other data, such as family history and medical information. By sharing your identifying 
data with the UPDB, we can obtain genealogy information about you and your family for 
this study. This will allow information about you and your family to be updated and 
evaluated for this study. The UPDB has extraordinary security measures to protect the 
identity and information of all study participants and their family members. No medical 
information about you or your family members collected from this study will be 
provided to the UPDB.  
 
 
If we share your information with groups outside of University of Utah Health Sciences Center, 
we will not share your name or identifying information.  We will label your information with a 


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code number, so they will not know your identity. 
 
 
If you do not want us to use information about your health, you should not be part of this 
research.  If you choose not to participate, you can still receive health care services at University 
of Utah Health Sciences Center.  
 
What if I decide to Not Participate after I sign the Consent and Authorization Form? 
You can tell us anytime that you do not want to be in this study and do not want us to use your health 
information.  You can also tell us in writing.  If you change your mind, we will not be able to collect new 
information about you, and you will be withdrawn from the research study. However, we can continue 
to use information we have already started to use in our research, as needed to maintain the integrity of 
the research.   
 
This authorization does not have an expiration date.   
 
You have a right to information used to make decisions about your health care. However, your 
information from this study will not be available during the study; it will be available after the study is 
finished. 
 
CONSENT 
I confirm that I have read this consent and authorization document and have had the opportunity to ask 
questions. I will be given a signed copy of the consent and authorization form to keep. 
 
I agree to take part in this research study and authorize you to use and disclose health information 
about me for this study, as you have explained in this document. 
 
 
________________________ 
Participant’s Name 
 
________________________ 
 
 
 
 
____________ 
Participant’s Signature 
 
Date 
 
________________________ 
Name of Person Obtaining Authorization and Consent 
 
________________________ 
 
 
 
 
____________ 
Signature of Person Obtaining Authorization and Consent 
 
Date 
 
 

Prot_000.pdf: 
Protocol Summary (ERICA) 
 
IRB_00038705 
Page 1 of 11 
 
IRB Approval 12/15/2020 
 
 
Systemic sclerosis (SSc) vasculopathy: Improved clinical 
monitoring and treatment 
 
Protocol Summary 
 
 
 
IRB Approval 
Date of 
Current 
Version: 
12/15/2020 
University of 
Utah IRB #: 
IRB_00038705 
Sponsor: US DEPARTMENT OF VETERANS AFFAIRS 
  
Principal 
Investigator: 
Tracy Frech 
Internal Staff 
and  Sub-
Investigators: 
Site Name 
Staff Names 
Veterans Affairs SLC Health Care 
System (VAMC) 
Tracy Frech 
 
Jordan Tucker 
 
Jessica Gonzalez 
 
Jennifer Godina 
 
Anthony Donato 
 
Samuel Bloom 
 
Kathryn Peterson 
 
Martha Finco 
 
Nadia Grant 
 
Julieanne Hall 
University of Utah 
Tracy Frech 
 
Melodie Weller 
 
Jordan Tucker 
 
Kalani Raphael 
 
Jessica Gonzalez 
 
Jennifer Godina 
 
James Fang 
 
Mary Scholand 
 
Joseph Allen 
 
PATRICE MIMCHE NSANGOU 
 
Eric Tuday 


Protocol Summary (ERICA) 
 
IRB_00038705 
Page 2 of 11 
 
IRB Approval 12/15/2020 
 
 
Andrew Gawron 
 
Sally Ibrahim 
 
Anthony Donato 
 
Samuel Bloom 
 
Kathryn Peterson 
 
Maureen Murtaugh 
 
Martha Finco 
 
Nadia Grant 
 
Julieanne Hall 
 
John Ryan 
 
This document was created using the ERICA Online System at the University of Utah. The document is created 
from study information approved by the IRB on the date listed above.  Any alteration to the original content of this 
document may not be considered to represent the study as approved by the IRB.  
 
 


Protocol Summary (ERICA) 
 
IRB_00038705 
Page 3 of 11 
 
IRB Approval 12/15/2020 
 
Background and Introduction 
 
Systemic sclerosis (SSc) is a complex autoimmune disease characterized by multi-organ 
vascular alterations (vasculopathy) with subsequent varying degrees of fibrosis. It is a 
devastating autoimmune disease with limited therapeutics available. While both genetic and 
environmental factors are recognized as important in pathogenesis, much work needs to be 
done to characterize these effects in the setting of a heterogeneous clinical phenotype. 
 
 
 
Purpose and Objectives 
 
This study is being done to try to find out the causes of systemic sclerosis which is an 
autoimmune condition associated with changes to blood vessels (vasculopathy) and abnormal 
scarring (fibrosis) of skin, lungs, heart, gastrointestinal tract, and kidneys. We want to 
determine if there is a gene responsible for this disease, and we are interested in finding 
biomarkers (a biochemical characteristic that can be used to measure the progress of disease or 
the effects of treatment) that will help doctors predict who is at risk for developing lung, 
kidney, and gastrointestinal vasculopathy and fibrosis manifestations of this disease, and how 
best to treat them. 
 
 
 
Study Population 
 
Age of Participants: 14-17 yo and 18+ 
 
Sample Size: 
At Utah: 
850  
All Centers: 
850 
 
Inclusion Criteria: 
A diagnosis of systemic sclerosis. 
We will include age cohort 14-17 to our already approved 18+ cohort 
  
Family members of patients with a diagnosis of systemic sclerosis to be used as a control 
group. 
Additionally, disgarded clinical forearm skin biospy specimens (de-identified) will used for 
comparison. 
Number of participants: 
University of Utah: 


Protocol Summary (ERICA) 
 
IRB_00038705 
Page 4 of 11 
 
IRB Approval 12/15/2020 
 
Affected: 500 
Controls: 300 
VA: 50 total 
 
 
Exclusion Criteria: 
None 
 
 
Design  
 
Prospective Biomedical Intervention or Experiment 
 
 
Serum, biopsy tissue and DNA collection and storage. 
 
Study Procedures 
 
Recruitment/Participant Identification Process: 
Dr. Frech will identify affected participants during the patients routine care visits from her 
scleroderma clinic, the general rheumatology clinics, or as an inpatient at the University of 
Utah and George E. Wahlen VA.  Dr. Frech and sub-investigators will also identify healthy-
control patients during routine care visits from the general rheumatology clinics at the 
University of Utah and George E. Wahlen VA.  We plan to enroll healthy controls from 
families of consented and enrolled affected subjects.  We will ask affected subjects if they 
want to approach friends or family members about participating as control subjects.  If 
affected subjects decide they want to approach friends or family members, they will be 
instructed to give interested individuals an ICF and to have each interested person individually 
contact study staff to discuss the study and their participation.  Those interested in 
participating will have their own separate study visit. 
Dr. Gourh will use the analysis from the UPDB to help detect genetic relationships in SSc and then analyze DNA from certain 
pedigrees. Dr. Pravitt Gourh may be involved in evaluating and examining the SSc patients at the University of Utah Hospital 
and Clinics. He may interview the family members and, if needed, examine them at the University of Utah Hospitals and 
Clinics. Dr. Gourh will also be involved in reviewing identifiable data from patients and their family members that may have 
already been collected and stored in the study.  
Dr. Gourh is an NIH fellow that is using his funding to better understand the genetic risk of SSc. With his help, this project 
will be funded. 
Dr. Gourh will not conduct any research at the VA Medical Center and will not have access to any information obtained at the 
VA.  
All study procedures and assessments will be performed at both the University of Utah and the 
George E Wahlen VA with the exception of the whole genome or exome sequencing. Dr. 
Pravitt Gourh from the NIH will not examine or see patients from the VA or collect any 
specimens from VA participants. 


Protocol Summary (ERICA) 
 
IRB_00038705 
Page 5 of 11 
 
IRB Approval 12/15/2020 
 
  
 
 
Informed Consent: 
Description of location(s) where consent will be obtained:  
University of Utah Medical Center Rheumatology Clinic 2 and at the George E. Wahlen VA 
Medical Center Internal Medicine Clinic 
 
Description of the consent process(es), including the timing of consent:  
No formal waiting period, unless requested by participant. Patients will be consented by Dr. 
Frech or her designated research staff. Consent form will be thoroughly reviewed with the 
patient and the patient will be given the opportunity to ask any questions. No study procedures 
will be performed prior to obtaining consent. The ICF will be signed by both parties and the 
patient will be given a copy for their records.  
 
Requested Waivers/Alterations of Consent: 
Waiver of Informed 
Consent 
We request a waiver of consent for those participants who have 
already been consented to this study. Patients in this study 
have already consented to genetic research with the aim of 
improving the understanding the role of genetics in 
scleroderma. Linking patients to IRB# 31854 will allow 
additional scleroderma  pedigrees to be created that assess 
potential links between scleroderma and other diseases. This 
will be a valuable tool and is consistant with the stated aims of 
the study. If/when participants are re-contacted for any further 
studies requiring face to face contact for this study, reconsent of 
participants will happen at that time. 
Waiver of Informed 
Consent 
We request a waiver of consent for patients who have already 
been consented to IRB#38705.  Patients in this study have 
already consented to genetic research with the aim of improving 
understanding of the role of genetics in scleroderma. Linking 
patients to pedigrees created by IRB#31215 will be a powerful 
tool in achieving this aim and is consistent with the stated aims 
of the study. If/when participants are re-contacted for any 
further studies requiring face-to-face contact for IRB #38705 or 
#31215, re-consent of participants will happen at that time 
Waiver of Informed 
Consent 
The purpose of this waiver is to collect disregarded forearm 
specimens for comparison to forearm specimens of scleroderma 
patients. 
 
Procedures: 
SSc participants and the controls (family members) will be identified from clinic (Clinic 2, 
SSc clinic, VASLCHSC).  If they are 18+, they will have serum drawn and biopsy performed 
in clinic. If they are part of the 14-17 yo cohort, they will only have a blood draw. 
STUDY PROCEDURES 
Baseline and Follow-Up Visits 


Protocol Summary (ERICA) 
 
IRB_00038705 
Page 6 of 11 
 
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No study-related procedures will be performed until patients have signed this consent form 
and agree to take part in this study.  
Baseline Visit 
This Baseline Visit will be scheduled to coincide with one of  routine care visits.  During this 
Baseline Visit the following procedures will be performed: 
• Provide a complete medical history, family medical history and review past and current 
medications. This information will be obtained from medical records and questions 
answered by the patient. Examples of the types of records we may review include but 
are not limited to routine echocardiograms, pulmonary function tests, upper and lower 
endoscopy reports, pathology reports, questionnaires, blood work (such as 
chemistries), stool studies, radiographic images, diet or symptom diaries, and urine 
analyses. This information we obtain for this study will only be collected if it was 
performed as a procedure/assessment as part of a patient's standard of care visit; 
• Have a physical exam with height, weight, and vital signs measured (such as blood 
pressure, heart rate, etc).  These procedures are routine and normally performed during 
a routine care visit; 
• Provide routine blood and urine samples that will be tested for clinical assessment and 
disease activity.  These samples are normally collected for routine care; 
• We may collect research-related blood samples including a DNA blood sample.  The 
DNA sample will only be collected one time during the course of this study. If a DNA 
blood sample is not collected at the baseline visit, it may be obtained at the next 
available follow up visit. These samples may be collected for study-related purposes, 
and would not be collected for routine care.  These samples are in addition to the 
samples collected for disease activity.  No more than 5 tablespoons of blood (includes 
blood drawn for routine and study-related purposes) will be collected for this visit; 
• We may ask for a skin biopsy. Biopsy specimens may provide key information about 
the causes of scleroderma. Family members and friends that agree to take part in this 
study, as part of the control group, may also be asked to provide a skin biopsy to use as 
a comparison to affected skin. Patients would not have this skin biopsy procedure as 
part of your routine care and this would be performed for study purposes only.  Dr. 
Frech will collect two 3-4 millimeter biopsies using a punch biopsy instrument; 
• Complete several questionnaires that will ask the patient to assess the impact of 
scleroderma on their quality of life and their physical and mental health. This will take 
about 20 minutes to complete. Participants will be asked to complete these 
questionnaires for the study and would not normally be asked to complete 
questionnaires during a routine care visit; 
• Have other tests that may be ordered by your doctor for routine care.  
Follow-Up Visits 
Participants will be asked to return for first follow-up visit six months after the 
Baseline Visit, and then for a follow-up visit every six months thereafter for the 
duration of the study. Every effort will be made to have follow-up visits coincide with 
routine Rheumatology care visits. Visits are piggy-backed on standard of care, 


Protocol Summary (ERICA) 
 
IRB_00038705 
Page 7 of 11 
 
IRB Approval 12/15/2020 
 
participants will be seen when their visits correlate with their standard of care visits. If 
participant is not seen every six months we will capture study data when the participant 
returns to clinic.  
During the Follow-Up Visit the following procedures will be performed: 
• Review  health and medication (s) for changes since the last visit. We would normally 
collect this information during a routine care visit.This information we obtain for this 
study will only be collected if it was performed as a procedure/assessment as part of a 
patient's standard of care visit; 
• Have a physical exam with height, weight, and vital signs measured (such as blood 
pressure, heart rate, etc).  These procedures are routine and normally performed during 
a routine care visit; 
• Provide routine blood and urine samples that will be tested for clinical assessment and 
disease activity.  These samples are normally collected for routine care; 
• We may collect research-related blood samples. These samples will be collected for 
study-related purposes, and would not be collected for routine care.  These samples are 
in addition to the samples collected for disease activity.  No more than 2-4 tablespoons 
of blood (includes blood drawn for routine and study-related purposes) will be 
collected per visit; 
• We may ask for a skin biopsy. Biopsy specimens may provide key information about 
the causes of scleroderma and may be collected up to three more times during your 
study participation. Patients would not have this skin biopsy procedure as part of their 
routine care and this would be performed for study purposes only.  Dr. Frech will 
collect two 3-4 millimeter biopsies using a punch biopsy instrument. 
• Complete several questionnaires that will ask the patient to assess the impact of 
scleroderma on their quality of life and their physical and mental health. This will take 
about 20 minutes to complete. Participants will be asked to complete these 
questionnaires for the study and would not normally be asked to complete 
questionnaires during a routine care visit; 
• Have other tests that may be ordered by your doctor for routine care. 
Questionnaires 
Patients will be asked to complete questionnaires in-person at every study related visit as 
described above. If they would like to complete them electronically, they will have the option 
to provide the research staff with an email address. The electronic version of the 
questionnaires are identical to the paper version but will be made available through a link 
provided in an email and will allow patients access to a study portal called “REDCap” 
from their smart phone, mobile device or computer. Patients may switch between completing 
the questionnaires using the study portal or the paper version. 
If you they the study portal to complete the questionnaires electronically, the email they 
receive will provide instructions on how to utilize the portal. The email address they provide 
to the study team will be used solely for the purpose of sending a link and instructions. It will 


Protocol Summary (ERICA) 
 
IRB_00038705 
Page 8 of 11 
 
IRB Approval 12/15/2020 
 
not be shared or disclosed in any other matter. Additionally, standard data rates that apply will 
be their responsibility. 
Other examinations 
Other examinations that may be performed at both baseline and follow-up visits include 
peripheral nerve testing and a nailfold capillary exam. The nailfold capillary exam is a simple 
and non-invasive test that uses a special microscope to look at the capillaries along the 
nailbed. This test can help determine any vascular changes or abnormalities associated with 
Raynaud’s phenomenon and/or SSc. The peripheral nerve test is also a simple and non-
invasive exam that assesses specific nerves and senses by placing the tip of a tuning fork on to 
certain extremities such as your toes and legs to see if patients can sense vibrations. 
We may also measure blood flow in patients with SSc and their family members. Blood flow 
will be measured with an ultrasound machine. This is a non-invasive procedure. A blood 
pressure cuff will be wrapped around the forearm or around the lower leg. Gel will be applied 
on the area of the arm or leg that will be used for measuring blood flow. The blood pressure 
cuff will be inflated to 250 mmHg, the upper end of the normal inflation range, for five 
minutes to stop blood flow of the artery that will be examined for change in diameter upon 
cuff deflation using the ultrasound machine. This procedure is referred to as the measurement 
of flow-mediated vasodilation (FMD). Since obstructing the blood flow for five minutes may 
be painful for some individuals it should be noted that if patients wish to stop this test at any 
point during the measurement the research personnel will do so. This assessment may take 
about 30 minutes and will be performed at every study visit. 
Another blood flow measurement may be collected by taking an image of the vessels under the 
tongue (sublingual) using a specific type of camera called a Laser Speckle Imaging (LSI) 
device. Patients will be asked to hold their mouth open wide and place the tip of their tongue 
on the roof of their mouth for a couple of minutes while the doctor captures images of the 
blood vessels under the tongue. This procedure is non-invasive and will take approximately 5 
minutes. 
Peripheral nerve testing, nailfold capillary exam, flow mediated dilation and sublingual 
imaging. These examinations will only be performed on the adult (18+) participants. 
If patients undergo any assessments, procedures, or treatment as part of their routine care for 
digital ulcers and/or hand contractures, we ask that we be allowed to obtain records and 
information related to this care and use the data as part of this study to learn more about 
vasculopathy and fibrosis. 
If an adverse event occurs (ie, bruising, bleeding) then it will be addressed in clinic. 
After subjects at the University of Utah are identified through these sources, patient PHI 
(names, dates of birth, gender, and phenotypic information) will be passed to the Genetics and 
Molecular Characteristics of Interstitial Lung Disease study (IRB#31215) on which Dr. Frech 
is a co-investigator. Dr. Scholand is the primary investigator on IRB# 31215 and a co-
investigator on this study. Subjects from the VA will be excluded in this portion of the study. 


Protocol Summary (ERICA) 
 
IRB_00038705 
Page 9 of 11 
 
IRB Approval 12/15/2020 
 
The information obtained from the control group (unaffected family members) in this 
study will be used in conjunction with IRB study #: 31854- An Improved Definition of 
Hereditability of Systemic Sclerosis (SSc), SSc Overlap Conditions, and Raynaud's 
Phenomenon Through Use of the Utah Population Data Base (UPDB). MRNs from the 
control subjects will be submitted to the UUHSC EDW through Dr. Frech's 31854 project in 
order to obtain UPDB numbers. This information (from controls only) will then be used to 
perform a kinship analysis under 31854 for SSc data identified from the University of Utah 
Health Sciences Center. Dr. Frech oversees both projects as the PI. Please refer to the study #: 
31854 for further information. 
The study will utilize the Master Subject Index that links the demographic records from the 
UUHSC EDW to the UPDB under IRB_00045234, Master Subject Index between the Utah 
Population Database and the University of Utah Health Sciences Center (Ken Smith, PI). 
All data will remain behind the HSC computer firewall on password protected computers. 
Only associates affiliated with this research project and project #s 38705 & 31215 will have 
access to study information. Any information discussed or shared via email between the 
investigators will be encrypted. 
The study staff for the Genetics and Molecular Characteristics of Interstitial Lung Disease 
study (IRB#31215) will submit the medical record numbers to the UUHSC EDW so that a 
UPDB number can be obtained from the Pedigree and Population Resource, the group that 
manages the UPDB. 
The Pedigree and Population Resource will develop pedigrees as well as link participants to 
any existing pedigrees identified under IRB #31215. All UPDB pedigree data will be stored 
electronically by the Pedigree and Population Resource on their secure server, and may be 
shared with investigators for this trial as well as Dr. Pravitt Gourh, an external investigator for 
this study. 
Pedigree information obtained in the IRB_31854 study will be coded by UPDB number, and 
phi will be removed.  Pedigrees for analysis will retain the UPDB number, diagnoses, 
environmental exposures, other de-identified test data, age at diagnosis, demographic data 
essential for analysis (e.g., gender, race), and pedigree structure.  This data, along with 
molecular data generated on pedigree members, will be shared by Drs. Scholand and Frech. 
The GI biopsy specimens from healthy controls will be identified through Drs. Peterson and 
Gawron during routine endoscopy schedule.  If they have extra tissue from a biopsy in a 
healthy control or irritable bowel specimen that is obtained for medically indicated reasons 
(not study purposes) they may bring the de-identified tissue to Tracy Frech for analysis.  Thus, 
Dr. Peterson & Dr. Gawron will de-identify the patients and it will not be linked to PHI.  The 
only information the investigators will have is that the patient does not have SSc and is healthy 
or has irritable bowel. 
Study participant's family members may also be consented and included in the study as control 
subjects. 


Protocol Summary (ERICA) 
 
IRB_00038705 
Page 10 of 11 
 
IRB Approval 12/15/2020 
 
Whole Genome or Exome Sequencing: Research samples collected as part of this study may 
be analyzed for genetic purposes. In addition to standard genetic tests, we may want to 
perform whole genome or whole exome sequencing of the DNA from affected patients, and 
DNA from the controls if they are willing to provide DNA samples. A detailed description of 
genome and exome sequencing is provided in the ICF. The sequencing would be done by Dr. 
Pravitt Gourh at the NIH. These samples would be shipped to his lab at the NIH in Bethesda, 
Maryland where they would be stored for an undetermined amount of time. This is an optional 
sub-study offered to participants at the University of Utah only. VA participants are excluded 
from this optional sub-study. 
Dr. Frech would like to share some de-identified, limited data sets with Dr. Baron and his 
group at Jewish General Hospital in Quebec, Canada. Dr. Baron's research in SSc mimics the 
data collected by Dr. Frech for the IRB 38705 project. Data would come from the assessments 
& related outcomes collected as part of the 38705 study. The UPDB data that is obtained as 
part of the linked project, IRB 31854, will not be used for this collaboration. 
 
 
Procedures performed for research purposes only:  
Research blood samples in the 14-17 year old cohort. 
Research blood samples and skin biopsies in the 18+ cohort. 
Nail fold capillary exam 
Flow mediated dilation 
Sublingual imaging 
For participants at the VA, the above procedures/assessments will be performed for resear
purposes only and at no cost to the veteran. 
  
 
 
Statistical Methods, Data Analysis and Interpretation 
 
Statistics will be run using SAS version 9.2.  None of the variables will have an 
assumption of normality. SSc patient characteristics will be summarized using 
means and frequencies when appropriate.  General linear models will be used 
to compare age-adjusted characteristics.  T-test will be used to compare 
biopsy outcomes by the patients defined by bivariate clinical 
characteristics.  Spearman correlation will be used to assess clinical and biopsy 
variables. 
 
 
  
 


Protocol Summary (ERICA) 
 
IRB_00038705 
Page 11 of 11 
 
IRB Approval 12/15/2020 
 
 

ICF_004.pdf: 
V A  D e p art m e nt of V et er a n s Aff air s  
V A  R E S E A R C H  C O N S E N T  F O R M  
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P arti ci p a nt N a m e:                                                                                                           D at e:   _ _ _ _ _ _ _ _ _                   
Titl e of St u d y:  “V a s c ul ar a n d A ut o n o mi c M al a d a pt ati o n s i n P ati e nt s wit h V a s c ul ar D y sf u n cti o n ”  
Pri n ci p al I n v e sti g at or:  R u s s ell S. Ri c h ar d s o n, P h. D.                                          V A M C: S alt L a k e Cit y ( 6 6 0)     
C o n s e nt V er si o n D at e:  V er si o n  (  M a y  2 0 1 5 )  
 
F O O T E R F O R I R B U S E O N L Y  
V er si o n: B 0 1 1 1  
 
« I m a g e: St a m p»  
« I n stit uti o n»  
« I R B» 
« A p pr o v e d » « A p pr o v e d D at e » 
« E x pir ati o n » 
« E x pir ati o n D at e » 
« N u m b er »  
V A F O R M  1 0 -1 0 8 6  J U N E 1 9 9 0  
 
 
 
 
 
D E S C RI P TI O N O F R E S E A R C H B Y I N V E S TI G A T O R  
 
T O P O T E N TI A L P A R TI CI P A N T S  
F e d er al r e g ul ati o n s r e q uir e writt e n i nf or m e d c o n s e nt b ef or e p arti ci p ati o n i n a r e s e ar c h st u d y. T hi s i s t o b e c ert ai n 
t h at r e s e ar c h p arti ci p a nt s k n o w t h e n at ur e a n d ri s k s of t h e st u d y, a s t h e y m a k e a d e ci si o n t o t a k e p art or n ot. Y o u 
ar e a s k e d t o r e a d t h e f oll o wi n g i nf or m ati o n a n d di s c u s s it wit h t h e i n v e sti g at or, s o t h at y o u will b e f ull y i nf or m e d 
a b o ut t hi s r e s e ar c h st u d y a n d h o w it m a y aff e ct y o u. Y o ur si g n at ur e o n t hi s f or m m e a n s t h at y o u h a v e b e e n f ull y 
i nf or m e d a n d t h at y o u fr e el y gi v e y o ur c o n s e nt t o p arti ci p at e. 
 
B A C K G R O U N D  
Dr. R u s s ell S. Ri c h ar d s o n a n d hi s c oll e a g u e s ar e c o n d u cti n g a r e s e ar c h st u d y t o fi n d o ut m or e a b o ut bl o o d v e s s el 
f u n cti o n  a n d  t h e  c o ntr ol  of  m u s cl e  bl o o d  fl o w  with  e x er ci s e  i n  s u bj e ct s  wit h c o n diti o n s  t h at  h a v e  a  v a s c ul ar  
d y sf u n cti o n  c o m p o n e nt,  s u c h  a s  H e art  F ail ur e  or  H e art  Tr a n s pl a nt ati o n , H y p ert e n si o n,  C hr o ni c  O b str u cti v e  
P ul m o n ar y Di s e a s e, a n d S cl er o d er m a . Y o u ar e b ei n g a s k e d t o t a k e p a rt i n a r e s e ar c h st u d y b e c a u s e y o u ar e 1 8 
y e ar s or ol d er a n d i n g o o d h e alt h, or h a v e b e e n di a g n o s e d wit h o n e or m or e of t h e s e c o n diti o n s. T h er e ar e t w o 
dr u g s u s e d i n t hi s st u d y t h at ar e c o n si d er e d i n v e sti g at i o n al, w hi c h m e a n s t h at t h e y ar e n ot a p pr o v e d f or g e n er al u s e 
b y t h e F e d er al Dr u g A d mi ni str ati o n ( F D A). H o w e v er, w e h a v e s p e ci al p er mi s si o n fr o m t h e F D A t o u s e t h e s e dr u g s 
f or t hi s st u d y. B ef or e y o u d e ci d e w h et h er or n ot t o p arti ci p at e it i s i m p ort a nt f or y o u t o u n d er st a n d w h y t h e r e s e ar c h 
i s b ei n g p erf or m e d a n d w h at it will i n v ol v e. Pl e a s e t a k e ti m e t o r e a d t h e f oll o wi n g i nf or m ati o n c ar ef ull y a n d di s c u s s it 
wit h fri e n d s a n d r el ati v e s if y o u wi s h. A s k t h e r e s e ar c h d o ct or or st aff if t h er e i s a n yt hi n g t h at i s n ot cl e ar or if y o u 
w o ul d li k e m or e i nf or m ati o n. L a b or at or y p er s o n n el a n d e m pl o y e e s of Dr. Ri c h ar d s o n or a n y of t h e c o -i n v e sti g at or s 
ar e i n eli gi bl e t o p arti ci p at e i n t hi s r e s e ar c h st u d y.  
 


V A  D e p art m e nt of V et er a n s Aff air s  
V A  R E S E A R C H  C O N S E N T  F O R M  
 P a g e 2 of 2 2  
P arti ci p a nt N a m e:                                                                                                           D at e:   _ _ _ _ _ _ _ _ _                   
Titl e of St u d y:  “V a s c ul ar a n d A ut o n o mi c M al a d a pt ati o n s i n P ati e nt s wit h V a s c ul ar D y sf u n cti o n ”  
Pri n ci p al I n v e sti g at or:  R u s s ell S. Ri c h ar d s o n, P h. D.                                          V A M C: S alt L a k e Cit y ( 6 6 0)     
C o n s e nt V er si o n D at e:  V er si o n  (  M a y  2 0 1 5 )  
 
F O O T E R F O R I R B U S E O N L Y  
V er si o n: B 0 1 1 1  
 
« I m a g e: St a m p»  
« I n stit uti o n»  
« I R B» 
« A p pr o v e d » « A p pr o v e d D at e » 
« E x pir ati o n » 
« E x pir ati o n D at e » 
« N u m b er »  
V A F O R M  1 0 -1 0 8 6  J U N E 1 9 9 0  
 
 
 
 
S T U D Y P R O C E D U R E S  
T h e st u d y ( a s e x pl ai n e d b el o w) i s di vi d e d i nt o s e v er al p art s. A pr eli mi n ar y vi sit i s r e q uir e d f or all p arti ci p a nt s t o 
d et er mi n e y o ur eli gi bilit y f or t h e st u d y. If  y o u ar e f o u n d t o b e eli gi bl e, y o u will b e a s k e d t o c o m pl et e s e v er al 
e x er ci s e  t e st s.  F or  y o ur  s e c o n d  vi sit,  y o u  m a y  a gr e e  t o  p arti ci p at e  i n  ei t h er  pr ot o c ol  1,  2,  or  3.  Y o u  m a y  
p arti ci p at e i n m or e t h a n o n e pr ot o c ol, b ut ar e n ot r e q uir e d t o d o s o. Y o u m a y e nr oll i n pr ot o c ol s 2 or 3 a n y  ti m e 
aft er  c o m pl eti o n  of  pr ot o c ol  1.  H o w e v er,  aft er  c o m pl eti n g  pr ot o c ol  2  or  3,  y o u  m u st  w ait  t w o  m o nt h s  b ef or e  
e nr olli n g i n a n a d diti o n al pr ot o c ol. Y o u m a y al s o p arti ci p at e i n pr ot o c ol 3 ( pr e -tr ai ni n g) wit h o ut a gr e ei n g t o t h e 
e x er ci s e  tr ai ni n g  p orti o n  of  t h e  st u d y.  T h e  pr ot o c ol s  y o u  a gr e e  t o  p arti ci p at e  i n  ar e  hi g hli g ht e d  o n  t hi s  
fl o w c h art: 
 
   


V A  D e p art m e nt of V et er a n s Aff air s  
V A  R E S E A R C H  C O N S E N T  F O R M  
 P a g e 3 of 2 2  
P arti ci p a nt N a m e:                                                                                                           D at e:   _ _ _ _ _ _ _ _ _                   
Titl e of St u d y:  “V a s c ul ar a n d A ut o n o mi c M al a d a pt ati o n s i n P ati e nt s wit h V a s c ul ar D y sf u n cti o n ”  
Pri n ci p al I n v e sti g at or:  R u s s ell S. Ri c h ar d s o n, P h. D.                                          V A M C: S alt L a k e Cit y ( 6 6 0)     
C o n s e nt V er si o n D at e:  V er si o n  (  M a y  2 0 1 5 )  
 
F O O T E R F O R I R B U S E O N L Y  
V er si o n: B 0 1 1 1  
 
« I m a g e: St a m p»  
« I n stit uti o n»  
« I R B» 
« A p pr o v e d » « A p pr o v e d D at e » 
« E x pir ati o n » 
« E x pir ati o n D at e » 
« N u m b er »  
V A F O R M  1 0 -1 0 8 6  J U N E 1 9 9 0  
 
 
 
 
 
P R E LI MI N A R Y D A Y ( 1 h o ur)  
 
1.  Y o u will r e p ort t o t h e V a s c ul ar L a b or at or y ( V A M e di c al C e nt er, B uil di n g 2, r o o m 1 D 2 3)  a n d a m e m b er of t h e 
r e s e ar c h t e a m will e s c ort y o u t o t h e d e p art m e nt of R a di ol o g y. A t e c h ni ci a n will s c an t h e bl o o d v e s s el s i n y o ur 
n e c k t o c h e c k f or f at d e p o sit s ( c all e d pl a q u e). T hi s pr o c e d ur e will t a k e a p pr o xi m at el y 1 5 mi n ut e s.   
 
2.  Aft er t h e s c a n, y o u will r et ur n t o t h e V a s c ul ar L a b or at or y a n d p erf or m a s eri e s of v a s c ul ar a n d e x er ci s e t e st s.  
 
3.  Fir st, y o u will p erf or m a m a xi m al e x er ci s e t e st ( 1 0 mi n ut e s) o n t h e pl a nt ar fl e xi o n er g o m et er, a m a c hi n e t h at 
e x er ci s e s t h e m u s cl e s of y o ur l o w er l e g u si n g a m oti o n si mil ar t o pr e s si n g t h e g a s p e d al of a c ar. T hi s t e st will 
d et er mi n e t h e m a xi m al str e n gt h of y o ur l o w er  l e g ( c alf m u s cl e).   
 
4.  N e xt,  y o u  will  p erf or m  a  s h ort  e x er ci s e  t e st  ( 1 0  mi n ut e s)  o n  t h e  k n e e -e xt e n s or  er g o m et er,  a  m a c hi n e  t h at  
e x er ci s e s t h e m u s cl e s of y o ur u p p er l e g u si n g a ki c ki n g m oti o n. T hi s t e st will d et er mi n e y o ur o n e -l e g m a xi m al 
ki c ki n g str e n gt h.  
 
5.  N e xt, y o u will s q u e e z e a s p e ci al h a n dl e a s h ar d a s y o u c a n t o d et er mi n e y o u m a xi m al gri p str e n gt h.  
 
6.  F or  t h e  l a st  e x er ci s e  t e st,  y o u  will  c o m pl et e  a  m a xi m al  w h ol e -b o d y e x er ci s e t e st  o n eit h er  a tr e a d mill or  a 
st ati o n ar y e x er ci s e bi c y cl e  d uri n g w hi c h y o ur eff ort will b e c o m e gr e at er e a c h mi n ut e o v er a p eri o d of a b o ut 1 0 -
1 5 mi n ut e s.  D uri n g  t h e t e st  y o u will b e br e at hi n g  t hr o u g h a m o ut h pi e c e w hi c h will m e a s ur e t h e a m o u nt  of  
o x y g e n y o u u s e e a c h mi n ut e. T h e a cti vit y of y o ur h e art will b e m o nit or e d t o e n s ur e t h at y o u h a v e n o h e art 
pr o bl e m s. T hi s el e ctr o c ar di o gr a m ( E C G) will i n v ol v e t h e c oll e cti o n of  el e ctri c al si g n al s fr o m y o ur h e art fr o m 
sti c k y p a d s a p pli e d t o y o ur c h e st a n d si d e.  Y o u m a y b e a s k e d t o p erf or m s e v er al t a s k s t o a s s e s s y o ur c o g niti v e 
a biliti e s a n d y o ur fit n e s s l e v el a n d t o w e ar a p e d o m et er f or a w e e k, w hi c h will m e a s ur e y o ur a cti vit y l e v el.  
 
7.  W o m e n will b e a s k e d a b o ut t h e p o s si bilit y of pr e g n a n c y a n d m et h o d s or birt h c o ntr ol, a n d will b e a s k e d t o 
s u b mit t o  a uri n e pr e g n a n c y t e st  pr o vi d e d b y t h e r e s e ar c h sit e  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _(I niti al s a n d D at e)  
 
B y i niti ali n g h er e, I a gr e e t o p arti ci p at e i n t h e pr ot o c ol d e s cri b e d a b o v e.  
 


V A  D e p art m e nt of V et er a n s Aff air s  
V A  R E S E A R C H  C O N S E N T  F O R M  
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P arti ci p a nt N a m e:                                                                                                           D at e:   _ _ _ _ _ _ _ _ _                   
Titl e of St u d y:  “V a s c ul ar a n d A ut o n o mi c M al a d a pt ati o n s i n P ati e nt s wit h V a s c ul ar D y sf u n cti o n ”  
Pri n ci p al I n v e sti g at or:  R u s s ell S. Ri c h ar d s o n, P h. D.                                          V A M C: S alt L a k e Cit y ( 6 6 0)     
C o n s e nt V er si o n D at e:  V er si o n  (  M a y  2 0 1 5 )  
 
F O O T E R F O R I R B U S E O N L Y  
V er si o n: B 0 1 1 1  
 
« I m a g e: St a m p»  
« I n stit uti o n»  
« I R B» 
« A p pr o v e d » « A p pr o v e d D at e » 
« E x pir ati o n » 
« E x pir ati o n D at e » 
« N u m b er »  
V A F O R M  1 0 -1 0 8 6  J U N E 1 9 9 0  
 
 
 
 
 
P R O T O C O L 1 ( 2- 3 h o ur s p er vi sit, 2- 4 vi sit s)  
 
If y o u d e ci d e t o p arti ci p at e i n t hi s p orti o n of t h e st u d y, y o u will b e a s k e d t o r e p ort t o t h e V a s c ul ar L a b or at or y ( V A 
M e di c al C e nt er, B uil di n g 2, r o o m 1 D 2 3)  f or 2- 4 vi sit s t h at will e a c h l a st 2- 3 h o ur s. All vi sit s will t a k e pl a c e wit hi n t w o 
w e e k s . B ef or e e a c h vi sit, y o u will t a k e o n e of t h e f oll o wi n g: ( 1) s u g ar pill s ( pl a c e b o), ( 2) o v er -t h e-c o u nt er a nti o xi d a nt 
vit a mi n s ( A, E, a n d al p h a-li p oi c a ci d), ( 3) A s u p pl e m e nt c all e d B H 4 ( 1 0 m g/ k g), or ( 4) B H4  + a nti o xi d a nt s.  A m e m b er 
of t h e i n v e sti g ati v e t e a m will pr o vi d e t h e s u p pl e m e nt ar y pill s t o y o u d uri n g t h e pr eli mi n ar y d a y vi sit d e s cri b e d a b o v e. 
T hi s pr ot o c ol i s a “ bli n d e d” d e si g n, w hi c h m e a n s t h at n eit h er y o u n or t h e i n v e sti g ati v e t e a m will k n o w w hi c h  gr o u p 
y o u  at t h at ti m e .  
 
1.  O n e a c h vi sit a r e sti n g bl o o d s a m pl e of a b o ut 1 5 ml ( a b o ut 4. 5 t e a s p o o n s) will b e t a k e n fr o m a bl o o d v e s s el 
n e ar t h e i n si d e of y o ur el b o w ( v e ni p u n ct ur e) b y q u alifi e d p er s o n n el at t h e V A H o s pit al.  T h e s e s a m pl e s will 
b e u s e d t o m e a s ur e bl o o d li pi d s, ot h er n or m al m e a s ur e m e nt s s u c h a s gl u c o s e, cr e ati n e, s o di u m, c al ci u m, 
a n d w at er s ol u bl e a nti o xi d a nt s ( s u b st a n c e s t h at h el p pr ot e ct t h e b o d y’ s c ell s fr o m d a m a g e). T hi s pr o c e d ur e 
will t a k e a b o ut 5 -1 0 mi n ut e s.  
 
2.  Bl o o d v e s s el f u n cti o n m e a s ur e m e nt s will b e m e a s ur e d i n t h e m or ni n g f oll o wi n g a n o v er ni g ht f a st of at l e a st 
1 2 h o ur s, a n d b ef or e p arti ci p ati n g  i n a n y str e n u o u s p h y si c al a cti vit y.  Pri or t o a n y t e sti n g, w o m e n will t a k e a 
uri n e pr e g n a n c y t e st. Aft er r e sti n g f or 1 0 mi n ut e s o n a t h er a p y t a bl e, bl o o d v e s s el h e alt h a n d f u n cti o ni n g will 
b e m e a s ur e d. I n o n e t e st, a n a ut o m ati c bl o o d pr e s s ur e c uff will b e wr a p p e d ar o u n d y o ur u p p er l eft ar m, a n d 
a h ar d pl a sti c wri st s u p p ort will mi ni mi z e m o v e m e nt of t h e ri g ht wri st d uri n g t h e bl o o d v e s s el m e a s ur e m e nt.  
W hil e  l yi n g  o n  t h e  t h er a p y  t a bl e,  a  t hi n  m et al  w a n d  will  b e  pl a c e d  o n  t h e  p ul s e  of  t h e  ri g ht  wri st.  
M e a s u r e m e nt  will  b e  o bt ai n e d  a n d  a v er a g e d  o v er  t hr e e  c o n s e c uti v e  3 0-s e c o n d  tri al s.  I n  a n ot h er  t e st,  a 
D o p pl er  ultr a s o u n d m a c hi n e  will b e u s e d t o m e a s ur e bl o o d fl o w i n v e s s el s i n t h e n e c k, wri st, a n d u p p er t hi g h .  
I n a d diti o n t o t h e bl o o d v e s s el m e a s ur e m e nt s, h ei g ht , w ei g ht , a n d s ki n f ol d t hi c k n e s s will b e m e a s ur e d a n d 
r e c or d e d. T h e m e a s ur e of bl o o d v e s s el f u n cti o n d o e s n ot p e n etr at e t h e b o d y i n a n y w a y, a n d r e q uir e s t h at 
y o u li e still d uri n g t h e m e a s ur e m e nt s. T hi s a s s e s s m e nt will t a k e a b o ut 2 0 - 30 mi n ut e s.  
 
3.  Bl o o d fl o w will b e m e a s ur e d wit h a  D o p pl er  ultr a s o u n d m a c hi n e t h at d o e s n ot p e n etr at e t h e b o d y i n a n y w a y. 
A bl o o d pr e s s ur e c uff will b e wr a p p e d ar o u n d y o ur f or e ar m or ar o u n d y o ur l o w er l e g. G el will b e a p pli e d o n 
t h e ar e a of t h e ar m or l e g t h at will b e u s e d f or m e a s uri n g bl o o d fl o w. T h e bl o o d pr e s s ur e c uff will b e i nfl at e d 
t o 2 5 0 m m H g, t h e u p p er e n d of t h e n or m al i nfl ati o n r a n g e, f or fi v e mi n ut e s t o st o p bl o o d fl o w of t h e art er y 
t h at  will  b e  e x a mi n e d  f or  c h a n g e  i n  di a m et er  u p o n  c uff  d efl ati o n. T hi s  pr o c e d ur e  i s  r ef err e d  t o  a s  t h e  
m e a s ur e m e nt of fl o w -m e di at e d v a s o dil ati o n ( F M D). Si n c e o b str u cti n g t h e bl o o d fl o w f or fi v e mi n ut e s m a y b e 
p ai nf ul  f or  s o m e  i n di vi d u al s  it  s h o ul d  b e  n ot e d  t h at  if  y o u  wi s h  t o  st o p  t hi s  t e st  at  a n y  p oi nt  d uri n g  t h e  
m e a s u r e m e nt t h e r e s e ar c h p er s o n n el will d o s o. T hi s a s s e s s m e nt will t a k e a b o ut 2 0 -3 0  mi n ut e s.  
 


V A  D e p art m e nt of V et er a n s Aff air s  
V A  R E S E A R C H  C O N S E N T  F O R M  
 P a g e 5 of 2 2  
P arti ci p a nt N a m e:                                                                                                           D at e:   _ _ _ _ _ _ _ _ _                   
Titl e of St u d y:  “V a s c ul ar a n d A ut o n o mi c M al a d a pt ati o n s i n P ati e nt s wit h V a s c ul ar D y sf u n cti o n ”  
Pri n ci p al I n v e sti g at or:  R u s s ell S. Ri c h ar d s o n, P h. D.                                          V A M C: S alt L a k e Cit y ( 6 6 0)     
C o n s e nt V er si o n D at e:  V er si o n  (  M a y  2 0 1 5 )  
 
F O O T E R F O R I R B U S E O N L Y  
V er si o n: B 0 1 1 1  
 
« I m a g e: St a m p»  
« I n stit uti o n»  
« I R B» 
« A p pr o v e d » « A p pr o v e d D at e » 
« E x pir ati o n » 
« E x pir ati o n D at e » 
« N u m b er »  
V A F O R M  1 0 -1 0 8 6  J U N E 1 9 9 0  
 
 
 
 
4.  T w o e x er ci s e pr ot o c ol s will b e u s e d t h at utili z e a si n gl e ar m or  si n gl e l e g. T h e ar m or  l e g will b e p a s si v el y 
m o v e d  t hr o u g h  a  n or m al  r a n g e  of  m oti o n  (t h e  p arti ci p a nt  will  st a y  r el a x e d  a n d  tr y  n ot  t o  e n g a g e  t h eir  
m u s cl e s). Q u alifi e d p er s o n n el of t h e V a s c ul ar L a b or at or y will b e s u p p orti n g a n d m o vi n g t h e ar m or l e g f or t h e 
p arti ci p a nt.  T h e  a cti v e  e x er ci s e  t e st s  r e q uir e  t h at  y o u  gi v e  m a xi m u m  eff ort  f or  eit h er  t h e  ar m  or  l e g  b y  
m o vi n g t h at a p p e n d a g e t hr o u g h a n or m al r a n g e of m oti o n a g ai n st s o m e r e si st a n c e. T h e ar m or l e g will b e 
t h e o nl y p art of t h e b o d y m o vi n g or pr o d u ci n g a n y eff ort. T h e  D o p pl er ultr a s o u n d m a c hi n e will b e u s e d t o 
m a k e  m e a s ur e m e nt s o n t h e bl o o d v e s s el of y o ur ar m or l e g b ef or e , d uri n g , a n d f or a s h ort ti m e aft er t h e 
e x er ci s e.  T hi s a s s e s s m e nt will t a k e a b o ut 4 5 -6 0  mi n ut e s.  
 
5.  W hil e lyi n g o n t h e t h er a p y t a bl e, a V A  p h y si ci a n will pl a c e a s m all d o s e of nitr o gl y c eri n  u n d er y o ur t o n g u e .  
U si n g t h e  D o p pl er  ultr a s o u n d m a c hi n e, bl o o d v e s s el m e a s ur e m e nt s will b e t a k e n b ef or e, d uri n g, a n d f or a 
s h ort ti m e aft er nitr o gl y c eri n a d mi ni str ati o n .  S o m e p e o pl e  e x p eri e n c e di z zi n e s s wit h nitr o gl y c eri n , s o t h e t e st 
will b e a d mi ni st er e d wit h y o u l yi n g d o w n, a n d y o u will b e a s k e d t o st a y l yi n g d o w n u ntil t h e eff e ct s h a v e g o n e 
a w a y c o m pl et el y.  T hi s pr o c e d ur e will t a k e a b o ut 2 0 -3 0 mi n ut e s.     
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _(I niti al s a n d D at e)  
 
B y i niti ali n g h er e, I a gr e e t o p arti ci p at e i n t h e pr ot o c ol d e s cri b e d a b o v e  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


V A  D e p art m e nt of V et er a n s Aff air s  
V A  R E S E A R C H  C O N S E N T  F O R M  
 P a g e 6 of 2 2  
P arti ci p a nt N a m e:                                                                                                           D at e:   _ _ _ _ _ _ _ _ _                   
Titl e of St u d y:  “V a s c ul ar a n d A ut o n o mi c M al a d a pt ati o n s i n P ati e nt s wit h V a s c ul ar D y sf u n cti o n ”  
Pri n ci p al I n v e sti g at or:  R u s s ell S. Ri c h ar d s o n, P h. D.                                          V A M C: S alt L a k e Cit y ( 6 6 0)     
C o n s e nt V er si o n D at e:  V er si o n  (  M a y  2 0 1 5 )  
 
F O O T E R F O R I R B U S E O N L Y  
V er si o n: B 0 1 1 1  
 
« I m a g e: St a m p»  
« I n stit uti o n»  
« I R B» 
« A p pr o v e d » « A p pr o v e d D at e » 
« E x pir ati o n » 
« E x pir ati o n D at e » 
« N u m b er »  
V A F O R M  1 0 -1 0 8 6  J U N E 1 9 9 0  
 
 
 
 
P R O T O C O L 2 ( C hr o ni c S u p pl e m e nt ati o n, 7 vi sit s):  
 
If y o u d e ci d e t o p arti ci p at e i n t hi s p orti o n st u d y, y o u will b e a s k e d t o r e p ort t o t h e V a s c ul ar L a b or at or y ( V A M e di c al 
C e nt er, B uil di n g 2, r o o m 1 D 2 3)  f or 7 vi sit s. F or e a c h vi sit, y o u will b e  a s k e d n ot t o e at or dri n k a n yt hi n g ot h er t h a n 
w at er f or 1 2 h o ur s b ef or e arri v al t o t h e l a b or at or y ( o v er ni g ht f a st).   
 
Y o u will b e a s k e d o n e of f o ur s u p pl e m e nt s f or 3 0 d a y s: ( 1) s u g ar pill s ( pl a c e b o), ( 2) o v er -t h e-c o u nt er a nti o xi d a nt 
vit a mi n s ( A, E, a n d alp h a -li p oi c a ci d), ( 3) A s u p pl e m e nt c all e d B H 4 ( 1 0 m g/ k g), or ( 4) B H4  + a nti o xi d a nt s.  Y o u will b e 
r a n d o ml y a s si g n e d i nt o o n e of t h e f o ur gr o u p s. A m e m b er of t h e i n v e sti g ati v e t e a m will pr o vi d e t h e s u p pl e m e nt ar y 
pill s t o y o u d uri n g t h e pr eli mi n ar y d a y vi sit d e s cri b e d a b o v e. T hi s pr ot o c ol i s a “ bli n d e d” d e si g n, w hi c h m e a n s t h at 
n eit h er y o u n or t h e i n v e sti g ati v e t e a m will k n o w w h at gr o u p y o u ar e i n d uri n g t h e 3 0 -d a y r e gi m e n.  
 
T w o of t h e s e v e n vi sit s ( D a y 0 a n d D a y 3 0) ar e l o n g er e x p eri m e nt al d a y s ( 5 -6 h o ur s). O n t h e s e vi sit s, t h e 
f oll o wi n g t hi n g s will h a p p e n: 
 
1.  T w o h o ur s pri or t o arri v al i n t h e l a b, y o u will b e a s k e d t o t a k e t w o d o s e s of eit h er a pl a c e b o ( s u g ar pill s) or 
o v er -t h e-c o u nt er vit a mi n s ( A, E, a n d al p h a -li p oi c a ci d) s o t h at w e c a n t e st t h e eff e ct s of b oo sti n g y o ur b o d y’ s 
n at ur al d ef e n s e s y st e m a g ai n st s o m e of t h e str e s s r e s p o n s e s p ot e nti all y r e s ulti n g fr o m v a s c ul ar d y sf u n cti o n .  
 
2.  Y o u will r e p ort t o t h e l a b at a p pr o xi m at el y 8 A. M. Pri or t o a n y t e sti n g, w o m e n will t a k e a uri n e pr e g n a n c y t e st.  
T w o c at h et er s  ( pl a sti c t u b e s) will b e pl a c e d i n bl o o d v e s s el s i n eit h er y o ur ar m or y o ur l e g. T h e s e c at h et er s will 
b e i n s ert e d b y a p h y si ci a n u si n g st eril e i n str u m e nt s a n d s u p pli e s. M e di c ati o n will b e u s e d t o n u m b y o ur s ki n a n d 
mi ni mi z e t h e di s c o mf ort of t hi s pr o c e d ur e. T h e s e c at h et er s will st a y i n y o ur ar m or l e g d uri n g t h e e ntir e pr ot o c ol. 
W e will m e a s ur e bl o o d pr e s s ur e a n d t a k e bl o o d s a m pl e s  fr o m t h e c at h et er s i n y o ur ar m or l e g s e v er al ti m e s 
d uri n g t h e st u d y. T h e t ot al a m o u nt of bl o o d wit h dr a w n i s 1 5 0 ml ( 1 0 t e a s p o o n s), or a p pr o xi m at el y 1/ 3 of w h at 
w o ul d b e wit h dr a w n d uri n g a t y pi c al bl o o d d o n ati o n ( 4 5 0 ml). T hr o u g h o ut t h e pr ot o c ol, w e will m e a s ur e bl o o d 
fl o w,  bl o o d  pr e s s ur e  a n d  h e art  r at e.  Bl o o d  fl o w  will  b e  m e a s ur e d  u si n g  t h e  D o p pl er  ultr a s o u n d  m a c hi n e. 
Bl o o d pr e s s ur e  will b e m e a s ur e d fr o m t h e c at h et er s i n y o ur ar m or l e g, a n d h e art r at e  will b e m e a s ur e d fr o m  
sti c k y p a d s pl a c e d o n y o ur c h e st.  
 
3.  Aft er t h e c at h et er s ar e i n s ert e d, t h e stiff n e s s of y o ur bl o o d v e s s el s  will b e d et er mi n e d. A n a ut o m ati c bl o o d 
pr e s s ur e  c uff  will  b e  wr a p p e d  ar o u n d  y o ur  u p p er  l eft  ar m,  a n d  a  h ar d  pl a sti c  wri st  s u p p ort  will  mi ni mi z e  
m o v e m e nt of t h e ri g ht wri st d uri n g t h e bl o o d v e s s el m e a s ur e m e nt.  W hil e l yi n g o n t h e t h er a p y t a bl e, a t hi n 
m et al w a n d will b e pl a c e d o n t h e p ul s e  of t h e ri g ht wri st. M e a s ur e m e nt will b e o bt ai n e d a n d a v er a g e d o v er 
t hr e e c o n s e c uti v e 3 0-s e c o n d tri al s.  
 
4.  N e xt, a fl o w-m e di at e d v a s o dil ati o n ( F M D) t e st  will b e p erf or m e d. F or t hi s t e st, y o u will li e d o w n o n a b e d a n d 
a bl o o d pr e s s ur e c uff will b e pl a c e d o n y o ur u p p er ar m or l e g ( a b o v e t h e k n e e) a n d i nfl at e d t o 2 5 0 m m H g, 
t h e u p p er e n d of t h e n or m al i nfl ati o n r a n g e, f or 5 mi n ut e s. T hi s pr o c e d ur e will t e m p or aril y st o p t h e fl o w of 


V A  D e p art m e nt of V et er a n s Aff air s  
V A  R E S E A R C H  C O N S E N T  F O R M  
 P a g e 7 of 2 2  
P arti ci p a nt N a m e:                                                                                                           D at e:   _ _ _ _ _ _ _ _ _                   
Titl e of St u d y:  “V a s c ul ar a n d A ut o n o mi c M al a d a pt ati o n s i n P ati e nt s wit h V a s c ul ar D y sf u n cti o n ”  
Pri n ci p al I n v e sti g at or:  R u s s ell S. Ri c h ar d s o n, P h. D.                                          V A M C: S alt L a k e Cit y ( 6 6 0)     
C o n s e nt V er si o n D at e:  V er si o n  (  M a y  2 0 1 5 )  
 
F O O T E R F O R I R B U S E O N L Y  
V er si o n: B 0 1 1 1  
 
« I m a g e: St a m p»  
« I n stit uti o n»  
« I R B» 
« A p pr o v e d » « A p pr o v e d D at e » 
« E x pir ati o n » 
« E x pir ati o n D at e » 
« N u m b er »  
V A F O R M  1 0 -1 0 8 6  J U N E 1 9 9 0  
 
 
 
 
bl o o d t o y o ur l o w er or l o w er l e g. Y o u m a y n oti c e s o m e ti n gli n g s e n s ati o n i n y o ur h a n d or f o ot d uri n g t hi s 
ti m e. Aft er 5 mi n ut e s t h e c uff will b e r el e a s e d, a n d w e will m e a s ur e t h e bl o o d fl o w a s it r et ur n s t o y o ur ar m or 
l e g. 
 
5.  F oll o wi n g t h e F M D t e st, w e will t a k e a  m u s cl e bi o p s y fr o m t h e t hi g h of o n e of y o ur l e g s. T hi s i s t o d et er mi n e 
w h e t h er y o ur m u s cl e s ar e n or m al a n d h o w t h e y a p p e ar u n d er t h e mi cr o s c o p e a n d c h e mi c all y. Bi o p si e s of y o ur 
l e g m u s cl e s will b e o bt ai n e d u si n g a s p e ci al n e e dl e. T o p erf or m a m u s cl e bi o p s y, w e will fir st cl e a n t h e s ki n wit h 
i o di n e ( or r u b bi n g al c o h ol, if y o u ar e all er gi c t o i o di n e) t o pr e v e nt i nf e cti o n. N e xt, a n ar e a of s ki n a n d t h e ti s s u e s 
o n t h e o ut er fr o nt p orti o n of  eit h er of  y o ur l o w er t hi g h s will b e n u m b e d u si n g a n e st h eti c a n d a s m all ( 1/ 8”) 
i n ci si o n m a d e wit h a s c al p el. T h e s p e ci al bi o p s y n e e dl e will b e i ns ert e d t hr o u g h t h e i n ci si o n a n d i nt o y o ur t hi g h 
m u s cl e s e v er al ti m e s a n d a s m all a m o u nt of ti s s u e will b e r e m o v e d ( n o m or e t h a n t h e si z e of a p e n cil er a s er). 
Aft er t h e bi o p s y i s c o m pl et e d, d e e p pr e s s ur e will b e a p pli e d t o t h e sit e f or a p pr o xi m at el y 2 0 mi n u t e s t o r e d u c e 
t h e ri s k of bl e e di n g a n d t h e n a st eril e stri p of t a p e will b e u s e d t o cl o s e t h e i n ci si o n.  
 
6.  Aft er t h e m u s cl e bi o p s y, w e will u s e a t e c h ni q u e c all e d mi cr o n e ur o gr a p h y  t o l o c at e t h e n er v e i n y o ur ot h er l e g 
( wit h n o c at h et er s) t o m e a s ur e n er v e a cti vit y. Fir st, w e will s e n d a v er y s m all el e ctri c c urr e nt (l e s s t h a n 4 V) 
t hr o u g h  a  p e n cil-s h a p e d  pr o b e  w hi c h  will  b e  pl a c e d  o n  y o ur  s ki n  b e hi n d  y o ur  k n e e.  W h e n  t h e  n er v e  i s  
sti m ul at e d, i n v ol u nt ar y t wit c hi n g a n d/ or ti n gli n g s e n s ati o n s of t h e l o w er l e g or f o ot will o c c ur. T h e t wit c hi n g or 
ti n gli n g will di s a p p e ar w h e n t h e sti m ul ati o n i s st o p p e d. T hi s pr o c e d ur e u s u all y l a st s l e s s t h a n t w o mi n ut e s, s o 
o nl y 6 -8 sti m uli ar e s e nt t hr o u g h t h e pr o b e. O n c e t h e n er v e i s f o u n d, t w o st eril e el e ctr o d e s ( a b o ut t h e si z e of  a n 
a c u p u n ct ur e n e e dl e s) will b e i n s ert e d t hr o u g h t h e s ki n i n y o ur l e g. O n e el e ctr o d e i s a r ef er e n c e pl a c e d j u st 
a b o v e  t h e  n er v e  sit e  ( 2  c m)  a n d  t h e  ot h er  el e ctr o d e  i s  u s e d  f or  r e c or di n g.  W h e n  t h e  ti p  of  t h e  r e c or di n g  
el e ctr o d e e nt er s t h e n er v e, y o u will n oti c e eit h er i n v ol u nt ar y m u s cl e t wit c h e s or ti n gli n g i n t h e l e g or f o ot. At t hi s 
p oi nt, o nl y mi n or a dj u st m e nt s i n t h e p o siti o n of  t h e n e e dl e will b e m a d e u ntil w e b e gi n t o r e c or d t h e n er v e 
si g n al.  
 
7.  T h e n e xt p art of t h e st u d y will i n v ol v e t w o t e st s of h o w w ell y o ur b o d y r e s p o n d s t o c h a n g e s i n bl o o d pr e s s ur e 
b y  a cti v ati n g  pr e s s ur e -s e n siti v e  n er v e s  l o c at e d  i n  t h e  bl o o d  v e s s el s  of  y o ur  n e c k  ( c ar oti d  art er y).  T hi s  
pr o c e d ur e i n v ol v e s u s e of a n e c k c oll ar  t h at cr e at e s a s e al e d c h a m b er of air ar o u n d t h e fr o nt of y o ur n e c k. 
T hi s c h a m b er i s att a c h e d t o a v a c u u m m ot or t h at cr e at e s s m all c h a n g e s i n air pr e s s ur e n e ar t h e s urf a c e of 
t h e s ki n o n y o ur n e c k, w hi c h will t e m p or aril y c h a n g e t h e a cti vit y of t h e “ pr e s s ur e s e n s or s” i n y o ur c ar oti d 
art er y. T hi s will c a u s e a s m all c h a n g e i n y o ur bl o o d pr e s s ur e a n d h e art r at e.  
 
8.  Aft er t h e n e c k c oll ar pr o c e d ur e, w e will i nj e ct a s m all a m o u nt of t w o diff er e nt dr u g s t o f urt h er e x a mi n e h o w 
w ell y o ur  b o d y r e s p o n d s t o c h a n g e s i n bl o o d pr e s s ur e.  T hi s t e st  u s e s a pr o c e d ur e c all e d “t h e m o difi e d 
O xf or d t e c h ni q u e ”. W e will fir st i nj e ct t h e dr u g P h e n yl e p hri n e ( P E), a c h e mi c al si mil ar t o o n e t h at y o ur o w n 
b o d y pr o d u c e s t h at m a k e s y o ur bl o o d v e s s el s m all er a n d m a k e y o ur bl o o d pr e s s ur e i n cr e a s e b y a b o ut 1 5 
m m H g. N e xt, w e will i nj e ct a v er y s m all a m o u nt of a dr u g c all e d S o di u m Nitr o pr u s si d e ( S N P)  i nt o t h e v ei n i n 
y o ur l e g. T hi s dr u g will m a k e y o ur bl o o d v e s s el bi g g er a n d m a k e y o ur bl o o d pr e s s ur e d e cr e a s e b y a b o ut 1 5 
m m H g. W e will i nj e ct P E a n d S N P 2 -3 ti m e s e a c h f or a b o ut 3 0 s e c o n d s at e a c h d o s e.  


V A  D e p art m e nt of V et er a n s Aff air s  
V A  R E S E A R C H  C O N S E N T  F O R M  
 P a g e 8 of 2 2  
P arti ci p a nt N a m e:                                                                                                           D at e:   _ _ _ _ _ _ _ _ _                   
Titl e of St u d y:  “V a s c ul ar a n d A ut o n o mi c M al a d a pt ati o n s i n P ati e nt s wit h V a s c ul ar D y sf u n cti o n ”  
Pri n ci p al I n v e sti g at or:  R u s s ell S. Ri c h ar d s o n, P h. D.                                          V A M C: S alt L a k e Cit y ( 6 6 0)     
C o n s e nt V er si o n D at e:  V er si o n  (  M a y  2 0 1 5 )  
 
F O O T E R F O R I R B U S E O N L Y  
V er si o n: B 0 1 1 1  
 
« I m a g e: St a m p»  
« I n stit uti o n»  
« I R B» 
« A p pr o v e d » « A p pr o v e d D at e » 
« E x pir ati o n » 
« E x pir ati o n D at e » 
« N u m b er »  
V A F O R M  1 0 -1 0 8 6  J U N E 1 9 9 0  
 
 
 
 
 
9.  Af t er  t hi s,  y o u  will  p erf or m  s e v er al  s h ort  b o ut s  of  ar m  a n d  l e g  e x er ci s e.  Fir st,  y o ur  ar m  a n d  l e g  will  b e  
p a s si v el y m o v e d t hr o u g h a n or m al r a n g e of m oti o n f or t hr e e mi n ut e s. N e xt, y o u will p erf or m t hr e e l e v el s of 
ar m  e x er ci s e t h at  i n v ol v e s s q u e e zi n g  a p a d d e d  h a n dl e o n c e e v er y s e c o n d f or  3 -mi n ( 2 0 -4 0 -6 0 % of  y o ur 
m a xi m al s q u e e zi n g str e n gt h), f oll o w e d b y t hr e e l e v el s of l e g “ k n e e e xt e n s or” e x er ci s e t h at i n v ol v e s p utti n g 
y o ur  l e g  t hr o u g h  a  ki c ki n g  m oti o n  o n c e  e v er y  s e c o n d  f or  3 -mi n  ( 2 0 -4 0 -6 0 %  of  y o ur  m a xi m al  ki c k i n g 
str e n gt h). Y o u will r e st f or 5 -1 0 mi n b et w e e n e a c h e x er ci s e b o ut. At t h e e n d of e a c h e x er ci s e b o ut, a bl o o d 
pr e s s ur e c uff will b e i nfl at e d t o 2 5 0 m m H g, t h e u p p er e n d of t h e n or m al i nfl ati o n r a n g e, f or t w o mi n ut e s. T hi s 
will tr a p s o m e bl o o d i n t h e v e s s e l s of y o ur ar m or l e g t h at h a s j u st e x er ci s e d, a n d m a y c a u s e s o m e ti n gli n g 
a n d mil d di s c o mf ort i n y o ur ar m or l e g.   
 
1 0.  Aft er  t h e e x er ci s e t e st,  y o u will r e st  f or  1 5 mi n,  a n d t h e n r e p e at  t h e e x er ci s e pr ot o c ol wit h a dr u g  i nf u si o n 
pr ot o c ol ( “t h e m o difi e d o xf or d t e c h ni q u e”, d e s cri b e d a b o v e) at t h e e n d of e a c h e x er ci s e b o ut.  
 
T h e r e m ai ni n g fi v e vi sit s t o t h e l a b or at or y ( 1 0, 2 0, 3 3, a n d 3 7) ar e s h ort er e x p eri m e nt al d a y s ( 2 -3 h o ur s). 
O n t h e s e vi sit s, t h e f oll o wi n g t hi n g s will h a p p e n:  
 
1.  Bl o o d v e s s el f u n cti o n m e a s ur e m e nt s will b e m e a s ur e d i n t h e m or ni n g f oll o wi n g a n o v er ni g ht f a st of at l e a st 
1 2 h o ur s, a n d b ef or e p arti ci p ati n g i n a n y str e n u o u s p h y si c al a cti vit y.  Pri or t o a n y t e sti n g, w o m e n will t a k e a 
uri n e pr e g n a n c y t e st. Aft er r e sti n g f or 1 0 mi n ut e s o n a t h er a p y t a bl e, bl o o d v e s s el h e alt h a n d f u n cti o ni n g will 
b e m e a s ur e d. A n a ut o m ati c bl o o d pr e s s ur e c uff  will b e wr a p p e d ar o u n d y o ur u p p er l eft ar m, a n d a h ar d 
pl a sti c wri st s u p p ort will mi ni mi z e m o v e m e nt of t h e ri g ht wri st d uri n g t h e bl o o d v e s s el m e a s ur e m e nt.  W hil e  
l yi n g o n t h e t h er a p y t a bl e, a t hi n m et al w a n d will b e pl a c e d o n t h e p ul s e of t h e ri g ht wri st. M e a s ur e m e nt will 
b e  o bt ai n e d  a n d  a v er a g e d  o v er  t hr e e  c o n s e c uti v e  3 0 -s e c o n d  tri al s.   I n  a d diti o n  t o  t h e  bl o o d  v e s s el  
m e a s ur e m e nt s, h ei g ht , w ei g ht  a n d s ki n f ol d t h i c k n e s s will b e m e a s ur e d a n d r e c or d e d.  T h e m e a s ur e of bl o o d  
v e s s el  f u n cti o n  d o e s  n ot  p e n etr at e  t h e  b o d y  i n  a n y  w a y,  a n d  r e q uir e s  t h at  y o u  li e  still  d uri n g  t h e  
m e a s ur e m e nt s.  T hi s a s s e s s m e nt will t a k e a b o ut 2 0 -3 0 mi n ut e s.  
 
2.  Bl o o d fl o w will b e m e a s ur e d wit h a n ultr a s o u n d m a c hi n e t h at d o e s n ot p e n etr at e t h e b o d y i n a n y w a y.  A 
bl o o d pr e s s ur e c uff will b e wr a p p e d ar o u n d y o ur f or e ar m or ar o u n d y o ur l o w er l e g.  G el will b e a p pli e d o n t h e 
ar e a of t h e ar m or l e g t h at will b e u s e d f or m e a s uri n g bl o o d fl o w.  T h e bl o o d pr e s s ur e c uff will b e i nfl at e d t o 
2 5 0 m m H g, t h e u p p er e n d of t h e n or m al i nfl ati o n r a n g e, f or fi v e mi n ut e s t o st o p bl o o d fl o w of t h e art er y t h at 
will  b e  e x a mi n e d  f or  c h a n g e  i n  di a m et er  u p o n  c uff  d efl ati o n.   T hi s  pr o c e d ur e  i s  r ef err e d  t o  a s  t h e  
m e a s ur e m e nt  of fl o w -m e di at e d v a s o dil ati o n ( F M D).  Si n c e o b str u cti n g t h e bl o o d fl o w f or fi v e mi n ut e s m a y b e 
p ai nf ul  f or  s o m e  i n di vi d u al s  it  s h o ul d  b e  n ot e d  t h at  if  y o u  wi s h  t o  st o p  t hi s  t e st  at  a n y  p oi nt  d uri n g  t h e  
m e a s ur e m e nt t h e r e s e ar c h p er s o n n el will d o s o. T hi s a s s e s s m e nt will t a k e a b o ut 4 5 -6 0 mi n ut e s.  
 
3.  T w o e x er ci s e pr ot o c ol s will b e u s e d t h at utili z e a si n gl e ar m a n d si n gl e l e g. T h e ar m a n d l e g will b e p a s si v el y 
m o v e d  t hr o u g h  a  n or m al  r a n g e  of  m oti o n  (t h e  p arti ci p a nt  will  st a y  r el a x e d  a n d  tr y  n ot  t o  e n g a g e  t h eir  
m u s cl e s).  Q u alifi e d p er s o n n el of t h e V a s c ul ar L a b or at or y will b e s u p p orti n g a n d m o vi n g t h e ar m or l e g f or 


V A  D e p art m e nt of V et er a n s Aff air s  
V A  R E S E A R C H  C O N S E N T  F O R M  
 P a g e 9 of 2 2  
P arti ci p a nt N a m e:                                                                                                           D at e:   _ _ _ _ _ _ _ _ _                   
Titl e of St u d y:  “V a s c ul ar a n d A ut o n o mi c M al a d a pt ati o n s i n P ati e nt s wit h V a s c ul ar D y sf u n cti o n ”  
Pri n ci p al I n v e sti g at or:  R u s s ell S. Ri c h ar d s o n, P h. D.                                          V A M C: S alt L a k e Cit y ( 6 6 0)     
C o n s e nt V er si o n D at e:  V er si o n  (  M a y  2 0 1 5 )  
 
F O O T E R F O R I R B U S E O N L Y  
V er si o n: B 0 1 1 1  
 
« I m a g e: St a m p»  
« I n stit uti o n»  
« I R B» 
« A p pr o v e d » « A p pr o v e d D at e » 
« E x pir ati o n » 
« E x pir ati o n D at e » 
« N u m b er »  
V A F O R M  1 0 -1 0 8 6  J U N E 1 9 9 0  
 
 
 
 
t h e p arti ci p a nt.  T h e a cti v e e x er ci s e t e st s r e q uir e t h at y o u gi v e m a xi m u m eff ort f or eit h er t h e ar m or l e g b y 
m o vi n g t h at a p p e n d a g e t hr o u g h a n or m al r a n g e of m oti o n a g ai n st s o m e r e si st a n c e. T h e ar m or l e g will b e 
t h e o nl y p art of t h e b o d y m o vi n g or pr o d u ci n g a n y eff ort. T hi s a s s e s s m e nt will t a k e a b o ut 2 0-3 0 mi n ut e s.  
 
4.  O n e a c h vi sit a r e sti n g bl o o d s a m pl e of a b o ut 1 5 ml ( a b o ut 4. 5 t e a s p o o n s) will b e t a k e n  fr o m t h e i n si d e of 
y o ur el b o w ( v e ni p u n ct ur e) b y q u alifi e d p er s o n n el at t h e V A H o s pit al.  T h e s e s a m pl e s will b e u s e d t o m e a s ur e 
bl o o d  li pi d s,  ot h er  n or m al  m e a s ur e m e nt s  s u c h  a s  gl u c o s e,  cr e ati n e,  s o di u m,  c al ci u m,  a n d  w at er  s ol u bl e  
a nti o xi d a nt s ( s u b st a n c e s t h at h el p pr ot e ct t h e b o d y’ s c ell s fr o m d a m a g e). T hi s pr o c e d ur e will t a k e a b o ut 5 -1 0 
mi n ut e s.
 
  
5.  Y o u m a y b e a s k e d t o t a k e t w o d o s e s ( 5 t a bl et s, 2 h o ur s pri or; 5 t a bl et s, 1. 5 h o ur s pri or) of o v er -t h e-c o u nt er 
vit a mi n s ( A, E, a n d al p h a -li p oi c a ci d) s o t h at w e c a n t e st t h e eff e ct s of b o o sti n g y o ur b o d y’ s n at ur al d ef e n s e 
s y st e m a g ai n st s o m e of t h e str e s s r e s p o n s e s p ot e nti all y r e s ulti n g fr o m h e art f ail ur e, h e art tr a n s pl a nt ati o n, or 
e x er ci s e.  A m e m b er of t h e i n v e sti g ati v e t e a m will pr o vi d e t h e s e pill s t o y o u i n t h e  l a b or at or y. If y o u h a v e a n y 
q u e sti o n s  c o n c er ni n g  t h e  m e di c ati o n s  y o u  ar e  pr e s e ntl y  t a ki n g,  a s k  a b o ut  t h e m  b ef or e  t a ki n g  y o ur  
m e di c ati o n s pri or t o t h e e x p eri m e nt.  
 
   
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _(I niti al s a n d D at e)  
B y i niti ali n g h er e, I a gr e e t o p arti ci p at e i n t h e pr ot o c ol d e s cri b e d a b o v e.  
 
 
 
 


V A  D e p art m e nt of V et er a n s Aff air s  
V A  R E S E A R C H  C O N S E N T  F O R M  
 P a g e 1 0  of 2 2  
P arti ci p a nt N a m e:                                                                                                           D at e:   _ _ _ _ _ _ _ _ _                   
Titl e of St u d y:  “V a s c ul ar a n d A ut o n o mi c M al a d a pt ati o n s i n P ati e nt s wit h V a s c ul ar D y sf u n cti o n ”  
Pri n ci p al I n v e sti g at or:  R u s s ell S. Ri c h ar d s o n, P h. D.                                          V A M C: S alt L a k e Cit y ( 6 6 0)     
C o n s e nt V er si o n D at e:  V er si o n  (  M a y  2 0 1 5 )  
 
F O O T E R F O R I R B U S E O N L Y  
V er si o n: B 0 1 1 1  
 
« I m a g e: St a m p»  
« I n stit uti o n»  
« I R B» 
« A p pr o v e d » « A p pr o v e d D at e » 
« E x pir ati o n » 
« E x pir ati o n D at e » 
« N u m b er »  
V A F O R M  1 0 -1 0 8 6  J U N E 1 9 9 0  
 
 
 
 
 
P R O T O C O L 3 ( P R E -T R AI NI N G, o n e 6 -8 h o ur vi sit)  
 
If y o u d e ci d e t o p arti ci p at e i n t hi s p orti o n st u d y, y o u will b e a s k e d t o r e p ort t o t h e V a s c ul ar L a b or at or y ( V A M e di c al 
C e nt er, B uil di n g 2, r o o m 1 D 2 3)  f or a vi sit d e s cri b e d b el o w t h at will l a st 6-8 h o ur s. Y o u will b e a s k e d n ot t o e at or 
dri n k a n yt hi n g ot h er t h a n w at er f or 8 h o ur s b ef or e arri v al t o t h e l a b or at or y ( o v er ni g ht f a st),  
 
1.  Y o u will r e p ort t o t h e l a b at a p pr o xi m at el y 8 A. M.  Pri or t o a n y t e sti n g, w o m e n will t a k e a uri n e pr e g n a n c y t e st. 
T w o c at h et er s  ( pl a sti c t u b e s) pl a c e d i n bl o o d v e s s el s i n eit h er y o ur ar m or y o ur l e g. T h e s e c at h et er s will b e 
i n s ert e d b y a p h y si ci a n u si n g st eril e i n str u m e nt s a n d s u p pli e s. M e di c ati o n will b e u s e d t o n u m b y o ur s ki n a nd 
mi ni mi z e t h e di s c o mf ort of t hi s pr o c e d ur e. T h e s e c at h et er s will st a y i n y o ur ar m or l e g d uri n g t h e e ntir e pr ot o c ol. 
W e will m e a s ur e bl o o d pr e s s ur e a n d t a k e bl o o d s a m pl e s  fr o m t h e c at h et er s i n y o ur ar m or l e g s e v er al ti m e s 
d uri n g t h e st u d y. T h e t ot al a m o u nt of bl o o d wit h dr a w n i s 1 5 0 ml ( 1 0 t e a s p o o n s), or a p pr o xi m at el y 1/ 3 of w h at 
w o ul d b e wit h dr a w n d uri n g a t y pi c al bl o o d d o n ati o n ( 4 5 0 ml). T hr o u g h o ut t h e pr ot o c ol, w e will m e a s ur e bl o o d 
fl o w,  bl o o d  pr e s s ur e  a n d  h e art  r at e.  Bl o o d  fl o w  will  b e  m e a s ur e d  u si n g  t h e  D o p pl er  ultr a s o u n d  m a c hi n e.  
Bl o o d pr e s s ur e  will b e m e a s ur e d fr o m t h e c at h et er s i n y o ur ar m or l e g, a n d h e art r at e  will b e m e a s ur e d fr o m 
t hr e e sti c k y p a d s pl a c e d o n y o ur c h e st.  
 
2.  Aft er t h e c at h et er s ar e i n s ert e d, t h e stiff n e s s of y o ur bl o o d v e s s el s  will  b e d et er mi n e d. A n a ut o m ati c bl o o d 
pr e s s ur e  c uff  will  b e  wr a p p e d  ar o u n d  y o ur  u p p er  l eft  ar m,  a n d  a  h ar d  pl a sti c  wri st  s u p p ort  will  mi ni mi z e  
m o v e m e nt of t h e ri g ht wri st d uri n g t h e bl o o d v e s s el m e a s ur e m e nt.  W hil e l yi n g o n t h e t h er a p y t a bl e, a t hi n 
m et al w a n d will b e pl a c e d o n t h e p ul s e of t h e ri g ht wri st. M e a s ur e m e nt will b e o bt ai n e d a n d a v er a g e d o v er 
t hr e e c o n s e c uti v e 3 0-s e c o n d tri al s.  
 
3.  N e xt, a fl o w-m e di at e d v a s o dil ati o n ( F M D) t e st  will b e p erf or m e d. F or t hi s t e st, y o u will li e d o w n o n a b e d a n d 
a bl o o d pr e s s ur e c uff will b e pl a c e d o n y o ur u p p er ar m or l e g ( a b o v e t h e k n e e) a n d i nfl at e d t o 2 5 0 m m H g, 
t h e u p p er e n d of t h e n or m al i nfl ati o n r a n g e, f or 5 mi n ut e s. T hi s pr o c e d ur e will t e m p or aril y st o p t h e fl o w of 
bl o o d t o y o ur l o w er or l o w er l e g. Y o u m a y n oti c e s o m e  ti n gli n g s e n s ati o n i n y o ur h a n d or f o ot d uri n g t hi s 
ti m e. Aft er 5 mi n ut e s t h e c uff will b e r el e a s e d, a n d w e will m e a s ur e t h e bl o o d fl o w a s it r et ur n s t o y o ur ar m or 
l e g. 
 
4.  Aft er t h e F M D t e st, w e will u s e a t e c h ni q u e c all e d mi cr o n e ur o gr a p h y  t o l o c at e t h e n er v e i n y o ur ot h er l e g 
( wit h n o c at h et er s) t o m e a s ur e n er v e a cti vit y. Fir st, w e will s e n d a v er y s m all el e ctri c c urr e nt (l e s s t h a n 4 V) 
t hr o u g h  a  p e n cil-s h a p e d  pr o b e  w hi c h  will  b e  pl a c e d  o n  y o ur  s ki n  b e hi n d  y o ur  k n e e.  W h e n  t h e  n er v e  i s  
sti m ul at e d, i n v ol u nt ar y t wit c hi n g a n d/ or ti n gli n g s e n s ati o n s of t h e l o w er l e g or f o ot will o c c ur. T h e t wit c hi n g or 
ti n gli n g will di s a p p e ar w h e n t h e sti m ul ati o n i s st o p p e d. T hi s pr o c e d ur e u s u all y l a st s l e s s t h a n t w o mi n ut e s, s o 
o nl y 6 -8 sti m uli ar e s e nt t hr o u g h t h e pr o b e. O n c e t h e n er v e i s f o u n d, t w o st eril e el e ctr o d e s ( a b o ut t h e si z e of a n 
a c u p u n ct ur e n e e dl e s) will b e i n s ert e d t hr o u g h t h e s ki n i n y o ur l e g. O n e el e ctr o d e i s a r ef er e n c e pl a c e d j u st 
a b o v e  t h e  n er v e  sit e  ( 2  c m)  a n d  t h e  ot h er  el e ctr o d e  i s  u s e d  f or  r e c or di n g.  W h e n  t h e  ti p  of  t h e  r e c or di n g  


V A  D e p art m e nt of V et er a n s Aff air s  
V A  R E S E A R C H  C O N S E N T  F O R M  
 P a g e 1 1  of 2 2  
P arti ci p a nt N a m e:                                                                                                           D at e:   _ _ _ _ _ _ _ _ _                   
Titl e of St u d y:  “V a s c ul ar a n d A ut o n o mi c M al a d a pt ati o n s i n P ati e nt s wit h V a s c ul ar D y sf u n cti o n ”  
Pri n ci p al I n v e sti g at or:  R u s s ell S. Ri c h ar d s o n, P h. D.                                          V A M C: S alt L a k e Cit y ( 6 6 0)     
C o n s e nt V er si o n D at e:  V er si o n  (  M a y  2 0 1 5 )  
 
F O O T E R F O R I R B U S E O N L Y  
V er si o n: B 0 1 1 1  
 
« I m a g e: St a m p»  
« I n stit uti o n»  
« I R B» 
« A p pr o v e d » « A p pr o v e d D at e » 
« E x pir ati o n » 
« E x pir ati o n D at e » 
« N u m b er »  
V A F O R M  1 0 -1 0 8 6  J U N E 1 9 9 0  
 
 
 
 
el e ctr o d e e nt er s t h e n er v e, y o u will n oti c e eit h er i n v ol u nt ar y m u s cl e t wit c h e s or ti n gli n g i n t h e l e g or f o ot. At t hi s 
p oi nt, o nl y mi n or a dj u st m e nt s i n t h e p o siti o n of  t h e n e e dl e will b e m a d e u ntil w e b e gi n t o r e c or d t h e n er v e 
si g n al .  
 
5.  T h e n e xt p art of t h e st u d y will i n v ol v e t w o t e st s of h o w w ell y o ur b o d y r e s p o n d s t o c h a n g e s i n bl o o d pr e s s ur e 
b y  a cti v ati n g  pr e s s ur e -s e n siti v e  n er v e s  l o c at e d  i n  t h e  bl o o d  v e s s el s  of  y o ur  n e c k  ( c ar oti d  art er y).  T hi s  
pr o c e d ur e i n v ol v e s u s e of a n e c k c oll ar  t h at cr e at e s a s e al e d c h a m b er of air ar o u n d t h e fr o nt of y o ur n e c k. 
T hi s c h a m b er i s att a c h e d t o a v a c u u m m ot or t h at cr e at e s s m all c h a n g e s i n air pr e s s ur e n e ar t h e s urf a c e of 
t h e s ki n o n y o ur n e c k, w hi c h will t e m p or aril y c h a n g e t h e a cti vit y of t h e “ pr e s sur e s e n s or s” i n y o ur c ar oti d 
art er y. T hi s will c a u s e a s m all c h a n g e i n y o ur bl o o d pr e s s ur e a n d h e art r at e.  
 
6.  Aft er t h e n e c k c oll ar pr o c e d ur e, w e will i nj e ct a s m all a m o u nt of t w o diff er e nt dr u g s t o f urt h er e x a mi n e h o w 
w ell  y o ur  b o d y r e s p o n d s  t o  c h a n g e s  i n  bl o o d pr e s s ur e.  T hi s t e st  u s e s a pr o c e d ur e c all e d “t h e m o difi e d 
O xf or d t e c h ni q u e ”. W e will fir st i nj e ct t h e dr u g P h e n yl e p hri n e ( P E), a c h e mi c al si mil ar t o o n e t h at y o ur o w n 
b o d y pr o d u c e s t h at m a k e s y o ur bl o o d v e s s el s m all er a n d m a k e y o ur bl o o d pr e s s ur e i n c r e a s e b y a b o ut 1 5 
m m H g. N e xt, w e will i nj e ct a v er y s m all a m o u nt of a dr u g c all e d S o di u m Nitr o pr u s si d e ( S N P)  i nt o t h e v ei n i n 
y o ur l e g. T hi s dr u g will m a k e y o ur bl o o d v e s s el bi g g er a n d m a k e y o ur bl o o d pr e s s ur e d e cr e a s e b y a b o ut 1 5 
m m H g. W e will i nj e ct P E a n d S N P 2 -3 ti m e s e a c h f or a b o ut 3 0 s e c o n d s at e a c h d o s e.  
 
7.  Aft er  t hi s,  y o u  will  p erf or m  s e v er al  s h ort  b o ut s  of  ar m  a n d  l e g  e x er ci s e.  Fir st,  y o ur  ar m  a n d  l e g  will  b e  
p a s si v el y m o v e d t hr o u g h a n or m al r a n g e of m oti o n f or t hr e e mi n ut e s. N e xt, y o u will p erf or m t hr e e l e v el s of 
ar m  e x er ci s e t h at  i n v ol v e s s q u e e zi n g  a p a d d e d h a n dl e o n c e e v er y s e c o n d f or  3 -mi n ( 2 0 -4 0 -6 0 % of  y o ur 
m a xi m al s q u e e zi n g str e n gt h), f oll o w e d b y t hr e e l e v el s of l e g “ k n e e e xt e n s or” e x er ci s e t h at i n v ol v e s p utti n g 
y o ur  l e g  t hr o u g h  a  ki c ki n g  m oti o n  o n c e  e v er y  s e c o n d  f or  3 -mi n  ( 2 0 -4 0 -6 0 %  of  y o ur  m a xi m al  ki c ki n g  
str e n gt h). Y o u will r e st f or 5 -1 0 mi n b et w e e n e a c h e x er ci s e b o ut. At t h e e n d of e a c h e x er ci s e b o ut, a bl o o d 
pr e s s ur e c uff will b e i nfl at e d t o 2 5 0 m m H g, t h e u p p er e n d of t h e n or m al i nfl ati o n r a n g e, f or t w o mi n ut e s. T hi s 
will tr a p s o m e bl o o d i n t h e v e s s el s of y o ur ar m or l e g t h at h a s j u st e x er ci s e d, a n d m a y c a u s e s o m e ti n gli n g 
a n d mil d di s c o mf ort i n y o ur ar m or l e g.   
 
8.  Aft er  t h e e x er ci s e t e st,  y o u will r e st  f or  1 5 mi n,  a n d t h e n r e p e at  t h e e x er ci s e pr ot o c ol wit h a dr u g i nf u si o n 
pr ot o c ol ( “t h e m o difi e d o xf or d t e c h ni q u e”, d e s cri b e d a b o v e) at t h e e n d of e a c h e x er ci s e b o ut.  
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _(I niti al s a n d D at e)  
 
B y i niti ali n g h er e, I a gr e e t o p arti ci p at e i n t h e pr ot o c ol d e s cri b e d a b o v e . 


V A  D e p art m e nt of V et er a n s Aff air s  
V A  R E S E A R C H  C O N S E N T  F O R M  
 P a g e 1 2  of 2 2  
P arti ci p a nt N a m e:                                                                                                           D at e:   _ _ _ _ _ _ _ _ _                   
Titl e of St u d y:  “V a s c ul ar a n d A ut o n o mi c M al a d a pt ati o n s i n P ati e nt s wit h V a s c ul ar D y sf u n cti o n ”  
Pri n ci p al I n v e sti g at or:  R u s s ell S. Ri c h ar d s o n, P h. D.                                          V A M C: S alt L a k e Cit y ( 6 6 0)     
C o n s e nt V er si o n D at e:  V er si o n  (  M a y  2 0 1 5 )  
 
F O O T E R F O R I R B U S E O N L Y  
V er si o n: B 0 1 1 1  
 
« I m a g e: St a m p»  
« I n stit uti o n»  
« I R B» 
« A p pr o v e d » « A p pr o v e d D at e » 
« E x pir ati o n » 
« E x pir ati o n D at e » 
« N u m b er »  
V A F O R M  1 0 -1 0 8 6  J U N E 1 9 9 0  
 
 
 
 
 
P R O T O C O L 3 ( T R AI NI N G, 1 -2 h o ur s p er vi sit, 2 -3 vi sit s p er w e e k f or 1 2 w e e k s)  
 
If y o u c h o s e t o p arti ci p at e i n t h e e x er ci s e tr ai ni n g p orti o n of t h e st u d y, y o u will b e a s k e d t o vi sit t h e l a b t hr e e 
ti m e s p er w e e k f or a p pr o xi m at el y 3 0 mi n ut e s t o p erf or m s u p er vi s e d k n e e-e xt e n s or tr ai ni n g. F or t h e s e vi sit s w e will 
m o nit or y o ur h e art r at e b y pl a ci n g t hr e e sti c k y p a d s o n y o ur c h e st. I n a d diti o n t o t h e s e e x er ci s e -o nl y vi sit s, y o u will 
b e a s k e d t o r et ur n t o t h e l a b o n c e e v er y t w o w e e k s  t o m o nit or y o ur i m pr o v e m e nt s d u e t o e x er ci s e tr ai ni n g. T h e 
pr ot o c ol f or t h e s e vi sit s will b e si mil ar t o t h e pr o c e d ur e s d e s cri b e d a b o v e;  
 
W e e k 2 ( 2 -3 h o ur s):  Y o u will r e p ort t o t h e l a b at a p pr o xi m at el y 8 A. M  a n d h a v e a v e n o u s c at h et er pl a c e d i n y o ur ar m 
n e ar y o ur el b o w. Aft er t hi s c a t h et er i s i n s ert e d, y o u will u n d er g o t h e bl o o d v e s s el stiff n e s s  t e st, t h e F M D t e st , t h e 
n e c k c oll ar  t e c h ni q u e, t h e m o difi e d O xf or d  t e st, a n d p erf or m ar m a n d l e g e x er ci s e , all a s d e s cri b e d a b o v e.    
 
W e e k 4 ( 3 -4 h o ur s):  Y o u will r e p ort t o t h e l a b at a p pr o xi m at el y 8 A. M  a n d h a v e a v e n o u s c at h et er pl a c e d i n y o ur ar m 
n e ar y o ur el b o w. Aft er t hi s c at h et er i s i n s ert e d, w e will l o c at e a n er v e i n y o ur l e g u si n g mi cr o n e ur o gr a p h y . Y o u will 
t h e n u n d er g o t h e bl o o d v e s s el stiff n e s s  t e st, t h e F M D t e st , t h e n e c k c oll ar  t e ch ni q u e, t h e m o difi e d O xf or d  t e st, 
a n d p erf or m ar m a n d l e g e x er ci s e , all a s d e s cri b e d a b o v e.    
 
W e e k 6 ( 6 -8 h o ur s):  T hi s vi sit r e pr e s e nt s t h e “ h alf -w a y p oi nt” i n t h e tr ai ni n g pr o gr a m. T h e pr ot o c ol will b e i d e nti c al t o 
t h e c o m pr e h e n si v e t e sti n g d o n e pri or t o tr ai ni n g, d e s cri b e d a b o v e (P R O T O C O L 3 P R E -T R AI NI N G).  
 
W e e k 8 ( 3 -4 h o ur s):  Y o u will r e p ort t o t h e l a b at a p pr o xi m at el y 8 A. M  a n d h a v e a v e n o u s c at h et er pl a c e d i n y o ur ar m 
n e ar y o ur el b o w. Aft er t hi s c at h et er i s i n s ert e d, w e will l o c at e a n er v e i n y o ur l e g  u si n g mi cr o n e ur o gr a p h y . Y o u will 
t h e n u n d er g o t h e bl o o d v e s s el stiff n e s s  t e st, t h e F M D t e st , t h e n e c k c oll ar  t e c h ni q u e, t h e m o difi e d O xf or d  t e st, 
a n d p erf or m ar m a n d l e g e x er ci s e , all a s d e s cri b e d a b o v e.    
 
W e e k 1 0 ( 2 -3 h o ur s):  Y o u will r e p ort t o t h e l a b  at a p pr o xi m at el y 8 A. M  a n d h a v e a v e n o u s c at h et er pl a c e d i n y o ur 
ar m n e ar y o ur el b o w. Aft er t hi s c at h et er i s i n s ert e d, y o u will u n d er g o t h e bl o o d v e s s el stiff n e s s  t e st, t h e F M D t e st , 
t h e n e c k c oll ar  t e c h ni q u e, t h e m o difi e d o xf or d  t e st, a n d p erf or m ar m a n d  l e g e x er ci s e, all a s d e s cri b e d a b o v e.    
 
W e e k 1 2 ( 6 -8 h o ur s):  T hi s vi sit r e pr e s e nt s t h e “ p o st -tr ai ni n g” p orti o n of t h e st u d y. T h e pr ot o c ol will b e i d e nti c al t o t h e 
c o m pr e h e n si v e t e sti n g d o n e pri or t o tr ai ni n g a n d at w e e k 6, d e s cri b e d a b o v e ( P R O T O C O L 3 P R E- T R AI NI N G).  
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _(I niti al s a n d D at e)  
 i niti ali n g h er e, I a gr e e t o p arti ci p at e i n t h e pr ot o c ol d e s cri b e d a b o v e. 


V A  D e p art m e nt of V et er a n s Aff air s  
V A  R E S E A R C H  C O N S E N T  F O R M  
 P a g e 1 3  of 2 2  
P arti ci p a nt N a m e:                                                                                                           D at e:   _ _ _ _ _ _ _ _ _                   
Titl e of St u d y:  “V a s c ul ar a n d A ut o n o mi c M al a d a pt ati o n s i n P ati e nt s wit h V a s c ul ar D y sf u n cti o n ”  
Pri n ci p al I n v e sti g at or:  R u s s ell S. Ri c h ar d s o n, P h. D.                                          V A M C: S alt L a k e Cit y ( 6 6 0)     
C o n s e nt V er si o n D at e:  V er si o n  (  M a y  2 0 1 5 )  
 
F O O T E R F O R I R B U S E O N L Y  
V er si o n: B 0 1 1 1  
 
« I m a g e: St a m p»  
« I n stit uti o n»  
« I R B» 
« A p pr o v e d » « A p pr o v e d D at e » 
« E x pir ati o n » 
« E x pir ati o n D at e » 
« N u m b er »  
V A F O R M  1 0 -1 0 8 6  J U N E 1 9 9 0  
 
 
 
 
RI S K S  
W h e n  p erf or mi n g  a n y of  t h e r e q uir e m e nt s f or  t hi s pr oj e ct,  t h er e will b e q u alifi e d p er s o n n el pr e s e nt  at  a ll ti m e s.  
H o w e v er, pl e a s e b e a w ar e of t h e f oll o wi n g ri s k s a n d di s c o mf ort s : 
 
P R O T O C O L 1:  
Bl o o d dr a w ri s k s:  T h er e i s a p o s si bilit y of br ui si n g fr o m bl o o d dr a w s.  It s h o ul d b e n ot e d t h at all bl o o d c oll e cti o n 
pr o c e d ur e s will b e p erf or m e d i n a cl e a n e n vir o n m e nt  b y q u alifi e d p er s o n n el (i. e., n ur s e or p hl e b ot o mi st).  T h e s af et y 
of t h e s u bj e ct i s of ut m o st i m p ort a n c e d uri n g t h e bl o o d dr a w s, t h er ef or e st a n d ar d pr e c a uti o n s will b e u s e d i n cl u di n g 
t h e cl e a ni n g of t h e v e ni p u n ct ur e sit e wit h al c o h ol, t h e u s e of n e w st eril e di s p o s a bl e n e e dl e s/ s yri n g e s a n d c h a n gi n g 
of di s p o s a bl e gl o v e s i n b et w e e n s u bj e ct s b y t h e p hl e b ot o mi st.  
 
E x er ci s e ri s k s:  Y o u m a y e x p eri e n c e t e m p or ar y m u s c ul ar s or e n e s s t h at i s n or m all y e x p eri e n c e d w h e n p erf or mi n g a 
n e w  e x er ci s e.   P h y si c al  ri s k  i n  t hi s  pr oj e ct  will  b e  mi ni mi z e d  b y  h a vi n g  e a c h  s e s si o n  s u p er vi s e d  b y  tr ai n e d  
p er s o n n el.  
 
Ot h er ri s k s:  Y o u m a y e x p eri e n c e mi n or di s c o mf ort d uri n g t h e m e a s ur e m e nt of ar m bl o o d pr e s s ur e a n d d uri n g t h e 
c uff o c cl u si o n d u e t o t h e i nfl ati o n of t h e bl o o d pr e s s ur e c uff.  H o w e v er, t h e tr ai n e d p er s o n n el will m a k e s ur e t h at t h e 
bl o o d pr e s s ur e c uff i s c o m pl et el y d efl at e d a s s o o n a s t h e m e a s ur e m e nt i s c o m pl et e d. Y o u m a y e x p eri e n c e mi n or 
di s c o mf ort  d uri n g  t h e  fl o w  m e di at e d  v a s o dil ati o n  ( F M D)  m e a s ur e m e nt  d u e  t o  t h e  5  mi n ut e s  of  c u ff  o c cl u si o n.  
H o w e v er, t h e tr ai n e d p er s o n n el will m a k e s ur e t h at t h e bl o o d pr e s s ur e c uff i s c o m pl et el y d efl at e d a s s o o n a s t h e 
m e a s ur e m e nt i s c o m pl et e d.   
 
P R O T O C O L S 2 & 3:  
C at h et er ri s k s:   I n s erti o n of t h e pl a sti c c at h et er s i n y o ur art eri e s a n d v ei n s c arri e s a l o w ri s k t h at o n c e t h e c at h et er s 
h a v e b e e n r e m o v e d, i nf e cti o n s w elli n g a n d di s c o mf ort  m a y o c c ur at t h e i n s erti o n sit e s, or t h at s o m e bl e e di n g m a y 
o c c ur aft er t h e c at h et er s h a v e b e e n r e m o v e d.  T h er e i s al s o t h e p o s si bilit y of s w elli n g, f ai nti n g, di z z i n e s s, a n d p o s si bl e 
p ai n a n d  br ui si n g a s a r e s ult of c at h et er i n s erti o n. A cl ot or e x c e s si v e bl e e di n g at t h e p u n ct ur e sit e c o ul d r e s ult i n a 
p arti al bl o c k a g e of t h e bl o o d fl o w t o t h e ar m or l e g, w hi c h i n e xtr e m e c a s e s c o ul d l e a d t o l o s s of t h e li m b. All of  t h e s e 
p ot e nti al pr o bl e m s will b e mi ni mi z e d b y u si n g st eril e e q ui p m e nt a n d a p pl yi n g pr e s s ur e t o t h e c at h et er l o c ati o n s aft er 
t h e c at h et er s h a v e b e e n r e m o v e d. 
 
E x er ci s e ri s k s:  T h er e i s a v er y s m all ri s k t h at p erf or mi n g e x er ci s e r e v e al s a pr o bl e m wit h y o ur h e art ( e x p o si n g y o u t o 
t h e ri s k of a h e art att a c k or irr e g ul ar h e art b e at t h at c o ul d r e q uir e h o s pit ali z ati o n), a n d p arti c ul arl y wit h t h e bl o o d v e s s els 
w hi c h  s u p pl y  t h e  h e art  ( c or o n ar y  art eri e s).  T h e s e  pr o bl e m s  c o ul d  r a n g e  fr o m  i n s uffi ci e nt  bl o o d  fl o w  t o  t h e  h e art 
( m y o c ar di al i s c h e mi a), h e art att a c k ( m y o c ar di al i nf ar cti o n), or irr e g ul ar h e art b e at ( arr h yt h mi a), a n d t h e s e s eri o u s h e art 
c o n diti o n s c o ul d b e f at al. S y m pt o m s f or t h e s e c o n diti o n s w o ul d b e p ai n i n t h e c h e st, e x c e s si v e s h ort n e s s of br e at h, or 
a b n or m al iti e s o n t h e el e ctr o c ar di o gr a m ( E C G) d uri n g e x er ci s e. T hi s pr o c e d ur e (t h e E C G) i s p erf or m e d t o b e a s s ur e a s 
p o s si bl e t h at t h er e ar e n o a cti v e h e art pr o bl e m s d uri n g t h e st u d y. H o w e v er, if t h e s e pr o bl e m s d e v el o p, e x er ci s e will b e 


V A  D e p art m e nt of V et er a n s Aff air s  
V A  R E S E A R C H  C O N S E N T  F O R M  
 P a g e 1 4  of 2 2  
P arti ci p a nt N a m e:                                                                                                           D at e:   _ _ _ _ _ _ _ _ _                   
Titl e of St u d y:  “V a s c ul ar a n d A ut o n o mi c M al a d a pt ati o n s i n P ati e nt s wit h V a s c ul ar D y sf u n cti o n ”  
Pri n ci p al I n v e sti g at or:  R u s s ell S. Ri c h ar d s o n, P h. D.                                          V A M C: S alt L a k e Cit y ( 6 6 0)     
C o n s e nt V er si o n D at e:  V er si o n  (  M a y  2 0 1 5 )  
 
F O O T E R F O R I R B U S E O N L Y  
V er si o n: B 0 1 1 1  
 
« I m a g e: St a m p»  
« I n stit uti o n»  
« I R B» 
« A p pr o v e d » « A p pr o v e d D at e » 
« E x pir ati o n » 
« E x pir ati o n D at e » 
« N u m b er »  
V A F O R M  1 0 -1 0 8 6  J U N E 1 9 9 0  
 
 
 
 
st o p p e d i m m e di at el y a n d y o u  will b e r ef err e d t o y o ur l o c al p h y si ci a n f or pr o p er f oll o w -u p.  Fi n all y, t h e p erf or m a n c e of 
e x er ci s e m a y al s o r e s ult i n m u s cl e s or e n e s s t h at mi g ht l a st s e v er al d a y s.  
 
Dr u g  i nj e cti o n  ri s k s:  T h e  i nj e cti o n  of  p h e n yl e pri n e  ( P E)  a n d  s o di u m  nitr o pr u s si d e  ( S N P)  will  c a u s e  y o ur  bl o o d  
pr e s s ur e t o ri s e a n d f all. W e will u s e a l o w d o s e of b ot h of t h e s e dr u g s t o pr e v e nt l ar g e c h a n g e s i n bl o o d pr e s s ur e.   
 
Ot h er Dr u g Ri s k s:  
 
Nitr o gl y c eri n: th e  f oll o wi n g si d e eff e ct s/ ri s k s h a v e b e e n o b s er v e d i n cli ni c al tri al s : G a str oi nt e sti n al: A b d o mi n al p ai n ( 5 % 
), Di arr h e a ( 8 % ), N a u s e a ( gr e at er t h a n or e q u al t o 4 % ), V o miti n g ( 8 % ); N e ur ol o gi c: H e a d a c h e ( 1 5 % ); R e s pir at or y: 
N a s al di s c h ar g e ( 1 1 % ), P ai n i n t hr o at ( 1 0 % ), U p p er r e s pir at or y i nf e cti o n ( 1 2 % t o 1 7 % )  
 
T etr a h y dr o bi o pt eri n  ( B H 4) : C o n c o mit a nt  u s e  of  dr u g s  k n o w n  t o  i n hi bit  f ol at e  m et a b oli s m  ( e g,  m et h otr e x at e);  
di h y dr o pt eri di n e r e d u ct a s e e n z y m e i n hi biti o n m a y d e cr e a s e B H 4  l e v el s; C o n c o mit a nt u s e wit h nitri c o xi d e-m e di at e d 
v a s or el a x ati o n dr u g s ( e g, sil d e n afil, v ar d e n afil, t a d al afil); a d diti v e eff e ct s m a y r e d u c e bl o o d pr e s s ur e; C o n c o mit a nt u s e 
wit h  l e v o d o p a;  c o n v ul si o n s,  e x a c er b ati o n  of  c o n v ul si o n s,  o v er -sti m ul ati o n,  a n d  irrit a bilit y  h a v e  b e e n  r e p ort e d  wit h  
s a pr o pt eri n f or a n o n -p h e n yl k et o n uri a i n di c ati o n.  
 
Mi cr o n e ur o gr a p h y ri s k s:  T hi s pr o c e d ur e m a y i n v ol v e di s c o mf ort w h e n t h e el e ctr o d e i s i n s ert e d t hr o u g h t h e s ki n 
a n d i nt o t h e n er v e i n y o ur l e g. T hi s di s c o mf ort i n cl u d e s a “ pi n s -a n d -n e e dl e s” s e n s ati o n a n d m u s cl e t wit c h e s w hi c h 
s h o ul d  n ot  l a st  m or e  t h a n  t w o  mi n ut e s.  O n c e  t h e  el e ctr o d e  i s  i n  p o siti o n,  a n y  di s c o mf ort  s h o ul d  g o  a w a y.  It  i s  
p o s si bl e  t h at  y o ur  l e g  m u s cl e s  m a y f e el  tir e d  f or  a  d a y or  t w o  aft er  t h e  st u d y.  T h er e  i s  al s o  a  p ot e nti al  ri s k  of  
t e m p or ar y  “ pi n s-a n d -n e e dl e s”  s e n s ati o n  or  i n cr e a s e d  s e n siti vit y  t o  t o u c h  i n  t h e  l e g  f oll o wi n g  mi cr o n e ur o gr a p h y.  
T h e s e si d e eff e ct s o c c ur i n l e s s t h a n 1 0 % of v ol u nt e er s, a n d if e x p eri e n c e d, will o nl y b e t e m p or ar y. T h er e p o s si bilit y 
of i nf e cti o n a n d br ui si n g at t h e sit e of el e ctr o d e i n s erti o n.  
 
N e c k c oll ar ri s k s: Pr e s s ur e a n d s u cti o n pr o d u c e d b y t h e n e c k c oll ar c o ul d di sl o d g e f at d e p o sit s ( c all e d pl a q u e) i n y o ur 
bl o o d v e s s el s, a n d t h e s e pl a q u e s c o ul d t h e n m o v e t hr o u g h y o ur bl o o d str e a m a n d bl o c k bl o o d fl o w i n s m all er v e s s el s. 
T hi s bl o c k a d e of bl o o d fl o w c o ul d c a u s e a str o k e, w hi c h c o ul d b e f at al. T o pr e v e nt t hi s, o n t h e pr eli mi n ar y vi sit all 
p arti ci p a nt s will b e s cr e e n e d f or t h e b uil d -u p of f at wit hi n t h e c ar oti d art er y u si n g D o p pl er i m a gi n g t e c h ni q u e s.. If y o u 
h a v e a n y hi st or y of pl a q u e f or m ati o n or if t hi s e x a m r e v e al s a n y si g nifi c a nt pl a q u e, w e will n ot p erf or m t h e n e c k 
c oll ar pr o c e d ur e.   
 
Pr e g n a n c y ri s k s:  T h e ri s k s f or s o m e of t h e pr o c e d ur e s i n cl u d e d i n pr ot o c ol s 2 a n d 3 t o a n u n b or n f et u s ar e n ot 
k n o w n. T h u s, if y o u  ar e pr e g n a nt, y o u m a y n ot p arti ci p at e i n t h e s e pr ot o c ol s. If y o u ar e n ot pr e g n a nt b ut ar e of 
c hil d b e ari n g  a g e,  y o u  m u st  u s e  a p pr o pri at e  c o ntr a c e pti v e s  t o  pr e v e nt  pr e g n a n c y  w hil e  p arti ci p ati n g  i n  t h e s e  
pr ot o c ol s.  A d dit io n all y, y o u will b e a s k e d t o s u b mit t o a uri n e pr e g n a n c y  t e st pr o vi d e d b y t h e r e s e ar c h sit e. S h o ul d 
y o u b e c o m e pr e g n a nt w hil e e nr oll e d, y o u will b e wit h dr a w n fr o m t h e st u d y.  


V A  D e p art m e nt of V et er a n s Aff air s  
V A  R E S E A R C H  C O N S E N T  F O R M  
 P a g e 1 5  of 2 2  
P arti ci p a nt N a m e:                                                                                                           D at e:   _ _ _ _ _ _ _ _ _                   
Titl e of St u d y:  “V a s c ul ar a n d A ut o n o mi c M al a d a pt ati o n s i n P ati e nt s wit h V a s c ul ar D y sf u n cti o n ”  
Pri n ci p al I n v e sti g at or:  R u s s ell S. Ri c h ar d s o n, P h. D.                                          V A M C: S alt L a k e Cit y ( 6 6 0)     
C o n s e nt V er si o n D at e:  V er si o n  (  M a y  2 0 1 5 )  
 
F O O T E R F O R I R B U S E O N L Y  
V er si o n: B 0 1 1 1  
 
« I m a g e: St a m p»  
« I n stit uti o n»  
« I R B» 
« A p pr o v e d » « A p pr o v e d D at e » 
« E x pir ati o n » 
« E x pir ati o n D at e » 
« N u m b er »  
V A F O R M  1 0 -1 0 8 6  J U N E 1 9 9 0  
 
 
 
 
 
Ot h er ri s k s:  Y o u m a y e x p eri e n c e mi n or di s c o mf ort d uri n g t h e m e a s ur e m e nt of ar m bl o o d pr e s s ur e a n d d uri n g t h e 
c uff o c cl u si o n d u e t o t h e i nfl ati o n of t h e bl o o d pr e s s ur e c uff.  H o w e v er, t h e tr ai n e d p er s o n n el will m a k e s ur e t h at t h e 
bl o o d pr e s s ur e c uff i s c o m pl et el y d efl at e d a s s o o n a s t h e m e a s ur e m e nt i s c o m pl et e d. Y o u m a y e x p eri e n c e mi n or 
di s c o mf ort  d uri n g  t h e  fl o w  m e di at e d  v a s o dil ati o n  ( F M D)  m e a s ur e m e nt  d u e  t o  t h e  5  mi n ut e s  of  c uff  o c cl u si o n.   
H o w e v er, t h e tr ai n e d p er s o n n el will m a k e s ur e t h at t h e bl o o d pr e s s ur e c uff i s c o m pl et el y d efl at e d a s s o o n a s t h e 
m e a s ur e m e nt i s c o m pl et e d.   
 
Bi o p s y ri s k s ( P R O T O C O L 2 O N L Y): D uri n g t h e m u s cl e bi o p s y pr o c e d ur e, t h er e i s p ot e nti al f or p ai n a n d di s c o mf ort 
a n d p ot e nti al s w elli n g  a n d y o u will f e el s o m e di s c o mf ort li k e a b ur ni n g s e n s ati o n w hil e t h e a n e st h eti c i s i nj e ct e d. It i s 
p o s si bl e t o r e a c h t o xi c l e v el s wit h t hi s a n e st h eti c (li d o c ai n e),  b ut t hi s p ot e nti al i s r e d u c e d b y u si n g a l o w 
c o n c e ntr ati o n a n d s m all a m o u nt s. P ai n i n a m u s cl e w h e n t h e ti s s u e i s r e m o v e d i s al s o pr o b a bl e. T h e bi o p s y sit e 
m a y b e mil dl y t e n d er f or 2 -3 d a y s.  T h er e i s al s o a s m all c h a n c e of br ui si n g,  bl e e di n g or i nf e cti o n  at t h e bi o p s y sit e, 
h o w e v er d e e p pr e s s ur e a n d st eril e t e c h ni q u e s will mi ni mi z e t hi s ri s k. P ot e nti al ri s k of bl e e di n g aft er t h e st u d y will b e 
mi ni mi z e d b y c o m pli a n c e t o t h e i n v e sti g at or s r e q u e st t o li mit e x er ci s e t o mi ni m al l e v el s f or 4 8 h o ur s. A d diti o n all y, 
t h er e i s a p o s si bilit y of di z zi n e s s a n d f ai nti n g d uri n g t h e bi o p s y pr o c e d ur e. T h er e i s a mi ni m al c h a n c e of s c arri n g. 
H o w e v er, a s t h e i n ci si o n i s a p pr o xi m at el y 3 m m ( 1/ 8 i n c h) i n l e n gt h ( w hi c h w o ul d b e t h e e xt e nt of t h e s c ar) t h e ri s k 
of a p o or c o s m eti c o ut c o m e i s v er y s m all.   
 
B E N E FI T S  
T h e  b e n efit s  t o  p arti ci p ati o n  ar e  t h at  y o u  m a y r e c ei v e  i nf or m ati o n  a b o ut  y o ur  bl o o d  v e s s el  f u n cti o n  a n d  m u s cl e  
str e n gt h . T h e i n v e sti g at or s m a y l e ar n m or e a b o ut t h e c h ar a ct eri sti c s of  bl o o d v e s s el f u n cti o n i n p ati e nt s wit h h e art 
f ail ur e,  a n d h e art  tr a n s pl a nt ati o n,  c o m p ar e d t o a h e alt h y p o p ul ati o n.  It  m a y l e a d t o i nt er v e nti o n al str at e gi e s (i. e.  
t h er a pi e s or tr e at m e nt s) t o i m pr o v e bl o o d v e s s el f u n cti o n i n p ati e nt s wit h h e art f ail ur e a n d h e art tr a n s pl a nt ati o n.      
 
F U T U R E C O N T A C T O P TI O N  
 
Pl e a s e i n di c at e  b el o w w h et h er or n ot y o u w o ul d li k e u s t o c o nt a ct y o u i n t h e f ut ur e f or ot h er r e s e ar c h o p p ort u niti e s.  
M a y w e c o nt a ct y o u i n t h e f ut ur e f or ot h er Ut a h V a s c ul ar R e s e ar c h L a b St u di e s ?  
 
_ _ _ _ _ _ Y e s, I gi v e m y p er mi s si o n f or t h e st u d y t e a m t o c o nt a ct m e i n t h e f ut ur e.  
 
_ _ _ _ _ _ N o, I d o n ot wi s h t o b e c o nt a ct e d i n t h e f ut ur e.  
 
A L T E R N A TI V E P R O C E D U R E S  
T h er e ar e n o alt er n ati v e pr o c e d ur e s; y o u m a y si m pl y c h o o s e n ot t o p arti ci p at e i n t hi s st u d y.  


V A  D e p art m e nt of V et er a n s Aff air s  
V A  R E S E A R C H  C O N S E N T  F O R M  
 P a g e 1 6  of 2 2  
P arti ci p a nt N a m e:                                                                                                           D at e:   _ _ _ _ _ _ _ _ _                   
Titl e of St u d y:  “V a s c ul ar a n d A ut o n o mi c M al a d a pt ati o n s i n P ati e nt s wit h V a s c ul ar D y sf u n cti o n ”  
Pri n ci p al I n v e sti g at or:  R u s s ell S. Ri c h ar d s o n, P h. D.                                          V A M C: S alt L a k e Cit y ( 6 6 0)     
C o n s e nt V er si o n D at e:  V er si o n  (  M a y  2 0 1 5 )  
 
F O O T E R F O R I R B U S E O N L Y  
V er si o n: B 0 1 1 1  
 
« I m a g e: St a m p»  
« I n stit uti o n»  
« I R B» 
« A p pr o v e d » « A p pr o v e d D at e » 
« E x pir ati o n » 
« E x pir ati o n D at e » 
« N u m b er »  
V A F O R M  1 0 -1 0 8 6  J U N E 1 9 9 0  
 
 
 
 
 
C O N FI D E N TI A LI T Y  
T h e r e c or d s of t hi s st u d y will b e k e pt pri v at e.  I n p u bli s h e d r e p ort s, t h er e will b e n o i nf or m ati o n i n cl u d e d t h at will 
m a k e it p o s si bl e t o i d e ntif y t h e r e s e ar c h p arti ci p a nt.  N o s o ci al s e c urit y n u m b er s will b e c oll e ct e d.  C o nfi d e nti alit y will 
b e  m ai nt ai n e d  b y  c o di n g  all  i nf or m ati o n  w it h  i n di vi d u al  i d e ntifi c ati o n  n u m b er s.  T h e  m a st er  li st  a n d  all  r e s e ar c h  
r e c or d s will b e st or e d s e c ur el y a n d k e pt i n a l o c k e d fil e c a bi n et i n t h e Pri n ci p al I n v e sti g at or’ s offi c e. A n y i nf or m ati o n 
st or e d el e ctr o ni c all y will b e o n a p a s s w or d pr ot e ct e d c o m p ut er  a c c e s si bl e o nl y b y t h e i n v e sti g at or s.  O nl y q u alifi e d 
r e s e ar c h p er s o n n el a n d U ni v er sit y of Ut a h I n stit uti o n al R e vi e w B o ar d (I R B) will h a v e a c c e s s t o d at a b a s e c o nt ai ni n g 
st u d y i nf or m ati o n.   N o  i n di vi d u al  or  gr o u p  ot h er  t h a n  t h e  r e s e ar c h  t e a m  a n d  t h e  F D A  wi ll b e gi v e n i nf or m ati o n,  
u nl e s s s p e cifi c all y r e q u e st e d b y y o u.   All s u bj e ct -r el at e d m at eri al s a n d d at a will b e h el d c o nfi d e nti al a n d will b e 
st or e d i n t h e PI’ s r e c or d s f or a p eri o d n ot l e s s t h a n 5 y e ar s.  Aft er t hi s ti m e, all s u bj e ct -r el at e d m at eri al s a n d d at a will 
b e d e str o y e d i n a c c or d a n c e wit h t h e V A r e c or d c o ntr ol s c h e d ul e.  R e s e ar c h r e c or d s will b e k e pt c o nfi d e nti al t o t h e 
e xt e nt pr o vi d e d b y l a w.   
 
P E R S O N T O C O N T A C T  
If y o u h a v e a n y q u e sti o n s, c o m pl ai nt s or c o n c er n s a b o ut t hi s st u d y, or y o u t hi n k y o u m ay h a v e b e e n i nj ur e d fr o m 
b ei n g i n t hi s st u d y, y o u c a n c o nt a ct M eli s s a A. Wit m a n  at ( 6 0 3) 9 1 8 -6 6 8 4, m eli s s a. wit m a n @ ut a h. e d u , Dr. D. W alt er 
Wr a y  at  ( 8 5 8)  2 0 5 -3 0 7 8,  w alt er. wr a y @ h s c. ut a h. e d u,  or  Dr.  R u s s ell  S.  Ri c h ar d s o n  at  ( 7 6 0)  2 0 7 -4 5 7 0, 
r.ri c h ar d s o n @ h s c. ut a h. e d u. E a c h of t h e s e i n di vi d u al s m a y b e r e a c h e d at t h e s e n u m b er s a n d e-m ail a c c o u nt s 2 4 -
h o ur s - a-d a y.  
 
I N S TI T U TI O N A L R E VI E W B O A R D 
C o nt a ct t h e I n stit uti o n al R e vi e w B o ar d (I R B) if y o u h a v e q u e sti o n s r e g ar di n g y o ur ri g ht s a s a r e s e ar c h p arti ci p a nt. 
Al s o, c o nt a ct t h e I R B if y o u h a v e q u e sti o n s, c o m pl ai nt s or c o n c er n s w hi c h y o u d o n ot f e el y o u c a n di s c u s s wit h t h e 
i n v e sti g at or.  T h e  U ni v er sit y  of  Ut a h  I R B  m a y  b e  r e a c h e d  b y  p h o n e  at  ( 8 0 1)  5 8 1-3 6 5 5  or  b y  e -m ail  at  
ir b @ h s c. ut a h. e d u.   
 
M E DI C A L T R E A T M E N T O R C O M P E N S A TI O N F O R I N J U R Y   
T h e V A h a s t h e a ut h orit y t o pr o vi d e m e di c al tr e at m e nt t o p arti ci p a nt s i nj ur e d b y p arti ci p ati o n i n a V A st u d y.  If y o u 
ar e i nj ur e d a s a r e s ult of b ei n g i n t hi s st u d y, t h e V A will pr o vi d e t h e n e c e s s ar y m e di c al tr e at m e nt i n a c c or d a n c e wit h 
f e d er al l a w. If y o u w a nt t o m a k e a l e g al cl ai m a g ai n st t h e V A or a n y o n e w h o w or k s f or t h e V A, s p e ci al l a w s m a y 
a p pl y. T h e F e d er al T ort Cl ai m s A ct ( 2 8 U. S. C. 1 3 4 6( b), 2 6 7 1 -2 6 8 0) i s a f e d er al l a w t h at c o ntr ol s w h e n a n d h o w a 
p er s o n c a n bri n g a cl ai m a g ai n st t h e U. S. G o v er n m e nt. If y o u si g n t hi s d o c u m e nt y o u a r e n ot gi vi n g u p y o ur ri g ht t o 
m a k e a l e g al cl ai m a g ai n st t h e U nit e d St at e s.  
 
V O L U N T A R Y P A R TI CI P A TI O N  
P arti ci p ati o n i n r e s e ar c h i s e ntir el y v ol u nt ar y.  Y o u m a y r ef u s e t o p arti ci p at e or wit h dr a w at a n y ti m e w it h o ut j e o p ar d y 
t o t h e m e di c al c ar e y o u m a y r e c ei v e at t hi s i n stit uti o n or l o s s of ot h er b e n efit s t o w hi c h y o u ar e e ntitl e d. If y o u d e ci d e t o 


V A  D e p art m e nt of V et er a n s Aff air s  
V A  R E S E A R C H  C O N S E N T  F O R M  
 P a g e 1 7  of 2 2  
P arti ci p a nt N a m e:                                                                                                           D at e:   _ _ _ _ _ _ _ _ _                   
Titl e of St u d y:  “V a s c ul ar a n d A ut o n o mi c M al a d a pt ati o n s i n P ati e nt s wit h V a s c ul ar D y sf u n cti o n ”  
Pri n ci p al I n v e sti g at or:  R u s s ell S. Ri c h ar d s o n, P h. D.                                          V A M C: S alt L a k e Cit y ( 6 6 0)     
C o n s e nt V er si o n D at e:  V er si o n  (  M a y  2 0 1 5 )  
 
F O O T E R F O R I R B U S E O N L Y  
V er si o n: B 0 1 1 1  
 
« I m a g e: St a m p»  
« I n stit uti o n»  
« I R B» 
« A p pr o v e d » « A p pr o v e d D at e » 
« E x pir ati o n » 
« E x pir ati o n D at e » 
« N u m b er »  
V A F O R M  1 0 -1 0 8 6  J U N E 1 9 9 0  
 
 
 
 
wit h dr a w fr o m t h e st u d y y o u si m pl y n e e d t o i nf or m o n e of t h e i n v e sti g at or s w h o will e n s ur e t h at y o u ar e s af el y r e m o v e d 
fr o m t h e st u d y.  
 
U N F O R E S E E A B L E RI S K S  
I n a d diti o n t o t h e ri s k s li st e d a b o v e, y o u m a y e x p eri e n c e a pr e vi o u sl y u n k n o w n ri s k or si d e eff e ct. 
 
RI G H T O F I N V E S TI G A T O R T O WI T H D R A W  
I n t h e u nli k el y e v e nt t h at y o u ar e f o u n d t o b e a n u n s uit a bl e c a n di d at e f or t h e s e st u di e s or c h a n g e s n e e d t o b e m a d e t o 
t h e st u d y t h e r e s e ar c h t e a m m a y at a n y ti m e c h o s e t o e n d y o ur p arti ci p ati o n, wit h o ut y o ur c o n s e nt. T h e i n v e sti g at or 
c a n wit h dr a w y o u wit h o ut y o ur a p pr o v al.  P o s si bl e r e a s o n s f or wit h dr a w al i n cl u d e:  
- St art t a ki n g m e di c ati o n t h at will aff e ct t h e o ut c o m e of t h e st u d y (i. e. p art of t h e e x cl u si o n crit eri a).  
- N ot c o m pl yi n g wit h pr o p o s e d g ui d eli n e s f or t e sti n g (i. e. b ei n g i n a f a st e d a n d r e st e d st at e).  
- If y o u b e c o m e pr e g n a nt w hil e e nr oll e d i n t h e st u d y (i. e. p art of t h e e x cl u si o n crit eri a). 
 
C O S T S T O P A R TI CI P A N T S A N D C O M P E N S A TI O N  
T h er e ar e n o c o st s t o y o u f or a n y of t h e pr o c e d ur e s d e s cri b e d a b o v e.   
 
F or t h e pr eli mi n ar y d a y, y o u will b e p ai d $ 2 0 u p o n c o m pl eti o n.  
F or Pr ot o c ol 1 , y o u will b e p ai d $ 4 0 u p o n t h e c o m pl eti o n of t w o v i sit s or $ 1 0 0 u p o n c o m pl eti o n of  f o ur vi sit s, $ 1 5/ hr 
pr o -r at e. 
F or Pr ot o c ol 2,  y o u will b e p ai d $ 3 0 0 u p o n c o m pl eti o n of t h e 3 7 -d a y r e gi m e n, $ 1 5/ hr pr o -r at e. 
F or Pr ot o c ol 3 , y o u m a y c h o o s e t o p arti ci p at e o nl y i n t h e pr e-tr ai ni n g p orti o n of t h e st u d y, or e nr oll i n t h e e x er ci s e 
tr ai ni n g pr o gr a m.  
 
 
If y o u d o n ot e nr oll i n t h e e x er ci s e tr ai ni n g p orti o n of t h e pr ot o c ol, y o u will r e c ei v e a t ot al of $ 1 0 0 u p o n 
c o m pl eti o n  of t h e “ pr e -tr ai ni n g” vi sit, $ 1 5/ hr pr o-r at e. 
 
If y o u  e nr oll i n t h e e x er ci s e tr ai ni n g p orti o n of t h e pr ot o c ol, y o u will r e c ei v e $ 5 0 0 ( $ 1 5/ hr pr o-r at e) u p o n 
c o m pl eti o n of t h e e x er ci s e tr ai ni n g  
 
V et er a n -p arti ci p a nt s will n ot b e r e q uir e d t o p a y f or c ar e r e c ei v e d a s a p arti ci p a nt i n a V A r e s e ar c h pr oj e ct e x c e pt a s 
f oll o w s: C ert ai n v et er a n s ar e r e q uir e d t o p a y c o-p a y m e nt s f or m e di c al c ar e a n d s er vi c e s pr o vi d e d b y t h e V A. 
V et er a n s r e c ei vi n g m e di c al c ar e a n d s er vi c e s fr o m t h e V A t h at ar e n ot r e n d er e d a s p art of t h e V A -a p pr o v e d 
r e s e ar c h st u d y, m u st p a y a n y a p pli c a bl e c o-p a y m e nt f or s u c h c ar e a n d s er vi c e s .   
 
N E W I N F O R M A TI O N  
S o m eti m e s d uri n g t h e c o ur s e of a r e s e ar c h pr oj e ct, n e w i nf or m ati o n b e c o m e s a v ail a bl e a b o ut s o m e of t h e t e sti n g 
pr ot o c ol s b ei n g u s e d. If t hi s h a p p e n s, y o ur r e s e ar c h d o ct or will t ell y o u a b o ut it a n d di s c u s s wit h y o u w h et h er y o u 


V A  D e p art m e nt of V et er a n s Aff air s  
V A  R E S E A R C H  C O N S E N T  F O R M  
 P a g e 1 8  of 2 2  
P arti ci p a nt N a m e:                                                                                                           D at e:   _ _ _ _ _ _ _ _ _                   
Titl e of St u d y:  “V a s c ul ar a n d A ut o n o mi c M al a d a pt ati o n s i n P ati e nt s wit h V a s c ul ar D y sf u n cti o n ”  
Pri n ci p al I n v e sti g at or:  R u s s ell S. Ri c h ar d s o n, P h. D.                                          V A M C: S alt L a k e Cit y ( 6 6 0)     
C o n s e nt V er si o n D at e:  V er si o n  (  M a y  2 0 1 5 )  
 
F O O T E R F O R I R B U S E O N L Y  
V er si o n: B 0 1 1 1  
 
« I m a g e: St a m p»  
« I n stit uti o n»  
« I R B» 
« A p pr o v e d » « A p pr o v e d D at e » 
« E x pir ati o n » 
« E x pir ati o n D at e » 
« N u m b er »  
V A F O R M  1 0 -1 0 8 6  J U N E 1 9 9 0  
 
 
 
 
w a nt t o c o nti n u e i n t h e st u d y. Y o u m a y d e ci d e t o wit h dr a w at t h at ti m e. If y o u d e ci d e t o c o nti n u e i n t h e st u d y, y o u 
will  b e  a s k e d  t o  si g n  a n  u p d at e d  c o n s e nt  f or m.  Al s o,  o n  r e c ei vi n g  n e w  i nf or m ati o n  y o ur  r e s e ar c h  d o ct or  mi g ht  
c o n si d er it t o b e i n y o ur b e st i nt er e st s t o wit h dr a w y o u fr o m t h e st u d y a n d h e/ s h e will e x pl ai n t h e r e a s o n s.  
 
N U M B E R O F P A R TI CI P A N T S  
W e e x p e ct t o e nr oll a p pr o xi m at el y 1 4 0 p arti ci p a nt s at t h e V A h o s pit al. T hi s i s n ot p art of a N ati o n al st u d y.  
TI S S U E B A N KI N G  
 
W e will c oll e ct bl o o d a n d m u s cl e ti s s u e s a m pl e s t o d et er mi n e t h e a m o u nt of “ o xi d ati v e str e s s” i n y o ur bl o o d a n d 
m u s cl e ti s s u e. T h e s e s a m pl e s will b e k e pt i n a l o c k e d fr e e z er i n t h e V A, i n a d e si g n at e d r o o m wit hi n o ur l a b or at or y 
w hi c h i s m a n a g e d s ol el y b y t h e pri n ci p al i n v e sti g at or a n d a c c e s si bl e o nl y t o i m m e di at e m e m b er s of t h e r e s e ar c h 
t e a m. T h e o nl y i d e ntifi a bl e i nf or m ati o n o n t h e s a m pl e s will b e y o ur i niti al s a n d d at e of c oll e cti o n, b ut y o u m a y c h o o s e 
t o h a v e y o ur s a m pl e s “ d e-i d e ntifi e d”, i n w hi c h c a s e a d e si g n at e d n u m b er will b e u s e d i n pl a c e of y o ur i niti al s.  
  
 
 
B a n ki n g of t h e s e ti s s u e s i s n ot m a n d at or y f or p arti ci p ati o n i n t hi s st u d y. Y o u m a y c o nt a ct t h e pri n ci p al i n v e sti g at or t o 
r e q u e st r e m o v al of y o ur s a m pl e s fr o m t h e ti s s u e b a n k.  S a m pl e s m a y b e s h ar e d wit h ot h er r e s e ar c h er s at t h e l o c al 
i n stit uti o n (i. e. Pri m ar y C hil dr e n’ s M e di c al C e nt er, V A S L C H C S) a n d at ot h er i n stit uti o n s. Y o u will n ot r e c ei v e a n y 
r e s ult s fr o m t e sti n g p erf or m e d o n y o ur bl o o d or ti s s u e s a m pl e s.  
 
 
If y o u gi v e p er mi s si o n f or y o ur s a m pl e( s) t o b e s a v e d f or f ut ur e r e s e ar c h b y t h e V A S L C H C S or it s r e s e ar c h p art n er s, 
t h e  I n stit uti o n al  R e vi e w  B o ar d  m a y  r e vi e w  a n d  a p pr o v e  e a c h  n e w  pr oj e ct.  T h e  I n stit uti o n al  R e vi e w  B o ar d  m a y  
r e q uir e t h at y o u b e c o nt a ct e d f or y o ur p er mi s si o n pri or t o t h e u s e of t h e s a m pl e( s) i n a n e w  pr oj e ct if it d et er mi n e s 
n e w c o n s e nt i s r e q uir e d f or y o ur pr ot e cti o n.  Ti s s u e or bl o o d s a m pl e s o bt ai n e d fr o m y o u i n t hi s r e s e ar c h m a y h el p i n 
t h e d e v el o p m e nt of a c o m m er ci al pr o d u ct b y t h e U ni v er sit y of Ut a h or it s r e s e ar c h p art n er s.  T h er e ar e n o pl a n s t o 
pr o vi d e fi n a n ci al c o m p e n s ati o n t o y o u s h o ul d t hi s o c c ur.”  
 
Pl e a s e r e a d e a c h s e nt e n c e b el o w, t hi n k a b o ut y o ur c h oi c e, a n d m ar k “ Y E S ” or “N O ”. N o m att er w h at y o u d e ci d e 
t o d o, y o ur d e ci si o n will n ot aff e ct y o ur m e di c al c ar e. M a y t h e V A S L C H C S or it s r e s e ar c h p art n er s r et ai n y o ur 
bl o o d a n d m u s cl e ti s s u e s a m pl e( s) aft er t h e e n d of t hi s r e s e ar c h pr oj e ct f or u s e i n f ut ur e r e s e ar c h ?  
 
 Y E S,  
m y s a m pl e( s) m a y b e s a v e d f or f ut ur e h e art di s e a s e r e s e ar c h  
 
Initi al s & D at e _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 N O,  
m y s a m pl e( s) m u st b e d e str o y e d at t h e e n d of t hi s r e s e ar c h pr oj e ct  
 
I niti al s & D at e _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 


V A  D e p art m e nt of V et er a n s Aff air s  
V A  R E S E A R C H  C O N S E N T  F O R M  
 P a g e 1 9  of 2 2  
P arti ci p a nt N a m e:                                                                                                           D at e:   _ _ _ _ _ _ _ _ _                   
Titl e of St u d y:  “V a s c ul ar a n d A ut o n o mi c M al a d a pt ati o n s i n P ati e nt s wit h V a s c ul ar D y sf u n cti o n ”  
Pri n ci p al I n v e sti g at or:  R u s s ell S. Ri c h ar d s o n, P h. D.                                          V A M C: S alt L a k e Cit y ( 6 6 0)     
C o n s e nt V er si o n D at e:  V er si o n  (  M a y  2 0 1 5 )  
 
F O O T E R F O R I R B U S E O N L Y  
V er si o n: B 0 1 1 1  
 
« I m a g e: St a m p»  
« I n stit uti o n»  
« I R B» 
« A p pr o v e d » « A p pr o v e d D at e » 
« E x pir ati o n » 
« E x pir ati o n D at e » 
« N u m b er »  
V A F O R M  1 0 -1 0 8 6  J U N E 1 9 9 0  
 
 
 
 
If y e s, m a y t h e V A S L C H C S or it s r e s e ar c h p art n er s k e e p y o ur n a m e a n d ot h er i d e ntif yi n g i nf or m ati o n wit h y o ur 
s a m pl e( s) ?  
 
 Y E S,  
m y p er s o n al  i d e ntifi er s a n d m e di c al i nf or m ati o n c a n b e k e pt wit h m y s a m pl e( s). All 
i nf or m ati o n will b e k e pt s e c ur e a n d c o nfi d e nti al. 
 
I niti al s & D at e _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 N O,  
m y n a m e a n d i d e ntifi er s m u st b e r e m o v e d fr o m m y s a m pl e( s). M y s a m pl e( s) c a n n ot b e 
li n k e d b a c k t o m e. 
 
I niti al s & D at e _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
If y o u gr a nt e d p er mi s si o n f or t h e s a m pl e( s) t o b e u s e d i n f ut ur e r e s e ar c h b y t h e V A S L C H C S or it s r e s e ar c h 
p art n er s, t h e I n stit uti o n al R e vi e w B o ar d will r e vi e w a n d a p pr o v e e a c h n e w pr oj e ct. T h e I n stit uti o n al R e vi e w B o ar d 
m a y r e q uir e t h at y o u b e c o nt a ct e d f or y o ur p er mi s si o n pri or t o t h e u s e of t h e s a m pl e( s) i n a n e w  pr oj e ct if it 
d et er mi n e s c o n s e nt i s r e q uir e d f or y o ur pr ot e cti o n.  
 
Y o u h a v e t h e ri g ht t o wit h dr a w y o ur c o n s e nt i n t h e f ut ur e. Y o u n e e d t o n otif y t h e i n v e sti g at or of y o ur d e ci si o n. If y o u 
d e ci d e t o r e m o v e i d e ntifi er s fr o m y o ur s a m pl e( s), y o u will n ot b e a bl e t o wit h dr a w y o ur s a m pl e l at er b e c a u s e it 
c a n n ot b e li n k e d b a c k t o y o u.  
R E S E A R C H P A R TI CI P A N T S' RI G H T S  
I h a v e r e a d or h a v e h a d r e a d t o m e all of t h e pr e c e di n g i nf or m ati o n.  Dr./ Mr./ M s.                                                                
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  h a s e x pl ai n e d t h e st u d y t o m e a n d a n s w er e d all of m y q u e sti o n s.  I h a v e b e e n 
t ol d of t h e ri s k s or di s c o mf ort s a n d p o s si bl e b e n efit s of t h e st u d y. I h a v e b e e n t ol d of ot h er c h oi c e s of tr e at m e nt 
a v ail a bl e t o m e.  
I d o n ot h a v e t o t a k e p art i n t hi s st u d y, a n d m y r ef u s al t o p arti ci p at e will i n v ol v e n o p e n alt y or l o s s of ri g ht s 
t o w hi c h I a m e ntitl e d. I m a y wit h dr a w fr o m t hi s st u d y at a n y ti m e wit h o ut p e n alt y or l o s s of V A or ot h er 
b e n efit s t o w hi c h I a m e ntitl e d.  
T h e r e s ult s of t hi s st u d y m a y b e p u bli s h e d, b ut I will n ot b e i d e ntifi e d i n p u bli c ati o n s b y n a m e, p h ot o gr a p h, or ot h er 
i d e ntifi er s.  M y r e c or d s, i n cl u di n g m y n a m e a n d r e s ult s of m y p arti ci p ati o n, m a y b e r e v e al e d a s r e q uir e d b y l a w s a n d 
r e g ul ati o n s of st at e a n d f e d er al a g e n ci e s. A c o p y of t hi s c o n s e nt f or m will b e fil e d i n m y m e di c al r e c or d c h art at t h e 
V A S alt L a k e Cit y H e alt h C ar e S y st e m.   
If I h a v e a n y q u e sti o n s a b o ut t hi s st u d y or if a n y pr o bl e m s ari s e d uri n g t h e st u d y, I c a n c all:   


V A  D e p art m e nt of V et er a n s Aff air s  
V A  R E S E A R C H  C O N S E N T  F O R M  
 P a g e 2 0  of 2 2  
P arti ci p a nt N a m e:                                                                                                           D at e:   _ _ _ _ _ _ _ _ _                   
Titl e of St u d y:  “V a s c ul ar a n d A ut o n o mi c M al a d a pt ati o n s i n P ati e nt s wit h V a s c ul ar D y sf u n cti o n ”  
Pri n ci p al I n v e sti g at or:  R u s s ell S. Ri c h ar d s o n, P h. D.                                          V A M C: S alt L a k e Cit y ( 6 6 0)     
C o n s e nt V er si o n D at e:  V er si o n  (  M a y  2 0 1 5 )  
 
F O O T E R F O R I R B U S E O N L Y  
V er si o n: B 0 1 1 1  
 
« I m a g e: St a m p»  
« I n stit uti o n»  
« I R B» 
« A p pr o v e d » « A p pr o v e d D at e » 
« E x pir ati o n » 
« E x pir ati o n D at e » 
« N u m b er »  
V A F O R M  1 0 -1 0 8 6  J U N E 1 9 9 0  
 
 
 
 
Dr./ Mr./ M s.                                                       at                                                 D U RI N G T H E D A Y a n d Dr. / Mr./ M s.          
at                                   A F T E R H O U R S. If a n y m e di c al pr o bl e m s o c c ur i n c o n n e cti o n wit h t hi s st u d y, t h e V A S alt 
L a k e Cit y H e alt h C ar e S y st e m will pr o vi d e e m er g e n c y c ar e.  
If I h a v e c o n c er n s or q u e sti o n s a b o ut t hi s r e s e ar c h st u d y t h at t h e i n v e sti g at or h a s n ot a n s w er e d, I c a n c o nt a ct a n 
offi ci al of t h e I n stit uti o n al R e vi e w B o ar d f or H u m a n St u di e s b y c alli n g 8 0 1 -5 8 1 -3 6 5 5 or t h e V A S alt L a k e Cit y H e alt h 
C ar e S y st e m R e s e ar c h C o m pli a n c e Offi c er at 8 0 1 -5 8 4 -1 2 7 1.  
I a m a w ar e of m y ri g ht s a s a p arti ci p a nt, a n d I v ol u nt aril y c o n s e nt t o p arti ci p at e i n t hi s st u d y. I c o nfir m t h at I h a v e 
r e a d t hi s c o n s e nt a n d a ut h ori z ati o n d o c u m e nt w hi c h e x pl ai n s w h at t hi s st u d y i s a b o ut a n d h o w a n d w h y it i s b ei n g 
d o n e. I will r e c ei v e a si g n e d c o n s e nt f or m or a p h ot o c o p y of it . 
 
I a gr e e t o p arti ci p at e i n t hi s r e s e ar c h st u d y a s y o u h a v e e x pl ai n e d i n t hi s d o c u m e nt. 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
P arti ci p a nt’ s N a m e  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
P arti ci p a nt’ s Si g n at ur e  
_ _ _ _ _ _ _ _ _ _ _  
D at e  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
N a m e of p e r s o n o bt ai ni n g c o n s e nt  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Si g n at ur e of p er s o n o bt ai ni n g c o n s e nt  
_ _ _ _ _ _ _ _ _ _ _ _ _  
D at e  
 
A U T H O RI Z A TI O N F O R U S E O F M Y P R O T E C T E D H E A L T H I N F O R M A TI O N  
 
Y o u h a v e b e e n a s k e d t o b e p art of a r e s e ar c h st u d y u n d er t h e dir e cti o n of R u s s ell S. Ri c h ar d s o n, P h. D.  a n d hi s 
r e s e ar c h t e a m.  T h e p ur p o s e of t hi s st u d y i s t o fi n d o ut m or e a b o ut bl o o d v e s s el f u n cti o n a n d t h e c o ntr ol of m u s cl e 
bl o o d fl o w wit h e x er ci s e i n s u bj e ct s t h at h a v e H e art F ail ur e or h a v e r e c ei v e d a H e art Tr a n s pl a nt.  
  
B y si g ni n g t hi s d o c u m e nt, y o u a ut h ori z e t h e V et er a n s  H e alt h A d mi ni str ati o n ( V H A) t o p er mit  R u s s ell S. Ri c h ar d s o n, 
P h. D.  a n d t h e r e s e ar c h t e a m t o u s e a n d di s cl o s e t h e f oll o wi n g i nf or m ati o n a b o ut y o u.  
 
 
 
 
 
 


V A  D e p art m e nt of V et er a n s Aff air s  
V A  A ut h ori z ati o n f or U s e of Pr ot e ct e d H e alt h 
I nf or m ati o n f or R e s e ar c h P ur p o s e s 
 P a g e 2 1  of 2 2  
P arti ci p a nt N a m e:                                                                                                           D at e:   _ _ _ _ _ _ _ _ _                   
Titl e of St u d y:  “V a s c ul ar a n d A ut o n o mi c D y sf u n cti o n i n H e art F ail ur e a n d H e art Tr a n s pl a nt P ati e nt s ”  
Pri n ci p al I n v e sti g at or:  R u s s ell S. Ri c h ar d s o n, P h. D.                                         V A M C: S alt L a k e Cit y ( 6 6 0)     
C o n s e nt V er si o n D at e: V er si o n  (M ar c h  2 0 1 5 )  
 
 
Y o u c a n c h o o s e w h et h er or n ot y o u will p arti ci p at e i n t hi s r e s e ar c h st u d y. H o w e v er, i n or d er t o p arti ci p at e y o u h a v e 
t o si g n t hi s c o n s e nt a n d a ut h ori z ati o n f or m. 
 
T hi s i s t h e i nf or m ati o n w e will u s e:  
- 
N a m e  
- 
A d dr e s s  
- 
T el e p h o n e n u m b er  
- 
F a mil y m e di c al hi st or y  
- 
C urr e nt a n d p a st m e di c ati o n s or t h er a pi e s  
- 
I nf or m ati o n fr o m a p h y si c al e x a mi n ati o n, s u c h a s bl o o d pr e s s ur e r e a di n g, h e art r at e, br e at hi n g r at e, a n d 
t e m p er at ur e 
- 
All ot h er t e st s a n d pr o c e d ur e s t h at will b e p erf or m e d i n t h e st u d y  
 
B y si g ni n g t hi s A ut h ori z ati o n, I a m gi vi n g p er mi s si o n f or t h e Pri n ci p al I n v e sti g at or a n d t h eir r e s e ar c h t e a m 
t o u s e a n d di s cl o s e t h e c at e g ori e s of m y pr ot e ct e d h e alt h i nf or m ati o n t h at t h e Pri n ci p al I n v e sti g at or h a s 
c h e c k e d b el o w:  
  Dr u g A b u s e  
  Al c o h oli s m or al c o h ol a b u s e  
  T e sti n g f or or I nf e cti o n wit h H u m a n I m m u n o d efi ci e n c y Vir u s ( HI V)  
  Si c kl e C ell A n e mi a  
 
Ot h er s w h o will h a v e a c c e s s t o y o ur i nf or m ati o n f or t hi s r e s e ar c h pr oj e ct ar e t h e U ni v er sit y of Ut a h’ s I n stit uti o n al 
R e vi e w B o ar d (t h e c o m mitt e e t h at o v er s e e s r e s e ar c h st u d yi n g p e o pl e) a n d a ut h ori z e d m e m b er s of t h e V A S alt L a k e 
Cit y H e alt h C ar e S y st e m ( V A S L C H C S) w or kf or c e w h o n e e d t h e i nf or m ati o n t o p erf or m t h eir d uti e s (f or e x a m pl e: t o 
pr o vi d e tr e at m e nt, t o e n s ur e i nt e grit y of t h e r e s e ar c h, a n d f or a c c o u nti n g or billi n g m att er s). Offi c e s wit hi n t h e V A 
s u c h  a s  t h e  Offi c e  R e s e ar c h  O v er si g ht,  t h e  Offi c e  of  R e s e ar c h  D e v el o p m e nt,  t h e  I n s p e ct or  G e n er al  a n d  t h e  
G o v er n m e nt A c c o u nti n g Offi c e w h o h a v e a ut h orit y t o r e vi e w a n d e v al u at e t h e c o n d u ct of r e s e ar c h m a y h a v e a c c e s s 
t o y o ur i nf or m ati o n. 
I n c o n d u cti n g t hi s st u d y, w e m a y s h ar e y o ur i nf or m ati o n wit h gr o u p s o ut si d e t h e V A S L C H S C. T h e i nf or m ati o n w e 
s h ar e m a y i n cl u d e i nf or m ati o n t h at dir e ctl y i d e ntifi e s y o u. T h e s e ar e t h e gr o u p s:  
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T h e  F e d er al  Dr u g  A d mi ni str ati o n  ( F D A),  a  f e d er al  a g e n c y  t h at  n e e d s  t o  c o nfir m  t h e  a c c ur a c y  of  t h e  
r e s ult s s u b mitt e d t o t h e g o v er n m e nt; 
I n di vi d u all y-i d e ntifi a bl e h e alt h i nf or m ati o n di s cl o s e d p ur s u a nt  t o t h e a ut h ori z ati o n m a y n o l o n g er  b e pr ot e ct e d b y 
F e d er al l a w s or r e g ul ati o n s a n d m a y b e s u bj e ct t o r e -di s cl o s ur e b y t h e r e ci pi e nt.  


V A  D e p art m e nt of V et er a n s Aff air s  
V A  A ut h ori z ati o n f or U s e of Pr ot e ct e d H e alt h 
I nf or m ati o n f or R e s e ar c h P ur p o s e s 
 P a g e 2 2  of 2 2  
P arti ci p a nt N a m e:                                                                                                           D at e:   _ _ _ _ _ _ _ _ _                   
Titl e of St u d y:  “V a s c ul ar a n d A ut o n o mi c D y sf u n cti o n i n H e art F ail ur e a n d H e art Tr a n s pl a nt P ati e nt s ”  
Pri n ci p al I n v e sti g at or:  R u s s ell S. Ri c h ar d s o n, P h. D.                                         V A M C: S alt L a k e Cit y ( 6 6 0)     
C o n s e nt V er si o n D at e: V er si o n  (M ar c h  2 0 1 5 )  
 
 
Y o u m a y r e v o k e t hi s a ut h ori z ati o n.  T hi s m u st b e d o n e i n writi n g.  Y o u m u st eit h er gi v e y o ur r e v o c ati o n i n p er s o n 
t o t h e Pri n ci p al I n v e sti g at or or t h e Pri n ci p al I n v e sti g at or’ s st aff, or m ail it t o: R u s s ell S. Ri c h ar d s o n, P h. D., V A M C 
S L C, G R E C C 1 8 2, 5 0 0 F o ot hill Dri v e, S L C, U T 8 4 1 4 8.  If y o u r e v o k e t hi s a ut h ori z ati o n, w e will n ot b e a bl e t o c oll e ct 
n e w i nf or m ati o n a b o ut y o u, a n d y o u will b e wit h dr a w n fr o m t h e r e s e ar c h st u d y.  H o w e v er, w e c a n c o nti n u e t o u s e 
i nf or m ati o n w e h a v e alr e a d y st art e d t o u s e i n o ur r e s e ar c h, a s n e e d e d t o m ai nt ai n t h e i nt e grit y of t h e r e s e ar c h.  
T hi s a ut h ori z ati o n d o e s n ot h a v e a n e x pir ati o n d at e.  
 
N o n -r e s e ar c h-r el at e d tr e at m e nt, p a y m e nt, e nr oll m e nt, or eli gi bilit y f or b e n efit s c a n n ot b e c o n diti o n e d o n y o u 
c o m pl eti n g a n a ut h ori z ati o n.  
 
I a ut h ori z e y o u t o u s e a n d di s cl o s e h e alt h i nf or m ati o n a b o ut m e f or t hi s st u d y, a s y o u h a v e e x pl ai n e d i n 
t hi s d o c u m e nt. 
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P arti ci p a nt’ s N a m e or L e g al 
R e pr e s e nt ati v e ( pl e a s e pri nt)  
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P arti ci p a nt’ s Si g n at ur e or L e g al 
R e pr e s e nt ati v e ( Att a c h a ut h orit y t o si g n:  
H e alt h C ar e P o w er of Att or n e y or L e g al 
G u a r di a n a p p oi nt m e nt) 
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D at e