Orthostatic Blood Pressure and Arterial Stiffness in Persons With SCI: The Effect of RAAS System
Conditions: Arterial Stiffness, Renin Angiotensin Aldosterone System, Orthostatic Hypotension, Spinal Cord Injury, Hypotension
Sponsor: James J. Peters Veterans Affairs Medical Center

Orthostatic Blood Pressure and Arterial Stiffness in Persons with Spinal Cord Injury: The Effect 
of the Renin-Angiotensin-Aldosterone System 
 
Version Date: 8.6.2020 
 
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Orthostatic Blood Pressure and Arterial Stiffness in Persons with Spinal Cord Injury: The 
Effect of the Renin-Angiotensin-Aldosterone System 
 
 
 
 
PI: Jill Wecht, EdD; Trevor Dyson-Hudson, MD 
Co-Investigators: Caitlyn Katzelnick, MS; Michael LaFountaine, EdD; William Bauman, MD; 
Genevieve Pinto Zipp, EdD; Runlin Zhang, Matthew Maher. 
 
 
 
 
 
NCT Number: 
NCT04510974 
 
 
 
 
Date: 8/6/2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Orthostatic Blood Pressure and Arterial Stiffness in Persons with Spinal Cord Injury: The Effect 
of the Renin-Angiotensin-Aldosterone System 
 
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ABSTRACT: 
 
Background: Approximately 17,000 new spinal cord injury (SCI) occur each year in the United 
States. With advances in acute medical care, longevity has increased in persons with SCI; 
however, morbidity due to cardiovascular disease (CVD) occurs at an earlier age compared to 
the general population.  Additionally, individuals with chronic SCI are at a heightened risk of 
CVD due to autonomic nervous system (ANS), physical inactivity and increased inflammatory 
processes. Arterial stiffness (AS) is recognized as an independent risk factor for CVD, and pulse 
wave velocity (PWV) has proven to be a valid tool to predict and track structural arterial changes 
that reflect arteriosclerosis. In persons with SCI an increase in AS has been noted when 
compared to the uninjured population; however, possible contributors to this increase are not yet 
fully understood.  
After a SCI, sympathetic control in the regions below the lesion level are severely 
disrupted; however, parasympathetic function is preserved. Due to the dissociation between the 
two systems, those with lesions above T6 experience low resting BP and further decreases in BP 
when changing postures (OH). Decreased plasma norepinephrine (NE) has been noted in 
individuals with cervical lesions when compared to individuals with thoracic injuries and 
controls. Additionally, lower levels of NE have been found to be associated with an increased 
incidence of OH in persons with SCI. As a consequence, individuals with high-level injuries 
have a heightened reliance on RAAS to maintain and stabilize BP.  
A mechanism for increased AS in the uninjured population is over activation of the renin-
angiotensin-aldosterone system (RAAS). Angiotensin II (ANG II), a hormone produced through 
RAAS, modulates vascular stiffness by reducing elastin, promotes collagen formation and 
increases oxidative stress. Due to decentralized cardiovascular autonomic control, individuals 
with SCI have a heightened reliance on RAAS to maintain and stabilize blood pressure (BP), 
especially during an orthostatic challenge. Participants: A total of 33 subjects, 22 individuals 
with SCI and 11 age-matched uninjured controls. Objectives: To study the hazardous effects of 
a highly activated RAAS on vasculature, the participant will be placed on a tilt table in the 
supine position and progressively tilted (30º, 45 º and 60 º for 10 minutes at each angle of tilt). 
PWV will be measured during supine and hormonal assessments (active plasma renin) will be 
assessed at supine and 60 degree tilt to determine if RAAS specific hormones contribute to 
increased AS in each cohort. The study aims are: 1) To investigate the influence of orthostatic 
change of BP and NE responses to orthostasis; and 2) To determine if increased reliance on the 
RAAS for orthostatic BP regulation contributes to differences in supine AS in individuals with 
SCI.  
 
SPECIFIC AIMS: 
Aim 1:  To investigate the influence of orthostatic change in BP on plasma renin responses to 
HUT.  
Hypothesis 1A: There will be an inverse relationship between the change in BP and change in 
plasma renin from supine rest to 60°HUT in individuals with high-level SCI.    
  
Hypothesis 1B: There will be no relationship between the change in BP and change in plasma 
renin from supine rest to 60° HUT in persons with low-level SCI and uninjured                    
controls.  

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Aim 2:  To investigate the influence of orthostatic change in BP and NE on the RAAS 
responses to HUT.  
 
Hypothesis 2A: There will be a linear relationship between the change in orthostatic BP and 
change in plasma NE concentration from supine rest to 60° HUT.    
  
Hypothesis 2B: Plasma renin activity will be inversely related to plasma NE concentrations 
during HUT in persons with SCI. 
 
Aim 3: To determine if increased reliance on the RAAS for orthostatic BP regulation 
contributes to differences in supine AS. 
 
Hypothesis 3A: There will be significant group differences for change in plasma renin during 
HUT, in that plasma renin will be significantly increased during HUT in participants with high-
level SCI, but will remain unchanged in individuals with low-level SCI and uninjured controls.  
 
Hypothesis 3B:  Change in plasma renin during the HUT maneuver will be directly associated 
with supine PWV in individuals with high-level SCI.  
 
Hypothesis 3C: There will be no relationship between the change in plasma renin during the 
HUT maneuver and supine PWV in persons with low-level SCI and uninjured controls.  
 
 
REVIEW OF LITERATURE: 
 
After a SCI, descending sympathetic preganglionlic neurons are disrupted causing loss of 
supraspinal regulation of cardiovascular function[1, 2],which results in numerous clinical issues. 
The level of the spinal lesion greatly influences the amount of cardiovascular regulation 
dysfunction after SCI. In individuals with injuries below T6, the sympathetic and 
parasympathetic control of the heart and splanchnic bed are intact, both of which are essential for 
short- and long- term BP regulation [2]. On the other hand, individuals with higher-level injuries, 
the parasympathetic control remains integral, while sympathetic autonomic control is lost 
(Krasioukov, 2009). This results in persistent hypotension and severe drops in BP when moving 
to the upright position (OH) [1, 3-7]. 
OH has a higher prevalence in individuals with cervical compared to individuals with 
thoracic lesions, irrespective of whether their lesion was complete or incomplete[8, 9].  
According to a Consensus statement from the American Autonomic Society and American 
Academy of Neurology, OH is defined as a decrease in systolic BP (SBP) of 20+ mmHg and/or a 
fall in diastolic BP (DBP) of 10+ mmHg within 3-minutes of moving from supine to the upright 
position, with or without symptoms [10]. Interestingly, decreased plasma NE has been noted in 
individuals with cervical lesions when compared to individuals with thoracic injuries and 
controls [11-14]; and furthermore, there was no significant increase in NE level when individuals 
with tetraplegia underwent HUT [15, 16].  Additionally, lower levels of NE have been found to 
be associated with an increased incidence of OH in persons with SCI [17]. Individuals with 

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lesions below the cervical spine have normal to high levels of plasma NE concentrations [13, 
14]and, as a result, are less prone to hypotension and OH [3, 18, 19]. 
Additionally, OH after SCI is thought to be largely related to inability to centrally 
regulate vascular tone [20]. The loss of the reflex vasoconstriction of the splanchnic bed and 
lower extremity vasculature results in venous blood pooling, which results in reduced blood 
volume in end-diastolic volume, leading to a decrease in cardiac output and left ventricular 
stroke volume [21]. In addition, due to paralysis of the lower extremities and physical inactivity, 
persons with SCI lose their ability to use skeletal muscle pump by activating muscle contraction. 
Individuals with paraplegia and uninjured controls demonstrated increased total peripheral 
resistance during a head-up tilt(HUT) compared to cervical injuries [22]. This suggests that the 
SNS was increased in controls and individuals with low-level injuries because they were able 
toincrease venous return in order to maintain BP.  
Although many individuals with SCI demonstrate OH, symptoms associated with OH 
decrease over time (light-headedness, blurred vision, fatigue, weakness, etc.) [19]. Evidence 
demonstrates that increased dependency on the RAAS is believed to play an integral part in 
reducing the severity of postural hypotension and the associated symptoms [12, 16, 19, 23, 24]. 
Renin was shown to increase in individuals with tetraplegia during HUT, an orthostatic 
challenge, at a much quicker and higher rise compared to individuals with thoracic injuries and 
uninjured controls [12, 23, 25].  
The RAAS plays an essential role in maintaining long-term BP and is an enzymatic 
cascade in which renin is released into the blood and acts on angiotensinogen to form 
angiotensin I, which forms ANG II by the angiotensin converting enzyme (ACE) [26, 27]. 
Despite the important benefits of the RAAS in regulating BP homeostasis, recent evidence that 
chronic overproduction of this system may result in remodeling and restructuring of peripheral 
and coronary blood vessels by augmenting the generation of reactive oxygen species, [28, 29], 
accompanied by an increase in oxidative stress, and production of inflammation, thrombosis and 
fibrosis [28]. Recent evidence has demonstrated that the use of ACE inhibitors or ANG II 
receptor blockers (ARBs) reduce vascular remodeling [30-32], and diminish collagen production 
and increase the elastin to collagen ratio [31]. A meta-analysis demonstrated that the use of 
ARBs and ACE inhibitors decreased the risk of myocardial infarction, stroke, cardiovascular 
mortality and total mortality in uninjured subjects [33], suggesting that the excessive ANG II 
production may lead to an increased risk of CVD.  
AS has been identified as an independent risk factor for CVD [31, 34, 35] and PWV is 
considered to be the gold standard measurement because of its high reliability and validity [36]. 
Increased AS has been documented in individuals with SCI compared to age-matched uninjured 
controls [2, 37-41], even after matching for age, body composition and activity level [20]. It is 
well appreciated that the increase in AS is due to the natural aging process [42], however, we 
recently reported that AS was not associated with age in the SCI population, suggesting 
premature cardiovascular dysfunction in persons with SCI [41].  
Additionally, there is evidence supporting a direct linear association between AS and 
LOI, with AS increasing with ascending LOI [41]. In this same study, we reported that 
individuals with increased AS reported experiencing OH [41], because OH may cause structural 
vascular adaptations secondary to persistence and episodic hypotension [43]. Interestingly, our 
team recently demonstrated that there was significant inverse relationship between seated SBP 
and AS [41]; and furthermore, Wecht et al. (2005) demonstrated that anti-hypotensive agents 
(Midodrine and L-NAME) reduced orthostatic dependency on the RAAS because plasma renin 

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and serum aldosterone levels were comparable with baseline levels. We speculate that this may 
be related to a reliance on RAAS for orthostatic BP maintenance, which may have detrimental 
effects on AS[24]. Groothuis et al. (2010) demonstrated that ANG II contributed to increased 
supine leg vascular resistance in individuals with thoracic injuries (T4-T12), but did not 
contribute to AS in controls[44]. Although increased AS has been reported in individuals with 
SCI, controversy abounds and additional evidence is needed to gain a better understanding of 
impact of morphologic and physiologic vascular adaptations that occur following SCI on 
orthostatic BP regulation and AS.  
 
 
 
SIGNIFICANCE OF RESEARCH:  
 
Evidence has shown that PWV is increased 2-3 m/s in persons with SCI compared to 
able-bodied individuals [45, 46] which corresponds a staggering 40 year acceleration of age-
related cardiovascular decline[47]. Evidence of causality suggests that decreases in AS, 
subsequent to administration of ARBs or ACE inhibitors, reduced vascular remodeling and 
decreased the risk of myocardioal infarction, stroke and cardiovascular mortality in the uninjured 
population [33].  Additionally, the effects of OH on AS have not been studied in the SCI 
population, even though, persistent and episodic OH have been associated with elevated risk of 
stroke and cognitive deficits, including memory, processing speed and executive function in the 
uninjured population[48-51]. Documenting the impact of the RAAS on AS in the SCI 
population, will provide a necessary step in initiating a change in clinical treatment of 
hypotension and OH, which may lead to improved regulation and preservation of cardiovascular 
health and longevity.  
 
 
RESEARCH DESIGN &METHODOLOGY: 
 
Subjects– 22 individuals with SCI and 11 age-matched non-SCI controls will be recruited for 
eligibility to participate in the study. Individuals with SCI will be recruited from the Northern 
New Jersey SCI Model (NNJSCIS) System database, which contains over 1000 people with 
traumatic SCI. The control subjects will be recruited from prior study enrollment at Kessler 
Foundation and hospital personnel.  
 
Inclusion Criteria: 
• 
All subjects: 
• 
Between ages 21 and 70 years old.  
• 
Additional Inclusion Criteria: SCI subjects:  
• 
Traumatic injury,  
• 
High-level injury: C1-T1 and Low-level injury: T6-T12,  
• 
Non-ambulatory,  
• 
American Spinal Injury Association Injury Scale (AIS) A, B or C, 
• 
1+ year(s) post injury.  
 
Exclusion Criteria: 

Orthostatic Blood Pressure and Arterial Stiffness in Persons with Spinal Cord Injury: The Effect 
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• 
Acute illness or infection,  
• 
Current smokers within 1 year,  
• 
Documented history of controlled or uncontrolled hypertension or diabetes,  
• 
Any other neurological condition other than a SCI (multiple sclerosis, Parkinson’s 
disease),  
• 
CVD (coronary heart disease, congestive heart failure, peripheral artery disease, 
stroke). 
 
Procedure: All subjects will be asked to visit the Kessler Foundation (KF) laboratory for 1 day 
of testing. The study will take about 3 hours to complete per subject. Subjects will be asked to 
arrive between 8:00 am and noon at the KF testing facility after a normal breakfast and a good 
night sleep.  Subjects will remain seated for 5-minute hemodynamic assessment. After, subjects 
will be transferred to the tilt table to lay supine for 10 minutes prior to another 5-minute 
hemodynamic assessment. Arterial stiffness, renin and NE will be collected in the supine 
position. Subjects will then be progressively tilted to 30°, 45° and 60 ° for 10 minutes at each 
angle and 5 minutes of hemodynamic assessments will be measured at each angle. At 60 °, renin 
and NE will be collected.  
• Cardiovascular Assessments:  While the subject is seated 3 ECG electrodes will be 
affixed to the chest and abdomen for continuous monitoring of HR and respiration rate 
(RR).  Brachial BP will be monitored at 1 minute intervals using a standard adult BP cuff 
placed at the right upper arm, and beat-to-beat finger arteriolar BP will be continuously 
monitored from the right middle finger throughout testing.  MAP (mmHg) will be 
calculated from brachial BP using the formula: [systolic BP + (2 X diastolic BP)]/3.  
Beat-to-beat HR, RR and BP data will be viewed in real-time and stored for subsequent 
analysis using customized programs created with LabView graphical software.   
• Arterial Stiffness: aPWV (aortic pulse wave velocity) will be measured using the 
SphygmoCor CPV system (AtCor Medical Pty Ltd., West Ryde, NSW., Australia) at the 
carotid and femoral sites measured from the participant’s supra-sternal notch to each 
artery. The aPWV measurement will be taken in two steps: a tonometry reading of site A 
(carotid artery) with an ECG signal simultaneously recorded captured after 10 seconds of 
good data, followed by a 10 second reading of site B (femoral artery) with an ECG 
signal. 
• Tilt table: will be used to perform an orthostatic provocation, which will be a progressive 
HUT from supine position to 30º, 45 º and 60 º for 10 minutes at each angle of tilt. 
Adjustment of the tilt table to each angle will be accomplished in less than 5 seconds, and 
subjects will be questioned at each angle of tilt regarding symptoms of syncope (i.e., 
blurry vision, dizziness, light-headedness, or nausea). The tilt table will be padded and 
motorized. Restraining straps will be used on the lower extremities and trunk to ensure 
subject safety during higher inclinations of HUT and to avoid lower-extremity muscle 
contractions in the control subjects. The straps will be wide and padded for subject 
comfort and to insure that stimulation of sympathetic spinal reflexes was not evoked. 
• Hormonal Assessment: Blood will be drawn from a vein in the arm or hand twice each 
study visit to measure plasma renin level and NE. One sample of each will be taken in the 
supine position after baseline hemodynamic data collection and the other will be taken 
when tilted to 60º. Alcohol will be used to sterilize the area. A rubber band will be placed 
around the arm proximal to the vein. A small needle will be inserted into the vein to 

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collect blood. Once the blood has been collected, the needle will be removed and the 
puncture site will be covered. Samples will be immediately spun, down plasma separated 
and stored at -80 º C for subsequent high performance liquid chromatography (HPLC) 
analysis of renin and NE concentrations which will be performed at the Bronx VA 
research lab.  
 
Table 1. Protocol Timeline 
  
  
  
Time Point 
Seated 
Seated Supine 
30° Tilt 
45° Tilt 
60° Tilt 
Time (min) 
0-10 
10-15 
15-50 
50-60 
60-70 
70-80 
Heart Rate 
 
X 
X 
X 
X 
X 
Breathing Rate 
 
X 
X 
X 
X 
X 
Blood Pressure 
 
X 
X 
X 
X 
X 
Blood Draw 
 
 
X 
 
 
X 
Arterial Stiffness 
  
  
X 
  
  
  
 
 
 
RISKS AND DISCOMFORTS: 
 
1. Heart Rate, Arterial Stiffness and Blood Pressure:   These are non-invasive procedures 
that involve minimal risk; however some subjects may experience discomfort when the 
ECG electrodes are removed from the skin and when the blood pressure cuffs are 
inflated.   
2. Blood Draws: Subject may experience some discomfort when the needle is being place in 
the arm vein. Expected risks may include bruise or infection at the site of skin puncture, 
temporary faintness and rarely temporary loss of consciousness. 
3. Tilt table: Subjects may feel dizzy, lightheaded or nauseous letting the staff passively 
reposition the subject from lying down to 30, 45 and 60-degree tilt. A staff member will 
be supporting the subject during this tilt, but if he or she feels uncomfortable, the staff 
will stop the test at any time.   
 
 
DATA ANALYSIS: 
 
Aim 1:  To investigate the influence of orthostatic change in BP on plasma renin responses to 
HUT.  
Hypothesis 1A: There will be an inverse relationship between the change in BP and change in 
plasma renin from supine rest to 60° HUT in individuals with high-level SCI.    
  
Hypothesis 1B: There will be no relationship between the change in BP and change in plasma 
renin from supine rest to 60° HUT in persons with low-level SCI and uninjured controls.  
Instrumentation 

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Statistical Analysis: To determine the relationship between change in BP and change in plasma 
rennin, we will use Pearson’s correlation coefficient or Spearman’s correlation coefficient with 
alpha. The independent variable is change in SBP from supine rest to 60° HUT and the 
dependent variable is change in renin from supine rest to 60° HUT. The alpha level will be set at 
0.05.  
 
 
 
Aim 2:  To investigate the influence of orthostatic change in BP and NE on the RAAS 
responses to HUT.  
Hypothesis 2A: There will be a linear relationship between the change in orthostatic BP and 
change in plasma NE concentration from supine rest to 60° HUT.    
  
Hypothesis 2B: Plasma renin activity will be inversely related to plasma NE concentrations 
during HUT in persons with SCI. 
 
Statistical Analysis: To determine the relationship between change in BP and NE, we will use 
Pearson’s correlation coefficient or Spearman’s correlation coefficient with alpha. The 
independent variable is change in SBP from supine rest to 60° HUT and the dependent variable 
is change in NE from supine rest to 60° HUT. The alpha level will be set at 0.05.  
 
 
Aim 3: To determine if increased reliance on the RAAS for orthostatic BP regulation 
contributes to differences in supine AS. 
 
Hypothesis 3A: There will be significant group differences for change in plasma renin during 
HUT, in that plasma renin will be significantly increased during HUT in participants with high-
level SCI, but will remain unchanged in individuals with low-level SCI and uninjured controls.  
 
Statistical Analysis: Differences in change in plasma renin during HUT between groups will be 
analyzed using univariate group by ANOVA, with the interaction effect being the statistical 
effect of interest. The alpha level will be set at 0.05. The G*Power calculations indicate that with 
a total sample size of 33, there will be a power = 0.8.13 to detect the effect size.  
 
Hypothesis 3B:  Change in plasma renin during the HUT maneuver will be directly associated 
with supine PWV in individuals with high-level SCI.  
 
Hypothesis 3C: There will be no relationship between the change in plasma renin during the 
HUT maneuver and supine PWV in persons with low-level SCI and uninjured controls.  
 
Statistical Analysis: To determine the relationship between change in plasma renin and supine 
PWV, we will use Pearson’s correlation coefficient or Spearman’s correlation coefficient with 
alpha. The independent variable is change in renin from supine rest to 60° HUT and the 
dependent variable is PWV during supine rest. The alpha level will be set at 0.05.  
 

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STUDY COMPENSATION: 
Subjects will receive $100 for their participation.  
 
PUBLICATION OF RESEARCH: 
It is anticipated that the observations made in this study will be presented at National meetings 
and will be submitted for publication in peer-reviewed journals, including those in the fields of 
Spinal Cord Medicine.  
 
COST ANALYSIS: 
Kessler Foundation will be not responsible for any costs associated with this project. This 
protocol will be funded by the NJ Commission on Spinal Cord Research (CSCR18FEL010).  
 
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Orthostatic Blood Pressure and Arterial Stiffness in Persons with Spinal Cord Injury: The Effect 
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