hemodynamic responses to an exercise stress test in … · 2019-06-05 · draft 1 hemodynamic...

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Hemodynamic Responses to an Exercise Stress Test in Parkinson’s Disease Patients without Orthostatic

Hypotension

Journal: Applied Physiology, Nutrition, and Metabolism

Manuscript ID apnm-2018-0638.R1

Manuscript Type: Article

Date Submitted by the Author: 09-Nov-2018

Complete List of Authors: Roberson, Kirk; University of Miami, Kinesiology and Sport SciencesSignorile, Joseph; University of Miami, Kinesiology and Sport SciencesSinger, Carlos; University of Miami School of MedicineJacobs, Kevin; University of Miami, Kinesiology and Sport SciencesEltoukhy, Moataz; University of Miami, Kinesiology and Sport SciencesRuta, Nicolette; University of Miami, Kinesiology and Sport SciencesMazzei, Nicole; University of Miami, Kinesiology and Sport SciencesBuskard, Andrew; University of Miami, Kinesiology and Sport Sciences

Keyword: Hemodynamics, exercise < exercise, Blood Pressure, Parkinson’s Disease, Exercise Test, Heart Rate, Dysautonomia

Is the invited manuscript for consideration in a Special

Issue? :Not applicable (regular submission)

https://mc06.manuscriptcentral.com/apnm-pubs

Applied Physiology, Nutrition, and Metabolism

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Hemodynamic Responses to an Exercise Stress Test in Parkinson’s Disease Patients without

Orthostatic Hypotension

Kirk B. Robersona, Joseph F. Signorilea,b, Carlos Singerc,d, Kevin A. Jacobse, Moataz Eltoukhyf,

Nicolette Rutaa, Nicolle Mazzeia, Andrew N.L. Buskarda

aLaboratory of Neuromuscular Research & Active Aging, Department of Kinesiology and Sport

Sciences, University of Miami, Coral Gables, FL, USA

bCenter on Aging, Miller School of Medicine, University of Miami, Miami, FL, USA

cDepartment of Neurology, Miller School of Medicine, University of Miami, Miami, FL, USA

dDirector, Division of Parkinson’s Disease and Movement Disorders, Miami, FL, USA

eLaboratory of Clinical and Applied Physiology, Department of Kinesiology and Sport Sciences,

University of Miami, Coral Gables, FL, USA

fSports Medicine and Motion Analysis Laboratory, Department of Kinesiology and Sport

Sciences, University of Miami, Coral Gables, FL, USA

Corresponding Author: Dr. Kirk Roberson

Address: 1507 Levante Ave., Coral Gables, FL, 33146

Telephone: (252)-802-0429

Fax: (305)-284-4183

Email: [email protected]

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ABSTRACT

The presence of postganglionic sympathetic denervation is well established in Parkinson’s

disease (PD). Denervation at cardiac and blood vessel sites may lead to abnormal cardiovascular

and hemodynamic responses to exercise. The aim of the present investigation was to examine

how heart rate (HR) and hemodynamics are affected by an exercise test in PD patients without

orthostatic hypotension. Thirty individuals without orthostatic hypotension, fourteen individuals

with PD and sixteen age-matched healthy controls, performed an exercise test on a cycle

ergometer. Heart rate, blood pressure, and other hemodynamic variables were measured in a

fasted state during supine rest, active standing, exercise, and supine recovery. Peak HR and

percent of age-predicted maximum HR (HRmax) achieved were significantly blunted in PD

(p<.05, p<.01). HR remained significantly elevated in PD during recovery compared to controls

(p=.03, p<.05). Systolic, diastolic, and mean arterial pressures were significantly lower at

multiple time-points during active standing in PD compared to controls. Systemic vascular

resistance (SVRI) decreased significantly at the onset of exercise in PD, and remained

significantly lower during exercise and the first minute of supine recovery. End diastolic volume

(EDVI) was significantly lower in PD during supine rest and recovery. Our results indicate for

the first time that normal hemodynamics are disrupted during orthostatic stress and exercise in

PD. Despite significant differences in EDVI at rest and during recovery, and SVRI during

exercise, cardiac index was unaffected. Our finding of significantly blunted HRmax and HR

recovery in PD patients has substantial implications for exercise prescription and recovery

guidelines.

Key words: Hemodynamics; Exercise; Blood Pressure; Parkinson’s Disease; Exercise Test;

Heart Rate; Dysautonomia

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INTRODUCTION

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that has long been

characterized by the presence of motor symptoms, first described by James Parkinson in the 19th

century (Parkinson 2002). Classic motor symptoms include bradykinesia, muscular rigidity, and

postural and gait impairment (Gibb and Lees 1988). These symptoms are associated with loss of

dopaminergic neurons and intracytoplasmic inclusions in surviving substantia nigra pars

compacta neurons. Although movement abnormalities remain central to the diagnosis of PD,

non-motor features are increasingly more accepted.

Autonomic dysfunction has been extensively reported in PD, with the major clinical

manifestations being disruption of normal hemodynamics at rest, and during standing and

exercise (Jellinger 1990, Kim et al. 2014). Furthermore, cardiovascular dysautonomia, has been

identified as a premotor feature in multiple types of PD, which worsens with disease progression

(Kim et al. 2014). A retrospective cohort study reported that peak heart rate (HR), percentage of

age-predicted maximum HR (HRmax) achieved, and peak blood pressure (BP) were significantly

lower during a cardiac stress test in individuals later diagnosed with PD compared to those who

remained unaffected by the disease (Palma et al. 2013). Moreover, Perez et al. (2015), provided

evidence that sympathetic denervation may affect the heart and the vascular system

simultaneously. Researchers have begun to detail the mechanisms and physiological

consequences of cardiovascular dysautonomia in PD (Barbic et al. 2007, Kim et al. 2014);

however, few have attempted to identify the presence of cardiovascular abnormalities before,

during, and after an exercise stress test. Though limited, the majority of findings indicate that

peak BP and HR during exercise appear blunted in PD patients compared to healthy individuals

(DiFrancisco-Donoghue et al. 2009, Kanegusuku et al. 2016, Reuter et al. 1999). Determining

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the mechanisms by which these factors are affected during exercise by examining the

hemodynamic variables that regulate each may provide a critical missing link for researchers

seeking targets for the diagnosis and treatment of PD. Therefore, the purpose of this study was to

identify measures of cardiac and systemic vascular regulation responsible for abnormal BP and

HR responses seen in PD patients. We hypothesized that peak systolic blood pressure (SBP) and

HR would be significantly lower in PD patients. Additionally, we hypothesized that heart rate

recovery (HRR) would be blunted in PD patients, and that systemic vascular resistance index

(SVRI) would significantly decrease upon active standing in PD when compared to healthy

individuals and remain significantly lower during exercise.

METHODS

Fourteen individuals with PD (68±12 yrs; Hoehn and Yahr stage 1-3) and 16 healthy controls

(66±7 yrs) completed the study. Participants were recruited from local communities using flyers,

internal databases and through referrals by the School of Medicine’s Division of Parkinson’s

Disease and Movement Disorders. The inclusion criteria were that volunteers be between 45 and

85 years of age, be diagnosed as Stage 1, 2, or 3 on the Hoehn and Yahr scale for PD, or be a

healthy individual with no unresolved disease. Participants were excluded if they had been

advised by their physician not to exercise; had participated within the past 3 months in an

exercise program incorporating vigorous exercise 3 or more days per week; were prescribed any

medications that could affect cardiovascular measures; were diagnosed with orthostatic

hypotension or displayed symptoms of orthostatic hypotension during the active standing phase

of the stress test; had additional neurological disorders which might mask or confound symptoms

typically present in PD; or, were unable to provide informed consent. All forms, questionnaires,

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and protocols were approved by the University's Institutional Review Board and all participants

signed an informed consent prior to participation.

The study timeline is presented in Figure 1. On day 1, participants completed all necessary

forms and received detailed information regarding the study including testing equipment, test

protocols, and potential risks and benefits associated with the testing. To assess eligibility criteria

in regard to each participant’s current exercise routine, and to collect information on overall

participation in physical activity, the Global Physical Activity Questionnaire (GPAQ) was

administer face-to-face during the first meeting. The GPAQ was developed by the World Health

Organization and uses a standardized protocol for the surveillance of physical activity in

countries across the world (Armstrong and Bull 2006). Information on participation in three

domains of physical activity, as well as sedentary behavior is collected. A Hoehn and Yahr stage

assessment was also performed.

All participants underwent a symptom-limited, sub-maximal exercise test. Participants

arrived at the laboratory between 6-10 am following a 12-hour fast. Patients were asked to fast to

avoid any confounding effects of post-prandial hypotension, which has been associated with PD.

Patients were instructed to arrive in the “on” state, meaning that all parkinsonian medications

were taken prior to arriving. They were asked to take their usual medications no later than 45-60

minutes before testing to ensure adequate response time. The testing session lasted

approximately 1 hour and incorporated 4 stages: resting, active standing, exercise testing, and

recovery.

Upon arrival at the laboratory, body weight was measured using a medical dual-beam scale

(Detecto Corp, Webb City, MO., USA), which also included a stadiometer to measure height.

Body surface area (BSA) was determined using the Mosteller formula (Mosteller 1987) and

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calculated as follows: . Following anthropometric 𝐵𝑆𝐴 = [ 𝑊𝑒𝑖𝑔ℎ𝑡 (𝑘𝑔) ∗ 𝐻𝑒𝑖𝑔ℎ𝑡 (𝑐𝑚)] ÷ 60

measurements, participants were placed in a supine position on a padded table. A 12-lead ECG

was applied to monitor cardiac electrical activity. Hemodynamic measures included SBP,

diastolic blood pressure (DBP), mean arterial blood pressure (MAP), SVRI, stroke volume index

(SVI), end diastolic volume index (EDVI), and cardiac index (CI). These were measured

throughout rest, exercise, and recovery. Following the 20-minute resting phase, participants

stood quietly for 5 minutes to assess orthostatic tolerance (active standing phase). To assess

orthostatic hypotension, the following criteria were used: a sustained reduction of systolic blood

pressure of at least 20 mmHg or diastolic blood pressure of 10 mmHg, or both, within 3 min of

standing (Freeman et al. 2011). If these criteria were met, participants were not allowed to

complete the remainder of the study, and all data was removed from the database. The effects of

orthostatic hypotension on blood pressure response during orthostatic stress and exercise are well

documented and could significantly alter the study’s findings (Asahina et al. 2012, Low et al.

2013, Smith et al. 1995,). Moreover, as described by Vianna et al. (2016), PD patients with OH

may also have altered HR responses to orthostatic stress. Therefore, these individuals were

excluded in an effort to ensure that any observed differences in BP are due to PD pathology, and

not a result of orthostatic hypotension.

For the exercise test, participants were fitted on a Monarch electronically-braked cycle

ergometer (Model 839E, Vansbro, Sweden). Testing began with a 3-minute warm-up at a

workload of 15W. Participants were asked to maintain a pedaling speed of 50-70 rpm. Following

the warm-up, workload increased 20W for each subsequent 3-minute stage. Participants

exercised until they reached 85% HRmax, became symptomatic, or requested to stop. Rating of

perceived exertion, BP, and HR were recorded at the 2-minute mark of each stage using the 15-

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point Borg rating scale, an automatic electronic BP cuff (Tango M2, Suntech Medical),

electronic ECG software (Cardiosoft, GE Healthcare), respectively. All other hemodynamic

measures were monitored beat-by-beat using impedance cardiography (PhysioFlow Enduro,

Paris, France). Briefly, the PhysioFlow provides information on cardiac function through an

analysis of trans-thoracic bio-impedance recording in association with the ECG signal. It

measures impedance changes by injecting a high frequency, low magnitude electrical current

towards the thorax between paired electrodes positioned on the neck and xiphoid process. Two

additional electrodes are used to record the ECG signal. A more detailed description, as well as

measures of device validity are presented elsewhere (Billat et al. 2012, Charloux et al. 2000,

Richard et al. 2001). At the completion of the exercise test, participants sat quietly on the cycle

ergometer for 2 minutes to allow assessment of HRR. Following this passive rest, participants

returned to the supine position for 10 more minutes of recovery.

Statistical Analysis

Descriptive statistics were calculated to provide participants’ characteristics. Additionally, all

data collected from the GPAQ were cleaned and analyzed using coding provided by EpiInfo,

based on guidelines established by the World Health Organization. A repeated-measures

ANOVA was used to examine significant within- and between-group differences for all

hemodynamic measures. Bonferroni post hoc analyses were used to assess pairwise differences.

All significance tests were two-tailed with a significance level of p < .05 set a priori. Effects

sizes were assessed using Hedge’s g with 0.80 considered large, 0.50 considered medium, and

0.20 considered small. A power analysis using a minimum power of 0.80 with an alpha level set

at 0.05, yielded a sample size of 14 participants per group. All analyses were performed using

SPSS, version 24 statistical package (IBM SPSS Statistics, Armonk, NY).

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RESULTS

Thirty participants were included in the analysis: 16 healthy controls (CON) and 14 PD patients.

Baseline characteristics are shown in Table 1. PD patients weighed significantly less at baseline

than their age-matched counterparts (MD (mean difference)=-13.6, p=.01); therefore, index

values (relative to body surface area) were calculated for all hemodynamic measures. No

significant between-group differences were detected in rating of perceived exertion at peak

exercise (CON=15.0 ± 2.0; PD=16.1 ± 2.4). Table 2 provides the percentage of participants from

each group who completed each corresponding stage of the exercise test.

Heart Rate Responses to Active Standing

Results for HR and HRmax are displayed in Table 3. HR significantly increased from baseline

for all time-points in the PD group during active standing, while significant increases were first

noted at 5 minutes for CON. There was a significant between-group difference for HR at 1-

minute of active standing with a higher HR for PD than CON (MD=6.5, p=.03, g=0.80).

Heart Rate Responses during Exercise and Recovery

Peak HR during exercise was significantly higher in the CON group (MD=9.7, p=.03,

g=0.80). HRR at 2 minutes post-exercise was significantly lower in PD than CON (MD=-14.4,

p<.01, g=-1.10), whereas HR 5 minutes into recovery was significantly higher in PD compared

to CON (MD=8.1, p=.045, g=0.75). Results for percentage of HRmax achieved were similar to

those for HR.

Blood Pressure

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Results for SBP, DBP, and MAP are displayed in Table 4. At rest, only DBP was

significantly lower in PD than CON (MD=-7.8, p=.015, g=-0.92). For PD, SBP did not

significantly increase above rest until stage 3, and the difference returned to a non-significant

level by minute 1 of recovery. However, for CON, SBP significantly increased at 1-minute of

active standing. Compared to resting values, SBP was significantly higher for CON in stages 3-5,

but not at later time-points. Significant between-group differences in MAP occurred at minutes

one and three of active standing, but values failed to reach significance for all other time points.

Additional Hemodynamic Measures

Results for remaining hemodynamic values are displayed in Figure 2. PD patients did not

complete stage 5, therefore, no data point is present in each of the graphs in Figure 2. For CON,

there was a significant decrease in SVRI during warm-up (MD=-735.6, p<.001), and remained

significantly below rest for all remaining time-points. A similar trend was observed for the PD

group. Although not significant, mean SVRI values at rest were lower in PD than CON (MD=-

270.2, p=.059, g=-0.70). SVRI showed a significant between-group difference favoring PD by

stage 1 (MD=-335.9, p=.03, g=-0.81). Values remained significantly lower at stage 2 (MD=-

338.6, p=.01, g=-0.98); but were not significant for stages 3 and 4. SVRI was again significantly

lower in PD at minute 1 of recovery (MD=-328.6, p=.017, g=-0.90), but not at minutes 5 or 10.

EDVI was significantly lower in PD compared to CON during minutes 3 (MD=-10.2, p=.04, g=-

0.79) and 5 (MD=-12.2, p=.02, g=-0.84) of active standing. Additionally, EDVI was

significantly lower in PD compared to CON during recovery (1 min: MD=-9.7, p=.01, g=-0.95; 5

min: MD=-7.1, p=.04, g=-0.78]. For SVI, no significant between-group differences were

observed at any time-point. For both groups, CI significantly increased during the warm-up

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(CON: MD=1.4, p<.01; PD: MD=1.9, p<.001), and remained significantly elevated for all

remaining time-points. There were no significant between-group differences at any time-points.

DISCUSSION

The principal findings of this study were that participants with PD had lower HR at peak

exercise, diminished BP response to active standing, and altered hemodynamic responses at rest,

during exercise, and in recovery. Additionally, it appears that strategies for maintaining

perfusion during orthostatic stress may be different in PD compared to CON.

Expectedly, values for peak HR and percentage of HRmax achieved were blunted for PD

compared to CON. These findings are in agreement with several previous studies revealing that

on average, PD patients are only able to achieve 75-85% of their HRmax; this finding appears to

occur independent of testing modality [DiFrancisco-Donoghue et al. 2009, Kanegusuku et al.

2016, Palma et al. 2013, Speelman et al. 2012, Werner et al. 2006). Numerous studies in PD

patients have reported autonomic imbalances that may directly underlie abnormalities in HR

(Orimo et al. 2007, Shibata et al. 2009), though a definitive relationship has yet to be established.

The predominant theory suggests that impaired ability to increase HR in PD patients, to a similar

extent as healthy individuals at peak exercise, is due primarily to cardiac sympathetic

denervation (Nakamura et al. 2010, Shibata et al. 2009), and that sympathetic denervation can

begin early in the disease process (Orimo et al. 2007, Strano et al. 2016).

Our results demonstrate that PD patients also have a significantly reduced ability to regulate

HR following exercise. Cole and colleagues reported that normal HRR could be defined as a

difference in HR of ≤ 42 bpm 2 minutes after a sub-maximal exercise test (Cole et al. 2000). On

average, HRR in PD was ~25 bpm, while the average for CON was ~39 bpm. Studies have

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indicated that parasympathetic return is the primary factor in regulating HR following exercise

(Kannankeril et al. 2004), and parasympathetic dysfunction has been reported to occur

concurrently with sympathetic dysfunction in PD patients (Shibata et al. 2009), providing a

potential mechanism. Another unique finding was that HR and percentage of HRmax remained

significantly elevated in PD compared to CON during supine recovery. A single study by Reuter

et al. (1999), measured HR into recovery following an exercise stress test. Although their data

did not yield significant responses at these time points, mean values were higher in the PD group

compared to CON. It is unclear, based on our outcome measures, why this was observed. As was

the case for HRR, parasympathetic dysfunction may provide a possible explanation.

Findings regarding BP responses during orthostatic stress and exercise are equivocal,

particularly in studies involving PD patients without orthostatic hypotension. Results are mixed,

with some studies demonstrating no difference in BP between PD and control groups during

exercise (Nakamura et al. 2010, Werner et al. 2006), while others reported significant differences

at both sub-maximal and maximal intensities (Kanegusuku et al. 2016, Reuter et al. 1999).

Nonetheless, there is consensus among researchers that BP responses of PD patients are blunted

at peak exercise intensities. In contrast to our hypothesis, there were no significant between-

group differences in SBP or MAP at peak exercise, although large mean differences were

apparent. This finding, while not significant, is in agreement with results reported by

Kanegusuku et al. (2016), which revealed lower SBP values in PD patients compared to CON at

sub-maximal and peak intensities.

This study was the first to our knowledge to assess measures of cardiac response, systemic

blood flow, and SVRI during exercise in PD patients. Although there are no normative data for

these measures in persons with PD, age-specific norms do exist for healthy individuals (Cain et

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al. 2009). Data show that SVI and EDVI decrease with age, particularly after age 60. Compared

to normative values, resting SVI and EDVI in both groups were slightly higher than mean values

presented for a similar age group. One study by Perez and colleagues reported resting values for

SVRI and SVI (Perez et al. 2015). Mean values for our PD group, although slightly lower, fell

within the standard deviations presented in their study. Patterns of change for SVI and SVRI in

PD patients during a tilt table test in their study reflect those seen in the current study, with mean

SVI values decreasing and mean SVRI values increasing during tilt.

During exercise, changes in SVI and CI were comparable to those of other studies using

treadmills and cycling (Mile et al. 1984, Thadani and Parker 1978, Vella et al. 2011). It should

be noted, however, that these studies included predominately younger subjects. Mean values for

SVRI at rest were higher for both groups than those reported in a younger population (Connes et

al. 2012), but were comparable to reported values for an age-matched healthy population at rest

and peak exercise (Maeder et al. 2010). This finding is not unexpected, as SVRI generally

increases with age (Amery et al. 1978). An important and previously unreported finding is that

PD patients had a significantly steeper decline in SVRI at the onset of exercise compared to

CON. It is possible that a decreased ability to regulate vascular tone due to Lewy body

aggregation and sympathetic denervation in the superior mesenteric artery (Puvi-Rajasingham et

al. 1997), renal cortex (Goldstein et al. 2002), and other peripheral sites (Wakabayashi and

Takahashi 1997) that constrict as exercise intensity increases, may have contributed to such a

decline. Future research measuring changes in local and regional vascular resistance during

exercise in this population is needed. Interestingly, despite significantly lower EDVI values in

PD, SVI was not significantly affected. This in turn, enabled maintenance of CI during all time-

points. SVI is affected by preload, myocardial contractility, and afterload. Sympathetic

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denervation in PD patients has been suggested to be more pronounced in the left ventricle

(Hakusui et al. 1994), which would theoretically limit sympathetic-induced increases in

contractility and SVI. However, a study by Perez et al. (2015), indicates that in the absence of

orthostatic hypotension, the degree of denervation does not produce any effect on inotropic

function. Preload, as reflected by EDVI, was lower in PD; therefore, reduced afterload may have

allowed for SVI compensation.

Study Limitations

We acknowledge several limitations of the present study. There was not an assessment to

examine the degree of cardiac sympathetic denervation for each participant. Individuals with

greater denervation may have a greater reduction in cardiac contractility, although this has not

been conclusively established. In an effort to study a more general population of PD patients, this

study included patients with a variety of parkinsonian medications and doses; therefore,

responses may have been altered as a result of medication. However, previous studies reported

no effect of parkinsonian medication on cardiovascular responses (DiFranciso-Donoghue et al.

2009, Goldstein et al. 2005). Due to the nature of our measurements, it was appropriate to

exclude individuals prescribed any cardiovascular medication. This reduced the generalizability

of our findings and does not adequately address expected responses for healthy individuals or PD

patients with hypertension or other cardiovascular disease. Differences in cardiocirculatory

regulation have been noted in men and women, although some have reported that this effect

diminishes with aging (Kuo et al. 1999, Reckelhoff 2001). Nonetheless, the imbalance in each

group may have affected some outcome measures. Results are limited to sub-maximal tests

performed on a cycle ergometer and may be different than those performed at a maximum

intensity or using a different exercise modality; however, sub-maximal tests are more common in

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clinical practice, thus we feel the use of this test was warranted given the similarity of previous

results between sub-maximal and maximal protocols and the lesser degree of risk imposed on PD

patients. Finally, total calculated physical activity was greater in CON compared to PD patients.

While some participants were excluded based on their reported exercise routine, we could not

entirely account for this difference between groups. Thus, training status may have affected some

outcome measures. Although we do acknowledge this limitation, no previous study has

attempted to quantify the physical activity of their participants, and many simply did not report

training status (DiFranciso-Donoghue et al. 2009, Nakamura et al. 2010, Reuter et al. 1999).

Moreover, others required recent exercise experience with the testing modality (Werner et al.

2006)), or reported that those undergoing physiotherapy were allowed in the study (Kanegusuku

et al. 2016). Based on this and the similarity of our findings regarding HR and BP with the

majority of previous studies, it is likely that our results reflect the pathophysiological

manifestations of PD and not differences in activity levels.

Conclusions

Measures of BP were lower for PD patients at rest, as were HR and SVRI responses at the

onset of exercise. HR response was also blunted in PD patients at peak exercise and in recovery,

when compared to healthy controls. Our finding that PD patients were largely unable to reach

their age-predicted target HR implies that their capacity to conduct high-intensity exercise using

predicted values may be limited. Future research is needed using stress echocardiography or

more invasive techniques to determine how cardiac function and peripheral blood flow are

affected in PD. Cardiovascular dysautonomia is present in many PD patients, even in the pre-

motor stage, and identification of changes in hemodynamics may offer additional biomarkers for

the early diagnosis of PD and aid in assessing the progression of disease severity.

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ACKNOWLEDGMENTS

Partial funding for the study was provided by the University’s School of Education and Human

Development. We would like to thank all of the loyal study participants of the Laboratory of

Neuromuscular Research and Active Aging, the Division of Parkinson’s Disease and Movement

Disorders, and our undergraduate students for their continued dedication and help.

CONFLICTS OF INTEREST

None of the authors in this study have any conflicts of interest to report. All work was completed

at the University and no outside or external agencies contributed to the product in any way. The

authors declare that the results of the study are presented clearly, honestly, and without

fabrication, falsification, or inappropriate data manipulation.

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Table 1. Baseline characteristics and GPAQ measures for all participants

PD (n=14) (3 F, 11 M) CON (n=16) (7 F, 9 M)

Age (yr) 68.9 ± 12.1 66.4 ± 7.4

Height (cm) 166.7 ± 9.9 167.5 ± 15.3

Weight (kg) 68.6 ± 12.5 82.1 ± 14.1†

Hoehn and Yahr Stage 1 (n=4), 2 (n=5), 3 (n=5) -

MDS-UPDRS Part III 31.5 ± 14.3 -

Total (METs/wk) 1392.5 ± 925.6 3874.6 ± 2183.7†

Work (METs/wk) 480.0 ± 1370.3 1070.0 ± 2135.3

Travel (METs/wk) 478.0 ± 647.5 383.6 ± 613.8

Recreation (METs/wk) 945.0 ± 880.5 2130.0 ± 1855.6

Sedentary (hr/day) 6.1 ± 3.6 3.9 ± 2.9

All data are presented as means ± SD; CON=healthy controls; MDS-UPDRS=movement

disorders society-unified Parkinson’s disease rating scale; MET=metabolic equivalent;

PD=Parkinson’s disease; † indicates significant between-group difference, p < .05.

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Table 2. Percentage of participants who completed each stage of the exercise test

PD (n=14) (%) CON (n=16) (%)

Stage 1 14 (100) 16 (100)

Stage 2 13 (93) 16 (100)

Stage 3 10 (71) 13 (81)

Stage 4 6 (43) 12 (75)

Stage 5 0 (0) 6 (38)

PD=Parkinson’s disease; CON=healthy controls

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Table 3. Changes from baseline and between-group differences in measures of heart rate at all time-points

Heart Rate (bpm)

Mean (SE)

Percent Age-Predicted HRmax

Mean (SE)

Time Point PD CON

Between-

Group

Difference

(p-value)

PD CON

Between-

Group

Difference

(p-value)

Rest 65 (2) 61 (2) .30 43 (2) 40 (2) .24

Stand 1 73 (2)* 67 (2) .03† 49 (2)* 44 (2) .04†

Stand 3 72 (2)* 67 (2) .13 48 (2)* 43 (2) .11

Stand 5 71 (2)* 67 (2)* .16 48 (2)* 44 (2)* .13

WU 89 (3)* 80 (3)* .06 54 (2)* 56 (2)* .51

Stage 1 98 (4)* 88 (3)* .05 65 (3)* 57 (2)* .04†

Stage 2 105 (4)* 99 (4)* .27 70 (3)* 65 (3)* .18

Stage 3 113 (3)* 104 (3)* .05 73 (1)* 68 (1)* .02†

Stage 4 119 (5)* 119 (4)* .10 77 (3)* 77 (2)* .79

Stage 5 - 131 (3)* - - 83 (1)* -

Peak 117 (3)* 126 (3)* .046† 78 (1)* 83 (1)* <.01†

Post-Ex 94 (3)* 88 (3)* .20 62 (2)* 57 (2)* .13

Heart Rate Recovery 25 (3) 39 (3) <.01† - - -

REC 1 82 (3)* 76 (3)* .11 55 (2)* 49 (2)* .08

REC 5 81 (3)* 73 (3)* .045† 54 (2)* 47 (2)* .03†

REC 10 78 (3)* 71 (3)* .06 52 (2)* 46 (2)* .046†

CON=healthy controls; HRmax=age-predicted maximum heart rate; REC=recovery; SE=standard

error of the mean; PD=Parkinson’s disease; WU=warm up; * indicates significantly different

from rest, p < .05; † indicates significant between-group difference, p < .05.

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Table 4. Changes from baseline and between-group differences in measures of blood pressure at

all time-points

Systolic Blood Pressure

(mmHg)

Mean (SE)

Diastolic Blood Pressure

(mmHg)

Mean (SE)

Mean Arterial Pressure

(mmHg)

Mean (SE)

Time

PointPD CON

Between-

Group

Differences

(p-value)

PD CON

Between-

Group

Differences

(p-value)

PD CON

Between-

Group

Differences

(p-value)

Rest128

(4)

136

(4)

.18 77

(2)

85

(2)

.02† 95

(3)

102

(2)

.07

Stand

1

130

(4)

141

(4)*

.06 82

(2)

89

(2)

.01† 99

(2)

106

(2)

.03†

Stand

3

136

(4)

148

(4)

.046† 83

(2)

90

(2)

.02† 102

(2)

109

(2)*

.03†

Stand

5

137

(4)

147

(4)

.11 85

(2)

88

(2)

.26 103

(3)*

108

(2)

.21

WU143

(5)

142

(5)

.95 76

(4)

81

(4)

.29 99

(4)

102

(3)

.66

Stage

1

142

(5)

146

(5)

.62 75

(3)

83

(3)

.09 99

(3)

104

(3)

.23

Stage

2

158

(6)*

157

(6)

.87 81

(4)

84

(3)

.63 108

(4)

108

(4)

.98

Stage

3

159

(7)*

167

(6)*

.41 81

(4)

82

(4)

.86 108

(4)*

111

(4)*

.66

Stage

4

18

(12)*

179

(8)*

.96 76

(6)

88

(4)

.10 100

(9)

118

(6)*

.11

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Stage

5

- 196

(2)*

- - 88

(13)

- - 124

(9)*

-

Peak 166

(7)*

181

(6)*

.11 81

(4)

87

(4)

.32 107

(5)*

119

(5)*

.12

Post-

Ex

150

(5)*

151

(5)

.91 80

(3)

88

(3)

.09 106

(3)

109

(3)

.46

REC 1 135

(5)

140

(5)

.45 77

(3)

83

(3)

.16 97

(3)

102

(3)

.30

REC 5132

(5)

131

(4)

.91 77

(3)

83

(3)

.12 96

(3)

99 (3) .56

REC

10

133

(5)

132

(5)

.86 76

(2)

80

(2)

.26 97

(3)

99 (3) .61

CON=healthy controls; PD=Parkinson’s disease; REC=recovery; SE=standard error of the mean;

WU=warm up; * indicates significantly different from rest, p < .05; † indicates significant

between-group difference, p < .05.

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FIGURE LEGENDS

Figure 1. Study timeline.

Figure 2. Time course changes and between-group differences in measured hemodynamic

variables.

a) Systemic Vascular Resistance Index; b) End Diastolic Volume Index; c) Stroke Volume

Index; d) Cardiac Index; all values are displayed as means ± SE; black dots=PD; white

dots=CON; † indicates a significant between-group difference at the observed time-point, p <

.05.

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