Postural Orthostatic Tachycardia Syndrome (POTS) faces two major challenges that aim to be addressed through this study. Firstly, POTS has no defined cause, which confounds POTS treatments in that treatments are broad, such as increasing saline intake in order to increase blood volume.¹ More specific treatments to target the cause of POTS would allow for better treatments of POTS patients, and potentially a cure for the disorder. Second, misdiagnoses of POTS patients is very common in POTS patients.² Taking a cardiac MRI while a patient is under gravitational stress would potentailly help solve both of these problems since we could see if anything is wrong with the POTS patients' hearts during gravitational stress. However, cardiac MRIs cannot be taken of POTS patients while under actual gravity, since patients must be lying down in order to take a cardiac MRI. This is where the Lower Body Negative Pressure, or LBNP machine comes in. The LBNP can potentially simulate gravity using fluid dynamics, allowing for a cardiac MRI of a POTS patient under gravitational stress to be taken. Our study aims to see whether the LBNP can effectively simulate gravitational stress on POTS patients and their symptoms.

1.1 Background

All participants in the study signed a consent form sent by email in advance to the study. These participants were also asked to hold pre-existing medications that could interfere with the results of the study. POTS patients that participated in previous studies and new POTS patients at the Calgary Autonomic Lab were recruited. Healthy controls with matching sex and age (+/- 3 years) were selected from volunteers that responded to advertising for the study. During testing, participants were fitted with a non-invasive beat-to-beat finger blood pressure cuff and a 3-lead electrocardiogram to capture heart rate (HR) and blood pressure (BP). During the Valsalva maneuver and sinus arrhythmia, an ipad is used to coordinate patient actions such as pressure as well as breathing intervals.

1.3 Instrumentation

Estimates of stroke volume (SV), cardiac output (CO), and systemic vascular resistance (SVR) were obtained by applying Modelflow Waveform Analysis on the Finapres finger blood pressure cuff waveform. (https://pmc.ncbi.nlm.nih.gov/articles/PMC3043797/) cite this

2.1 Methodology

Patients first completed a ten minute recumbent baseline, wherein they lied down for ten minutes. Following this, patients completed Autonomic Function Testing while recumbent, with a one minute period between each test. Afterward, patients were tilted to 80° for ten minutes. Then, the tilt table was returned to horizontal, and the LBNP was turned on after a 5 minute period to allow for recovery. Another baseline of ten minutes was completed by the patient, but with LBNP on. Finally, patients completed breathing tests one more time, but under the influence of LBNP this time. Throughout this entire process, continuous data of the patients’ HR, CO, SV, BP, and SVR were collected.

Symptom severity was assessed using the Vanderbilt Orthostatic Symptom Score (VOSS) during baseline before both the tilt test and LBNP, and after 10 minutes of both the tilt test and LBNP.⁸ Primary measurements of the study were HR and SV. This is because POTS is characterized by an increase in HR, and symptoms develop because not enough blood is going to the head. Therefore, HR and SV are primary results since they describe how often the heart beats, and how much blood the heart pumps. Secondary measurements of the study included BP, CO, VOSS, Valsalva ratio, and peak heart rate during hyperventilation. 

3.1 Data Processing

Continuous data such as HR, BP, SV, SVR, and CO were collected in Labchart Reader. Matlab was used to analyze data collected for baseline, during autonomic function testing, and during gravitational stress from the head up tilt test and LBNP into data subsets. Data subsets were then collected and put into a spreadsheet by Matlab. SPSS was used to perform statistical tests as well as organize and store mean data, standard error of the mean, standard deviation, and obtaining p-values.

3.2 Statistical Analysis

A paired t-test was performed through SPSS to compare study outcomes between the tilt test and LBNP for both POTS patients and controls along with a comparison between baseline and LBNP for only POTS patients. 10th minute averages of the variables were used as POTS is defined by an increase of heart rate within 10 minutes of orthostatic stress. A paired t-test was conducted to compare study outcomes between values of autonomic function testing with and without LBNP for POTS patients and controls.

1.1 Postural Orthostatic Tachycardia Syndrome

Postural Orthostatic Tachycardia Syndrome (POTS) is a form of chronic orthostatic intolerance (OI).¹ POTS diagnostic criteria requires chronic orthostatic intolerance symptoms, and heart rate increases by ≥ 30 beats per minute within 10 minutes of standing if the patient is older than 19.¹ Additionally, systolic blood pressure cannot drop by more than 20 mmHg or diastolic blood pressure cannot drop by more than 10 mmHg.¹ Common symptoms of POTS include lightheadedness, tachycardia, shortness of breath, chest pain, and palpitations.² Orthostatic intolerance is defined as the existence of syndromes in patients when standing that are relieved when the patient becomes recumbent.¹ According to a survey from 2019 done by Shaw et al,² 94% of diagnosed POTS patients are female, and 93% of POTS patients are Caucasian, with most POTS patients developing symptoms around the age of 14.

1.2 Hemodynamics during orthostatic stress in healthy individuals

In healthy individuals, blood pools to the legs as a reaction to gravity; assumption of the upright posture leads to an instant flow of blood of around 500 ml from the thorax to lower abdomen and below.³ The shift of blood reduces arterial pressure and subsequently triggers the baroreceptors in arteries in the neck and the aorta. These are mechanoreceptors that derive information from blood pressure and transfer blood pressure information to the brain.⁴ This triggers a sympathetic activation that increases the healthy individual's heart rate by 10-20 beats per minute, and leads to a ~5 mmHg increase in blood pressure in the arteries shortly after.³

1.3 Hemodynamics during orthostatic stress in POTS

In POTS patients, exaggerated blood pooling in the lower body is a common occurrence when they stand.⁵ The return of blood flow to the heart is impeded as the blood vessels do not constrict sufficiently, thus more blood pools in the lower body the longer the patient is in an upright position.⁵ The exaggerated blood pooling in the lower body leads to an increase in heart rate by at least 30 bpm as the heart needs to pump faster to ensure blood reaches each part of the body.⁵ Without an increased heart rate, blood pressure decreases due to the lower volume of blood unlike healthy patients who have functional baroreceptors to regulate blood pressure. ⁵ Additionally, since less blood is flowing overall to the upper half of the body, this causes symptoms of POTS such as lightheadedness due to not enough blood flow to the brain.³

1.4 Tilt Table Test

Patients are situated on a rotatable table and reclined to around 70 degrees to test the hemodynamic response to orthostatic conditions.⁶ The tilt table test is a safe environment for POTS patients because the straps keep patients constrained while still not preventing the appearance of symptoms, providing a more controlled environment for measuring heart rate and blood pressure.⁶ The tilt test should generally be conducted for at least ten minutes.¹ 

1.5 Lower Body Negative Pressure 

Lower Body Negative Pressure (LBNP) chambers create negative pressure on the lower body, which allows for the simulation of varying degrees of gravity.⁷ LBNP machines simulate gravity by creating a partial vacuum around the lower body, decreasing pressure in this region.⁷ Since fluid flows from areas of high pressure to areas of low pressure, blood flows down to the lower body.⁷ This simulates the effects of varying degrees of gravity by adjusting how much pressure is acting on the lower body.⁸ Crucially, this device allows for gravity to be simulated while recumbent. This allows for cardiac MRIs to be performed while the patient is undergoing simulated gravitational stress. A preliminary study by Skow et al⁹ measured cardiovascular responses in POTS patients during LBNP and found that 82% of POTS patients reported symptoms during LBNP. Although POTS patients experienced an increase in heart rate compared to healthy controls, this difference was not statistically significant.⁹ This might be because the sample size was relatively low; 10 healthy controls were compared to 11 POTS patients.⁹ This indicates that further testing is needed to deepen our understanding of POTS and its causes. 

1.6 Valsalva Maneuver

One of the ways to test autonomic function is the Valsalva method.¹⁰ The Valsalva maneuver is when you forcefully exhale against a closed airway (glottis), the exhalation aims for the patient to keep a constant pressure of 40 mmHg, as that specific value allows for easier reproducibility compared to other values.¹¹ In normal cases, the Valsalva Maneuver is a drug-free method to return heart rate back to normal. It can be used to measure the heart rate response to deep breathing (DB), and provides a Valsalva ratio (VR) based on beat-to-beat intervals during and after the maneuver. The VR is a marker of parasympathetic activity and is calculated by dividing maximum heart rate by the lowest heart rate occurring within 30 seconds of the maximum. However, the Valsalva maneuver can also be a test for assessing baroreflex.  During the 4 phases of the Valsalva maneuver, POTS patients behave noticeably different from healthy controls. During phase 1, the patient inhales with their mouth and nose airways closed, blood pressure rises due to the mechanical compression of the aorta; this leads to the baroreflex causing heart rate to slightly decrease.¹¹ In early phase 2, patients breath out with their airways closed, venous return occurs due to the baroreflex response, decreasing cardiac output.¹¹ This leads to a decrease in blood pressure as blood returns in late phase 2. When the carotid baroreceptors act, blood pressure goes back up in normal patients, however blood pressure stays low in POTS patients because of their impaired baroreceptors.¹² In phase 3, where the patient is done blowing, blood pressure goes down again while heart rate remains relatively unchanged as their bodies recover.¹¹ In phase 4, moments after the patient is finished, heart rate decreases while blood pressure increases, overall having a higher blood pressure than before the maneuver and increased stroke volume.¹¹ The difference is especially noticeable in late phase 2 and phase 4 when the baroreflex has differing responses to low blood pressure as well as overshooting in phase 4. The Valsalva Maneuver is an important test to do because of its high reliability in measurements, ability to assess autonomic function, and test baroreflex, making it an effective diagnosis methods for testing the Autonomic Nervous System.¹¹ 

1.7 Hyperventilation

Hyperventilation is defined as breathing in excess of the metabolic needs of the body, breathing out CO₂ faster than it is produced.¹³ The Hyperventilation test is a short breathing test done to assess blood pressure and heart rate changes as individuals breathe. The test lasts 30 seconds and takes the lowest blood pressure throughout the test, as well as the blood pressure at the 30 second mark. POTS patients generally have more exaggerated blood pressure drop along with an exaggerated heart rate increase due to their baroreceptors failing to respond properly.¹² 

1.8 Sinus Arrhythmia

Sinus arrhythmia is deep breathing in cycles of 5 seconds; inspiration leads to an increase in heart rate due to a reduced vagal tone while expiration leads to a decrease in heart rate as a result of an increased vagal tone.¹⁴ The heart rate’s response to deep breathing is affected mostly by age and rate of breathing as well as hypocapnia, position of subject, medication, depth of breathing, obesity, and inspiratory volume.¹¹ By measuring the peak and the nadir of the heart rates, a ratio is obtained. However occasionally, blunted heart rate ratios are obtained, where the ratio is close to 1, making it difficult to measure heart rate response as it is blurred. There is little difference between the lowest and highest heart rates as POTS patients breathe because of the impaired baroreceptors in POTS patients not appropriately adjusting heart rate.¹²

1.9 Significance

Further insight into how POTS affects the cardiovascular and autonomic nervous system of POTS patients can be gleaned from the study, specifically how blood pooling in POTS patients due to gravitational stress. Additionally, this study will determine whether the LBNP capsule effectively simulates the effects of gravitational stress in POTS patients. As previously mentioned, this would allow for cardiac MRI imaging of POTS patients during gravitational stress to be conducted.

1.10 Research Questions and Objectives

The first research question being focused on in this study is: What is the difference in hemodynamic response of POTS patients and healthy controls during LBNP compared to during tilt test? The short term goal for this investigation is determining whether the LBNP simulates gravity effectively, similar to a head upright tilt test. The second question being answered by this study is: What is the difference in hemodynamic response during autonomic function testing for POTS patients with and without the influence of LBNP while recumbent? The short term objective for this question is to determine whether the LBNP simulates gravity effectively, as there should be a difference in hemodynamic response with and without LBNP. The long term goals of this study is to determine more about potential causes of POTS, and to determine whether the LBNP capsule simulates gravity effectively.

Data, results, graphs in folder (copy and paste):

https://drive.google.com/drive/folders/1NrWiHrX_5OY0ZFM3qS9lzNWpSZhVT-Td?usp=sharing

For our first aim, reduction in SV is less pronounced, which led to HR not lowering as much during LBNP. Secondary outcomes stayed similar, indicating that the rest of the autonomic nervous system was functioning similarly during LBNP and HUTT. We can conclude that the LBNP simulates gravitational stress effectively for BP, CO, and SVR, but statistically significantly does not simulate HR and SV as effectively as HUTT.

For our second aim, the graphs show that the LBNP does induce orthostatic stress as there are statistically significant differentiations between LBNP and BSL. This result conflicts with a study conducted last year.⁹ However, parasympathetic activity is relatively unchanged because the graphs for SA ratio and Valsalva ratio were not statistically significant. We can conclude that LBNP-induced orthostatic stress does not significantly affect parasympathetic activity.

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2. Shaw BH, Stiles LE, Bourne K, et al. The face of postural tachycardia syndrome - insights from a large cross-sectional online community-based survey. J Intern Med. 2019;286(4):438-448. doi:10.1111/joim.12895

3. Raj SR. The Postural Tachycardia Syndrome (POTS): pathophysiology, diagnosis & management. Indian Pacing Electrophysiol J. 2006;6(2):84-99. Accessed October 25, 2024. https://pubmed.ncbi.nlm.nih.gov/16943900/

4. Armstrong M, Kerndt CC, Moore RA. Physiology, baroreceptors. In: StatPearls. StatPearls Publishing; 2024. Accessed October 29, 2024. https://pubmed.ncbi.nlm.nih.gov/30844199/

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6. Bryarly M, Phillips LT, Fu Q, Vernino S, Levine BD. Postural orthostatic tachycardia syndrome: JACC focus seminar. J Am Coll Cardiol. 2019;73(10):1207-1228. doi:10.1016/j.jacc.2018.11.059

7. Goswami N, Blaber AP, Hinghofer-Szalkay H, Convertino VA. Lower body negative pressure: Physiological effects, applications, and implementation. Physiol Rev. 2019;99(1):807-851. doi:10.1152/physrev.00006.2018

8. Esch BTA, Scott JM, Warburton DER. Construction of a lower body negative pressure chamber. Adv Physiol Educ. 2007;31(1):76-81. doi:10.1152/advan.00009.2006

9. Skow RJ, Foulkes SJ, Seres P, et al. Effect of lower body negative pressure on cardiac and cerebral function in postural orthostatic tachycardia syndrome: A pilot MRI assessment. Physiol Rep. 2024;12(6):e15979. doi:10.14814/phy2.15979

10. Low PA. Valsalva Maneuver. In: Aminoff MJ, Daroff RB, eds. Encyclopedia of the Neurological Sciences. Elsevier; 2014:591-592. doi:10.1016/b978-0-12-385157-4.00517-0

11. Low PA. Testing the autonomic nervous system. Semin Neurol. 2003;23(4):407-421. doi:10.1055/s-2004-817725

12. Palamarchuk IS, Baker J, Kimpinski K. The utility of Valsalva maneuver in the diagnoses of orthostatic disorders. Am J Physiol Regul Integr Comp Physiol. 2016;310(3):R243-R252. doi:10.1152/ajpregu.00290.2015

13. Folgering H. The pathophysiology of hyperventilation syndrome. Monaldi Arch Chest Dis. 1999;54(4):365-372. Accessed October 29, 2024. https://pubmed.ncbi.nlm.nih.gov/10546483/

14. Grossman P. Respiratory sinus arrhythmia (RSA), vagal tone and biobehavioral integration: Beyond parasympathetic function. Biol Psychol. 2024;186(108739):108739. doi:10.1016/j.biopsycho.2023.108739

We would like to express our sincere gratitude and acknowledge the University of Calgary's Department of Cardiac Sciences for their Matlab and SPSS licenses as well as giving us the opportunity to view studies at the Calgary Autonomic Lab, our project would not have been complete without their aid. We would like to thank Dr. Garcia-Diaz for her efforts in finding us our mentor along with her unwavering support in all aspects. We extend our gratitude to our mentor Kavithra Karalasingham as well as Dr. Satish Raj, who have both been the key pillars of our project, taking the time to not only give us opportunities to further our knowledge by viewing subject studies, but also set time aside for our weekly meetings and answer our numerous emails and editing our papers. John Nystrom has also been hugely helpful for our technical issues with data analysis and downloading apps such as Matlab or SPSS. There are many other individuals whom have been the greatest help and our project would not have been the same without them.