By Faith Gow

Introduction

Postural Orthostatic Tachycardia Syndrome (POTS) is a disorder of the autonomic nervous system in which patients present with an inappropriate high heart rate when standing, without a decrease in blood pressure (>20/10mmHg). An increase in heartrate of at least 30 beats per minute is typically seen. Patients also complain of many symptoms such as chest pain, light-headedness, loss of consciousness, fatigue, blurred vision, and exercise intolerance.  Symptoms are typically relieved as patients place themselves in a reclined position and increase if the patient resumes an upright position. A reduction in volume of blood in the abdomen and legs is the reasoning as to why symptoms are relieved when patients are not standing. Once the individual is positioned at a slant, gravity is not causing blood to pool to the legs. This means that more blood is getting back to the heart, and the cardiac output can be maintained without a high heart rate.  The condition involves the autonomic nervous system (the component of the nervous system which controls involuntary or vital bodily functions such as breathing), and the sympathetic nervous system (part of the autonomic nervous system) which plays a crucial role in the activation of the flight or fight response. It is hypothesized that autoantibodies (antibodies that target an organism’s own tissues) could initiate the response of the nervous system by activating adrenergic receptors (receptors which activate the autonomic nervous system) which prompts the autonomic nervous system to begin functioning (3). Previous literature (3) has provided evidence that shows patients with POTS contain antibodies which are functional and target adrenergic receptors (receptors that are targets of catecholamines which are hormones made by the adrenal glands when stress is present such as epinephrine) which we believe subjects without the disorder do not have. The idea that patients with POTS have auto-antibodies can be tested by stimulating the autonomic nervous system by using a tilt table, blood pressure cuff, and electrocardiograph followed by recording the data and comparing it to individuals without the condition. Blood may also be screened for the presence of autoantibodies.

 

Discussion

In a previous study (Raj, S.R. (2013) “Postural Tachycardia Syndrome (POTS).” Circulation), a 26-year-old woman diagnosed with POTS had a reported blood pressure of 103/72 mmHg and a heart rate of 73 bpm. After being in an upright position for 1 minute, her blood pressure and heart rate were recorded as 109/80 mmHg and 106 bpm. Blood pressure and heart rate then continued to increase and reached 118/75 mmHg and 122 bpm once 5 minutes of being in an upright position had passed. She experienced a significant increase in heart rate, without a decrease in blood pressure. These results were an indication that the patient’s autonomic nervous system did not have the ability to compensate for the change in positioning.

Owens, Andrew, et al. Figure 7 Postural Tachycardia Syndrome Peripheral Vasoconstriction… 1 Aug. 2018, www.researchgate.net/figure/Postural-tachycardia-syndrome-peripheral-vasoconstriction-orienting-response-reflecting_fig6_317847136.

During another study (2) , testing consisted of a head up tilt (tilting the patient upwards without ). Cardiac rhythm was monitored via electrocardiography (ECG). The study was conducted after participantin a horizontal position for 10 minutes. Female and male patients from the ages of 6 to 79 years of age participated in the study. 20 males and 23 females were classified as a presyncope group. A total of 21 males and 23 females were categorized as an unexplained syncope group (the group of patients who experienced syncope for no identifiable reason). There were 7 males and 8 females who had formerly presented with one episode of syncope. Furthermore, 14 males and 14 females had experienced two or more episodes of fainting. Many test subjects with a previous background of syncope or pre-syncope experienced a reoccurrence of their symptoms throughout the study. Overall, 49 percent of participants with a history of syncope and 64 percent of patients with a background of recurrent, unexplained syncope experienced a loss of consciousness while being tilted. All 14 healthy individuals who participated in the study finished without any indication of syncope. This is a good indication that the autonomic nervous system of the healthy test subjects had the ability to maintain a consistent and stable blood pressure at the time of stimulation. The data collected from patients with syncope provides evidence that the autonomic nervous systems of these test subjects were unable to maintain a constant blood pressure. In a third study (3), the hypothesis that patients with POTS have a larger quantity of adrenergic antibody activity was put to the test. Control subjects in good health were recruited from Oklahoma University’s Health Sciences Centre (OUHSC) and Vanderbilt University’s Medical Centre. There were 61 healthy controls whom were also screened to ensure the absence of former illnesses related to systemic or autoimmune response, syncope, or medications with the ability to alter hemodynamics. In addition, 37 participants whom had been given a diagnosis of POTS were recruited through Dysautonomia International. As patients were seated at the meetings, blood was drawn via venipuncture. Samples were analyzed activity relating to beta-1 adrenergic receptors (B1AR-AAb) and alpha-1 adrenergic receptors (a1AR-AAb) were measured.  Participants with POTS experienced a much larger amount of a1AR-AAb activity than subjects without POTS (3). The same results were seen when assessing B1AR-AAb (an autoantibody) activity (3). Fourthly, a study by (Gunning et al) assessed the elevation of autoantibodies in 55 subjects who were all previously diagnosed with POTS. ELISA kits (kits which detect antibodies within the blood) were used to screen for antibodies against 9 divergent G-protein coupled receptor (receptors which bind substances from outside the cell and transmit signals from the substances to a G protein molecule inside the cell) antibodies. 52 of the patients in the study were female and the majority of participants complained of fatigue, headaches/migraines, aching muscles, and palpitations. In patients with symptom scores that were lower, no autoantibodies or a miniature amount of antibodies were present. 89% of patients had elevated amounts of antibodies against the alpha 1 receptor and 53% against the muscarinic acetylcholine receptor. Another study by (Yu et al) included 17 patients with a diagnosis of POTS, 6 patients with a fainting disorder, and 10 healthy patients who were tested for AT1R-AAb antibodies (anti-angiotensin II type-1 receptor antibodies). Additionally, 6 patients with vasovagal syncope and 10 healthy participants were examined. All involved in the study were screened for the potential to both change and initialize AT1R ligand responsiveness (the response of angiotensin II receptors to molecules that bind to it). Out of the 17 subjects with POTS, 12 showed extensive AT1R antibody activity (antibodies which target angiotensin II receptors). Again, this indicates that the presence of autoantibodies is common in individuals with POTS. The study of the presence of acetylcholine receptor antibodies by (Watari et al) also affirms this. 34 subjects with POTS were monitored for the presence of gAChR antibodies (antibodies which target acetylcholine receptors) using serum samples they gave. The luciferase immunoprecipitation system was used to do this (a system which evaluates antibodies through measuring luminescence from the reporter enzyme which is fused with a specific antigen). 29% of patients with POTS had tests which indicated the presence of antibodies (24% of samples showed anti-gAChRa3 antibodies and 6% of samples showed anti-gAChRβ4 antibodies). Additionally, 7 healthy participants and 10 POTS patients had 30 cc of blood analyzed for antibodies in a study by (Wang  et al). Immunoblotting (a technique which uses antibodies to identify proteins) was the method used in this study. IgGs (type of antibody released by plasma B cells) from both healthy participants and patients with POTS were immunoblotted against human heart membrane proteins. 18 protein spots were seen which where immunoreactive against the IgGs of the patients. Other specific and unique proteins were detected which include proteins which are directly related to conditions such as cardiomyopathy. The results obtained from the conduction of all studies provide evidence that the autonomic nervous systems of patients with orthostatic intolerance (including POTS) are unable to function in the same manner as individuals in prime health, and that an increased presence of functional autoantibodies is observable in patients with POTS compared to patients without the condition. Both of these factors together could possibly be considered a cause of POTS. This information could serve an extremely important purpose in the future since it can be used to further develop treatments for the disorder . As researchers continue to confirm that an excess amount of autoantibodies is a cause of POTS, physicians and researchers can further investigate and initiate treatments in order to more effectively manage POTS.

 

Conclusion

The central sign of POTS includes an increase in heart rate of 30bpm when moving from a horizontal position to an upright position, which directly correlates with the autonomic nervous system. Previous literature (1,2,3,4,,5,6,7) shows that patients with POTS have autonomic nervous systems that are unable to compensate for fluid shifting due to gravity when upright. Research has also  indicated an increased presence of functioning autoantibodies in POTS. As autoantibodies have the ability to activate the autonomic nervous system, it is feasible to infer that antibodies could be a primary cause of POTS. Knowing this information also allows for further investigation in regard to treatments or processes that could help control the condition, or possibly even cure it.

 

Acknowledgments

I would like to thank Julianna Svishchuk, Kate Bourne, and Tristan Wild for their guidance in the creation of this paper. I would also like to thank STEM Fellowship for providing me with this opportunity.

References

Yu X, Li H, Murphy TA, Nuss Z, Liles J, Liles C, et al. Angiotensin II Type 1 Receptor Autoantibodies in Postural Tachycardia Syndrome. Journal of the American Heart Association. 2018;7(8).

Watari M, Nakane S, Mukaino A, Nakajima M, Mori Y, Maeda Y, et al. Autoimmune postural orthostatic tachycardia syndrome. Annals of Clinical and Translational Neurology. 2018Feb28;

Wang X-L, Chai Q, Charlesworth MC, Figueroa JJ, Low P, Shen W-K, et al. Autoimmunoreactive IgGs from patients with postural orthostatic tachycardia syndrome. PROTEOMICS – Clinical Applications. 2012Aug;6(11-12):615–25.

Raj, S.R. (2013) “Postural Tachycardia Syndrome (POTS).” Circulation

Madanmohan, E.S. P, Narayan, S.K., Prashanth, U., Kamath, M.G., Udupa, K., Sethuraman, K.R., Srinivsan, S., Kumar, R.A. (2003) “TILT TABLE TESTING IN THE DIAGNOSTIC EVALUATION OF PRESYNCOPE AND SYNCOPE: A CASE-SERIES REPORT.” Indian Journal of Physiology and Pharmacology

Gunning WT, Kvale H, Kramer PM, Karabin BL, Grubb BP. Postural Orthostatic Tachycardia Syndrome Is Associated With Elevated G‐Protein Coupled Receptor Autoantibodies. Journal of the American Heart Association. 2019;8(18).

Badiudeen, T., Forsythe, E.A., Bennett, G., Li, H., Yu, X., Beel, M., Nuss, Z., Blick, K.E., Okamoto, L.E., Arnold, A.C., Paranjape, S.Y., Black, B.K., Maxey, C., Kem, D.C. and Raj, S.R. (2019) “A Functional Cell-Based Bioassay for Assessing Adrenergic Autoantibody Activity in Postural Tachycardia Syndrome.” Journal of Translational Autoimmunity, Elsevier Ltd.

Graph

Owens, Andrew, et al. Figure 7 Postural Tachycardia Syndrome Peripheral Vasoconstriction… 1 Aug. 2018, www.researchgate.net/figure/Postural-tachycardia-syndrome-peripheral-vasoconstriction-orienting-response-reflecting_fig6_317847136.

Websites

“Postural Orthostatic Tachycardia Syndrome (POTS)”, Cleveland Clinic. Available from: https://my.clevelandclinic.org/health/diseases/16560-postural-orthostatic-tachycardia-syndrome-pots. [Accessed July 14th, 2019]

“What is dysautonomia?”, Dysautonomia International. Available from: http://www.dysautonomiainternational.org/page.php?ID=34. [Accessed July 14th, 2019]

“POTS (POT Syndrome, Postural Orthostatic Tachycardia Syndrome)”, MedicineNet. Available from: https://www.medicinenet.com/pot_syndrome/article.htm. [Accessed July 14th, 2019]

“Tilt Table Test”, American Heart Association. Available from: https://www.heart.org/en/health-topics/heart-attack/diagnosing-a-heart-attack/tilt-table-test. [Accessed July 14th, 2019]

 

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