Neurohormonal dysregulation (abnormal regulation of hormones that are generated by cells that can receive input from the nervous system) has been identified in a number of patients with Postural Orthostatic Tachycardia Syndrome (POTS). “Neuronal and hormonal perturbations in postural tachycardia syndrome,” published in Frontiers in Physiology, discusses data that supports this fact and reviews the neurologic and hormonal aspects of POTS as it pertains to the pathophysiology of this condition.
Postural Orthostatic Tachycardia Syndrome (POTS) is the most common disorder seen in autonomic specialty clinics and affects a disproportionate number of young women of childbearing age.
The primary symptom of POTS is an increase in heart rate by at least 30 beats per minute within 10 minutes when assuming an upright position. This is in the absence of orthostatic hypotension, a drop in systolic blood pressure of at least 20mmHg or a drop in diastolic blood pressure of at least 10mmHg. Other symptoms include: heart palpitations, light-headedness, shortness of breath, and chest pain.
These symptoms must accompany the increased heart rate and improve when lying down, and must occur for at least 6 months to be considered as POTS. However, one must ensure there are no conditions such as prolonged bedrest, anemia, dehydration, hyperthyroidism, or medications such as diuretics, antianxiety medications, vasodilators or antidepressants which could cause POTS-like symptoms.
Because the different pathophysiological mechanisms are not exclusive, POTS patients usually exhibit symptoms from several variants at the same time.
Neuropathic POTS is a condition with partial neuropathy (nerve malfunction), where there are problems with the sympathetic nerves in the lower limbs, which can account for blood flow abnormalities. Hypovolemia (too little plasma volume) is another issue seen in a majority of POTS patients. Being in a hypovolemic state leads to decreased return of blood to the heart through veins and causes presyncopal symptoms (feeling faint, without actually fainting), along with reflex tachycardia (increased heart in response to signals from cardiac nerves.
Studies have concluded there is an abnormal vascular response in the extremities that predispose POTS patients to arteriolar dysregulation (abnormal function of the smallest parts of arteries) and subsequent venous pooling. When compared to healthy subjects, both “low flow” and “high flow” patients had significantly greater decreases in thoracic blood flow during orthostasis.
One explanation for the adverse blood pooling is a partial autonomic neuropathy. Some POTS patients have inadequate sympathetic tone to the lower extremities, leading to diminished constriction in veins to keep blood pressure up. What results is less blood volume being returned to the heart venous return and decreased stroke volume (amount of blood pumped through the left ventricle per beat), with excessive orthostatic tachycardia (increased heart beat due to blood pooling in the lower part of your body).
Low blood volume (red cell volume and plasma volume) has been exhibited in multiple studies in POTS patients. It has been confirmed that here has also been a reduced aldosterone:renin (2 hormones responsible for regulating blood pressure and volume) ratio in POTS patients. This means that many POTS patients have inappropriately normal levels of plasma renin activity and lower levels of aldosterone despite their hypovolemia, when compared to healthy subjects.
Tachycardia is the most important symptom of a hyperadrenergic state (excessive adrenal function). POTS patients have an exaggerated sympathetic nervous activity (SNA) response, compared to healthy subjects during orthostatic and hypotensive challenge.
One cause of this exaggerated SNA response can be attributed to norepinephrine transporter (NET) dysfunction. The disproportionate response in heart rate can be explained by the heart’s essential reliance on the NET. This hyperadrenergic state can be “secondary,” such as in response to hypovolemia, or “primary,” such as one related to a genetic mutation.
There is also some data that the parasympathetic system may contribute to the tachycardia in POTS. Decreased cardiovagal activation (tested by monitoring heart rate response to deep breathing) due to reduced parasympathetic nervous system activity, and its contribution on POTS, is still unclear.
Attempts to manage the hyperadrenergic state center around heart rate control. There is conflicting data in the use of beta blockers to treat POTS patients as the blood pressure could be affected while trying to manage the heart rate.
The Role of Angiotensin II and AT1R Receptors
The Angiotensin II (Ang-II) hormone causes systemic vasoconstriction, raises blood pressure and is critical for maintaining fluid balance homeostasis through aldosterone secretion. Some POTS patients have Ang-II levels elevated as much as 2-3 times higher than compared to healthy people. POTS patients have a blunted systemic vascular and hypertensive response to Ang-II but the full implications is still unclear.
Angiotensin II receptor type 1 (AT1R) is found in a variety of different tissues, including adrenal, neuronal, cardiac, renal and vascular smooth muscle cells. Some of its actions are consistent throughout the body, while some will vary, based on the location of the receptor. Additionally, AT1R also plays an important role in modulating blood pressure, salt intake, thirst mechanisms and other neuroendocrine processes.
When compared to healthy subjects, it was found that there was defective cutaneous vasodilation of the smallest systems of blood vessels in POTS patients. The skin blood flow defect can be simulated in healthy subjects and can be reversed in POTS patients. These skin findings may play a role in dependent acrocyanosis. There are no studies assessing whether these skin findings have systemic vascular implications yet.
Angiotensin converting enzyme (ACE2) has vasodilatory properties and actions that generally oppose Ang-II. POTS patients have a lack of vasodilation. Thus, the source of this dysregulation is thought to represent a deficiency of ACE2 in the skin of POTS patients, although the source remains unclear. A specific genetic mutation could be the cause.
Alternatively, ACE2 dysfunction could be a downstream manifestation resulting from POTS. As most POTS patients are intolerant of physical activity, ACE2 dysfunction could be a product of general deconditioning.
The exact mechanism of how a defect in ACE2 might trigger the clinical manifestations of POTS is also still poorly understood. While there may be a deficiency in peripheral and cutaneous vasodilation secondary to an ACE2 defect, it is not clear how that produces orthostatic tachycardia and presyncopal symptoms. High Ang-II levels and low ACE2 activity remains to be explained.
Fludrocortisone causes significant sodium and water retention, and is considered a first-line treatment for POTS because of its ability to significantly improve symptoms. Other medications, such as desmopressin (DDAVP) and erythropoietin, have also shown promising results in the alleviation of symptoms of POTS patients. Many patients seek volume loading with intravenous saline to relieve the symptoms of POTS, but the results are short-lived and there are concerns about access complications.
Exercise increases the aldosterone:renin ratios, as well as the plasma and blood volumes in POTS patients. Other benefits of exercising 4 times a week lasting 30-45 minutes are a reduction in orthostatic tachycardia and improved quality of life. Exercise is the only intervention that has been shown to improve the aldosterone:renin ratio and increase plasma and blood volumes long term.
Alpha-1 agonists, such as phenylephrine infusions, have previously been shown to improve heart rate and enhance peripheral vasoconstriction (constriction of blood vessels in the extremities) in POTS patients. Midodrine is very effective at reducing orthostatic tachycardia and had very minimal effects on blood pressure.
“High-flow” POTS patients were much more responsive to the treatment of midodrine than “low-flow” POTS patients. Octreotide causes vasoconstriction and has been shown to significantly reduce orthostatic tachycardia in POTS patients to a similar extent that midodrine does.
Pyrostigmine is also used to manage orthostatic tachycardia by increasing parasympathetic tone. Since a defective norepinephrine transporter has been implicated in causing hyperadrenergic POTS, medications which inhibit norepinephrine reuptake worsen tachycardia. Because of this, the patient and health care provider must work to find a balance between managing anxiety with a chronic illness and coping with POTS.
Considerable research has taken place in the last 20 years to understand and explain POTS. However, since the etiology of POTS is not completely understood, and the pathophysiology for all manifestations of POTS is unclear, it requires a working relationship with all who provide care to the patient.
Summary written by Melissa Adams, BS RN
Article: Mar, P. L., & Raj, S. R. (2014). Neuronal and hormonal perturbations in postural tachycardia syndrome. Frontiers in Physiology, 5, 220. http://doi.org/10.3389/fphys.2014.00220