Postural Orthostatic Tachycardia Syndrome

Postural orthostatic tachycardia syndrome (POTS), the most common form of orthostatic intolerance in young people, affects approximately 500,000 people in the United States alone, typically young women at the peak of their education and the beginning of their working lives. This is a heterogeneous disorder, the pathophysiology and mechanisms of which are not well understood. There are multiple contributing factors and numerous potential mimics. This review details the most current views on the potential causes, comorbid conditions, proposed subtypes, differential diagnoses, evaluations, and treatment of POTS from cardiological and neurological perspectives. (J Am Coll Cardiol 2019;73:1207 – 28) © 2019 by the American College of Cardiology Foundation.

P ostural orthostatic tachycardia syndrome (POTS) is the most common form of orthostatic intolerance in young people (predominantly premenopausal women), with a prevalence of 0.2% (1) affecting an estimated 500,000 Americans based on a 1999 report (2). The current epidemiology is not known, but due to increased awareness of the syndrome, the prevalence of POTS may have Symptoms tend to be most bothersome in the morning, but frequently, patients have symptoms that persist throughout the day. The onset of POTS can be subacute (13.8%), insidious (5.9%), or acute (12.5%). It is frequently preceded by symptoms of a viral illness (in 42%) or may occur post-operatively (in 9.5%) (6).
As designated in its name, POTS is a syndrome, not a disease. A number of other symptoms and comorbidities are commonly associated with POTS. These include bloating, nausea, diarrhea, abdominal pain, fatigue, sleep disturbance, headache, and others.
Although these symptoms commonly occur in association with POTS, they may not be part of a single unifying, underlying disease process, or linked clearly by a common pathophysiology. Pre-syncope is much more common than syncope in POTS, but it is not infrequent that POTS coexists with episodes of neurally mediated (reflex) syncope (1). In many cases, patients relate a healthy and active premorbid state; some are competitive athletes or high-performing high school or college students before developing POTS.

RESPONSE TO ORTHOSTATIC STRESS
Because POTS is a postural and orthostatic disorder, a fine understanding of gravitational physiology and the physiology of the upright posture is essential to managing these patients. When a healthy person assumes the head-up posture, a multitude of hemodynamic changes occur, most in the first 30 s. When upright, gravity immediately causes blood to descend from the chest to the lower abdomen, buttocks, and legs. More slowly, there is a shift of plasma volume from the vasculature into the interstitial space. This fluid shift results in a decrease in effective circulating blood volume. The resulting fall in venous return reduces stroke volume and unloads the arterial baroreceptors by reducing their pulsatile distortion, even if mean arterial pressure is unchanged (7,8). The baroreflex rapidly produces a compensatory vagal withdrawal and sympathetic activation, which in turn increases HR, cardiac contractility, and peripheral vascular resistance. Clinically, this response usually manifests as a small (5 to 20 beats/min) increase in HR, a small decrease in systolic BP, and a slight increase in diastolic BP (9,10). Figure 2A shows the critical role that central blood volume plays in the acute regulation of the sympathetic nervous system with volume loading inducing virtual sympathetic silence and volume unloading causing marked sympathetic activation (11); Figure 2B shows the tight relationship between stroke volume and HR in men, healthy women, and women with POTS (4,12). Note that healthy women have smaller stroke volumes and higher HRs compared with healthy men, whereas women with POTS have both an exaggerated fall in stroke volume and an apparent compensatory rise in HR.
In the setting of hypovolemia, reduced circulating blood volume leads to more profound unloading of arterial baroreceptors, which leads to greater sympathetic activation and an elevated HR even at rest.
In severe hypovolemia, sympathetically mediated systemic vascular resistance increases; renin secretion also increases, with increased conversion of angiotensin II. This neurohumoral response leads to increased vasoconstriction of arteriolar smooth muscle as well as stimulation of aldosterone secretion, which increases sodium reabsorption. Antidiuretic hormone (ADH) release leads to increased reabsorption of water and sodium chloride. When upright in the setting of hypovolemia, venous return is severely compromised (13), and the HR is more significantly Postural Orthostatic Tachycardia Syndrome M A R C H 1 9 , 2 0 1 9 : 1 2 0 7 -2 8 elevated (>20 beats/min) often with orthostatic hypotension.
Indeed, any physiological stress resulting in central hypovolemia will be most impactful in the upright position. One common example is heat stress, which causes orthostatic intolerance even in healthy individuals. Under thermal stress, cutaneous vasodilation increases blood flow to the skin and redirects up to 50% to 70% of resting cardiac output to the skin to maintain core temperature (14). In order to maintain BP and offset large falls in systemic vascular resistance, HR and cardiac output rise, the latter potentially to double its resting value. Heat stress dramatically decreases orthostatic tolerance in healthy humans, and this is why orthostatic intolerance of all types (including POTS) is worsened by heat.

PATHOPHYSIOLOGY OF POTS
The pathophysiological mechanisms underlying POTS are thought to be heterogeneous (15). One analog of a gravity-dependent phenomenon that may provide insight into the pathophysiology of POTS is spaceflight. Since the inception of space missions, a postflight orthostatic intolerance on return to Earth has been noted following both short-and long-term flights, especially in women astronauts. Even after brief trips, approximately one-fourth to two-thirds of astronauts cannot stand for even 10 min upon return to earth (16)(17)(18). This orthostatic intolerance following exposure to a microgravity environment has been well described and studied (10, 17,[19][20][21][22][23]. In these subjects, physiological changes have been observed to occur including cardiac atrophy, a large fall in stroke volume, and hemodynamically appropriate reactive tachycardia and sympathetic activation (10, [16][17][18]21,22,24,25). These same mechanisms described in space flight have also been seen following prolonged bedrest deconditioning (23,(25)(26)(27). Though these mechanisms have not specifically been shown to "cause" POTS, there are remarkable similarities between the effects of spaceflight/bedrest and POTS, which may be informative in considering the potential pathophysiology of POTS.
Indeed, a period of enforced bedrest is often a common theme in patients with POTS, even those who have previously been quite active.
One feature that appears to be universally present in all POTS is cardiovascular deconditioning, a specific biological process characterized by cardiac atrophy and hypovolemia (4

POTS SUBTYPES
Even though deconditioning seems to be the "final common pathway" that results in orthostatic intolerance (30), multiple mechanisms have been proposed that may precipitate orthostatic intolerance and compound bedrest deconditioning that often culminates in POTS (26) (Figure 3). Although quite varied and lacking a unifying hypothesis of POTS, these mechanisms include the following. Postural orthostatic tachycardia syndrome (POTS) is defined as a clinical syndrome lasting at least 6 months that is characterized by: Postural Orthostatic Tachycardia Syndrome Definition: 1) an increase in heart rate ≥30 bpm within 5 to 10 min of quiet standing or upright tilt (or ≥40 bpm in individuals 12 to 19 years of age); 2) the absence of orthostatic hypotension (>20 mm Hg drop in systolic blood pressure); and 3) frequent symptoms that occur with standing such as lightheadedness, palpitations, tremulousness, generalized weakness, blurred vision, exercise intolerance, and fatigue.  Central blood volume plays a critical role in the acute regulation of the sympathetic nervous system; volume loading induces virtual sympathetic silence, and volume unloading causes marked sympathetic activation. (B) Changes in heart rate and stroke index in response to head-up tilt in POTS patients, healthy women, and healthy men. There is a tight relationship between stroke volume and heart rate in men, healthy women, and women with POTS (4,12). BL ¼ baseline; BP ¼ blood pressure; HR ¼ heart rate; LBNP ¼ lower body negative pressure; MSNA ¼ muscle sympathetic nerve activity; PAP ¼ pulmonary arterial pressure; other abbreviations as in Figure 1.
Bryarly et al. Postural Orthostatic Tachycardia Syndrome M A R C H 1 9 , 2 0  Postural Orthostatic Tachycardia Syndrome VOLUME DYSREGULATION Some POTS patients have been noted to have persistently low plasma volumes (32,(42)(43)(44), which evidence suggests is perhaps secondary to impaired function of the renin-angiotensin-aldosterone system. Some have inappropriately low plasma renin activity and aldosterone levels resulting in inadequate renal sodium retention (42,44). Others have elevated plasma angiotensin II levels suggesting inadequate angiotensin-converting enzyme 2 activity (42,44). There also appear to be some fluctua-  Several studies have found an increased prevalence of serum autoantibodies directed against neuronal targets in POTS patients. These include antibodies against ganglionic acetylcholine receptors (AChR) and antibodies against alpha-1 adrenergic receptors (6,47). Thus far, however, none of the autoantibody associations have been convincingly proven to be pathophysiologically or diagnostically important. In a cohort study of unselected POTS patients, the prevalence of ganglionic AChR antibodies (always at low antibody levels) was <5%, and this antibody frequency was not statistically different from population controls (48,49). Antibodies that appear to activate G-protein-coupled receptors (adrenergic receptor and muscarinic AChR) have been reported in small cohorts of POTS patients, but the clinical significance of these antibodies has not been clearly established.
Although autoimmune mechanisms may play a role in some POTS cases, this concept requires additional investigation. It is reasonable to consider the possibility of autoimmunity in POTS patients, but at this time, immunomodulatory therapies are not recommended unless definitive evidence of a systemic autoimmune disorder is found.

EFFECT OF SEX AND MENSTRUAL CYCLE
Intolerance to orthostasis tends to be more significant in young women compared with their male counterparts (29). Although the underlying mechanisms are not completely understood, sex-specific differences in hemodynamics and hormonal levels may in part contribute to this difference (50). Women with POTS often report fluctuations in the severity of POTS symptoms throughout their menstrual cycle, with worsening during either the pre-menstrual or early follicular phase when both estrogen and progesterone levels are dropping or low (6,9,45,51). The etiology of this subjective variation in symptoms through the menstrual cycle is yet to be delineated, though multiple mechanisms have been proposed. In healthy women, renin activity and aldosterone levels fluctuate through the menstrual cycle; however, hemodynamic parameters in response to orthostasis are not noted to change (52). When plasma volume, blood volume, and supine hemodynamics were measured in a cohort of POTS patients and controls, no variations were noted while comparing the mid-luteal phase to the early-follicular phase (45). No variations in BP or HR response during standing were noted during the menstrual cycle in this study. However, in POTS patients, cardiac output and stroke volume were lower, and total peripheral vascular resistance higher, during the early-follicular phase. Similarly, the menstrual cycle has not been shown to affect muscle sympathetic nerve activity; however, it may play a modest role in modulation of BP and vasoconstriction in women with POTS during orthostatic stress (53). In addition to differences in hormonal levels, physical characteristics of women including a smaller stroke volume and smaller, less distensible hearts (even when normalized to body mass), may also contribute to why women may be more prone to orthostatic intolerance (29,50,54). It is our experience that POTS is quite rare after menopause, though explanations for this age specificity are unsatisfying. The underlying hormonal changes, presumably relating to the balance between testosterone and estrogen, must be playing a role.

DIURNAL VARIABILITY
Many patients report worsening of their symptoms in the morning and improvement through the course of the day, which is often reflected in their hemodynamic parameters. Orthostatic HR increments have been shown to be larger in the morning than in the afternoon (55). Some patients who fulfill criteria for POTS when tested in morning do not always fulfill criteria in the afternoon. This difference is likely a reflection of the physiological changes that occur during sleep, from being supine for a prolonged period in the absence of any fluid intake.

DIFFERENTIAL DIAGNOSES
Orthostatic tachycardia alone is not sufficient to diagnose POTS; other diagnostic criteria apply, and other syndromes and intrinsic cardiac abnormalities must be excluded.
Neurally mediated syncope (NMS) ("vasovagal" or reflex) syncope is not synonymous with POTS and is a separate problem, but NMS can lead to similar symptoms of orthostatic intolerance particularly in the immediately pre-syncopal phase. In NMS, the patient's BP and HR are maintained during head-up posture until a precipitous drop in BP and often HR leads to pre-syncope and syncope. In POTS, the patient's BP should be maintained throughout HUT.
Although many POTS patients report pre-syncopal symptoms, the majority do not lose consciousness.
However, up to 30% of POTS patients may experience syncope, and these patients may have both NMS and POTS, because these disorders can occur together (9,65).  Postural orthostatic tachycardia syndrome (POTS) has been described as a "downward spiral." Often, several factors culminate, leading to diminished activity and bedrest; in a susceptible individual, significant deconditioning and debility can eventually develop. This often dominates the clinical picture, and the cycle can continue unabated until it is broken. GI ¼ gastrointestinal.
Bryarly et al.  Pheochromocytoma is a rare neuroendocrine tumor that can present with paroxysmal hyperadrenergic symptoms. However, unlike in POTS, these paroxysmal symptoms are not positional.
Evaluation for pheochromocytoma is best made by measuring plasma metanephrines (67).
The tachycardia of POTS is a sinus tachycardia.
Sinus tachycardia is usually a normal physiological response to conditions in which the sympathetic nervous system is activated and the parasympathetic nervous system is inhibited, such as exercise, fever/ infection, anemia, anxiety, and pain. These common causes of appropriate sinus tachycardia will not be discussed in detail, but they should always be considered in the differential for a sinus tachycardia.  Figure 4).    Postural Orthostatic Tachycardia Syndrome M A R C H 1 9 , 2 0 1 9 : 1 2 0 7 -2 8 "BRAIN FOG". "Brain fog" is a commonly described, but imprecise, symptom in patients with POTS and similar conditions. When this symptom was studied in detail, it was more consistently described as being a cognitive complaint similar to mental fatigue; additionally, brain fog was not limited to the upright posture and was made worse by poor sleep (83). Its underlying mechanism is unclear and is likely  (84,85). A negative correlation between supine HR and sleep efficiency has been noted; a potential etiology for this link is less refreshing sleep due to increased sympathetic activation (84).
When asked to quantify and qualify their symptoms, POTS patients score higher on fatigue scales than they do sleepiness scales, which suggests the underlying  Bryarly et al.
GI DYSMOTILITY. The co-occurrence of GI symptoms and POTS has been well-described, but the extent of this connection is still not well understood.  (92). This higher incidence of orthostatic intolerance may be related to perceptual amplification and hypervigilance, which have been well-described in pain conditions (77).

BASIC EVALUATIONS
In a standard primary care, clinical cardiology, or neurology practice, the majority of POTS patients can be easily diagnosed with few tools ( Figure 5).

CARDIOLOGICAL EVALUATIONS
Depending on the presentation, additional laboratory evaluations may include a complete metabolic profile, complete blood count (to evaluate for anemia), thyroid function testing, or more specialized testing (discussed later in the text) ( Figure 6). Additional cardiac evaluations may be considered as clinically indicated. A 12-lead ECG may capture cardiac conduction abnormalities and is reasonable to obtain.
Holter monitoring is useful to evaluate paroxysmal Bryarly et al.    The patient is subsequently asked to stand, and plasma catecholamines are again measured after 5 min of standing. A normal response is an approximate doubling of the NE level from a supine to a  Bryarly et al.   Ivabradine is a unique medication that reduces intrinsic HR by specifically blocking the cardiac "funny" channel, the I f current that controls the pacemaker activity of the sinus node. It is approved for use in heart failure patients with resting HR $70 beats/min not controlled with beta-blockers.
In limited studies, ivabradine has also been shown to reduce HR in POTS (112,113). It is generally welltolerated but has not been well-studied in this condition, and therefore, should not be used routinely.