Postural Orthostatic Tachycardia Syndrome (POTS): A critical assessment

Recently, the trend has been to include almost any symptom that occurs in a patient with postural tachycardia as being “POTS-related” and thus due to autonomic dysfunction rather than to consider such symptoms as non-specific or related to an undiagnosed comorbidity. Furthermore, postural tachycardia is not necessarily a sign of autonomic dysfunction. A large online survey of POTS patients reports a host of symptoms commonly including lightheadedness, tachycardia, presyncope, headache and difficulty concentrating. 27 Although an important addition to the literature, the online survey cannot distinguish between individuals who have postural tachycardia for some other “non-POTS” medical reason, and those who have POTS. 28 The same symptoms may occur in patients who have no evidence for either autonomic dysfunction or POTS. 11 , 29 Symptoms alone may be due to a functional problem especially if symptoms are not associated with a verifiable autonomic disturbance. A further diagnostic dilemma related to symptoms that are not associated with particular postures such as bloating, nausea, diarrhea and abdominal pain, and systemic symptoms including fatigue, sleep issues and migraine headaches, and cognitive issues, including the common, but poorly understood, symptom of “brain fog”. 30 These symptoms are often considered “hallmarks” of POTS even if no other demonstrable autonomic dysfunction exists. Such non-specific symptoms may be associated with many clinical disorders or may even occur in the absence of any known medical affliction. The broad inclusion of poorly understood and often ill-defined symptoms have increased the apparent POTS population substantially but with an unfortunate lack of diagnostic focus and therapeutic utility.

A concerning trend in the management of POTS is that patients have been given (or have given themselves) a diagnosis of POTS based on vague clinical symptoms alone following a self-triggered cursory internet search. 27 Not uncommonly, clinicians meet patients for the first time already carrying a self-diagnosis of POTS or that have been given that diagnosis elsewhere based on insubstantial clinical evidence; the patient now has a personal agenda for therapeutic interventions. Medical clinics making a POTS diagnosis should take the responsibility for subsequent care, as only then can the diagnosis be substantiated or other bases for the POTS-like symptoms be properly identified. Further, there is a critical need for medical centers and professional societies to determine if the excessively inclusive diagnostic criteria for POTS has created a problem due to unduly ‘high’ diagnostic sensitivity but very low diagnostic specificity.

Marked dilution of the POTS designation has had important clinical consequences that complicated matters for clinicians. The presence of several key chronic clinical features seem crucial to even consider the diagnosis ( Table 3 ). Despite the symptoms that patients with POTS report, 9 , 11 , 21 , 27 , 59 symptoms alone are not diagnostic. In any event, symptoms of orthostatic intolerance should disappear when the patient is recumbent. This important diagnostic feature must be considered especially since so many symptoms are currently ascribed to POTS. Loss of postural intolerance as the crucial unique feature of POTS has undermined the key pathophysiologic feature that leads to a therapeutic strategy. POTS is a chronic condition. In the initial report, 60 latency from symptom onset to diagnosis was 13.6 ± 3 months. An appropriate duration of persistent, reproducible symptoms, while not carefully defined, is probably 3–6 months. 49 Symptoms of shorter duration can frequently be reported in any number of transient conditions (e.g. vestibular dysfunction, viral illness, medication use or adjustment). In essence, this would mean that diagnostic criteria should be consistently measurable during the time that a patient has consistent complaints. Occasionally, patients with presumed vasovagal syncope (who often have an initial tachycardia response before culminating in hypotension and bradycardia) are labeled as having POTS. This is particularly vexing as it leads to a misdiagnosis of the problem (i.e., reflex vasovagal syncope). A close association of syncope to POTS should not be expected based on the orthostatic hemodynamic response characteristic of POTS, i.e. absence of blood pressure fall with upright posture due to a substantial reflex tachycardia response. While non-specific lightheadedness is common, and despite a dissenting opinion, 61 most reports suggest that syncope (specifically, vasovagal syncope) is no more common in POTS patients than in the general population.

If “POTS”, as originally described, is to be transformed into a descriptor of a multifaceted clinical picture, then, at a minimum, its association with a postural trigger should be retained. Further, the syndrome might reasonably be characterized as a primary condition (i.e., primary idiopathic POTS) or due to some other cause (i.e., secondary POTS). Considering POTS to be a single heterogeneous entity with a common underlying cause appears unlikely. For many, it is not even possible to demonstrate presence of an apparent autonomic disturbance. 31 Regarding primary (idiopathic) POTS, two generally accepted forms exist: “partial dysautonomia” (neuropathic) and hyperadrenergic. 32 The partial dysautonomic form appears due to inadequate peripheral and splanchnic vasoconstriction with orthostatic stress. The “hyperadrenergic” form, manifest by excess norepinephrine spillover, may be due to greater norepinephrine production and release at the synapse or reduction in norepinephrine re-uptake. Orthostatic hypertension and migraines are hallmarks of hyperadrenergic POTS. There is often a family history of tachycardia. Multiple mechanisms have been considered to be causally linked to the development of primary idiopathic POTS including: viral illness (or any condition activating the innate immune response), peripheral denervation with supersensitivity, alpha-receptor hypersensitivity, acetylcholine and beta-receptor autoantibodies, a central hyperadrenergic state, norepinephrine transporter deficiency, decreased baroreceptor gain, idiopathic hypovolemia with associated altered aldosterone, renin and N-NOS and angiotensin II activity, an autoimmune response, mast cell activation and diminished cardiac size and mass, among others. 2 , 8 , 16 , 33 – 46 The numerous proposed etiologies for primary POTS contribute to the current state of confusion, and likely do more harm than good especially since evidence reported is largely anecdotal. Recent reports postulate that specific events trigger POTS, including surgery, multiple sclerosis, vaccinations and concussion, although there is little supporting evidence at this time. 47 – 50 For instance, the suggestion that head trauma 51 may be a causative factor is an example of a poorly documented association. Similarly, gastric bypass, with a significant loss of weight and muscle mass might reasonably be considered a possible cause of secondary POTS but a causal relationship is not well established. 52 Even syringomyelia and multiple sclerosis have been considered associated with POTS. 53 , 54 Finally, viral illnesses (respiratory and gastrointestinal) have perhaps been most commonly reported in association with POTS. While initial information 2 suggested an association, subsequent data from the same group were not confirmatory. 9 It has been theorized that POTS is associated with multiple coexisting conditions including autoimmunity, fibromyalgia, functional gastrointestinal disorders, anxiety and hyper-vigilance, joint hypermobility, chronic fatigue syndrome, concussion, and migraine. 49 However, no conclusive evidence points to a causal association between POTS and these conditions. Orthostatic intolerance and tachycardia, may mimic POTS but be a manifestation of a far more insidious and potentially treatable condition. It has been postulated that cardiovascular deconditioning with decreased blood volume, decreased stroke volume and cardiac atrophy leads to sympathetic activation and parasympathetic withdrawal in the upright position. 49 While this scenario may have existed (primarily as a transient occurrence in the early days of space flight with zero gravity when exercise was not possible), it was scrupulously excluded from consideration in the initial description of POTS. 55 Including deconditioned individuals (other than as part of the differential diagnosis) makes little sense; it is an expected physiologic adaptation to inactivity and resolves with increased activity. 56 – 58 One might even argue that primary POTS can be excluded if symptoms resolve rapidly after a short period of well-documented consistent prescribed exercise. Furthermore, if one were to postulate that deconditioning were the critical element a huge percentage of the population would fit into this category and yet do not have POTS.

There is little evidence to indicate that currently available pharmacologic intervention is effective for reversing or shortening the course of primary idiopathic POTS or even improving outcomes aside from a placebo effect. The initial step is to remove offending medications and consider the possibility that an underlying undiagnosed medical problem (including, for instance, inflammatory disease and salt and water depletion) is the cause of the “POTS-like” picture. Unfortunately, many patients are exposed to various medications and often without symptomatic benefit and without altering the trajectory of the condition. These commonly include: fludrocortisone, midodrine, modafinil, vasopressin, serotonin reuptake inhibitors, yo-himbine, methylphenidate, alpha methyl-dopa, clonidine, phenobarbital, octreotide, and beta-blockers. The use of such drugs has been reported 72 – 83 but prospective controlled studies supporting long-term benefit are lacking. Perhaps the therapeutic intervention with the most supportive data is low-dose propranolol 84 since this has been relatively well-tested versus placebo although it did not perform as well as cardiovascular exercise. 58 Without having an adequate control population and without properly defining the patients with the condition, the literature does not provide a clear picture of therapeutic responses to medical therapy. Recently, use of drugs, such as, ivabradine and droxidopa have been reported but studies supporting long-term benefit are lacking. 85 , 86 Some data suggest benefit of ivabradine in patients with vasovagal syncope with features mimicking POTS. 87 In one single center experience of ivabradine, postural orthostatic tachycardia syndrome was not even defined so it is not clear what was being treated and for which patients. 88 Given the unproven efficacy and the potential adverse effects of drugs currently used in POTS patients, it is prudent for clinicians to always start with more conservative strategies. Endurance and cardiovascular training (beginning in the semi-recumbant position, such as, with rowing), 89 increased water intake and other relatively harmless strategies are easy to implement and may help. Involvement in a rigorous cardiovascular exercise program has shown clear, and sustained, benefits in patients with POTS. 56 , 58

Identification and management of patients with POTS is a growing problem. There is a critical unmet medical need to define POTS clearly and search for an etiology of the syndrome. Symptoms ascribed to POTS are nonspecific and may not even be triggered primarily by postural change. Clinical symptoms alone cannot assure an appropriate diagnosis. These symptoms may be due to other treatable medical problems. Such symptoms when caused by an identifiable underlying medical condition(s) should be assigned to that condition(s) and not considered to be POTS (see: Fig. 1 ). POTS is a syndrome comprising a chronic, reproducible, orthostatic heart rate increase with associated symptoms and relief by recumbent posture and accompanied by evidence of autonomic dysfunction. We encourage careful classification of disease entities and conditions responsible for a POTS-like picture since, without better understanding the problems and consequences, improvement in patient care is unlikely ( Fig. 1 ). We do not support classification of diffuse and nonspecific symptoms as “POTS” if there is no uniform, reproducible and measurable physiologic, autonomic or hemodynamic identifying characteristics. A well-defined POTS population is an irrevocable prerequisite for further studies on a syndrome that may affect many people world-wide ( Table 4 ).

The present diagnosis of POTS is fraught with uncertainties that include: 1) whether testing is undertaken on tilt table or by active standing stand, 2) how to factor expected age-related heart rate changes, 3) how to eliminate confounders such as comorbid diseases, and 4) what to advise with respect to concomitant medications that could cause or suppress tachycardia. There is an urgent need for robust studies on sensitivity, specificity and reproducibility of the measurements. A major challenge is an acceptable definition of what constitutes the “POTS” gold standard. It is also critical to define the potential participation of ancillary conditions since their recognition may better focus treatment strategy. Given the many vagaries, it is currently unclear who actually has POTS. The range of heart rates in otherwise healthy humans is wide and nearly 20% of healthy individuals of younger ages have heart rates that meet criteria for POTS. 24 , 25 Thus, a significant proportion of asymptomatic individuals may fall into the “POTS” range of orthostatic heart rate change. Specifics of the time course of heart rate changes in the upright position are not standardized. The first 30 s of an 80° upright posture have been excluded by some and, while avoiding the instability of initial orthostatic hypotension, the nature of this early evolution may be very important in the subsequent alteration of orthostatic vital signs. The basis for exclusion of the first 30 s was the expectation that an initial physiologic tachycardia associated with transition to upright posture occurs during the first 30–45 s and is finalized first after 3 min of continued orthostatic challenge. 62 Although the tilt-table test was used in the initial description of POTS, the possibility of any method for testing transition of BP and heart rate from supine to the upright posture may be acceptable. 63 However, tilt-table testing and active standing may not provide the same results. 23 Further, even in health, the tilt-table test response may not be reproducible. In one report of tilt-table testing in 40 individuals, in which each individual had 10 upright tilt measurements, the heart rate response was not reproducible. 64 Therefore, there is no reason to assume that a solitary or any tilt-test is valid 64 or represents the “gold standard” to secure a diagnosis – or not. The repeatability of an active standing test may be even worse. Factors that may critically influence the outcome include how long the patient was supine before either the tilt or active standing test, and the patient’s volume status at the time. Using impedance methods it can take hours for an older adult to reach a steady state supine, or about 30 min in youngsters. 65 Evaluation by active stand or tilt-test or both needs careful evaluation as it has for elderly patients. 66 The problem with the tilt-test as a diagnostic tool in POTS also raises questions about the validity of any one measurement of heart rate response to standing to secure a POTS diagnosis. Therefore, it is important to evaluate at least several orthostatic heart rate measurements over time and at various times of the day; it may even be necessary to repeat testing on the same day (with comparison to normal controls). If heart rate changes with upright posture are consistent, then it can be concluded that they are independent of any specific external influence (e.g., food or water intervention). This proposed strategy is similar to diagnosing hypertension, where an isolated reading is not grounds for therapeutic intervention. Repeated measurements by a reliable pulse and blood pressure measuring device at home may be helpful. Problems related to time of day and hydration are potentially critical since water ingestion can simply eliminate the orthostatic tachycardia response purported to be due to POTS. 67 , 68 The HRS consensus statement definitions of POTS excludes patients with orthostatic hypotension. 21 However, little work has been done regarding the first few seconds and minutes of standing regarding transient drop in blood pressure with prompt recovery during, or preceding, tachycardia. Little is known about beat-to-beat heart rate and blood pressure changes during movement to upright posture in normal individuals and in those deemed to have POTS. The issue of reproducibility of hemodynamic responses has not been evaluated carefully. While it seems unlikely that POTS patients will have reproducible heart rate elevations with every position change, nevertheless, if POTS is a chronic condition and symptoms are deemed to be associated with the physiological changes, then reproducibility of the heart rate change should be expected most of the time (i.e. similar to the measurement of hypertension, which may be variable, but should be reproducible enough to ascertain a diagnosis). In general, variations in response will depend on fluid loading and changes based on food and diet, but this should also correlate with an associated improvement in orthostatic symptoms. Fluid intake, salt intake, and glucose loads will have an effect on physiological heart rate and blood pressure response to orthostatic stress. 69 – 71

Postural Orthostatic Tachycardia Syndrome (POTS), originally identified in 1982 1 and characterized further in 1993, 2 was initially considered a condition in which symptoms were closely tied to, and caused by, orthostatic intolerance due to autonomic dysfunction. Clinical features of POTS resembled previously described syndromes including: neurasthenia, effort syndrome, soldier’s heart syndrome, Da Costa’s syndrome and, more recently (1970s), mitral valve prolapse syndrome. 3 – 7 These ‘older’ syndromes have largely disappeared, whereas, POTS, at least in the manner it is currently employed, seems to more than fill the void. Initially, POTS was thought to be due to autonomic dysfunction, albeit, of modest severity based on findings obtained during clinical laboratory studies (e.g., tilt-table test results, phase 2 Valsalva responses, quantitative sudomotor axon reflex tests, thermoregulatory sweat tests, peripheral nerve conduction, and excessive plasma catecholamines) 2 . 8 Later, additional possibly responsible mechanisms were added including: neuropathy involving the distal vasculature sparing cardiac innervation, cardiovascular deconditioning, and cardiac beta-adrenoreceptor supersensitivity. 9 This latter expansion of the syndrome’s causation inevitably broadened the range of associated conditions considered “POTS like” to include: volume depletion, inflammatory disorders and autoimmune diseases. Consequently, the original unified and meaningful initial POTS description of a select group of patients with orthostatic intolerance and sinus tachycardia has evolved to encompass a multitude of patients with a constellation of complaints. In many instances the presenting symptoms are nonspecific in nature, encompass multiple body systems and often are not even associated with orthostatic intolerance. There may not be any identifiable autonomic disorder at all. 10 – 12 A further consequence of a less concrete POTS picture is that it is likely that clinical care may be affected adversely as clinicians are now contending with: 1) ill-defined diagnostic criteria, 2) symptoms unrelated to evident abnormal orthostatic or autonomic physiologic measurements, 3) inappropriate merging of POTS “pathophysiology” with underlying diseases, 4) attribution of syndrome-related complications in individual patients to a host of unproven etiologic theories and 5) inclusion of reversible conditions, such as, medication effects and drug use. Importantly, many treatable serious diseases present with tachycardia and these diagnoses can be missed if the patient is considered to have POTS as cause for the problem. This communication was initiated to clarify the origins of the definition of POTS, to highlight gaps in definition that have resulted in diagnostic confusion and affected clinical care, to develop a direction for patient assessment and management and to consider areas of future research.