Overview of Postural Orthostatic Tachycardia Syndrome (POTS) for General Cardiologists

Abstract

Postural tachycardia syndrome (POTS) is a chronic autonomic disorder characterized by excessive heart rate elevation upon standing or head-up tilt, in the absence of orthostatic hypotension. This debilitating condition affects primarily young to middle-aged individuals, particularly women, and substantially influences quality of life. The main presenting symptoms are lightheadedness, palpitations, exercise intolerance, and cognitive impairment. POTS is of particular importance to cardiologists, given its prominent cardiovascular symptoms. The diagnostic criteria for POTS include a sustained heart rate increase of more than 30 beats per minute upon standing or head-up tilt; symptoms of orthostatic intolerance lasting at least 3 months; and exclusion of other causes. The exact etiology of POTS is unknown, but multiple possible etiologies leading to a similar clinical phenotype have been proposed. Early intervention and appropriate management can improve symptoms. Treatment strategies include lifestyle modifications, pharmacotherapy, and tailored conditioning programs. Non-pharmacologic options are the first line treatment. Prognosis varies widely: POTS can be a temporary condition for some individuals but a chronic and debilitating condition for others. Further research is necessary to elucidate the pathophysiology and optimize treatment strategies for this condition.

Main article text

Introduction

Postural tachycardia syndrome (POTS) is a chronic, debilitating autonomic disorder that affects primarily young to middle-aged individuals, particularly pre-menopausal women [1]. POTS is one of the most common forms of orthostatic intolerance and is characterized by an excessive increase in heart rate upon standing or head-up tilt, in the absence of orthostatic hypotension [2]. POTS presents a myriad of symptoms, including lightheadedness, palpitations, exercise intolerance, and cognitive impairment, which substantially affect the quality of life of the millions of individuals with POTS. This syndrome must be distinguished from other conditions with similar symptoms and clinical presentation. POTS is of particular importance to cardiologists, given the prominent cardiac symptom of palpitations from tachycardia upon standing. Herein, we discuss the definition of POTS, as well as the etiology, epidemiology, pathophysiology, history, physical findings, evaluation, management, and prognosis of POTS, on the basis of the available literature.

What is POTS?

POTS is a heterogeneous syndrome with multiple possible etiologies leading to a similar clinical phenotype [3]. Although patients with POTS have varying presentation, major national/international societies have reached a consensus regarding the criteria required for diagnosis [1, 3–6]. To meet the definition of POTS, patients must have all of the following:

• A sustained heart rate increase of greater than 30 beats per minute (or 40 beats per minute in patients 12–19 years old) within 10 minutes of standing or a head-up tilt test.

• Symptoms of orthostatic intolerance, such as lightheadedness, palpitations, headache, flushing, fatigue, tremulousness, blurred vision, presyncope, or difficulty concentrating. Individuals may have varying symptoms, but the symptoms experienced must worsen in the upright position and improve in a supine position.

• Symptoms must last at least 3 months.

Importantly, POTS is excluded if patients meet any of the following criteria:

• Heart rate increase associated with orthostatic hypotension, defined as a sustained decrease in blood pressure of greater than or equal to 20/10 mmHg after standing [4].

• Orthostatic tachycardia secondary to other explainable causes. Conditions that may cause orthostatic tachycardia include acute hypovolemia, anemia, adrenal insufficiency, carcinoid tumor, hyperthyroidism, Cushing syndrome, pheochromocytoma, reactions from medications, panic attacks, severe anxiety, prolonged bed rest, and recreational drug use [5, 7].

Patients may also experience symptoms unrelated to orthostatic intolerance. Symptoms may be intermittent or constant, and may include cardiovascular symptoms (chest pain, palpitations, or dyspnea), GI symptoms (nausea, abdominal pain, bloating, constipation, or diarrhea), neurologic symptoms (anxiety, headache, difficulty concentrating, memory problems, or tingling), skin symptoms (flushing), dysuria, joint pain, dry mouth, or dry eyes [8]. Patients may show other signs of autonomic dysfunction, including paroxysmal or resting sinus tachycardia; fluctuations in blood pressure, including both hyper- and hypotensive tendencies; and peripheral vasomotor symptoms, such as Raynaud’s phenomenon [9–12]. Patients with POTS have also been found to have varying degrees of GI dysmotility, which may be associated with autonomic dysfunction [13].

Several diseases have been shown to be present alongside POTS. The observed comorbid diagnoses include migraine, hypermobile Ehlers-Danlos syndrome, chronic fatigue syndrome, small fiber neuropathy, and mast cell activation syndrome [3, 14–16]. In a large survey of patients with POTS, 40% experienced migraine headaches, 25% had Ehlers Danlos syndrome, 16% had an autoimmune disease, and 9% had mast cell activation syndrome [8]. Current understanding of the prevalence and the link between these conditions and POTS is lacking.

Epidemiology and Natural History

POTS affects millions of individuals worldwide. Patients with POTS are predominantly women (4–5:1) of childbearing age [17]. In a large community-based online survey of patients with POTS, 93% of patients were white, and 94% of patients were women of childbearing age [8]. Approximately half the patients included in the study had developed symptoms by adolescence [8].

The natural history of POTS is not well studied. POTS can be precipitated by several immunological stressors, including viral infection, menarche, physical trauma, pregnancy, and surgery [3, 8]. The recent COVID-19 pandemic might have influenced the incidence of POTS, because as many as one-third of highly symptomatic patients with long-COVID meet the diagnostic criteria for POTS [9].

Outcomes among children diagnosed with POTS appear to improve with treatment and are worse among patients receiving therapy after experiencing symptoms for an extended duration [18]. In adults, the data are more limited; however, evidence suggests that symptoms can improve with treatment. Unfortunately, many patients do not experience complete remission of symptoms, even after long follow-up durations [19]. POTS may also substantially limit quality of life and may render some individuals functionally impaired, thus resulting in extensive economic effects [3]. In one survey of 94 patients, 24% were disabled and unable to work because of POTS [20].

Etiology

The exact etiology of POTS has not been well explored. However, multiple etiologies are believed to contribute to a final common pathophysiological pathway ultimately leading to a similar clinical phenotype [17].

The multiple etiologies of POTS are often characterized as POTS “subtypes.” This classification is substantially limited, because clinical features overlap between subtypes, and the definitions for subtypes vary [17]. Although these subtypes may not be precise classifications of the pathophysiology of POTS, they enable the multiple possible etiologies of POTS to be clearly conceptualized and may help guide the selection of appropriate treatments. Commonly described POTS subtypes are hyperadrenergic, neuropathic, hypovolemic, and autoimmune [3, 17]. Another subtype is associated with mast cell activation disorder (MCAD) [3, 17].

As many as 50% of patients with POTS have the “hyperadrenergic” subtype [1]. As proposed by several consensus statements, these patients typically demonstrate increased systolic blood pressures no less than 10 mmHg after 10 minutes of standing, and plasma norepinephrine levels greater than or equal to 600 pg/mL after standing [10, 15]. Importantly, norepinephrine measurement is not routinely applied in most tilt test laboratories, and the diagnosis is usually established according to a characteristic hyperadrenergic hemodynamic response with associated symptoms. Patients in this group may experience symptoms associated with sympathetic activation upon standing, such as palpitations, anxiety, and tremor. Central sympatholytic medications are a preferable addition to basic therapy.

“Neuropathic” POTS is another commonly observed subtype of POTS. Some patients with “neuropathic” POTS may have small-fiber neuropathy leading to partial sympathetic denervation of the lower limbs [15, 21]. Sympathetic neuropathy causes impaired vasoconstriction and pooling of venous blood in the lower extremities [22]. The body responds with an exaggerated increase in heart rate and cardiac output to maintain systemic mean arterial pressure [22]. Patients with this subtype of POTS may have sudomotor abnormalities during thermoregulatory sweat testing or quantitative sudomotor axon reflex testing [15, 23]. “Neuropathic” POTS may be associated with gastrointestinal symptoms, such as constipation, diarrhea, abdominal pain, bloating, and nausea [15]. In one retrospective study of patients with POTS, half the patients had sudomotor abnormalities, and 34.9% had adrenergic impairment [23]. Thus, “neuropathic” POTS may represent as much as half of the population with POTS.

“Hypovolemic” POTS is characterized by low red blood cell volume and low plasma volume, both of which contribute to a decreased cardiac stroke volume [24–26]. These patients may paradoxically have relatively low renin and aldosterone levels in response to both orthostatic challenge and hypovolemia [25, 26]. Therefore, these patients may have deficits in vascular and adrenal responsiveness [25, 26].

Some cases of POTS may be associated with autoimmunity. Autoantibodies to the ganglionic acetylcholine, alpha 1 adrenergic, beta 1 adrenergic, beta 2 adrenergic, and angiotensin II type 1 receptors have been found in patients with POTS [15, 27]. The common finding of a viral infection preceding POTS onset is a further potential indication that POTS might have an autoimmune basis. The autoimmune etiology of POTS is not well understood and warrants further research. In rare cases, severe treatment-refractory POTS may benefit from immunotherapy with subcutaneous immunoglobulin or plasmapheresis [28]. Trials are ongoing to determine the long-term efficacy and safety of these treatments.

Finally, inappropriate release of histamine and excessive mast cell activation in MCAD have been proposed as causes of orthostatic tachycardia and symptoms of orthostatic intolerance, including lightheadedness, flushing, and shortness of breath seen in POTS [14]. Anti-histamine medications may be considered for treatment of this POTS subtype.

Evaluation

The evaluation of POTS involves a comprehensive assessment of patients’ medical history, physical examination, active stand testing, and laboratory testing. The goal of evaluation is to identify the underlying cause of POTS, and to develop an appropriate treatment and plan.

1. A detailed medical history is essential in the evaluation of POTS. Patients should be asked about the onset and progression of symptoms, precipitating factors, exacerbating factors, and existing medical conditions. Medications (diuretics, birth control, and anticholinergics) must also be reviewed. Information about family history and lifestyle factors can also aid in identifying potential contributing factors.

2. A thorough physical examination can provide important information about the underlying cause of POTS [10]. Patients should be evaluated for signs of autonomic dysfunction, such as orthostatic intolerance, tachycardia, and syncope. Cardiologists should also evaluate the cardiovascular system for signs of structural or functional abnormalities.

3. Active stand testing is a simple assessment for POTS and is considered the standard of care in evaluating patients with symptoms of orthostatic intolerance [2]. A blood pressure cuff is used to measure blood pressure and heart rate after a patient quietly lies supine for at least 10 minutes [2]. Afterward, the patient stands and remains standing unassisted for 10 minutes. Blood pressure and heart rate are measured at 1 minute, 3 minutes, 5 minutes, and 10 minutes of standing. The diagnostic criteria for POTS can then be applied to diagnose POTS.

4. Laboratory testing is an essential component of the evaluation of POTS to help rule out secondary causes of orthostatic tachycardia [10]. Testing includes a complete blood count to evaluate anemia; a complete metabolic panel to assess electrolyte abnormalities or signs of hypovolemia; and thyroid function tests to assess thyroid disease. Additionally, laboratory testing may include measurement of serum catecholamines to assess pheochromocytoma; serum tryptase and other serum/urine mast cell mediators to assess MCAD; and autoimmune markers, if appropriate.

5. Cardiac studies: A tilt table test, which consists of supine rest followed by a passive head-up tilt period with blood pressure and heart rate monitoring, is commonly used to diagnose POTS. The diagnostic criteria for POTS are then applied to diagnose POTS. An electrocardiogram is often obtained to identify any conduction abnormalities. Holter/event monitoring may be ordered to identify any patterns of heart rate variability or inappropriate sinus tachycardia, and to exclude arrhythmias. If structural/functional abnormalities are suspected on the basis of an electrocardiogram or physical examination, an echocardiogram may be useful.

6. Referral to specialists: In some cases, patients with POTS may benefit from referral to specialists in other fields, such as gastroenterology or neurology. These specialists can provide additional expertise in the evaluation and management of POTS-associated extracardiac symptoms, such as gastrointestinal dysmotility, migraine, neuropathic pain, or sleep disturbances.

Treatment/Management

The management of POTS is focused on improving patient symptoms. The primary goal of treatment is to increase blood volume, and thereby alleviate symptoms of dizziness, lightheadedness, and palpitations while standing.

The approaches to managing POTS include non-pharmacologic and pharmacologic interventions. Non-pharmacologic interventions are considered the first line treatment. No medications are currently approved by the US Food and Drug Administration for POTS; therefore, pharmacologic interventions are not considered a first line treatment. However, many cases of POTS are refractory to non-pharmacologic interventions and require pharmacologic intervention.

Non-pharmacologic interventions:

1. Exercise training: Exercise training has been shown to be an effective treatment for POTS [24, 29]. This training can improve cardiovascular fitness, increase blood volume, and ameliorate symptoms of fatigue and brain fog [24]. Patients are advised to start with a low-intensity exercise program consisting of horizontal exercise, such as rowing or swimming, and to gradually increase the intensity and duration as they are able. Beginning with horizontal rather than upright exercise (e.g., walking) is critical for avoiding elicitation of POTS symptoms. Specific POTS training programs are available, such as the modified exercise protocol from the Children’s Hospital of Philadelphia. In patients with comorbid chronic fatigue syndrome, caution with exercise training is advised, because post-exertional malaise might potentially prevent exercise training.

2. Increased salt and water intake: Patients with POTS are advised to consume a diet high in salt and to drink at least 2 liters of water daily, if tolerated [1, 30]. This treatment helps increase blood volume and decrease the severity of symptoms.

3. Compression stockings: Compression stockings extending to the top of the thighs and preferably the abdomen can be used to help increase blood flow and decrease the severity of symptoms [31, 32]. Compression stockings work by applying pressure to the lower legs, thereby decreasing the pooling of blood in the legs and increasing blood flow to the upper body. Cardiologists should advise patients regarding proper fitting and use of compression stockings to ensure maximum benefit.

4. Lifestyle modifications: Patients with POTS are advised to make certain lifestyle modifications, such as avoiding triggers that can exacerbate symptoms (e.g., heat, alcohol, caffeine, or prolonged standing), and getting adequate rest and sleep. Cardiologists should work with patients to identify triggers and develop strategies to manage symptoms.

Pharmacologic interventions (Table 1):

Table 1

Pharmacologic Interventions for POTS [7].

Medication	Starting dose	Adverse reactions
Propranolol	10 mg three times daily	Hypotension, bradycardia
Fludrocortisone	0.1 mg once daily	Hypokalemia, edema, hypertension
Midodrine	2.5 mg three times daily	Supine hypertension
Pyridostigmine	30 mg twice daily	Vomiting, bradycardia
Ivabradine	2.5 mg twice daily	Bradycardia
Clonidine	0.2 mg twice daily	Cognitive clouding

• Beta-blockers: Non-selective beta-blockers (propranolol) and selective beta-blockers (atenolol or metoprolol) are commonly a first line treatment for hyperadrenergic POTS [33]. Beta-blockers work by decreasing heart rate, thus mitigating symptoms of palpitations and tachycardia. Potential adverse effects include hypotension and worsening fatigue.

• Fludrocortisone: Fludrocortisone is a synthetic mineralocorticoid used to increase blood volume in patients with POTS [1]. This treatment works by increasing the reabsorption of sodium in the kidneys, thus resulting in water retention and increased blood volume. Fludrocortisone can decrease lightheadedness. Cardiologists should monitor patients closely for potential adverse effects, including fluid retention, hypokalemia, and hypertension.

• Midodrine: Midodrine is an alpha-1 adrenergic agonist that causes systemic vasoconstriction and is used to increase blood pressure in patients with POTS [34, 35]. Midodrine works by constricting the blood vessels, thus increasing blood pressure and decreasing symptoms of dizziness and lightheadedness. Potential adverse effects include supine hypertension and urinary retention.

• Pyridostigmine: Pyridostigmine is an acetylcholinesterase inhibitor that increases levels of acetylcholine in the autonomic ganglia. The consequent increase in parasympathetic tone decreases tachycardia and mitigates symptoms of POTS [36]. Potential adverse effects include vomiting and bradycardia.

• Ivabradine: Ivabradine is a relatively new medication used to decrease the heart rate in patients with POTS [37, 38]. This treatment works by selectively inhibiting the funny current (If) in the sinoatrial node, thereby decreasing heart rate without affecting blood pressure. Adverse effects include bradycardia and atrial fibrillation.

• Clonidine: Clonidine is a central-acting alpha-2 agonist that may be beneficial in treating hyperadrenergic subtypes with hypertension as a predominant symptom [10]. Adverse reactions include sedation and cognitive clouding.

Beyond non-pharmacologic and pharmacologic interventions, several other management strategies may be helpful for patients with POTS, as follows:

• Patient education: Patient education is an important part of managing POTS [3]. Patients should be educated on the chronic and debilitating nature of POTS; the causes and symptoms; and strategies for avoiding triggers and managing symptoms.

• Psychological support: Many patients with POTS experience anxiety and depression because of their symptoms [39]. Psychological support, such as cognitive-behavioral therapy or counseling, may be helpful in these patients [40].

• Cardiac rehabilitation: Cardiac rehabilitation programs may be beneficial for patients with POTS who can participate in exercise training [41]. These programs provide a supervised exercise program, as well as education and support for managing symptoms. Importantly, tailored cardiac rehabilitation programs must be designed for patients, because no validated cardiac rehabilitation programs specifically for patients with POTS are currently available.

• Multidisciplinary care: Given the complex nature of POTS, a multidisciplinary approach to care may be helpful [41]. This approach may include input from cardiologists, neurologists, and gastroenterologists, as well as physical therapists and occupational therapists.

• POTS in pregnancy: Cardiologists must be aware of additional considerations when managing pregnant patients with POTS. In these patients, non-pharmacologic therapy is considered preferable to pharmacologic options. Non-pharmacologic therapy includes increased fluid and salt intake (2.5 L and at least 7 g per day, respectively), the use of waist-high maternity compression stockings, and light exercise [30]. In the 2^nd and 3^rd trimesters, supine exercise is not recommended, because of the possibility of compression of the inferior vena cava and aorta [42]. Pharmacologic therapy (such as medications discussed above) may be considered for patients with moderate to severe POTS. However, using one medication at the lowest therapeutic dose is preferable, when possible [42]. Before conception, counseling and review of medications that may alter symptoms of POTS during pregnancy are essential [42].

Differential Diagnosis

To avoid misdiagnosis, clinicians must be aware that many conditions are similar to POTS. These conditions may present with orthostatic tachycardia or orthostatic intolerance, but the symptoms either are explained by other causes or do not meet the definition of POTS. For example, patients with vasovagal syncope may show signs of orthostatic intolerance and potentially orthostatic tachycardia. If a patient has symptoms of orthostatic intolerance without orthostatic tachycardia, POTS is not diagnosed, and the condition is considered “postural symptoms without tachycardia” [5]. Differentiating POTS from other conditions characterized by tachycardia, particularly inappropriate sinus tachycardia (IST) and paroxysmal supraventricular tachycardia, is also important [43, 44]. The tachycardia of POTS and IST is sinus. However, unlike POTS, IST is non-positional; therefore, patients with IST display nocturnal supine tachycardia on ambulatory monitoring [2, 43]. Supraventricular tachycardia can be differentiated from the tachycardia of POTS through ambulatory monitoring, or on the basis of improvement with vagal maneuvers, depending on the type of supraventricular tachycardia [2, 43].

The differential diagnosis for POTS should exclude other causes of tachycardia and orthostatic intolerance, including orthostatic hypotension, hypovolemia, arrythmias, pheochromocytoma, thyroid disease, adrenal insufficiency, and exposure to certain medications (stimulants or tricyclic antidepressants). Cardiologists may also want to exclude structural heart disease (valvular disease, cardiac tumors, congenital heart disease, or ventricular outflow obstruction) as a cause of orthostatic tachycardia when evaluating POTS, if clinically indicated [2].

Recent data suggest that POTS is the most common autonomic disorder after COVID-19 [9, 45]. In one report, 2%–14% of COVID-19 survivors developed POTS within 6–8 months after infection [46]. The predominant symptoms were tachycardia and palpitations. The proposed pathophysiology is the production of autoantibodies after infection with SARS-CoV-2, the coronavirus causing COVID-19, which in turn activate the sympathetic system and cause autonomic dysregulation and tachycardia [47]. The risk of POTS is also elevated after COVID-19 vaccination, but this risk is lower than the risk of POTS after COVID-19 infection [48].

Prognosis

The prognosis of POTS varies widely depending on the underlying cause, the severity of symptoms, and the response to treatment [19]. In some cases, POTS may be a temporary condition that resolves with appropriate management, whereas in other cases, it may be a chronic and debilitating condition requiring ongoing treatment and monitoring.

Patients with POTS often experience substantial impairments in quality of life [20]. A survey of 94 patients with POTS has found that the functional limitations are similar to those of chronic obstructive pulmonary disease and congestive heart failure [20]. In the same survey, 24% of individuals reported being disabled and unable to work because of POTS [20]. Patients with POTS have also been shown to have more sleep problems and excessive daytime sleepiness than healthy control participants [49]. Finally, patients with POTS experience substantial financial effects secondary to symptoms of POTS. In a survey of 5556 adults with POTS, 70.5% of patients reported lost income due to POTS symptoms, and 66.8% of those employed stated that they would work for longer hours if they did not have their illness symptoms [50].

Studies have suggested that as many as 80% of patients with POTS report some improvement in symptoms with treatment, although the degree of improvement varies [51].

In general, the prognosis of POTS is better for patients with a younger age of onset, milder symptoms, and no underlying medical conditions [17]. Patients with comorbidities, such as Ehlers-Danlos syndrome, autoimmune disorders, or diabetes, may have poorer prognosis, because these conditions can contribute to the development of POTS. Importantly, POTS is not associated with mortality; however, long-term observations are lacking [1].

Complications

The complications of POTS can be substantial, particularly if the condition is not appropriately managed. Some of the most common complications of POTS include the following:

1. Falls and injuries: Patients with POTS may experience syncope or near-syncope upon standing, which can increase the risk of falls and injuries. These falls can result in fractures, head injuries, or other injuries.

2. Cognitive dysfunction: Patients with POTS may experience cognitive dysfunction (“brain fog”), including problems with memory, concentration, or attention leading to difficulties in school or work [52].

3. Mental health complications: Patients with POTS may experience mental health complications, including depression, anxiety, and social isolation [39].

4. Diminished quality of life: POTS can substantially affect patient quality of life [20]. Patients with POTS may experience limitations in daily activities, difficulty with work or school, and social isolation, all of which can decrease quality of life [20].

Patients with POTS must critically receive appropriate medical care and monitoring to prevent these complications and ensure the best possible outcome. Cardiologists can play a key role in the management of POTS, by working closely with other healthcare providers to develop a comprehensive treatment plan and provide ongoing care for patients with this condition.

Acknowledgements

All authors (AN, EK, AF, and MR) contributed to the writing of this article.

Conflict of Interest

We declare that we have no conflicts of interest with respect to the research, authorship, and publication of the manuscript titled “Overview of Postural Orthostatic Tachycardia Syndrome (POTS) for General Cardiologists.” There is no financial or personal relationship that could be perceived as a conflict of interest, and we have no affiliation with any organization with a direct or indirect interest in the subject of the manuscript.

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