Definition and Overview
Postural orthostatic tachycardia syndrome (POTS) is a chronic autonomic dysfunction in which the heart rate increases excessively while standing and is not accompanied by orthostatic hypotension. According to the 2015 American Heart Rhythm Society (HRS) expert consensus, POTS is diagnosed when the heart rate increases by more than 30 beats per minute within 10 minutes after standing for adults, or when the absolute heart rate exceeds 120 beats per minute and systolic blood pressure does not fall by more than 20 mmHg. For adolescents aged 12 to 19, the standard for increased heart rate is 40 beats per minute or more.
POTS is not a single disease but a syndrome involving multiple pathophysiological mechanisms. In addition to abnormal heart rate response when standing, it is accompanied by various symptoms such as dizziness, palpitations, chronic fatigue, brain fog, and exercise intolerance.
It is estimated that approximately 1 to 3 million people in the United States have POTS. Approximately 80% of patients are women of childbearing age, and the age of onset is mostly 15 to 50 years old. The female to male ratio is approximately 5:1. In a large cohort study at the Mayo Clinic, the average age of onset was 30 years, and it took an average of 5 years and 11 months from symptom onset to diagnosis. This reflects the reality that diagnosis is delayed due to lack of awareness of POTS.
The term POTS was first used by Schondorf and Low in 1993. Afterwards, diagnostic criteria were formalized in an international agreement in 2011, and treatment guidelines were established through an HRS agreement in 2015. In 2019, an expert consensus meeting was held hosted by the U.S. National Institutes of Health (NIH) to redefine the direction of research.
Causes and subtypes
The cause of POTS is not single, and subtypes are divided according to various pathophysiological mechanisms. It is also common for multiple mechanisms to overlap in one patient.
Neuropathic POTS
It is caused by damage to the peripheral autonomic nerves, especially sympathetic nerve fibers in the lower extremities and visceral regions. When standing up, blood is stored in the lower body due to insufficient contraction of the lower extremities and internal blood vessels, and the heart rate increases excessively to compensate. There are reports that small fiber neuropathy occurs in approximately 50% of POTS patients. A decrease in intraepidermal nerve fiber density is often confirmed in skin biopsies.
Hyperadrenergic POTS
This is a type in which excessive secretion of norepinephrine occurs when standing up. It is characterized by the concentration of norepinephrine in the blood rising to over 600 pg/mL in a standing state. It is observed in approximately 30-60% of all POTS patients, and systolic blood pressure may actually increase when standing. It is often accompanied by tremor, anxiety, and excessive sweating.
Hypovolemic POTS
This is a type in which the amount of circulating blood in the body is absolutely insufficient. There is a study showing that the plasma volume in POTS patients is reduced by about 13% compared to the control group. Due to insufficient blood volume, venous return to the heart decreases when standing up, and the heart rate increases to compensate. It is presumed that dysregulation of the renin-angiotensin-aldosterone system is involved.
Autoimmune POTS
This type occurs when autoantibodies attack receptors in the autonomic nervous system. Approximately 25% of POTS patients are positive for antinuclear antibodies (ANA), and cases of autoantibodies against adrenergic receptors, muscarinic receptors, and autonomic ganglion acetylcholine receptors have been reported. It is frequently accompanied by autoimmune diseases such as Sjögren's syndrome and Hashimoto's thyroiditis.
Post-infectious POTS
POTS symptoms begin within weeks to months after a viral or bacterial infection. The occurrence of POTS has previously been reported after mononucleosis (Epstein-Barr virus) and Lyme disease, but following the COVID-19 pandemic, POTS has rapidly increased worldwide. Approximately 2-14% of COVID-19 patients develop autonomic dysfunction after infection, many of whom meet the diagnostic criteria for POTS. Blitshteyn and Whitelaw (2021) reported that POTS was confirmed in the majority of 20 patients with post-COVID-19 autonomic disease. A molecular mimicry mechanism, in which the immune response attacks autonomic nerve fibers or receptors after infection, is strongly suggested.
symptoms
The common characteristic of POTS symptoms is that they worsen when standing up and are relieved when lying down.
cardiovascular symptoms
Excessive increase in heart rate when standing is a key finding. Patients most commonly complain of palpitations, which may also be accompanied by chest discomfort or chest pain. In some patients, a temporary increase in systolic blood pressure is observed when standing.
neurological symptoms
Dizziness and headache are the most common, and presyncope may also occur. Actual syncope is relatively rare, reported in approximately 30% of POTS patients. Cognitive decline, expressed as brain fog, is very common and includes difficulty concentrating, memory loss, and slower thinking speed. The cognitive function of POTS patients is significantly reduced in the standing state and normalizes in the supine position.
systemic symptoms
Chronic fatigue occurs in approximately 48-77% of POTS patients. Due to exercise intolerance, people experience extreme fatigue and worsening symptoms even with light physical activity. It is often accompanied by sleep disorders, and a vicious cycle is formed in which poor sleep quality further worsens fatigue.
digestive symptoms
Nausea, abdominal pain, bloating, and early satiety are common. Constipation or diarrhea may occur due to gastrointestinal motility disorders. In a Mayo Clinic study, approximately 39% of POTS patients complained of nausea.
Other symptoms
Sweating abnormalities (excessive sweating or anhidrosis), discoloration of the extremities (acrosyanosis, a purplish color of the lower extremities), blurred vision, tremors, shortness of breath, and facial flushing have been reported. The type and severity of symptoms vary from patient to patient, and symptoms are worsened by the menstrual cycle, temperature, dehydration, and standing for long periods of time.
diagnosis
The diagnosis of POTS is made based on clinical symptoms, hemodynamic response upon standing, and exclusion of other diseases.
Tilt Table Test
It is a standard diagnostic test. After laying the patient down on the examination table, rest for 5 to 10 minutes and then tilt the patient to an angle of 60 to 70 degrees. POTS is diagnosed if the heart rate increases by more than 30 beats per minute (more than 40 beats per minute for those aged 12 to 19) within 10 minutes after standing up, or if the absolute heart rate exceeds 120 beats per minute and the systolic blood pressure does not fall by more than 20 mmHg. False positives due to dehydration, drugs, or lying down for long periods of time should be ruled out.
Active Standing Test
It is a screening test that can be easily performed in an outpatient setting. Blood pressure and heart rate are measured 1, 3, 5, and 10 minutes after the patient stands up. The same diagnostic criteria as for the tilt table are applied, but because the patient stands up using his or her own muscles, the results may be slightly different.
Heart rate variability (HRV) analysis
It evaluates the sympathetic-parasympathetic balance of the autonomic nervous system by analyzing minute fluctuations in heartbeat intervals. In POTS patients, increased sympathetic nerve activity and decreased parasympathetic nerve function are often observed at rest. It is also used to monitor treatment effectiveness.
Measurement of blood catecholamines
Blood is drawn while standing to measure the concentration of norepinephrine in the blood. A norepinephrine level of 600 pg/mL or more when standing suggests hyperadrenergic POTS. Measure and compare in the supine and standing states.
autoantibody test
It is performed when autoimmune POTS is suspected. Antinuclear antibody (ANA), anti-SSA/SSB antibody, and autonomic ganglionic acetylcholine receptor antibody (ganglionic AChR antibody) are tested. If positive, it serves as a basis for immunotherapy.
Additional inspection
Thyroid function tests, 24-hour urinary sodium excretion, plasma volume measurements, quantitative sweat axon reflex testing (QSART), and skin biopsy (evaluation of small fiber neuropathy) may be performed to differentiate subtypes and determine the cause. It is essential to differentiate between diseases with similar symptoms, such as pheochromocytoma, inappropriate sinus tachycardia, anxiety disorder, and hyperthyroidism.
treatment
Treatment of POTS is based on non-pharmacological treatments and takes a step-by-step approach with the addition of medications when symptom control is insufficient.
Non-drug treatment
Non-pharmacological treatment is the basis of treatment for all POTS patients.
Water and salt replenishment are the most basic measures. Consumption of 2 to 3 liters of water and 6 to 10 g of salt per day is recommended. Increasing water and salt intake increases plasma volume and relieves symptoms when standing.
Compression stockings rated at 30 to 40 mmHg that reach the waist are effective. Compression garments that cover the abdomen reduce visceral blood retention more effectively than those worn only on the lower extremities.
Posture management is also helpful. Sleeping with the head of your bed raised 10 to 15 degrees can reduce nocturnal diuresis and relieve morning symptoms. Avoid sudden changes in posture, and activate lower extremity muscle pumps by crossing your legs or tiptoeing when standing.
medication
It is difficult to control all symptoms with a single drug, and drugs are selected according to subtype and main symptom.
Low-dose beta blockers (propranolol 10-20 mg, 2-3 times a day) are effective in controlling heart rate. Raj et al. (2009) found that 20 mg of propranolol significantly reduced heart rate while standing compared to placebo. Caution is needed as high doses may worsen fatigue and exercise intolerance.
Midodrine (2.5-10 mg, 3 times a day) is an alpha-1 agonist that improves venous return by constricting peripheral blood vessels. It helps maintain blood pressure when standing and reduces blood retention in the lower extremities.
Ivabradine (2.5-7.5 mg, twice a day) is a drug that lowers heart rate by selectively inhibiting the If current in the sinoatrial node. There are increasing reports that it significantly reduces heart rate and improves symptoms during standing in POTS patients.
Fludrocortisone (0.1 to 0.2 mg/day) increases plasma volume by promoting sodium and water reabsorption. Be aware of side effects such as hypokalemia, headache, and edema.
Pyridostigmine (30-60mg, 3 times a day) is a cholinesterase inhibitor that is used for mild forms of POTS by enhancing nerve transmission in the autonomic ganglion.
If autoimmune POTS is confirmed, intravenous immunoglobulin (IVIG) or immunomodulatory treatment may be attempted.
Neuromodulation treatment
A stellate ganglion block is a procedure that temporarily suppresses sympathetic nerve output by injecting a local anesthetic into the sympathetic ganglion when sympathetic nerve hyperactivation is significant. Transcranial magnetic stimulation (TMS) is a treatment method that helps restore the function of the autonomic nervous system control center through non-invasive brain stimulation.
exercise rehabilitation
Exercise is the non-pharmacological intervention with the strongest evidence base in the treatment of POTS.
Dallas protocol (Levine protocol)
Fu and Levine (2018) developed a progressive exercise program specifically designed for POTS patients. Approximately 71% of POTS patients who completed a 3-month structured exercise program had heart rate increases below diagnostic criteria and, in effect, no longer met criteria for POTS. This program consists of the following steps:
Stage 1 (1 to 2 months) is the supine exercise period. Exercise with low standing load, such as recumbent bike, rowing machine, or swimming, 3 to 4 times a week for 25 to 30 minutes each time. Aim for 70-75% of your maximum heart rate.
Stage 2 (2-3 months) is the gradual standing exercise phase. In addition to lying down exercises, gradually add standing exercises such as regular cycling and walking. Increase exercise frequency to 4-5 times a week and expand exercise time to 35-45 minutes per session.
Stage 3 (after 3 months) is the maintenance stage. Perform general aerobic exercise (jogging, regular cycling) 5-6 times a week, 45-60 minutes per session, and add strength training 1-2 times a week. As cardiovascular function improves, heart rate response normalizes when standing.
This program increases left ventricular volume by approximately 8% and expands plasma volume by approximately 6%. Symptoms may temporarily worsen in the first 1 to 2 weeks of exercise, but if you endure this period, they will gradually improve, so it is important not to give up.
Precautions when exercising
Standing exercises must be started after you have adapted to lying down exercises. Exercise in a hot environment causes blood vessels to dilate, so exercise in a cool environment. Drink plenty of water and electrolytes before and after exercise, and if symptoms worsen rapidly, stop exercising and lie down. Keeping an exercise diary will help you adjust the intensity appropriately.
life guide
fluids and salt
Drink 2 to 3 liters of water a day, often in small portions. Drinking 500 mL of water immediately after waking up helps relieve symptoms of standing up in the morning. Consume 6-10g of salt with food per day, but if you have heart disease or kidney disease, be sure to consult your doctor. Electrolyte drinks may be helpful, but avoid products with excessive sugar.
posture management
When getting up from lying down, first maintain a sitting position on the bed for 1 to 2 minutes and then slowly stand up. In situations where you have to stand for a long time, cross your legs or raise your toes to activate the lower extremity muscle pump. Even when sitting for long periods of time, perform ankle pump exercises (moving your toes up and down) periodically. If you sleep with the head of your bed raised by 10 to 15 cm with a brick or pedestal, nighttime urine output will decrease and morning plasma volume will be maintained.
environmental management
A hot environment dilates blood vessels and worsens symptoms. Use lukewarm water rather than hot showers, and avoid saunas and steam rooms. Keep the indoor temperature cool, and use a cooling vest or portable fan when going out. Limit excessive alcohol consumption as it causes dehydration and vasodilation.
meal management
Eating a large meal at once can increase blood flow to the intestines during the digestion process, which can worsen orthostatic symptoms. It is advisable to eat small portions frequently. High-carbohydrate meals can cause postprandial low blood pressure, so a low-carbohydrate, high-protein diet is recommended.
daily tips
Keep a symptom diary to identify aggravating factors (menstrual cycle, weather, sleep, diet, etc.). Wear compression stockings and drink plenty of water when boarding an airplane or traveling in a car for long periods of time. A regular sleep rhythm (waking up at the same time every day) helps stabilize the autonomic nervous system. If possible, inform your workplace or school about the disease and create an environment where you do not have to maintain a standing posture for long periods of time.