POTS and Chronic Orthostatic Intolerance

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[Circulatory Findings in POTS]

Classical POTS is shown with a rapid rise in heart rate and little fall in blood pressure. The study was terminated after 10 minutes as per routine. 

 

The orthostatic tachycardia syndrome is a disabling disease state described at least since 1940  and is the most common reason for referral for orthostatic intolerance  in adults. It is an emerging form of orthostatic intolerance in children. Patients have day-to-day disability - a feature not shared with most patients with simple faint. With some exception, traditional tests of autonomic function are normal in these patients. Patients are often unable to hold jobs or attend schools. Drs. Schondorf and Low of the Mayo Clinic described a postural tachycardia syndrome (POTS) which is the most frequently used name for the illness. Dr. David Robertson of the Vanderbilt autonomic laboratories, has stated that this is the most common form of chronic orthostatic disability, and is present in almost all patients with day-to-day orthostatic intolerance. Therefore the illness may also be appropriately designated "Chronic Orthostatic Intolerance". Our understanding of its pathophysiology remains incomplete. The central physical finding is upright tachycardia although hypotension and resting tachycardia may also be present. An operational definition of the syndrome  includes symptoms of orthostatic intolerance associated with an increase in heart rate from the supine to upright position of more than 30 beats per minute or to a heart rate greater than 120 beats per minute within 10 minutes of head-up tilt (HUT). These numbers may require modification for children. Such a response is depicted in the figure. In the case shown, the patient became immediately symptomatic following the start of HUT and required the table to be put down within a very few minutes. Although this patient was not hypotensive, hypotension may follow or occur with tachycardia. Often hypotension is delayed beyond the onset of the symptoms and the tachycardia, and therefore only manifests during the artificially sustained orthostasis enforced during HUT. Onset of symptoms often follows an infectious disease and may be related to inflammatory mediators. We reported the first pediatric cases of POTS. Our data showed that POTS physiology underlies orthostatic intolerance in the large majority of adolescents with the chronic fatigue syndrome (CFS). POTS is common, affecting an undisclosed number of patients mostly in the age range of 12 to 50 years, mostly female (approximately 80%). There is an as yet undetermined but increasing apparent prevalence in children and adolescents. Onset of symptoms often follows an infectious disease and may be related to inflammatory mediators or to epigenetic triggers. We reported the first pediatric cases of POTS. Our data showed that POTS physiology underlies orthostatic intolerance in the large majority of adolescents with the chronic fatigue syndrome (CFS) . 

 

Mechanisms

POTS is caused by alterations of the autonomic nervous system, although, mild to moderate all-cause hypovolemia mimics POTS.

 Vagal Withdrawal and the Sinus Node
In some mildly ill individuals, POTS is related to loss of parasympathetic slowing of the heart with few peripheral circulatory abnormalities. Upright heart rates rarely exceed 120 bpm. Oten agents that increase cardiac parasympathetic activity such as beta blockers
, cardiac glycosides , acetylcholinesterase inhibitors (pyridostigmine) or ivabradine (not FDA approved) relieve symptoms.  

Others may have excessive beta adrenergic sensitivity of the sinus node. This condition is denoted "inappropriate sinus tachycardia" , and is regarded as distinct from POTS but less common. Supine heart rates >100bpm are observed, symptoms are less severe than in POTS, and beta blocker therapy can be efficacious.

 Neuropathic POTS and Hyperadrenergic POTS 
The remainder of patients are often partitioned among "neuropathic POTS", in which "partial dysautonomic" adrenergic denervation occurs, and "hyperadrenergic POTS", in which sympathetic overactivity prevails.  

Neuropathic POTS
As originally described, decreased adrenergic vasoconstriction in the legs causes decreased norepinephrine spillover ,  vasodilation , and increased blood flow even supine . When upright, redistributive central hypovolemia caused by leg blood pooling leads to reflex tachycardia . In another neuropathic variant decreased adrenergic vasoconstriction and redistribution of central blood to the splanchnic vasculature causes reflex tachycardia. Intense leg vasoconstriction produces acrocyanosis. Autonomic autoimmune neuropathy , presenting as POTS, causes similar reflex tachycardia. Central hypovolemia produces hyperpnea and hypocapnia in 50% of our patients . Treatment with vasoconstrictors (e.g. midodrine) and pyridostigmine can help.

 Hyperadrenergic POTS
The adrenergic synapse can be altered at pre-synaptic or post-synaptic levels. Pre-synaptic abnormalities include increased sympathetic nerve activity even when supine. While this has been reported 38 , the finding is not consistent 51 .  

Increased synaptic norepinephrine is observed in the norepinephrine transporter (NET) deficiency heterozygote , and in more prevalent epigenetic NET downregulation .  Pre-synaptic and post-synaptic adrenergic activity may be enhanced by local chemical milieu, including angiotensin-II excess caused by ACE-2 deficit and nitric oxide deficiency - a hyperadrenergic variant with tachycardia, pallor, vasoconstriction and absolute hypovolemia. Angiotensin [type 1] receptor blockers have shown benefit. Beta blockers may also help.

 Distinguishing among POTS Variants, a Matter of Opinion
Distinguishing among POTS variants may be difficult for the pediatrician (and for the OI expert) despite apparent straight forward differences. Some would say that POTS with increased upright blood pressure is hyperadrenergic, others would say that increased plasma catecholamines (or better, increased norepinephrine spillover) is required. Excessive orthostatic BP is a matter for consensus since both systolic and diastolic BP normally increase upon standing: how much is too much is unclear. As a heuristic, POTS patients with high supine HR, cool to touch and pasty white in appearance when supine, often have hyperadrenergic POTS. Standing HR is elevated to the 130-180 range during quiet standing indicating hyperadrenergic drive; vagal withdrawal alone increases HR to the 100-120 range. Those with upright HR < 120bpms are more likely neuropathic. Recent (unpublished) work with sympathetic nerve recordings have demonstrated normal sympathetic activity when supine, and supranormal activity upright. This supports adrenergic enhancement (NET deficiency, Ang-II excess) in patients with “hyperadrenergic POTS”. Confusing matters further, neuropathic patients can have increased upright catecholamines even though spillover is decreased in the lower extremities .

Gravitational Deconditioning – Caveat Bedrest! 
One confounding and alarming issue is the tendency for POTS patients to bedrest. Prolonged bedrest emulates microgravity and has deleterious effects
including OI , profound reductions in blood volume and cardiac size, redistribution of blood, osteoporosis, skeletal muscle pump atrophy and more . Vasoconstriction is impaired . Bedrest causes a self-perpetuating state of OI which can emulate or intensify POTS. It is paramount for POTS patient to leave bed and recondition. Well-structured exercise protocols are essential and must accommodate patients start off bedrested . Reconditioning invariably improves patient well-being. Recent work support the idea that POTS patients are also exercise deconditioned compared to matched volunteers . While exercise deconditioning may or may not be causal in POTS, it is clear that exercise reconditioning is beneficial and should be advocated for all POTS patients.

 

 

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POTS and Chronic Orthostatic Intolerance
Chronic Fatigue Syndrome