key: cord-0782371-tym2ou0l
authors: Goldstein, David S.
title: The possible association between COVID-19 and postural orthostatic tachycardia syndrome
date: 2020-12-11
journal: Heart Rhythm
DOI: 10.1016/j.hrthm.2020.12.007
sha: 3f27cd53d2fcbdda61206d8f640acc2c7501bcfc
doc_id: 782371
cord_uid: tym2ou0l

nan

Coronavirus disease-2019 (COVID-19), the illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), involves other body organs besides the lungs. In recovered patients "long haul" COVID-19 may include dysautonomia, in which changes in functioning of one or more components of the autonomic nervous system (ANS) adversely affect health. This viewpoint focuses on the dysautonomia postural tachycardia syndrome (POTS).

POTS is characterized by a sustained heart rate increment ≥ 30 bpm within 10 min of standing or head-up tilt. Cardiologic symptoms include chest pain, palpitations, exercise intolerance, and orthostatic intolerance.

Other symptoms may include fatigue, "brain fog," gastrointestinal issues (e.g., abdominal pain, bloating, gastroparesis, and nausea), chronic pain (e.g., headache, temperomandibular joint disorder, fibromyalgia), and sleep abnormalities. Co-morbidities include Ehlers-Danlos syndrome, mast cell activation syndrome (MCAS), sensory neuropathy, or autoimmune disorders (e.g., lupus, Sjogren's syndrome). These aspects extend beyond cardiology.

Both long-haul COVID and POTS are multi-system, multi-disciplinary syndromes.

Thinking in terms of the "extended ANS" (EAS) may help comprehend how these syndromes come about and how to test for and treat them. 1

The ANS has been defined by three components-the sympathetic nervous system (SNS), the parasympathetic nervous system (PNS), and the enteric nervous system (ENS). The EAS expands the meaning of "autonomic" in two ways-neuroendocrine and neuroimmune.

Cannon taught that activation of the SNS and adrenal gland in emergencies helps maintain homeostasis, a word he invented. Since then other neuroendocrine systems have been described that are closely linked to components of the ANS. These include the hypothalamic-pituitaryadrenocortical (HPA) system, the renin-angiotensin-aldosterone system (RAAS), and the arginine vasopressin system. Across a variety of stressors, responses of plasma EPI levels are more closely tied to those of adrenocorticotropin (ACTH, the anterior pituitary hormone of the HPA axis) than of NE. These findings support a close association between the sympathetic J o u r n a l P r e -p r o o f adrenergic system (SAS) and HPA axis. The sympathetic noradrenergic system and the SAS are closely connected to the RAAS. Occupation of beta-1 adrenoceptors in renal juxtaglomerular cells release renin, adrenomedullary chromaffin cells possess angiotensin receptors that when occupied evoke EPI secretion, and there is a central neural renin-angiotensin system that participates in the regulation of sympathetic outflow. Angiotensin-converting enzyme type 2 (ACE2) converts AII to angiotensin 1-7 (Ang 1-7), which opposes the effects of AII. The SARS-CoV-2 virus enters cells via binding to ACE2. In addition to being a pressor and the body's main water-retaining hormone, in the brain vasopressin augments baroreflexive restraint of sympathetic outflows.

A second aspect of the EAS is neuroimmunity. Cortisol is well known to be the major antiinflammatory compound of the HPA axis. The cytokine IL-6 activates the HPA axis 2 and stimulates production of aldosterone, demonstrating links between the immunological and neuroendocrine facets of the EAS. A cholinergic anti-inflammatory pathway involves cytokineinduced increases in vagal afferent traffic and vagal efferent inhibitory effects on inflammasomal cytokine release. 3 Vagal stimulation inhibits production of the cytokine TNFα, probably via the two main neurotransmitters of the ANS, acetylcholine and NE. No simple concept explains catecholaminergic influences on immunity. Although across a variety of stressful situations increases in EPI levels are associated with elevations of IL-6, bases for this relationship are poorly understood. Immune cells synthesize and release catecholamines, 4 but the functional significance is unknown.

In the 1990s Chrousos and Gold proposed the existence of a stress syndrome elicited by activation of the "central stress system." A recently proposed schema 1 embeds this system within the "central autonomic network" (CAN). 5 The CAN is the source of outflows to ANS components including the sympathetic noradrenergic system (SNS), for which NE is the neurotransmitter, the sympathetic adrenergic system (SAS), for which EPI is the hormone, and the parasympathetic nervous system (PNS), for which acetylcholine is the neurotransmitter.

When the central stress system is activated, PNS outflows generally decrease, which would be expected to promote tachycardia. Other manifestations of PNS inhibition include decreased gastrointestinal motility, decreased salivation and lacrimation, and decreased urinary bladder tone.

COVID-19 is associated with several central nervous system abnormalities including stroke, encephalopathy, encephalitis, anosmia, anorexia, headache, nausea, and delirium. A meta-analysis of literature from prior epidemics (SARS, Middle East Respiratory Syndrome) noted high frequencies of confusion, depressed mood, anxiety, impaired memory, and insomnia. 6 Conversely, POTS patients often report a recent viral illness. 7 There are several pathophysiological mechanisms that might be associated with post-COVID-POTS. They are not mutually exclusive, and to date there is no published evidence supporting any of them. One mechanism is hypovolemia. Fever, anorexia, nausea, excessive nocturnal sweating, and prolonged bed rest might operate together to decrease blood volume and secondarily increase cardiac SNS outflow. In POTS deconditioning can be part of a vicious cycle involving low stroke volume, high SNS or SAS outflows, exercise intolerance, and fatigue. These findings have been called "Grinch heart." 8 Second, the SARS-CoV-2 virus might infect and destroy extra-cardiac post-ganglionic SNS neurons, secondarily increasing cardiac SNS outflow in a manner analogous to neuropathic POTS. This might include splanchnic venous pooling or a failure of reflexive mesenteric vasoconstriction during orthostasis.

Third, SARS-CoV-2 virus could invade the brainstem and alter functions of medullary centers, resulting in increased central sympathetic outflows in a manner analogous to takotsubo cardiopathy. 9 Centrally mediated increases in sympathetic noradrenergic and SAS outflows as part of stress system activation might be associated with psychiatric morbidity such as anxiety or depression. There could be alterations in brain perfusion manifesting with "brain fog." 

The extended autonomic system, dyshomeostasis, and COVID-19

Interleukin-6 and the interleukin-6 receptor in the human adrenal gland: expression and effects on steroidogenesis

Physiology and immunology of the cholinergic antiinflammatory pathway

Subsecond spontaneous catecholamine release in mesenteric lymph node ex vivo

The central autonomic network: functional organization, dysfunction, and perspective

Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the COVID-19 pandemic

Postural orthostatic tachycardia syndrome: clinical presentation, aetiology and management

Cardiac origins of the postural orthostatic tachycardia syndrome

Takotsubo cardiomyopathy: A new form of acute, reversible heart failure

A case report of postural tachycardia syndrome after COVID-19