COVID-19–Induced Cardiac Dysautonomia: Case Report and Literature Review

Background

Most patients who have COVID-19 recover completely with no long-term sequelae. But some COVID-19–positive patients experience a variety of immediate and late complications. Some of the recently reported complications reported in COVID-19 patients include effects on the central nervous system (acute necrotizing encephalopathy, hyposmia, stroke, seizures), cardiovascular system (myocarditis, congestive heart failure, blood clots, myocardial infarction), kidney (acute kidney injury), gastrointestinal tract (GI bleeding, liver injury), eye (conjunctivitis), and lung (pneumonia, acute respiratory distress syndrome, ground glass opacities).¹

The most likely mechanism that has been proposed for central nervous system complications is COVID-19–induced cytokine storm and hyperinflammation in the brain resulting in demyelination and apoptosis of neuronal cells from immune system hyperactivation due to the virus and hypercoagulability.^1,2 Regulation of bodily functions during this physiological state is usually performed by synchronous functioning of the sympathetic and parasympathetic nervous system in order to reach normal hemostasis. Impairment or injury to the autonomic nervous system can result in symptoms related to dysregulation of blood volume, blood pressure, body temperature, and sweating. After a viral prodrome, approximately 28-41% of patients can present with typical clinical manifestations of postural orthostatic tachycardia syndrome (POTS), including palpitations, chest pain, shortness of breath, orthostatic lightheadedness, presyncope, and syncope.³ Although the exact mechanism for viral infection-mediated POTS needs to be further investigated, an autoimmune-mediated process has been proposed as a most likely mechanism.³ Moreover, patients with POTS have a higher incidence of autoimmune disorders and markers as compared to the general population.⁴ POTS is relatively underdiagnosed due to non-specific symptoms. Diagnosing post-COVID POTS in earlier stages is important so that appropriate therapeutic management can be administered in a timely manner to relieve its debilitating symptoms. We present a clinical scenario wherein a COVID-19–positive patient who had mild symptoms followed by complete recovery presented 4-6 weeks later with typical clinical manifestations of dysautonomic syndrome including dizziness, lightheadedness, palpitations, and fluctuating heart rate/blood pressure.

Case Presentation

A 33-year-old female was seen in the electrophysiology clinic for managing her orthostatic symptoms. Her past medical history was significant for anxiety and COVID-19 infection beginning in November 2020 and was associated with loss of taste and smell. The COVID-19 infection was mild and resolved uneventfully without any complications. Six weeks later, she started to develop palpitations, fluctuating heart rate (HR), diffuse body pains, dull achy chest pain in the night, shortness of breath, headache, and tingling pain in the thigh starting the second week of December 2020. She mentioned that her HR increased as high as 180 bpm on exertion, while going down to as low as 37 bpm with rest. She could feel her heart beating fast, which affected her lifestyle. She also complained of occasional lightheadedness. Pulse oximetry at home showed 98% saturation. She denied frank chest pain, syncopal episodes, lower extremity edema, or stroke-like symptoms. There was no history of recent hospitalizations or emergency department visits. ECG showed sinus rhythm with HR of 89 bpm. Pulse oximetry showed 96% oxygen saturation, blood pressure of 132/102 mmHg, and respiratory rate 18/min. Laboratory investigations, including liver, kidney, and thyroid function, were unremarkable. She recently repeated a chest x-ray and D-dimer, both of which were normal. Tilt table test, immune workup, echocardiography, and ganglionic acetylcholine receptor (α3-AChR) auto-antibody were ordered as well. The patient was treated conservatively with hydration, compression stockings, yoga therapy, an implantable loop recorder (ILR), and medical management (ivabradine and midodrine). Workup for autonomic failure revealed the presence of auto-antibodies against acetylcholine receptors α3-ACR (Ab) 75 pmol/L [normal range <53 (pmol/L)].

Discussion

We present a clinical case of mild COVID-19 resolving completely and presenting 4-6 weeks later with classic symptoms of POTS. Cardiac involvement of COVID-19 can be due to direct damage (myocarditis, heart failure, arrhythmia) or indirect damage (thromboembolism).⁵ In a recent study by Puntmann et al, cardiovascular magnetic resonance (CMR) imaging of severe COVID-19 patients revealed fibrosis and myocardial inflammation 2-3 months after diagnosis.⁶ These findings indicate that COVID-19–induced myocardial involvement can persist, even after resolution of the acute phase. Some recently published case reports revealed that acutely sick COVID-19 patients can also have associated symptoms of autonomic dysfunction such as postural tachycardia and hyperhidrosis.⁷

POTS is defined as increase in heart rate >30 bpm during head-up tilt table testing or within 10 minutes of standing in the absence of orthostatic hypotension.^8,9 It is more common in females as compared to males, and more prevalent in patients between the age of 10-54.^8,9 Women are more prone to develop POTS due to hormonal changes, smaller stroke volume, altered hemodynamics, and less distensible hearts.¹⁰ Its incidence is estimated to be around 17.9 per 100,000 patient years.^8,9 Various subtypes of POTS that have been described include neuropathic, volume dysregulation, hyperadrenergic, cerebral dysregulation, and mast cell activation disorder.^9,10 Some of the commonly associated disorders with POTS include migraine, fibromyalgia, irritable bowel syndrome, anxiety, chronic fatigue syndrome, and autoimmunity.^10,11 Most patients experience a triggering event a few weeks to months before having typical symptoms of POTS, including viral illness, trauma, pregnancy, or bariatric surgery.¹² The typical clinical presentation of POTS patients includes orthostatic symptoms such as lightheadedness, presyncope, syncope, chest pain, weakness, palpitations, loss of sweating, hyperhidrosis, and tremulousness, as well as non-orthostatic symptoms such as bloating, nausea, vomiting, abdominal pain, constipation, diarrhea, and bladder and papillary muscle dysfunction.⁹

It was previously reported that patients with POTS had a higher incidence of autoimmune disorders (Hashimoto’s thyroiditis, rheumatoid arthritis, systemic lupus erythematosus) and markers (antinuclear and antiphospholipid antibodies) as compared to the general population.⁴ Additionally, literature suggests that patients were developing autoimmune diseases such as autoimmune hemolytic phenomenon, autoimmune thrombocytopenia, Guillain-Barre syndrome, vasculitis, Kawasaki disease, antiphospholipid syndrome, and multiple sclerosis shortly after COVID-19 infection.¹³ The risk factors for developing COVID-19–induced autoimmunity include human leukocyte antigen polymorphisms, female gender (reproductive age), family history of autoimmune diseases, individual history of autoimmune diseases, and presence of autoimmune antibodies.¹³

Hyperresponsiveness of the immune system and autoimmunity are some of the underlying mechanisms leading to the development of POTS in acute COVID-19 patients. POTS that develops weeks to months after COVID-19 prodrome can be explained by transient lymphopenia, transient immunodeficiency of innate and acquired immunity, immune reconstitution, failure to recognize self-antigens, and autoimmunity.¹³ It is probable that auto-antibodies that develop in COVID-19 patients can cross-react with autonomous ganglia, leading to autonomic dysfunction and POTS. Particularly, involvement of the acetylcholine receptor through α3-AChR auto-antibodies can lead to autoimmune autonomic ganglionopathy (AAG).¹⁴ Antibodies against α3-AChR are present in 50% of AAG cases and it is imperative to check the titers of these antibodies in COVID-19 patients presenting with symptoms of POTS.¹⁴ Additionally, antibodies that can activate alpha-1 adrenergic receptors and G-protein-coupled receptors are found in a small subset of POTS patients.¹⁰ So it is important to consider autoimmunity in the differential diagnosis of COVID-induced POTS and perform autoimmune workup in patients with coexisting systemic autoimmune disorders. It was reported that 75% of POTS patients positive for α3-AChR antibodies can be responsive to immunotherapy¹⁴; this might apply to COVID-19 patients who develop autoimmune antibodies and widespread systemic autoimmunity.

Apart from autoimmunity, some other mechanisms proposed for COVID-19–induced POTS include hypovolemia, destruction of extracardiac postganglionic sympathetic fibers, and alteration of medullary center function, which can lead to increased sympathetic outflow activity and various manifestations of autonomic dysfunction.¹⁵ Moreover, COVID-19–induced POTS can be explained as a compensatory mechanism that develops as a result of cardiovascular deconditioning (reduced cardiac mass, reduced blood volume, reduced stroke volume, and reduced peak oxygen uptake) due to prolonged bed rest in these patients.^10,15

Our patient had mild COVID-19 infection that resolved completely without any complications, but presented 6 weeks later with symptoms including racing heart, fluctuating heart rate, dull chest pain, shortness of breath, and tingling in the right lateral thigh. Due to her prolonged window of time between her COVID-19 infection and her typical orthostatic symptoms, we suspect that autoimmunity is the most probable underlying mechanism for her POTS.

Workup routinely ordered to diagnose POTS includes electrocardiogram, 24-hour Holter monitoring, head-up tilt table test, autonomic testing, echocardiography (assessing ventricular function), carotid Doppler (assessing cerebral blood flow), plasma/urinary catecholamines, and immunologic workup.¹¹ Immunological workup completed in this patient included erythrocyte sedimentation rate (ESR), c-reactive protein (CRP), antinuclear antibody (ANA), anti-double stranded DNA (anti-dsDNA), antineutrophil cytoplasmic antibodies (ANCA), and ganglionic AchR antibodies (autoimmune ganglionopathy).

Supporting evidence indicates that POTS is usually managed with a combination of exercise, conservative management, and medical management.^8-11 Some of the non-pharmacological interventions proven successful in POTS patients include avoidance of precipitating factors, hydration, compression stockings, sleeping with the head elevated, and resistance exercises.¹⁰ Medications such as fludrocortisone (potent mineralocorticoid), midodrine (alpha-1 adrenergic agonist), beta-blockers, clonidine (alpha-1 agonist), pyridostigmine (acetylcholinesterase inhibitor), ivabradine (sinus node blocker), octreotide (somatostatin analogue), and erythropoietin (erythrocyte growth factor) have been tried in POTS patients with varied success.^8-11 In few patients, behavioral and cognitive therapy have also been used in POTS patients with associated anxiety, hypervigilance, fatigue, and functional gastrointestinal disorders.¹⁰ Surgical options such as sinus node modification are rarely considered on a case-by-case basis.¹¹ The physiological basis of these therapeutic interventions is to increase the intravascular volume, systemic vasoconstriction, increased venous return, and normalizing heart rate so that debilitating symptoms of POTS are resolved.¹⁵ Our patient was managed with conservative management including compression stockings, increased fluid intake, yoga therapy, and drug therapy (ivabradine and midodrine). An ILR was recommended to monitor silent brady- and tachyarrhythmias.

Conclusion

Clinicians should consider POTS in COVID-19 patients who present with typical orthostatic and non-orthostatic symptoms. Appropriate diagnostic workup and management is warranted for earlier diagnosis to prevent the morbidity associated with its debilitating symptoms.

Key Points

1. POTS can acutely present in COVID-19 patients, and sometimes a few weeks to months after initial uneventful recovery.
2. POTS is relatively underdiagnosed due its non-specific symptoms, and it should be considered in the differential diagnosis of COVID-19 patients presenting with typical and atypical orthostatic symptoms.
3. Immune workup, autonomic testing, head-up tilt table testing, and other diagnostic tests need to be performed in patients suspected with COVID-19–induced POTS so that necessary therapeutic interventions are administered in a timely manner.

1. Balachandar VI, Mahalaxmi M, Subramaniam, et al. Follow-up studies in COVID-19 recovered patients - is it mandatory? Sci Total Environ. 2020;729:139021-139021.
2. Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033.
3. Miglis MG, Prieto T, Shaik T, et al. A case report of postural tachycardia syndrome after COVID-19. Clin Auton Res. 2020;30(5):449-451.
4. Blitshteyn S. Autoimmune markers and autoimmune disorders in patients with postural tachycardia syndrome (POTS). Lupus. 2015;24(13):1364-1369.
5. Chang WT, Toh HS, Liao CT, Yu WL. Cardiac involvement of COVID-19: acomprehensive review. Am J Med Sci. 2021:361(1):14-22.
6. Puntmann VO, Carerj ML, Wieters I, et al. Outcomes of cardiovascular magnetic resonance imaging in patients recently recovered from coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2020;5(11):1265-1273.
7. Umapathi T, Poh MQW, Fan BE, et al. Acute hyperhidrosis and postural tachycardia in a COVID-19 patient. Clin Auton Res. 2020;30(6):571-573.
8. Kesserwani H. Postural orthostatic tachycardia syndrome misdiagnosed as anxiety: a case report with a review of therapy and pathophysiology. Cureus. 2020;12(10):e10881.
9. Carew S, Connor MO, Cooke J, et al. A review of postural orthostatic tachycardia syndrome. Europace. 2009;11(1):18-25.
10. Bryarly M, Phillips LT, Fu Q, Vernino S, Levine BD. Postural orthostatic tachycardia syndrome: JACC focus seminar. J Am Coll Cardiol. 2019;73(10):1207-1228.
11. Wells R, Spurrier AJ, Linz D, et al. Postural tachycardia syndrome: current perspectives. Vasc Health Risk Manag. 2017;14:1-11.
12. Kanjwal K, Jamal S, Kichloo A, Grubb BP. New-onset postural orthostatic tachycardia syndrome following coronavirus disease 2019 infection. J Innov Card Rhythm Manag. 2020;11(11):4302-4304.
13. Cañas CA. The triggering of post-COVID-19 autoimmunity phenomena could be associated with both transient immunosuppression and an inappropriate form of immune reconstitution in susceptible individuals. Med Hypotheses. 2020;145:110345.
14. Sandroni P, Low PA. Other autonomic neuropathies associated with ganglionic antibody. Auton Neurosci. 2009;146(1-2):13-17.
15. Goldstein DS. The possible association between COVID-19 and postural orthostatic tachycardia syndrome. Heart Rhythm. 2020:S1547-5271(20)31141-3.