key: cord-0917436-w4ko9des
authors: Ståhlberg, Marcus; Reistam, Ulrika; Fedorowski, Artur; Villacorta, Humberto; Horiuchi, Yu; Bax, Jeroen; Pitt, Bertram; Matskeplishvili, Simon; Lüscher, Thomas F.; Weichert, Immo; Thani, Khalid Bin; Maisel, Alan
title: Post-Covid-19 Tachycardia Syndrome: A distinct phenotype of Post-acute Covid-19 Syndrome
date: 2021-08-11
journal: Am J Med
DOI: 10.1016/j.amjmed.2021.07.004
sha: 85d79b6a37e6016b81d70be8cf4e666d6d5fdd2b
doc_id: 917436
cord_uid: w4ko9des

In this paper we highlight the presence of tachycardia in Post-acute Covid-19 Syndrome by introducing a new label for this phenomenon: Post-covid-19 tachycardia syndrome and argue that this constitutes a phenotype or sub-syndrome in PACS. We also discuss epidemiology, putative mechanisms, treatment options and future research directions in this novel clinical syndrome.

The novel SARS-CoV-2 virus has triggered a pandemic of Covid-19 lasting for more than one year with over 130.000.000 reported cases globally as of April 2021 (1). Due to its novelty and lack of historical data several aspects of Covid-19 remain unclear.

So far, Covid-19 research mostly focused on epidemiology, risk factors for disease severity, description of the clinical course and identification of optimal management strategies in hospitalized Covid-19 patients.

However, there is growing evidence that Covid-19 may cause persistent symptoms and organ damage that stretch beyond the three-month period after the infection, usually regarded as the normal convalescence phase. This is now considered to constitute a novel clinical long-term condition: Post-acute Covid-19 syndrome (2) . The clinical characteristics, pathophysiology and appropriate management strategies for Post-acute Covid-19 syndrome remain largely unknown.

Patients with Post-acute Covid-19 syndrome have a wide range of symptoms including fatigue, chest pain, reduced exercise tolerance, cognitive impairment, dyspnea, fever, headache, loss of smell and taste, but rapid heartbeats and palpitations are typical and frequent complaints (3) . We have recently reported that a sub-group of patients with Post-acute Covid-19 syndrome develop postural orthostatic tachycardia syndrome, a cardiovascular dysautonomia associated with sinus tachycardia and intolerance following orthostatic challenge (4). However, postural orthostatic tachycardia syndrome is likely not the sole explanation for elevated heart rate and several other conditions may explain tachycardia in Post-acute Covid-19 syndrome, e.g. inappropriate sinus tachycardia, deconditioning, hypoxia, anxiety, sinus nide dysfunction, myocarditis/heart failure and persistent fever.

In this paper we would like to highlight the presence of tachycardia in post- Moreover, tachycardia can be considered a universal and easily obtainable quantitative marker of Post-acute Covid-19 syndrome and its severity rather than patient-reported symptoms, blood testing and thoracic CT-scans. Not only does it reflect autonomic dysfunction, chronic inflammation, possible myocardial injury or neurophysiological distress but may reveal the general status of the patient being unhealthy. Holter ECG-monitoring and the plethora of mobile personal heart rhythm tracking devices may facilitate diagnosis and treatment monitoring in outpatient settings.

Postural orthostatic tachycardia syndrome is characterized by autonomic dysfunction causing a variety of symptoms including tachycardia following postural change (9) . It has previously been documented that viral infections can trigger postural orthostatic tachycardia syndrome (10) . The pathophysiological mechanism in postural orthostatic tachycardia syndrome remains elusive but there is evidence of autoimmunity, i.e. autoantibodies activating adrenergic-and muscarinic receptors (11), a hyperadrenergic state (12) , peripheral denervation, similar to taste and smell loss, causing blood pooling in the lower extremities and reflex tachycardia (13) and deconditioning (9) . In addition, magnetic resonance imaging studies revealed lesions in the midbrain suggesting that central sympathetic activation may be involved as well (14) . All these mechanisms may contribute to tachycardia in postural orthostatic tachycardia syndrome. Whether the same mechanisms are responsible for Post-acute Covid-19 syndrome -associated postural orthostatic tachycardia syndrome and to what extent they contribute to post-covid-19 tachycardia syndrome remain to be established.

Inappropriate sinus tachycardia is defined as an average heart rate exceeding 90 bpm on 24-hour ECG monitoring or a resting heart rate >100 bpm and may have several causes such as gain-of-function mutation in the cardiac pacemaker HCN4 channel (15) , cardiac intrinsic sinus node abnormality, autoimmunity, excess sympathetic activation or vagal withdrawal (8) . Clearly, serval pathophysiological mechanisms are shared between postural orthostatic tachycardia syndrome and inappropriate sinus tachycardia, but the mechanism for inappropriate sinus tachycardia in the context of Post-acute Covid-19 syndrome need to be established.

Regarding tachycardia in Post-acute Covid-19 syndrome, there may be several other factors contributing to the observed heart rate elevation. SARS-CoV-2 enters cells by attaching its spike protein to the ACE2 receptor, which is abundant in several different cell types and tissues, and the virus therefore can cause injury in several organs (16) . Structural injury to the lungs, kidneys, pancreas, and heart have been reported in Covid-19 acutely as well as months after the occurrence of first symptoms also in low-risk non -hospitalized patients (17, 18) . In addition, Covid-19 may damage the cardiovascular system by other mechanisms e.g. hyperinflammation, hypercoagulability with thrombosis and dysfunction of the renin-angiotensinaldosterone system (19, 20) . These factors may contribute to the observed and 

We suggest liberal use of at least basic cardiovascular assessment in patients with Post-acute Covid-19 syndrome to identify patients with post-Covid-19 tachycardia syndrome (and associated postural orthostatic tachycardia syndrome and inappropriate sinus tachycardia). A 24-h ambulatory ECG is recommended to detect arrhythmias, assess average heart rate, detect abnormal pulse reactions and link symptoms to heart rate abnormalities. Figure 2 displays two ECGs from patients who meet the criteria of Post-acute Covid-19 syndrome. The first ECG (Figure 2A) shows short runs of symptomatic sinus tachycardia (marked with orange arrows) and a typical excessive increase in heart rate in the morning when shifting from bedrest to upright body position (green arrow). These are 24-h ECG patterns raising suspicion of postural orthostatic tachycardia syndrome. The second ECG shows an elevated average sinus rate of 93 bpm, which is consistent with inappropriate sinus tachycardia.

Patients with Holter-ECG findings suggestive of postural orthostatic tachycardia syndrome and/or presenting with symptoms of orthostatic intolerance should optimally perform a head-up TILT test or, at least, an active standing test to confirm the diagnosis (9) . A 30 bpm increase in heart rate within the first ten minutes of head-up TILT or active standing test without concomitant blood pressure drop and with reproduction of symptoms is diagnostic of postural orthostatic tachycardia syndrome (9) .

A transthoracic echocardiogram should be performed to exclude cardiac abnormalities.

Cardiovascular magnetic resonance (CMR) studies have reported a prevalence of myocarditis ranging from 27-60% in patients recovering from Covid-19 (17, 22) . Since peri-myocarditis may cause tachycardia, we argue that CMR should be considered in the setting of typical or atypical chest pain, elevated cardiac biomarkers and/or typical ECG changes. Moreover, CMR should be performed when cardiovascular autonomic testing did not lead to a diagnosis of cardiac autonomic disturbance (postural orthostatic tachycardia syndrome or inappropriate sinus tachycardia), and the patient reports abnormal or rapid heartbeats.

Blood test are also recommended to evaluate extracardiac causes of tachycardia (autoimmune biomarkers, endocrine tests, inflammation biomarkers, autoimmune biomarkers and hemoglobin levels). Pulmonary pathology is a common source of tachycardia and basic evaluation should also include peripheral oxygen saturation (at rest and during physiological stress such as a six minute walk test), thoracic CT-scan and spirometry.

Current treatment of postural orthostatic tachycardia syndrome includes the selective sinus node inhibitor ivabradine (23) , −blockers (9) and compression garments (24) to stabilize cardiovascular regulation. Other pharmacological options to reduce associated symptoms are midodrine (symptoms of low blood pressure or cerebral hypoperfusion; peripheral blood pooling), pyridostigmine (muscle weakness; associated gastrointestinal dysfunction) and modafinil (brain-fog) (25) . A structured, regular and supervised rehabilitation program is also recommended (25).

Immunomodulation and drugs targeting possible associated mast cell activation syndrome have not been systematically evaluated in postural orthostatic tachycardia syndrome but might be considered ex iuvantibus if the typical clinical manifestation is present (26) .

Although postural orthostatic tachycardia syndrome in the context of Covid-19 may be different from the "traditional" postural orthostatic tachycardia syndrome (pre-Covid-19), we suggest starting patients with Post-acute Covid-19 syndrome and postural orthostatic tachycardia syndrome on heart rate lowering drugs and a rehabilitation program. Other pharmacological interventions may also be considered but should be carefully monitored.

Whether patients with post-Covid-19 tachycardia syndrome are responsive to heart rate lowering drugs and other symptomatic treatment previously used in postural orthostatic tachycardia syndrome remains to be established.

Basic and clinical research programs to characterize Post-Covid-19 tachycardia syndrome and determine similarities and disparities with other sub-syndromes of Postacute Covid-19 syndrome are highly warranted. A clear aim should be to improve our understanding of the pathophysiology of long-term post-Covid-19 complications and to find novel targets for interventions that may provide disease-modifying effects rather than focusing on pure symptom control.

We therefore call for large registries containing both clinical data and biomarkers and interventional studies testing the efficacy of drugs used previously in traditional postural orthostatic tachycardia syndrome, alone or in combinations with experimental drugs targeting putative mechanism in Post-Covid-19 tachycardia syndrome.

We highlight the phenomenon of abnormal sinus tachycardia in patients with postacute Covid-19 syndrome. We propose that Post-Covid-19 tachycardia syndrome should be considered a phenotype or sub-syndrome of Post-acute Covid-19

syndrome. This provides a safety net for those who have multiple symptoms besides the tachycardia and subsequently may not even mention this to their healthcare provider. 

Post-acute COVID-19 syndrome

6-month consequences of COVID-19 in patients discharged from hospital: a cohort study

Long-Haul Post-COVID-19 Symptoms Presenting as a Variant of Postural Orthostatic Tachycardia Syndrome: The Swedish Experience. JACC Case Rep

Symptoms and Functional Impairment Assessed 8 Months After Mild

Among Health Care Workers

Long-Haul COVID-19: Putative Pathophysiology, Risk Factors, and Treatments. Preprints

A case report of postural tachycardia syndrome after COVID-19

Inappropriate sinus tachycardia

Postural orthostatic tachycardia syndrome: clinical presentation, aetiology and management

Autoimmunity in postural orthostatic tachycardia syndrome: Current understanding

Serum Activity Against G Protein-Coupled Receptors and Severity of Orthostatic Symptoms in Postural Orthostatic Tachycardia Syndrome

Idiopathic postural orthostatic tachycardia syndrome: an attenuated form of acute pandysautonomia?

The neuropathic postural tachycardia syndrome

Medium-term effects of SARS-CoV-2 infection on multiple vital organs, exercise capacity, cognition, quality of life and mental health

A gain-of-function mutation in the cardiac pacemaker HCN4 channel increasing cAMP sensitivity is associated with familial Inappropriate Sinus Tachycardia

Molecules in pathogenesis: angiotensin converting enzyme 2 (ACE2)

Patterns of myocardial injury in recovered troponin-positive COVID-19 patients assessed by cardiovascular magnetic resonance

Multiorgan impairment in low-risk individuals with post-COVID-19 syndrome: a prospective, community-based study

Extrapulmonary manifestations of COVID-19

Antibodies in Critically Ill Coronavirus Disease 2019 Patients: A Before and After Study of Enhanced Anticoagulation

Follow-up study of the pulmonary function and related physiological characteristics of COVID-19 survivors three months after recovery

Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19)

Randomized Trial of Ivabradine in Patients With Hyperadrenergic Postural Orthostatic Tachycardia Syndrome

Compression Garment Reduces Orthostatic Tachycardia and Symptoms in Patients With Postural Orthostatic Tachycardia Syndrome

2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope

Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders

None