key: cord-0906640-8waj7d7t
authors: Hondo, Haruka; Kowase, Shinya; Asano, Shunichi; Osada, Jun; Aoki, Hajime; Yumoto, Kazuhiko
title: Theophylline to treat prolonged paroxysmal complete atrioventricular block without conduction disorder or structural heart disease after COVID-19 infection: A case report
date: 2021-12-31
journal: HeartRhythm Case Rep
DOI: 10.1016/j.hrcr.2021.12.020
sha: 18c2ec18fc3658a3e8e7c6c5a76b077db19306d5
doc_id: 906640
cord_uid: 8waj7d7t

nan

The novel coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory 20 syndrome coronavirus 2 (SARS-CoV-2), a positive-sense, single-stranded RNA virus. The 21 most common symptoms include cough, fever, fatigue, shortness of breath, sore throat, and 22

headache. Although respiratory failure is the primary complication seen in COVID-19 23 patients, the cardiovascular system can also be targeted with complications, including 24 myocardial injury, myocarditis, arrhythmias, heart failure, and acute myocardial infarction. 25

Some COVID-19 patients go into an advanced degree heart block and suffer cardiac arrest 26 related to complete heart block. 1 Here, we describe a case of paroxysmal complete 27 atrioventricular block in a patient with COVID-19. 28 29 Case report 30 A 43-year-old man with a history of essential hypertension and hyperuricemia presented with 31 fever, cough, and diarrhea for one week. His home medications included 5 mg of amlodipine, 32 80 mg of valsartan, and 20 mg of febuxostat once daily. His body mass index was 27.5. He 33 underwent a medical checkup annually and was never diagnosed with any heart disease or had 34 an abnormal electrocardiogram (ECG). Two days before the current presentation, he tested 35 positive for COVID-19 via a polymerase chain reaction (PCR) test. He presented to the 36 emergency department with worsening dyspnea. In the emergency department, his vital signs 37 were as follows: body temperature, 38°C; pulse rate, 125 bpm; blood pressure, 136/89 38 mmHg; respiratory rate, 28 respirations/minute; and oxygen saturation, 94% on a 2 L nasal 39 cannula oxygen. Chest radiography showed bilateral ground-glass opacity. The ECG on 40 admission revealed sinus rhythm without any ST-T wave changes or conduction disorder 41 ( Figure 1 ). 42

He was started on a combination treatment of remdesivir and dexamethasone by intravenous 43

infusion. Remdesivir was started on day one of hospitalization with a loading dose of 200 mg 44 on day one and 100 mg daily for four additional days. He was started on dexamethasone 6 mg 45 daily for ten days. 46

After four days of remdesivir administration, on the early morning of the fifth day of 47 hospitalization, the ECG demonstrated paroxysmal complete atrioventricular (AV) block 48 ( Figure 2 ). AV block was first noticed early in the morning when the patient was asleep and 49 did not have syncope. The second time, AV block was identified for 5 seconds during the day 50 with pre-syncope. Brain natriuretic peptide and troponin T levels were normal. Transthoracic 51 ultrasonic echocardiography (UCG) and cardiac magnetic resonance imaging (MRI) showed 52 no organic abnormalities or evidence of myocarditis due to COVID-19 infection. 53

On day 5, he underwent temporary transvenous pacemaker implantation in the VVI mode 54 J o u r n a l P r e -p r o o f decreased as he recovered from the COVID-19 infection and remdesivir's concentration fell 56 beyond its half-life. However, on day 13, AV blocks were observed more than 20 times per 57 day. AV block, in this case, was characterized by a sudden onset of complete AV block without 58 changes in P-P cycle length, long ventricular asystole of approximately 5 seconds, and 59 spontaneous return to sinus rhythm. Since we diagnosed this case as adenosine sensitive AV 60 block, we administered 200 mg of oral theophylline, an adenosine antagonist, twice daily. 61

After taking theophylline, the frequency of AV block decreased without an increase in the 62 heart rate. The AV block was not observed for three days; therefore, on day 21, the temporary 63 external pacemaker was removed (Figure 3) . A few seconds of AV block was seen once at 64 dawn on days 22 and 23, but the patient did not experience syncope or faintness. We 65 implanted an implantable loop recorder to continue monitoring on day 22, and he was 66 discharged on day 23. According to the remote monitoring data, the paroxysmal AV block 67 event has been confirmed about once a month. All AV block events occurred early in the 68 morning and did not have syncope. replication. 9 One of the leading theories of how remdesivir can induce sinus node, and AV 101 node dysfunction is based on its active metabolized triphosphate form and its close structural 102 resemblance to adenosine 5-triphosphate (ATP). 10 The ATP and its metabolized form of 103 adenosine are known to exert negative chronotropic and dromotropic effects on sinus node 104 automaticity and AV nodal conduction. This effect is mediated by ATP's ability to suppress 105 the sinus and AV nodes by transiently enhancing vagal tone in the heart. 11 The effect of 106 adenosine on the AV node is mainly due to the stimulation of high-affinity A1 receptors, which 107 are much more numerous in the AV node than in the sinoatrial node. Therefore, it can be 108 conduction system. Another mechanism possibly relates to remdesivir's affinity towards RNA 110 polymerases and subsequent mitochondrial dysfunction, resulting in cardiotoxicity. The 111 pharmacologically active triphosphate form has a half-life of 11 hours, and there is another 112 dephosphorylated nucleoside metabolite with a half-life of 20-25 hours. The timing of the AV 113 block in our case indicates a contribution from remdesivir. The AV block did not completely 114 disappear after remdesivir discontinuation, but the frequency decreased. 115

Paroxysmal AV block is characterized by the sudden appearance of a complete heart block. 116

The mechanism of the idiopathic paroxysmal AV block remains unclear. Recently, the role of 117 lower baseline adenosine levels and excessive susceptibility to exogenous adenosine has also 118 been suggested. 12 119 Blood adenosine levels were not measured in our patient. However, there was a possibility 120 of potentially low endogenous adenosine and excessive susceptibility to exogenous adenosine 121 due to remdesivir. Theophylline is an adenosine antagonist that has been identified as a 122 treatment option for brady-arrhythmic events. In two recent small observational studies, oral 123 theophylline appeared to be effective over a mean follow-up period of 16 and 17 months in 124 patients with an established diagnosis of idiopathic paroxysmal AV block and may be 125 considered an alternative to permanent pacing in such patients. 13 In this case, we think oral 126 

Heart block in patients 165 with coronavirus disease 2019: A case series of 3 patients infected with SARS-CoV-166

Heart brake: An unusual cardiac manifestation of 168 COVID-19

A case of complete 170 heart block in a COVID-19 infected patient

Bradyarrhythmias in patients with COVID-19: 172 marker of poor prognosis?

Emerging 174 arrhythmic risk of autoimmune and inflammatory cardiac channelopathies. J Am Heart 175 final report

Remdesivir: a review of its discovery and 183 development leading to emergency use authorization for treatment of COVID-19

Serious bradycardia and remdesivir for 186 coronavirus 2019 (COVID-19): a new safety concerns

Cardiac adverse events with remdesivir 189 in COVID-19 infection

What is the mechanism of 191 paroxysmal atrioventricular block in a patient with recurrent syncope?

Mechanism of syncope without prodromes 194 with normal heart and normal electrocardiogram

Heart block in patients with obstructive sleep 196 apnea: pathogenetic factors and effects of treatment