key: cord-0805695-hxj4ks3s
authors: Hiraiwa, Hiroaki; Goto, Yukari; Nakamura, Genki; Yasuda, Yuma; Sakai, Yoshinori; Kasugai, Daisuke; Jinno, Shinsuke; Tanaka, Taku; Ogawa, Hiroaki; Higashi, Michiko; Yamamoto, Takanori; Jingushi, Naruhiro; Ozaki, Masayuki; Numaguchi, Atsushi; Kondo, Toru; Morimoto, Ryota; Okumura, Takahiro; Matsuda, Naoyuki; Murohara, Toyoaki
title: Relative bradycardia as a clinical feature in patients with coronavirus disease 2019 (COVID-19): a report of two cases
date: 2020-07-25
journal: J Cardiol Cases
DOI: 10.1016/j.jccase.2020.07.015
sha: 5ef53f1653c9b61621bb270e8ec6a452195538c4
doc_id: 805695
cord_uid: hxj4ks3s

We treated two patients with COVID-19 pneumonia requiring mechanical ventilation. Case 1 was a 73-year-old Japanese man. Computed tomography (CT) revealed ground-glass opacities in both lungs. He had severe respiratory failure with a partial pressure of oxygen in arterial blood/fraction of inspiratory oxygen ratio (P/F ratio) of 203. Electrocardiogram showed a heart rate (HR) of 56 beats/min, slight ST depression in leads II, III, and aVF, and mild saddle-back type ST elevation in leads V1 and V2. High-sensitivity cardiac troponin T (cTnT) level was slightly elevated. Despite a high fever and hypoxemia, his HR remained within 50–70 beats/min. Case 2 was a 52-year-old Japanese woman. CT revealed ground-glass opacities in the lower left lung. Electrocardiogram showed a HR of only 81 beats/min, despite a body temperature of 39.2 °C, slight ST depression in leads V4, V5, V6, and a prominent U wave in multiple leads. She had an elevated cTnT and a P/F ratio of 165. Despite a high fever and hypoxemia, her HR remained within 50–70 beats/min. Both patients had a poor compensatory increase in their HR, despite their critical status. Relative bradycardia could be a cardiovascular complication and is an important clinical finding in patients with COVID-19.

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Coronavirus disease 2019 , caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first reported in Wuhan, China in December 2019 and has spread worldwide, presenting a serious ongoing problem [1, 2] .

Recent reports have presented that COVID-19 is related to direct myocardial injury, and patients have a risk of cardiovascular complications including myocardial infarction, myocarditis, heart failure, cardiogenic shock, and cardiac arrythmias [3] [4] [5] . Relative bradycardia is sinus bradycardia as a phenomenon of dissociation between heart rate and body temperature, insufficient increase in pulse despite high fever, and it is a characteristic feature of some particular infections [6, 7] . However, relative bradycardia associated with COVID-19 has not been reported previously. Herein, we report two Japanese cases of COVID-19 with severe pneumonia who demonstrated relative bradycardia despite the severity of their condition and requiring respiratory management. With increasing illness severity, neither patient showed a compensatory increase in heart rate (HR), even with increased body temperature and worsening hypoxemia. In addition, ST depression, saddle-back type ST elevation, and prominent U waves in the electrocardiogram and the elevation of cardiac troponin level were observed. Relative bradycardia may be an important clinical feature and could be a sign J o u r n a l P r e -p r o o f of potential myocardial injury in patients with COVID-19.

A 73-year-old Japanese man with hypertension and type 2 diabetes mellitus was diagnosed with COVID-19 and transferred to our hospital on mechanical ventilation. He was taking a calcium channel blocker, not an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker. His chest computed tomography (CT) revealed ground-glass opacities in both lungs (Fig. 1A) . However, his partial pressure of oxygen in arterial blood/fraction of inspiratory oxygen ratio (P/F ratio) was 203 on admission, despite administration of favipiravir. Next day, his electrocardiogram (ECG) showed a HR of 56 beats/min with sinus rhythm, slight ST depression in leads II, III, and aVF, and mild saddle-back type ST elevation in leads V1 and V2 ( Fig. 2A) . His highsensitivity cardiac troponin T (cTnT) level was slightly elevated (0.078 ng/mL, normal range: <0.014 ng/mL). The high-sensitivity C-reactive protein level (hs-CRP) was increased to a peak of 23.24 mg/dL on Day 7 (normal range: <0.14 mg/dL). The echocardiogram revealed good left ventricular systolic function, without asynergy through the clinical course. Despite a high fever (>38°C) and hypoxemia, his HR J o u r n a l P r e -p r o o f -7 -remained within 50-70 beats/min with sinus rhythm and was not increasing (Fig. 3A ).

On admission, his blood pressure was 126/55 mmHg using noradrenaline 0.12 μg/kg/min. The dose of noradrenaline was gradually decreased and noradrenaline was stopped on Day 4. Thereafter, his systolic blood pressure remained at 110-140 mmHg.

He was sedated with intravenous midazolam (2.5-10.0 mg/hour) until Day 17 when a tracheotomy was performed. He was discharged and transferred for rehabilitation on Day 37. After recovery his HR was 99 beats/min with sinus rhythm at a body temperature 36.5℃ and percutaneous oxygen saturation (SpO2) 99% breathing room air.

His blood pressure on discharge was 133/76 mmHg.

A 52-year-old Japanese woman with chronic renal failure due to diabetic nephropathy was diagnosed with COVID-19. Her chest CT revealed ground-glass opacities in the lower left lung (Fig. 1B) . On admission, her ECG showed a HR of only 81 beats/min with sinus rhythm, despite a body temperature of 39.2°C, and slight ST depression in leads V4, V5, V6 and a prominent U wave in multiple leads (Fig. 2B) . Her blood potassium level was 3. Her blood pressure on discharge was 139/76 mmHg.

Relative bradycardia is a condition with no significant compensatory increase in HR despite high fever, and may occur in specific infectious diseases including Legionnaire's disease, pneumonia caused by Chlamydia, typhoid fever, and Ebola J o u r n a l P r e -p r o o f hemorrhagic fever [6] . Although detailed mechanisms of relative bradycardia remain unknown, direct pathogenic effects on the heart muscle, the release of inflammatory cytokines (granulocyte colony-stimulating factor, interleukin-6, tumor necrosis factorα), or systemic autonomic dysregulation have been described [7] . inflammation in both patients. Therefore, relative bradycardia might be associated with not only sinoatrial node dysfunction due to direct viral involvement but also myocardial injury due to inflammatory cytokines. In addition, we speculate that relative bradycardia in COVID-19 could be related to its severity. Furthermore, disproportionately mild dyspnea has also been reported in patients with COVID-19 even when they are in a severely hypoxic state. This phenomenon might exacerbate hypoxemia in addition to relative bradycardia. Although the detailed mechanisms of relative bradycardia with especially in patients with acute heart failure. Therefore, it is necessary to pay attention to the occurrence of relative bradycardia. Further studies and more systematic data collection will be needed to explore our hypothesis in a larger population of patients with COVID-19 of various severity. This could lead to a more informed assessment of the incidence of relative bradycardia as a potential clinical sign of COVID-19 also with treatment implications.

The authors declare that there is no conflict of interest. 

Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China

Clinical characteristics of coronavirus disease 2019 in China

COVID-19 and cardiovascular disease

Potential effects of coronaviruses on the cardiovascular system: A review

Cardiac and arrhythmic complications in patients with COVID-19

The diagnostic significance of relative bradycardia in infectious disease

The clinical significance of relative bradycardia

Characteristic electrocardiographic manifestations in patients with COVID

HEART BRAKE-An unusual cardiac manifestation of coronavirus disease 2019 (COVID-19). JACC Case Rep 2020

We wish to thank all the co-medical staff involved in the treatment.J o u r n a l P r e -p r o o f