Although the clinical manifestations of COVID-19 are dominated by respiratory symptoms, some patients have severe cardiovascular damage [4]. In addition, some patients with underlying cardiovascular diseases might have an increased mortality risk [4]. Therefore, understanding the damage caused by SARS-CoV-2 to the cardiovascular system and the underlying mechanisms is of great importance, allowing for the timely and effective treatment of these patients.

ACE2 has been identified as a functional receptor for coronaviruses [9], including SARS-CoV-2 and SARS-CoV. ACE2 is expressed not only in the lungs but also in the cardiovascular system. Thus, ACE2-related signaling pathways might also play a role in heart injury. Other proposed mechanisms of myocardial injury include a cytokine storm triggered by an imbalanced response of Type 1 and Type 2 T helper cells [4,10], or damage to myocardial cells from respiratory dysfunction and hypoxemia caused by COVID-19. Previous data show that older patients (aged > 60 years) who are infected with SARS-CoV-2 tend to have more systemic symptoms and more severe pneumonia than younger patients (aged ≤60 years) [11]. Therefore, in patients with COVID-19, underlying cardiovascular disease can exacerbate the pneumonia and increase the severity of disease.

Generally, heart rate has a specific relationship with body temperature. As body temperature increases, heart rate will also increase [8]. However, increases in the body temperature of the three present cases did not correspond with appropriate increases in heart rate. This indicates reduced HRV, which could be due to a problem in coupling between the autonomic nervous system and the sinus node. Autonomic nervous system (ANS) imbalance, with a shift toward decreased vagal and increased sympathetic tone, has been proven to be associated with higher risk of cardiac mortality. The presence of autonomic dysfunction should alert clinicians to the possibility of coexisting cardiovascular risk factors. Early detection of the preclinical phase of cardiac autonomic dysfunction may lead to the implementation of more aggressive treatment and control of cardiovascular risk factors. Some data indicate that autonomic imbalance can be related to an increased risk of arrhythmias, and even sudden future death [12].

The sinus node is the natural pacemaker of the heart and possesses its own intrinsic activity; nevertheless, a variety of external and internal stimuli that change the balance between vagal and sympathetic tone influence the final basic heart rate. Heart rate changes may occur as a response to physical or mental stress, cardiac or noncardiac diseases, or pharmacological or invasive treatment. HRV describes variations in both instantaneous heart rate and RR intervals. HRV is considered an indirect measure of autonomic regulation of cardiac activity, and can reflect the coupling between the ANS and the sinoatrial node [13]. Studying the physiological signals (eg. heart rate) of critically ill patients can easily identify “hidden” information concerning inherent dynamics and overall variability within a time series [14]. Therefore, HRV has become an important and well-recognized tool in identifying patients at risk of cardiogenic death [12].  Time-domain–based HRV parameters decreased in patients may reflect higher risk of future mortality [12]. In the three present cases, decreases in HRV occurred earlier than did changes in cardiac markers. In future similar cases, staying alert to early changes in HRV may help to predict the occurrence of cardiac events in the early stage.

The reasons for reduced HRV in infectious disease still debated. The first theory focuses on reduction of vagal tone [15]. The second theory states that normal physiology has fractal-like properties with high levels of complexity, which explains phenomena such as HRV [16]. Severe disease reflects a “decomplexification” that can mainly be attributed to uncoupling between different restorative mechanisms [17]. Accumulating evidence, including human studies in cardiac transplant recipients with hearts devoid of autonomic nervous inputs, supports a potential third mechanism associated with an intracardiac origin of HRV, which was first proposed by Griffin et al [18]. According to that hypothesis, sinus node cells with an extreme heterogeneity in electrophysiological properties and intercellular connections of sinus node cells can be viewed as an amplifier of various input signals [19]. In infectious or cardiovascular diseases, an unfavorable metabolic milieu could affect ion channel gating properties or membrane receptor densities, with significant impact on the level and variability of pacemaker activity. In addition, a possible reduced responsiveness of sinus node cells to external stimuli could also negatively affect HRV [18].

At present, there are no specific antiviral drugs or vaccines against COVID-19 infection approved for therapeutic use in humans. Broad-spectrum antiviral drugs are the only available option, such as nucleoside analogues and HIV-protease inhibitors (lopinavir/ritonavir) that can attenuate virus infection until a specific antiviral becomes available [20]. All three of the present cases were treated with ritonavir. However, two studies of combination antiretroviral therapy used for patients with HIV reported that autonomic dysfunction was present in the treated patients [21,22]. Such autonomic dysfunction may be due to neuropathy-related adverse effects of antiretroviral therapy [23,24,25]. Moreover, the effect of combination antiretroviral therapy on metabolic disturbances could also lead to parasympathetic damage [26]. Many antiviral drugs can cause cardiac insufficiency, arrhythmia, or other cardiovascular disorders. Therefore, during the treatment of COVID-19, which necessitates the use of antivirals, the risk of cardiac toxicity must be closely monitored [27].

The clinical findings of these three cases suggest that either the mechanisms of COVID-19 and/or the antiviral drugs used for treatment might affect coupling between the autonomic nervous system and the sinus node, thus affecting HRV and inhibiting increases in heart rate as body temperature increases. The use of a 24-hour Holter monitor is recommended in the management of COVID-19 to better monitor heart rate. Early detection of the preclinical phase of cardiac autonomic dysfunction could indicate the need for aggressive treatment and control of cardiovascular risk factors, thus improving patient prognosis. Antiviral drugs should be used with caution in patients with heart injury.