Adverse Effects of Sympathetic Activation Should Not Be Neglected During the Coronavirus Disease 2019 Pandemic
The ongoing coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to significant global morbidity and mortality. The virus, belonging to the b-coronavirus cluster, shares similarities with the viruses causing severe acute respiratory distress syndrome (SARS) and Middle East respiratory syndrome (MERS). However, SARS-CoV-2 exhibits a higher binding affinity for angiotensin-converting enzyme 2 (ACE2), the receptor it uses to invade target cells. This increased affinity makes SARS-CoV-2 more infectious and challenging to control compared to SARS-CoV.
SARS-CoV-2 primarily affects the respiratory tract, where ACE2 is highly expressed. While most infected individuals experience mild flu-like symptoms, severe cases can rapidly progress to pneumonia, acute respiratory distress syndrome (ARDS), and shock. Although ARDS is the most common manifestation and cause of death, emerging evidence suggests that patients with pre-existing cardiovascular conditions, such as hypertension, diabetes mellitus, and ischemic heart disease, are at a higher risk of severe outcomes. Additionally, cardiovascular complications, including cardiac injury, arrhythmias, and blood pressure disorders, have been observed in COVID-19 patients, even in those without prior cardiovascular disease. These complications are associated with worse prognoses.
ACE2 is widely expressed not only in the lungs but also in the cardiovascular system. This dual expression suggests that cardiovascular complications in COVID-19 may result from direct viral infection or indirect injury due to a systemic inflammatory response, often referred to as a cytokine storm. However, pathological studies have shown limited interstitial mononuclear inflammatory infiltrates in heart tissue and a lack of substantial myocardial damage in COVID-19 patients, indicating that the virus may not directly impair the heart. For instance, a case involving a 64-year-old SARS-CoV-2-positive woman revealed profound cardiac decompensation characterized by reduced left ventricular ejection fraction, cardiogenic shock, and a predisposition to tachyarrhythmias. Notably, neither myocarditis nor cytokine storm was implicated, suggesting that sympathetic over-activation might have played a significant role.
The sympathetic nervous system is a critical player in cardiovascular disease. In the early stages of such diseases, compensatory activation of the sympathetic nerves is often observed, closely associated with disease severity. Persistent sympathetic activation can accelerate disease progression, contributing to the pathogenesis of chronic heart failure, ventricular arrhythmias, and essential hypertension—conditions commonly seen in COVID-19 patients. Moreover, sympathetic activation can trigger Takotsubo syndrome, a condition characterized by transient heart dysfunction, which is frequently overlooked or misdiagnosed. In COVID-19 patients, reverse Takotsubo syndrome has been observed in the early stages of acute myocarditis, potentially induced by sympathetic over-activation.
Long-lasting tachycardia, a common cardiovascular manifestation in SARS patients, persists until the third week of hospitalization and may result from sympathetic over-activation. Similarly, pre-existing cardiovascular diseases, such as hypertension, diabetes mellitus, and ischemic heart disease, are characterized by pronounced sympathetic activation, which may be directly linked to the severity of COVID-19.
Several mechanisms may explain the sympathetic activation following SARS-CoV-2 infection. First, hypoxia induced by respiratory distress syndrome can lead to over-activation of the sympathetic nervous system through the carotid body chemosensory input to the brainstem. Second, SARS-CoV-2’s neuroinvasive potential may cause neuroinflammation in key central sympathetic sites, including the nucleus of the solitary tract (NTS), hypothalamic paraventricular nucleus (PVN), and rostral ventrolateral medulla (RVLM). Third, inflammatory cytokines released during the systemic inflammatory response after viral invasion may cross the blood-brain barrier and impair these sympathetic sites. Lastly, extreme anxiety can further exacerbate endogenous catecholamine release, intensifying sympathetic activation.
Given these mechanisms, it is worth considering whether inhibitors of the sympathetic nervous system, such as central sympatholytic drugs, imidazoline receptor agonists, and beta-blockers, could be beneficial in managing COVID-19, especially in the absence of specific treatments or vaccines. For example, a recent study reported a modestly lower likelihood of a positive COVID-19 test result among patients using beta-blockers, which prevent sympathetic activation.
In conclusion, while the precise mechanisms of cardiovascular complications in COVID-19 remain to be fully elucidated, the adverse effects of sympathetic activation should not be overlooked. The sympathetic nervous system plays a significant role in the progression of cardiovascular diseases, and its over-activation can exacerbate conditions such as chronic heart failure, arrhythmias, and hypertension. Addressing sympathetic over-activation through pharmacological interventions may offer a potential therapeutic avenue for managing COVID-19-related cardiovascular complications. Further research is needed to explore the efficacy of sympathetic inhibitors in improving outcomes for COVID-19 patients.
doi.org/10.1097/CM9.0000000000001106
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