Adverse Effects of Sympathetic Activation Should Not Be Neglected During the Coronavirus Disease 2019 Pandemic
The ongoing coronavirus disease 2019 (COVID-19) pandemic has caused significant morbidity and mortality worldwide, with the number of infected individuals rising rapidly. The disease is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which belongs to the b-coronavirus cluster, a group that also includes the viruses responsible for severe acute respiratory distress syndrome (SARS) and Middle East respiratory syndrome (MERS). Similar to SARS-coronavirus (CoV), SARS-CoV-2 exploits angiotensin-converting enzyme 2 (ACE2) to invade target cells. However, SARS-CoV-2 exhibits a higher binding affinity for ACE2, making it more infectious and difficult to control compared to SARS-CoV.
SARS-CoV-2 primarily affects the respiratory tract, where ACE2 is highly expressed, leading to a mild flu-like syndrome in most cases. However, some patients with severe disease can rapidly progress to pneumonia, acute respiratory distress syndrome (ARDS), and shock. While ARDS is the most prevalent manifestation and cause of death, increasing evidence suggests that patients with cardiovascular risk factors and pre-existing cardiovascular diseases, such as hypertension, diabetes mellitus, and ischemic heart disease, are at higher risk of morbidity and mortality. Moreover, clinical and epidemiological evidence indicates that major cardiovascular complications, including cardiac injury, arrhythmias, and blood pressure disorders, can occur in a significant number of COVID-19 patients, even in those without underlying cardiovascular disease. These complications are associated with worse prognosis.
ACE2 is widely expressed not only in the lungs but also in the cardiovascular system. Therefore, cardiovascular complications in COVID-19 patients are thought to result from either direct viral infection or indirect injury due to a systemic inflammatory response, often referred to as a cytokine storm. However, pathological studies have reported scarce interstitial mononuclear inflammatory infiltrates in the heart tissue and a lack of substantial myocardial damage in COVID-19 patients, suggesting that the virus might not directly impair the heart. For instance, in a case involving a 64-year-old SARS-CoV-2-positive woman, neither myocarditis nor cytokine storm was reported as probable mediators of the recurrence of depressed cardiac function, given the relatively low biomarker levels. Instead, the patient developed profound cardiac decompensation during the SARS-CoV-2 infection, characterized by a reduced left ventricular ejection fraction, cardiogenic shock, and a proclivity for tachyarrhythmias, indicating over-activation of the sympathetic nerves.
A recent study also reported a modestly lower likelihood of a positive result for COVID-19 among patients using beta-blockers, which can prevent sympathetic activation. Therefore, before the mechanisms of cardiovascular complications accompanying SARS-CoV-2 infection are fully understood, the damage induced by sympathetic over-activation requires adequate attention. The sympathetic nervous system plays a prominent role in cardiovascular disease. In the early stages of cardiovascular disease, it often manifests as a compensatory activation of the sympathetic nerves, closely associated with disease severity. Persistent activation of the sympathetic nervous system accelerates disease progression and greatly contributes to the pathogenesis of chronic heart failure, ventricular arrhythmias, and essential hypertension, all of which are common cardiovascular complications in patients with COVID-19.
Sympathetic activation also triggers Takotsubo syndrome, which induces transient heart dysfunction and is often ignored and misdiagnosed. In the early stages of acute myocarditis, reverse Takotsubo syndrome has been observed in COVID-19 patients, potentially induced by sympathetic activation. Similarly, tachycardia is a common cardiovascular manifestation of SARS and persists until the third week of hospitalization, likely due to sympathetic over-activation. Moreover, pre-existing cardiovascular diseases, including hypertension, diabetes mellitus, and ischemic heart disease, are characterized by pronounced sympathetic activation, which may be closely and directly associated with COVID-19 severity.
Various mechanisms of sympathetic activation following SARS-CoV-2 infection could include but are not limited to the following aspects: First, the carotid body chemosensory input to the brainstem contributes to over-activation of the sympathetic nervous system due to hypoxia induced by respiratory distress syndrome. Second, the neuroinvasive potential of SARS-CoV-2 may induce neuroinflammation in significant central sympathetic sites, such as 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 virus invasion may penetrate the blood-brain barrier and impair the NTS, PVN, and RVLM. Fourth, extreme anxiety leads to further endogenous catecholamine release. Consequently, it is worth considering whether inhibitors of the sympathetic nervous system, such as central sympatholytic drugs, imidazoline receptor agonists, and beta-blockers, might achieve better results in the absence of a specific treatment or vaccine for COVID-19.
In conclusion, the adverse effects of sympathetic activation during the COVID-19 pandemic should not be neglected. The sympathetic nervous system plays a crucial role in the pathogenesis of cardiovascular complications associated with SARS-CoV-2 infection. Understanding the mechanisms of sympathetic activation and its impact on disease progression is essential for developing effective therapeutic strategies. Inhibitors of the sympathetic nervous system may offer potential benefits in managing COVID-19 patients, particularly those with pre-existing cardiovascular conditions. Further research is needed to elucidate the precise mechanisms and optimize treatment approaches.
doi.org/10.1097/CM9.0000000000001106
Was this helpful?
0 / 0