**1. Introduction**

Since the unfolding of COVID-19 pandemic starting in early 2020 it has become increasingly apparent that the disease has evolved from primarily affecting the respiratory system to being a systemic disease. A common manifestation of the latter involves the neurologic system, ranging from headache and myalgia to neuroinflammation and encephalopathies. Additionally, neuropsychiatric manifestations such as anxiety, stress, depression and post-traumatic stress disorder (PTSD) have been reported [1–4]. Another common manifestation affects the cardiovascular system, with pathologies ranging from pericarditis, myocarditis, right-hearted dysfunction, enodothelialitis and prothrombotic state (as reviewed in [5]). Any potential long-term effects of these disorders are yet to manifest in the coming months and years. Based on the available data, the interactions among chronic mild stress, neurological consequences and cardiovascular manifestations due to COVID-19 pandemic are likely to contribute to a significant public health problem worldwide. These interactions are explored below throughout the chapter.

Stress, depression and anxiety are being recognized as risk factors for the development of cardiovascular disease (CVD). COVID-19 pandemic has induced many stressors on everyday life, including fear of infection, lack of social interactions due to quarantine, helplessness due to inevitability, loss of income, misinformation spread mostly by social media, and food and household item shortage. Furthermore, the viral infection itself can cause detriment to the cardiovascular system via cerebrovascular ischemia, coagulopathy and endothelial dysfunction. Therefore, both individuals who become infected and those who do not, but are exposed to the chronic mild stress (CMS) of COVID-19 pandemic may be at risk of developing neurologic and cardiovascular consequences (please see a model in **Figure 1**). In any event, the stressors of the pandemic can be modeled by the CMS rodent model of depression. The CMS paradigm is typically conducted for 4 weeks and consists of the exposure of rodents to mild stressors such as exposure to strobe light and white noise, acute withdrawal of water, damp bedding and social isolation [6–9]. This procedure causes depression as evidenced by anhedonia (in rodents manifested as reduced 1–2% sucrose solution consumption and spontaneous wheel running), circadian rhythm disturbances and demeanor. This rodent model of human depression was used extensively to demonstrate the cardiovascular dysfunction following 4 weeks of exposure to the mild stressors, characterized by increased mean arterial pressure and sympathetic nervous system activity and decreased heart rate variability [6, 7, 9]. One study found that the 4 week period of stress exposure followed by 4 week period of stress reduction (i.e. no exposure to stressors) recovered the behavioral manifestations of depressions, such as sucrose consumption and spontaneous wheel running, but did not result in the reversal of the cardiovascular dysfunction measured by heart rate variability [9]. Such long term effects of stress exposure, as is seen in the COVID-19 pandemic, could therefore be detrimental in the postpandemic era, highlighting the importance of cardiovascular health monitoring in all individuals.
