Impact of Cardiovascular Diseases on COVID-19: A Systematic Review

Abstract

In December 2019, pneumonia of unknown cause broke out, and currently more than 150 countries around the world have been affected. Globally, as of 5: 46 pm CET, 6 November 2020, the World Health Organization (WHO) had reported 48 534 508 confirmed cases of COVID-19, including 1 231 017 deaths. The novel coronavirus disease (COVID-19) outbreak, caused by the SARS-CoV-2 virus, is the most important medical challenge in decades. Previous research mainly focused on the exploration of lung changes. However, with development of the disease and deepening research, more and more patients showed cardiovascular diseases, even in those without respiratory symptoms, and some researchers have found that underlying cardiovascular diseases increase the risk of infection. Although the related mechanism is not thoroughly studied, based on existing research, we speculate that the interaction between the virus and its receptor, inflammatory factors, various forms of the stress response, hypoxic environment, and drug administration could all induce the development of cardiac adverse events. Interventions to control these pathogenic factors may effectively reduce the occurrence of cardiovascular complications. This review summarizes the latest research on the relationship between COVID-19 and its associated cardiovascular complications, and we also explore possible mechanisms and treatments.

Figure 1

SARS-CoV-2 downregulates ACE2 to cause cardiovascular injuries. SARS-CoV-2 downregulates ACE2 by suppressing transcription of the ACE2 gene, cutting the extracellular segment of ACE2, and increasing internalization with ACE2, leading to increased Ang II expression and TACE activation, thus elevating the expression level of TNF-α and the risk of cardiovascular adverse events. The downregulation of ACE2 occurring in the heart, lung, hypothalamus, and kidney can all increase the load on the cardiovascular system.

Figure 2

Possible mechanisms for cardiovascular injuries after SARS-CoV-2 infection. a) Stress: Downregulation of ACE2 could lead to excessive Nox2 activation, inducing ROS accumulation. High levels of TNF-α and IL-6 can increase mitochondrial stress, leading to higher levels of oxidative stress. ER stress can destabilize atherosclerotic plaque through increasing NF-κB-induced GM-CSF. b) Hypoxia: SARS-CoV-2-related hypoxemia can affect the miR-146b-TRAF6-IL-6/CCL2 (MCP-1) axis and induce expression of HIMF, promoting the production of proinflammatory cytokines. c) Accumulation of proinflammatory cytokines contributes to cardiovascular complications. d) Drug-related injuries: Drugs administered in treating SARS-CoV-2 can cause cardiovascular complications. Chloroquine, lopinavir/ritonavir, and azithromycin can affect the normal rhythm of the heart. Lopinavir/ritonavir can also increase LDL and suppress HDL, destabilizing atherosclerotic plaque. Pegylated interferon-α can lead to the upregulation of TNF-α.

Figure 3

Injury mechanism of SARS-CoV-2 on cardiovascular system. After SARS-CoV-2 binds to the ACE2 receptor, it causes cardiovascular diseases through a variety of ways, such as acute cardiac injury, myocarditis, arrhythmia, coronary heart diseases, diabetes, and hypertension, and further results in higher morbidity. Among all myocardial injury markers, ferritin is most associated with prognosis. Mb changes are related to ICU care and silent myocardial injury. Hypertension and diabetes can affect the immune system and its drug therapy. ARBs can upregulate the expression of ACE2 and aggravate the process of COVID-19. Mb – creatine kinase-MB; ARBs – angiotensin II receptor blockers.