Anti-cancer Therapy Leads to Increased Cardiovascular Susceptibility to COVID-19

Abstract

Anti-cancer treatment regimens can lead to both acute- and long-term myocardial injury due to off-target effects. Besides, cancer patients and survivors are severely immunocompromised due to the harsh effect of anti-cancer therapy targeting the bone marrow cells. Cancer patients and survivors can therefore be potentially extremely clinically vulnerable and at risk from infectious diseases. The recent global outbreak of the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its infection called coronavirus disease 2019 (COVID-19) has rapidly become a worldwide health emergency, and on March 11, 2020, COVID-19 was declared a global pandemic by the World Health Organization (WHO). A high fatality rate has been reported in COVID-19 patients suffering from underlying cardiovascular diseases. This highlights the critical and crucial aspect of monitoring cancer patients and survivors for potential cardiovascular complications during this unprecedented health crisis involving the progressive worldwide spread of COVID-19. COVID-19 is primarily a respiratory disease; however, COVID-19 has shown cardiac injury symptoms similar to the cardiotoxicity associated with anti-cancer therapy, including arrhythmia, myocardial injury and infarction, and heart failure. Due to the significant prevalence of micro- and macro-emboli and damaged vessels, clinicians worldwide have begun to consider whether COVID-19 may in fact be as much a vascular disease as a respiratory disease. However, the underlying mechanisms and pathways facilitating the COVID-19-induced cardiac injury in cancer and non-cancer patients remain unclear. Investigations into whether COVID-19 cardiac injury and anti-cancer drug-induced cardiac injury in cancer patients and survivors might synergistically increase the cardiovascular complications and comorbidity risk through a "two-hit" model are needed. Identification of cardiac injury mechanisms and pathways associated with COVID-19 development overlapping with anti-cancer therapy could help clinicians to allow a more optimized prognosis and treatment of cancer survivors suffering from COVID-19. The following review will focus on summarizing the harmful cardiovascular risk of COVID-19 in cancer patients and survivors treated with an anti-cancer drug. This review will improve the knowledge of COVID-19 impact in the field of cardio-oncology and potentially improve the outcome of patients.

Keywords: ACE2; COVID-19; SARS-CoV-2; anti-cancer drug-induced cardiac injury; cytokine storm.

Figure 1

Overview of the COVID-19 risk factors and complications observed in COVID-19 patients leading to cardiac injury (figure created with Biorender.com).

Figure 2

The SARS-CoV-2 pathway in the host cells. The spike protein of the virus binds to the cellular receptor angiotensin-converting enzyme 2 (ACE2) and is cleaved by the type 2 transmembrane serine protease (TMPRSS2). This allows entry into the host cell by endocytosis. Following the entry of SARS-CoV-2, viral RNA is released into the cytoplasm and replicated. Viral RNA is translated by the endoplasmic reticulum (ER) by Golgi complex and form the endoplasmic reticulum–Golgi intermediate compartment (ERIG). Viral RNA enters into ERIG by budding to form novel virions. These virions are released from the infected cells by exocytosis. The ACE2 receptor is a negative regulator of the renin angiotensin system (RAS) and converts angiotensin II (Ang II) into angiotensin 1–7 [Ang(1–7)]. The downregulation of the RAS allows to maintain the cardiovascular homeostasis (figure created with Biorender.com).

Figure 3

Overview of the immune response to COVID-19. The proteins on SARS-CoV-2 membrane are recognized as pathogen-associated molecular pattern by the pattern recognition receptors (PRRs), such as Toll-like receptors (TLR) and retinoic acid-inducible gene-I (RIG-I)-like receptors. This recognition leads to the activation of T-cells, which differentiate in CD4⁺ T-cells, CD8⁺ T-cells, and T-helper cells that induce, respectively, the production of antibodies by B-cells, the deaths of infected cells, and the cytokine production, such as interleukins IL-2 and IL-6. Moreover, SARS-CoV-2 invasion leads to the recruitment of neutrophils and macrophage and induce a lymphopenia. The increase of neutrophils and macrophages associated with the cytokine production leads to a hyperinflammation called the cytokine storm. This cytokine storm leads to acute respiratory distress syndrome (ARDS) and myocardial damage. Green arrows refer to activating effects, orange arrows refer to recruitment effects, and the red lines refer to inhibiting effects (figure created with Biorender.com).

Figure 4

Molecular mechanisms involved during anthracycline (Hexagonal box with “A”) treatment and SARS-CoV-2 infection in cardiomyocyte leading to injury. Anthracycline can bind to nuclear and mitochondrial DNA and interfere with the cell replication process. The TOPO II enzyme can be inhibited by anthracycline, leading to the damaged DNA during cell replication. Anthracycline can also disturb the Ca²⁺ influx into the cell. The disruption of Ca²⁺ homeostasis by anthracycline in the mitochondria leads to an increase of reactive oxygen species (ROS) production and oxidative stress. Moreover, the expression of the Ca²⁺ pump SERCA2a in the sarcoplasmic reticulum is decreased by anthracycline, which induces contractile dysfunction. Anthracycline can also prevent the release of iron from ferritin and facilitate the reduction of anthracycline–Fe³⁺ complexes leading to ROS production. Combined, these anthracycline mechanisms lead to increased ROS production, DNA damage, and contractile dysfunction, which leads to cellular apoptosis. Please refer to Figure 2 legend for a detailed description of the SARS-CoV-2 pathway (figure created with Biorender.com).