==== Front Front Cardiovasc Med Front Cardiovasc Med Front. Cardiovasc. Med. Frontiers in Cardiovascular Medicine 2297-055X Frontiers Media S.A. 10.3389/fcvm.2020.568720 Cardiovascular Medicine Perspective Pandemic Perspective: Commonalities Between COVID-19 and Cardio-Oncology Brown Sherry-Ann 1* Zaharova Svetlana 1 Mason Peter 2 Thompson Jonathan 3 Thapa Bicky 3 Ishizawar David 2 Wilkes Erin 4 Ahmed Gulrayz 3 Rubenstein Jason 2 Sanchez Joyce 5 Joyce David 6 Kalyanaraman Balaraman 7 Widlansky Michael 2 1Cardio-Oncology Program, Division of Cardiovascular Medicine, Medical College of Wisconsin, Milwaukee, WI, United States 2Division of Cardiovascular Medicine, Medical College of Wisconsin, Milwaukee, WI, United States 3Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, United States 4Department of Pharmacy, Froedtert Health and Medical College of Wisconsin, Milwaukee, WI, United States 5Division of Infectious Diseases, Medical College of Wisconsin, Milwaukee, WI, United States 6Division of Cardiothoracic Surgery, Medical College of Wisconsin, Milwaukee, WI, United States 7Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, United States Edited by: Hendrik Tevaearai Stahel, Bern University Hospital, Switzerland Reviewed by: Abdelrahman Ibrahim Abushouk, Harvard Medical School, United States; Masanori Aikawa, Harvard Medical School, United States; Jun-ichi Abe, University of Texas MD Anderson Cancer Center, United States *Correspondence: Sherry-Ann Brown shbrown@mcw.eduThis article was submitted to Cardio-Oncology, a section of the journal Frontiers in Cardiovascular Medicine 04 12 2020 2020 04 12 2020 7 56872001 6 2020 06 11 2020 Copyright © 2020 Brown, Zaharova, Mason, Thompson, Thapa, Ishizawar, Wilkes, Ahmed, Rubenstein, Sanchez, Joyce, Kalyanaraman and Widlansky.2020Brown, Zaharova, Mason, Thompson, Thapa, Ishizawar, Wilkes, Ahmed, Rubenstein, Sanchez, Joyce, Kalyanaraman and WidlanskyThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Overlapping commonalities between coronavirus disease of 2019 (COVID-19) and cardio-oncology regarding cardiovascular toxicities (CVT), pathophysiology, and pharmacology are special topics emerging during the pandemic. In this perspective, we consider an array of CVT common to both COVID-19 and cardio-oncology, including cardiomyopathy, ischemia, conduction abnormalities, myopericarditis, and right ventricular (RV) failure. We also emphasize the higher risk of severe COVID-19 illness in patients with cardiovascular disease (CVD) or its risk factors or cancer. We explore commonalities in the underlying pathophysiology observed in COVID-19 and cardio-oncology, including inflammation, cytokine release, the renin-angiotensin-aldosterone-system, coagulopathy, microthrombosis, and endothelial dysfunction. In addition, we examine common pharmacologic management strategies that have been elucidated for CVT from COVID-19 and various cancer therapies. The use of corticosteroids, as well as antibodies and inhibitors of various molecules mediating inflammation and cytokine release syndrome, are discussed. The impact of angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) is also addressed, since these drugs are used in cardio-oncology and have received considerable attention during the COVID-19 pandemic, since the culprit virus enters human cells via the angiotensin converting enzyme 2 (ACE2) receptor. There are therefore several areas of overlap, similarity, and interaction in the toxicity, pathophysiology, and pharmacology profiles in COVID-19 and cardio-oncology syndromes. Learning more about either will likely provide some level of insight into both. We discuss each of these topics in this viewpoint, as well as what we foresee as evolving future directions to consider in cardio-oncology during the pandemic and beyond. Finally, we highlight commonalities in health disparities in COVID-19 and cardio-oncology and encourage continued development and implementation of innovative solutions to improve equity in health and healing. cardio-oncologyCOVID-19pandemictelemedicineinflammationcytokine release syndromeright ventriclehealth disparities ==== Body Introduction In early 2020, the World Health Organization (WHO) designated the new, highly contagious, and unnervingly fatal disease COVID-19 caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) a global pandemic. By June 1, 2020, the WHO reported more than 6 million confirmed cases and 370,000 deaths across nearly 220 countries and territories, with the US having the highest number of confirmed cases (1.7 million) and deaths (100,000) (1). Although initially thought to be primarily a lung disease, COVID-19 also involves marked toxicity to the cardiovascular system. As data has emerged, it has become clear to our cardio-oncology group (2–7) that much of the cardiovascular toxicity reported in COVID-19 is also observed in cardio-oncology, with overlap in underlying pathophysiology. Additionally, pharmacologic options frequently used or currently being studied in cardio-oncology are also proving beneficial in COVID-19. This begs the question of whether evaluating commonalities in the toxicities, pathophysiology, and pharmacology of COVID-19 and cardio-oncology would be informative for advancing understanding and avenues for research in cardio-oncology, as well as COVID-19. Cardio-oncology is an emerging field in medicine focused on the prevention, surveillance, detection, and management of injury to the cardiovascular system from cancer therapies or from cancer itself. The cardiovascular injuries are inflicted by an exogenous source, primarily pharmacologic or radiologic cancer therapy. In COVID-19, the cardiovascular injuries are also incited by an exogenous source, primarily SARS-CoV-2. Due to the exogenous nature of the original source of injury, in addition to pathophysiology mediating the injury, some authors refer to these cardiovascular injuries in COVID-19 as “toxicities” (8–10), which is also the term conventionally used in cardio-oncology (11–13). While cancer therapies and SARS-CoV-2 are two very different entities, the havoc they both wreak on the cardiovascular system is thought-provoking. In this perspective, we share the overarching viewpoint that these commonalities exist and are intriguing, and consequently, the dynamic research efforts surrounding COVID-19 may be able to inform new understanding and avenues for investigation in cardio-oncology. A clear understanding of the mechanisms of various forms of CVT in cardio-oncology remains elusive. Development of novel concepts, paradigms, and drug utilization trends based on observations identified in CVT related to COVID-19 may help advance research and clinical practice in cardio-oncology. To this end, we first present cardiovascular toxicities common to COVID-19 and cardio-oncology, then we expound on underlying pathophysiology. This is followed by description of pharmacologic options being pursued in both COVID-19 and cardio-oncology. Finally, we discuss ramifications of these commonalities in the context of Cardio-Oncologic care and research in the pandemic and beyond (Table 1). Table 1 Mechanisms, concepts, and paradigms: commonalities in toxicity, pathophysiology, and pharmacology of cardio-oncology and COVID-19. Common topic of study Cardio-oncology COVID-19 Mechanisms of left ventricular cardiomyopathy Elucidate mechanisms and optimal management of left ventricular systolic dysfunction in Cardio-Oncology Elucidate mechanisms and optimal management of left ventricular systolic dysfunction in COVID-19 Immune system activation Analyze pathophysiology and optimal management of immune response, cytokine release syndrome, and autoimmune adverse effects from ICIs or CAR-T cell therapy Analyze pathophysiology and optimal management of immune response, cytokine release syndrome, and related adverse effects in COVID-19 Long-term sequelae of inflammation Investigate long-term implications of inflammation induced by neoplastic agents Investigate long-term implications of myocardial inflammation in COVID-19 Endothelial dysfunction Interrogate role of endothelial dysfunction in ischemic and cardiomyopathic cardiovascular injuries from cancer drugs Interrogate role of endothelial dysfunction in ischemic and cardiomyopathic cardiovascular injuries from COVID-19 Coagulopathy and anticoagulation Study the burden, mechanisms, and optimal management of coagulopathy (arterial or venous) with need for anticoagulation or antiplatelet therapy in Cardio-Oncology Study the burden, mechanisms, and optimal management of coagulopathy and microthrombosis with beneficial response to anticoagulation in COVID-19 Role of RV and RVAD Explore significance of RV systolic dysfunction after anthracycline therapy Explore significance of RV systolic dysfunction in severe COVID-19 infection Prognostic value of RV strain Evaluate utility of RV strain to predict outcomes following anthracycline therapy Evaluate utility of RV strain to predict COVID-19 severity/mortality Utility of steroid therapy and biologics Determine the effectiveness and timing of steroid treatment and monoclonal antibodies for inflammation- or immune-related adverse events from ICIs or CAR-T cells Determine the effectiveness and timing of steroid treatment and monoclonal antibodies for inflammation-related adverse CV events in COVID-19 Neurohormonal therapy Establish cardioprotective contributions of neurohormonal therapies Establish whether neurohormonal therapies are protective in COVID-19 Potential drug Interactions Appraise the extent and impact of potential drug interactions between Cardiology drugs and Oncology drugs Appraise the extent and impact of potential drug interactions between Cardiology drugs and COVID-19 drugs Impact of health disparities Assess underlying factors and solutions to address health disparities in cardiovascular toxicities observed in Cardio-Oncology Assess underlying factors and solutions to address health disparities observed in cardiovascular injuries in COVID-19 Precision of risk prediction Develop precise methods of predicting cardiovascular toxicities and prognosis Develop precise methods of predicting risk and overall prognosis in COVID-19 CAR-T Cells, Chimeric Antigen Receptor T-Cells; COVID-19, Coronavirus Diseases of 2019; CV, cardiovascular; ICI, Immune Checkpoint Inhibitor; RV, Right Ventricle; RVAD, Right Ventricular Assist Device. Common Toxicities in COVID-19 and Cardio-Oncology CVT in COVID-19 and Cardio-Oncology In COVID-19, SAR-CoV-2 causes direct and indirect cardiovascular injury, which typically manifests as cardiomyopathy, myopericarditis, ischemia, or arrythmia (14–25). SARS-CoV-2 has been discovered in cardiac tissue (15, 25), similar to SARS-CoV-1 infection in which 35% of patients had viral RNA expressed in cardiac tissue (26). Patients with pre-existing CVD and cancer or CVD risk factors (e.g., diabetes mellitus, chronic kidney disease, obesity, and advanced age) are among those at highest risk of poor outcomes, i.e., increased morbidity and mortality from COVID-19 (10, 22, 27–30). According to a retrospective analysis of 72,314 cases in China, patients with pre-existing CVD morbidities had a five-fold increase in mortality, and a COVID-19-related death rate of 10.5% (22). Indirectly, patients with CVD morbidities are inherently more susceptible to the adverse effects of viral infection and the body's adaptive response. The systemic effects of COVID-19 causing fever, hypoxia, hypotension, and tachycardia may not be well-tolerated in patients with underlying cardiomyopathy or obstructive coronary artery disease, and this may manifest as further myocardial injury, and increased incidence of decompensated heart failure and type II myocardial infarction (20). Evidence of myocardial injury (e.g., elevated troponin), is common in patients hospitalized with COVID-19 (10). When present, elevated cardiac biomarkers such as brain natriuretic peptide and serum troponin have been associated with increased mortality in patients with COVID-19 (18). Similarly, a wide spectrum of cancer therapies has been associated with CVT, such as cardiomyopathy, myopericarditis, ischemia, and arrhythmias (11, 31). Radiation therapy can lead to all of these toxicities in the absence of chemotherapy. Various chemotherapy and targeted cancer therapy regimens can also result in CVT. Anthracyclines most commonly associate with cardiomyopathy, and can also bring about conduction abnormalities, myocarditis, or pericardial disease. Tyrosine kinase inhibitors commonly associate with hypertension, and less commonly with cardiomyopathy or ischemia. Immune checkpoint inhibitors are most notorious for myocarditis, and can also prompt pericarditis, cardiomyopathy, conduction abnormalities, and ischemia. Many other CVT are noted in cardio-oncology, with a variety of drug classes. In addition, tachycardia and elevated biomarkers may also portend poor prognosis in cardio-oncology (32, 33). There is therefore much overlap of CVT and prognostic factors in cardio-oncology with CVT and prognostic biomarkers in COVID-19. Furthermore, some types of cancers and cancer treatments weaken patients' immune systems and increase risk of any infection. Cancer patients' immunosuppression often also associates with blunted or delayed symptoms, which could in turn delay urgent therapy and increase mortality in COVID-19. Interesting to consider is any potential synergistic CVT in patients on cancer therapies in COVID-19. A prospective cohort of 800 cancer patients with COVID-19 analyzed in late April 2020 linked COVID-19 mortality with older age, male gender and comorbidities such as hypertension and cardiovascular disease (14). There was no association between receipt of cytotoxic chemotherapy, targeted therapies, radiation therapy, or other cancer therapies and COVID-19 mortality in this cohort. Similarly, a retrospective cohort of 928 cancer patients from the USA, Canada and Spain associated advanced age, smoking, progressive malignancy and increased comorbidities COVID-19 mortality, but failed to show associations with cancer type and type of anticancer therapy with COVID-19 mortality (34).Thus, the role of chemotherapy and other cancer systemic therapies in COVID-19 mortality remains uncertain. Emerging Role of Right Ventricular Failure Recent studies emerging in parallel in the pandemic and in cardio-oncology indicate that the RV may play an important role in the prognosis of patients with COVID-19 or CVT from cancer therapy; RV failure generally associates with worse outcomes in a variety of populations, and patients with COVID-19 or CVT from cancer therapies may be no different (35–38). While the mechanisms of insult to the RV in COVID-19 are different from those in cardio-oncology, similar changes are noted in the ventricle and these may have prognostic value. Importantly, RV longitudinal strain (RVLS) has emerged as a key player in the prediction of RV failure in both COVID-19 and cardio-oncology (36, 38). In COVID-19, RVLS inversely associates with myocardial injury, mechanical ventilation, acute respiratory distress syndrome (ARDS), and mortality, as well as signs of systemic inflammation such as heart rate, D-dimer, and C-reactive protein, as well as thromboembolism (38). In addition to RVLS, RV dilation and systolic dysfunction also predict mortality in COVID19 (39). Abnormalities in RV strain, size, and systolic function in COVID-19 may result from ARDS, pulmonary hypertension with increased pulmonary vascular resistance due to acute lung injury or thromboembolism, in addition to CO2 retention, positive pressure ventilation, or other causes of acute myocardial injury (19, 40–46). In one COVID-19 study, of 10 patients with RV dilation, 50% had PE noted on CTA; and of 21 total deaths in that COVID-19 cohort, 62% had RV dilation (39). Some patients with apparent ARDS do not respond as expected to low pressure ventilation strategies per ARDSNet ventilation protocols (47). Prone positioning in COVID-19 improves oxygenation and reduces the risk and need for mechanical ventilation or extracorporeal membrane oxygenation (ECMO) in patients on mechanical ventilation, but the maneuver appears to also reduce the risk of RV failure in ARDS including COVID-19 (48–50). Anecdotally, we have observed that the typical progression from hypoxemic respiratory failure to multi-system organ failure with escalating pressor requirements can be blunted with insertion of a percutaneous right ventricular assist device (RVAD) connected to an oxygenator. In all cases, the pressor requirement has been eliminated upon initiation of RVAD flows. These observations are consistent with our experiences in using these devices to treat other forms of RV failure which are frequently misdiagnosed as distributive shock. In cardio-oncology, changes are also noted in RV strain, structure, function, and size in patients with breast cancer and lymphoma who receive anthracycline chemotherapy (36, 51). Although the left ventricle is more commonly studied, the RV also shows impairment in contractility, with temporal changes of decreased RVLS and increased right ventricular end systolic volume (RVESV) preceding reduction in right ventricular ejection fraction (RVEF) (36). Additionally, patients with end-stage heart failure as a result of cardiomyopathy from anthracycline therapy benefit from RV assist device support (52). The underlying pathophysiology of RV dysfunction in anthracycline CVT is likely similar to LV dysfunction. LV dysfunction results from release of cytokines and inflammatory markers, related to generation of reactive oxygen species, disruption of mitochondrial biogenesis, and activation of apoptosis, and double-stranded DNA breaks (53–55). This is a recent and novel area of inquiry in cardio-oncology. Additional studies are needed to determine whether RV size, function, and longitudinal strain can predict CVT and mortality in cardio-oncology (36), as has been found in COVID-19. Health Disparities in CVT A multi-ethnic study of more than 3,500 individuals with COVID-19 was published in the New England Journal of Medicine (NEJM) (56). While <40% of patients in the study were hospitalized, African Americans composed almost 80% of inpatients admitted with COVID-19 and associated CVT. A higher rate of comorbidities associated with the risk for hospitalization, and African Americans had higher rates of comorbidities. This is similar to general trends in health disparities, in which African Americans have higher rates of CVD, obesity, hypertension, and diabetes than Caucasians (57), and are therefore at higher risk for CVT related to COVID-19. These disparities were found to associate with inequities in socioeconomic demographics in the NEJM report, as in prior studies (56, 57). Notably, ACE (I/D) polymorphisms have been implicated in COVID-19 and related CVT, and vary across racial groups (58). However, this alone does not explain the disparities observed in COVID-19. The D/D polymorphism that associates with the development and severity of sarcoidosis (59), which is more prevalent, complex, and mortal in African-Americans (60), is the same polymorphism that is suggested to associate with protection in COVID-19 (61–63). Nevertheless, African Americans have had the highest proportions of severe and fatal illness from COVID-19 and consequent CVT. In the same way, CVT in cardio-oncology has been reported at higher rates in African Americans, with similar underlying reasons (64–68). Implications of Common Toxicities It is worth continuing to study shared toxicities in COVID-19 and cardio-oncology. For example, increased attention to emerging special topics such as RV strain, function, and predictive value in COVID-19 may help elucidate sequelae of commonalities to optimize care and survival of our patients in COVID-19 and also in cardio-oncology (Figure 1). Perhaps studying the pathophysiology and host characteristics in patients with abnormal RV size, function, and longitudinal strain in COVID-19 could also help us better understand the pathophysiology of abnormal RV size, function, and longitudinal strain in some patients after anthracycline therapy. Further, it will be important to address the disproportionate percentages of African-Americans with severe and fatal CVT related to both COVID-19 (69–73) and cancer therapies in cardio-oncology (64–68). Figure 1 A conceptual framework of commonalities in CV toxicities, pathophysiology, and pharmacology common to COVID-19 and cardio-oncology. CV toxicities common to COVID-19 and cardio-oncology include myocardial injury, cardiomyopathy, myopericarditis, ischemia, conduction abnormalities, and RV failure, in part mediated by immune system activation, cytokine release syndrome, and arterial and venous coagulopathy. All of these are also examples of oncologic CV toxicities that can result from pharmacologic or radiation therapies. Indeed, the pathophysiology and modulation of SARS-CoV-2 infection remains under investigation, with components of viral infection/invasion, macrovascular endothelial dysfunction, cytokine release syndrome/inflammation, microvascular dysfunction/thrombosis, neurohormonal regulation, coagulopathy, and increased metabolic stress. Several pharmacologic considerations have risen to the surface during the pandemic, involving steroids, cancer immunotherapy, biologic antibodies and inhibitors, drug repurposing, the role of cyp450 and drug transporters in drug-drug interactions, anticoagulation, and neurohormonal regulation. ARB, Angiotensin Receptor Blocker; ACEI, Angiotensin Converting Enzyme Inhibitor; CV, Cardiovascular; COVID-19, Coronavirus Disease of 2019; RV, Right Ventricle; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus. Common Pathophysiology in COVID-19 and Cardio-Oncology Pathophysiology of COVID-19 and Cardio-Oncology Potential mechanisms of cardiovascular injury in COVID-19 include hemodynamic derangement or hypoxemia, increased metabolic stress, demand ischemia, microvascular dysfunction or thrombosis due to hypercoagulability, or systemic inflammation and cytokine storm, which may also destabilize existing coronary artery plaques (16, 74–76). Although not yet demonstrated with SARS-CoV-2, an autopsy study of people who died from SARS-CoV-1 infection demonstrated that 35% of patients had viral RNA expressed in cardiac tissue (26). Further, a recent study illustrated in vitro direct infection of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) by SARS-CoV-2 (77). Microscopy and RNA-sequencing provided evidence that SARS-CoV-2 enters hiPSC-CMs via the cell surface receptor ACE2. The study also demonstrated that in response to SARS-CoV-2 infection, the hiPSC-CMs upregulated the innate immune response and antiviral clearance gene pathways, in addition to downregulating ACE2 expression. ACE2 receptors are the SARS-CoV-2 entry point into human cells (10, 78). Patients with pre-existing CVD or CV risk factors, which associate with heightened systemic inflammation, have higher levels of ACE2 receptor expression than the general population (10, 79, 80). In normal physiology, ACE2 is counter-regulatory and anti-inflammatory (79, 80). Interestingly, a particular angiotensin converting enzyme (ACE) genetic polymorphism (D/D), although not a ACE2 polymorphism, associates with decreased ACE2 levels and has been suggested to be protective in patients with COVID-19 (61–63). The physiologic effects of ACE and ACE2 are typically in some degree of homeostatic equilibrium, with ACE mediating inflammation, oxidative stress, and vasoconstriction, and ACE2 also being vasodilatory (81). SARS-CoV-2 may remove ACE2 from this homeostatic pathway due to both the virus and the receptor being internalized from the cell surface in COVID-19 (81). The inflammatory response elicited by SARS-CoV-2 is implicated in direct suppression of cardiac contractility (75). Evidence of new contractile dysfunction was reported in ~30% of patients with critical illness related to COVID-19, and cardiac or circulatory shock is a common pathway to fatal outcomes (82, 83). This is reminiscent of CVT in cardio-oncology, in which increased metabolic stress, cytokine release, inflammation, macrovascular endothelial dysfunction, microvascular dysfunction, thrombosis, and neurohormonal dysregulation can all result in impairment of cardiac contractility underlying cardiomyopathy. Immune System Activation Two recent studies evaluating immunologic characteristics of peripheral blood samples from COVID-19 patients have emerged from China (84, 85). In these studies, severe cases of COVID-19 were associated with depletion of CD8+ T-cells, suggesting that upregulation of immune checkpoint molecules that downregulate T-cells may play an important role in impairing the immune response to the virus. These early studies should be interpreted with caution given the small sample sizes, and continued investigation will shed light on the mechanisms of immune dysregulation induced by COVID-19. Immune checkpoint inhibitors (ICIs) are drugs that target immune checkpoint molecules such as programmed death 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). These drugs have dramatically improved overall survival for patients with a wide range of malignancies (86). Inflammatory cytokines, such as interferon-γ and type I interferons, induce PD-L1 expression on immune and tumor cells (87). Interaction of the PD-L1 and PD-1 proteins leads to T-cell exhaustion, and blockade of this interaction with PD-1/PD-L1 inhibitors restores effector function to CD8+ T-cells, allowing for destruction of malignant cells. Chief among concerns with ICIs during the pandemic is whether ICIs can increase COVID-19-related complications, particularly CVT. A retrospective study found patients receiving ICIs to be at higher risk of hospitalization and severe outcomes from COVID-19 (88). Strong conclusions are difficult to draw from this small, retrospective, single-center study in which only 31 patients received ICIs. A prospective observational study from the UK Coronavirus Center Monitoring Project found no association between COVID-19 mortality and ICI treatment in the 44 patients who received ICIs (89). Ongoing large-scale prospective data may shed further light on this interaction. Many cancer patients receiving ICIs possess comorbidities that enhance risk for poor outcomes related to COVID-19. ICIs and COVID-19 can cause overlapping organ toxicities, particularly pulmonary and cardiac, which inform risk-benefit decisions on ICI use during the pandemic. ICIs can induce immune-mediated cardiotoxicity, including myocarditis, pericarditis, heart failure, arrhythmias, and MI. These events are uncommon, occurring in <3% of patients who receive ICIs, but carry high risk of mortality (90). The pathophysiology of the immunologic mechanisms of cardiotoxicity with ICIs and COVID-19 likely differ, but macrophages may play roles in both pathways, which could contribute to anecdotal response to glucocorticoid responsiveness for ICI and COVID-19 toxicities (Table 2). The renin-angiotensin system has been implicated in the pathophysiology of both COVID-19 and tumorigenesis, with data suggesting the RAAS pathway promotes an immunosuppressive tumor microenvironment (91–93). However, much like COVID-19, the impact of ACE inhibitors on survival outcomes with ICIs is currently unclear (94). Given the prevalence of ICI use, it is essential to exert a coordinated effort to track COVID-19 incidence in patients receiving ICIs, as well as rates of pulmonary and cardiac sequelae and mortality to truly understand the long-term impact of the virus on this large population. Table 2 Clinical characteristics of similar CV toxicity in ICI therapy, CAR T-cell therapy, and COVID-19. ICI and CV toxicity CAR-T cell and CV toxicity COVID-19 and CV toxicity Incidence <1% NA/unknown NA/unknown Pathophysiology T-cell mediated Cytokine storm, high IL-6 Hypoxia, Cytokine storm Risk of VTE High High High Management Steroid Tocilizumab, and/or steroid Supportive management, +/– dexamethasone ACEI/ARB continue Yes Yes Yes Long-term CV effect Unknown Unknown Unknown ACEI, ACE Inhibitor; ARB, Angiotensin Receptor Blocker; CAR-T Cells, Chimeric Antigen Receptor T-Cells; CRS, Cytokine Release Syndrome; CV, Cardiovascular; COVID-19, Coronavirus Diseases of 2019; ICI, Immune Checkpoint Inhibitor; IL-6, Interleukin 6; NA, Not Applicable; VTE, Venous Thromboembolism. Cytokine Release Syndrome In COVID-19, the inflammatory cytokine IL-6 has also been shown to play a role in critically ill patients, in whom “cytokine release storm” or “cytokine release syndrome” (CRS) pathophysiology leads to cardiopulmonary complications and multisystem failure (95). Clinical manifestations of CRS include fever, chills, fatigue, myalgias, arthralgias, nausea, vomiting, and diarrhea (96). In the patient with CRS, cardiovascular manifestations include tachycardia, hypotension, elevated troponin, heart failure, and in severe cases, cardiogenic shock (96, 97). IL-6 could possibly mediate cardiac dysfunction and hemodynamic instability (98). In general, IL-6 elevation has associated with cardiovascular complications such as atherosclerosis, MI, and heart failure. IL-6 and other cytokines are key components of the human body host defense system against infection, yet high levels of these cytokines in a hyperinflammatory response can lead to CRS (99, 100). Cytokine release syndrome can be a fatal complication due to exaggerated inflammatory response in COVID-19, partially mediated by immune cells fighting the viral infection by increasing inflammatory cytokines via activation of intracellular NF-κB (101), but also in large part mediated by the ACE2 and AT1 receptors, which are generally highly expressed on epithelial cells in the lung and endothelium (20, 102–104). A main function of ACE2 is to convert angiotensin II (Ang II) into angiotensin-(1-7), a counter-regulatory peptide that dampens the inflammatory effects of Ang II via AT1 (101, 105). After the SARS-CoV-2 S-protein attaches to ACE2 on respiratory epithelium, ACE2 is down-regulated (77). The resulting SARS-CoV-2-mediated imbalance of serum Ang II/angiotensin-(1-7) drives net activation of AT1 signaling [which is dependent on serum Ang II/angiotensin-(1-7)] in pulmonary epithelial cells. It is well-established that COVID-19 infection causes hyperactivation of the angiotensin 1 receptor (AT1), which leads to disproportionate activation of nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome in lung epithelial cells and endothelium (106, 107), as well as activation of STAT3 and the NF-κB pathway, producing potent pro-inflammatory cytokines IL-6, IL-1β, and IL-18 (101, 108–110). The detrimental pathophysiological consequence of the hyperinflammatory response includes enhanced activation of reactive oxygen species (ROS) release, fibrosis, vasoconstriction, and programmed cell death, that contribute to the CRS pathophysiology. Interestingly, ACE2 and AT1 are known to be expressed at extremely low levels on hematopoietic stem cells (HSC) and endothelial progenitor cells (EPC) (111). A recent study demonstrated for the first time that ACE2 is expressed on very small embryonic-like stem cells (VSELs) (112). Pre-clinical data demonstrated that interaction of ACE2 receptor with the COVID-19 spike protein activated the NLRP3 inflammasome in VSELs and HSC leading to programmed cell death (112); the contribution of this to CRS is yet unclear. Unlike traditional chemotherapy, CAR-T cell therapy is a novel form of immunotherapy in cardio-oncology to treat individuals with refractory hematologic malignancies, and is commonly associated with toxicity related to CRS. CAR-T cell therapy utilizes genetically engineered T-cells to attack cancer cells (113). The activation of CAR-T cells when engaged with antigen in a malignant cell leads to its CAR-T cell proliferation, which further activates monocytes and macrophages, leading to release of proinflammatory cytokines and chemokines such as IL-6, IL-8, IL-10, interferon-gamma (INF-y), monocyte chemoattractant protein-1b, and granulocyte-macrophage colony-stimulating factor (114, 115). These proinflammatory cytokines are potential mediators for CRS in patients with cancer, with a similar cascade in patients with COVID-19. Coagulopathy Arterial and venous coagulopathy has emerged as an important factor in COVID-19 pathophysiology and cardio-oncology, especially in critically ill patients (116–120), in part related to underlying endothelial cell dysfunction and inflammation in patients with COVID-19 or cancer (117, 121, 122). Severe COVID-19 infection requiring critical care admission has been associated with increased incidence of venous thromboembolism (VTE) (117, 123), due to hyperinflammation and a hypercoagulable state (124, 125). The incidence has been reported to be 3 to 4-fold greater than in the general population (117, 123). In critically ill patients in the general population, the cumulative incidence of VTE is around 9.6% (126, 127), while in COVID-19 patients it is reported to be between 31 and 42% (117, 123). Thrombotic events in COVID-19 mostly categorize VTE, but in some patients, a significant number of arterial thrombosis are also being reported. In one study, 3.7% of the 31% reported cases had ischemic strokes, while in another study population two ischemic strokes and one limb ischemia were reported (117, 123). Endotheliitis with underlying hyperinflammation, along with hypoxia leading to increased blood viscosity, are suspected to cause increased coagulopathy in severe COVID-19 infection (128, 129). Excess cytokine release also results in macroscopic or microscopic endothelial injury, leading to a prothrombotic state (130). Elevation of D-dimer above normal values on admission or over time during the disease process has been associated with poor outcomes in patients with severe COVID-19 (125). Close monitoring of D-dimer, aPTT/PT, fibrinogen, and platelet count in hospitalized COVID-19 patients is recommended as derangement of these coagulation parameters can be an early sign of disseminated intravascular coagulation (DIC) (125). A similar phenomenon is observed in cancer patients (131). Similar factors are associated with thrombosis, with circulating microparticles, procoagulants, and endothelial dysfunction contributing to disruption of normal blood flow and hyperviscosity (120, 132, 133). Cancer also poses a 4 times increased risk of VTE as compared to general population while chemotherapy increases the risk to 6.5 times (134). Patients who receive CAR-T cell therapy are also at increased risk for venous thromboembolism, potentially mediated by CRS and high levels of IL-6 (135, 136), in the setting of underlying hypercoagulability due to the presence of the cancer itself. Other pharmacologic cancer therapies can also associate with thrombosis. Cisplatin and tyrosine kinases often lead to coronary or peripheral arterial thrombosis related to endothelial injury, thromboxane synthesis, and platelet activation and aggregation, placing patients at 1.5- to 1.7-fold or as high as 6-fold increased risk of acute coronary syndromes [see review in expert consensus statement (137)]. Endothelial Dysfunction Furthermore, many chemotherapeutics associate with endothelial dysfunction and consequent ischemia in the absence of thrombosis. In these cases, ischemia is due to vasospasm. This phenomenon can be caused by 5-fluorouracil (5-FU), capecitabine (5-FU pro-drug), paclitaxel, docetaxel, cisplatin (especially when combined with bleomycin or vincristine), cyclophosphamide, and tyrosine kinase inhibitors (e.g., sorafenib and sunitinib) [see review in expert consensus statement (137)]. Undiagnosed underlying coronary artery disease is thought to be a likely pre-disposing condition. Likewise, endothelial dysfunction and consequent ischemia in the absence of thrombosis are also suspected in some patients with COVID-19 who present with ACS and non-obstructed coronary arteries; severe hypoxia, CRS, plaque rupture, vasospasm, and microthromboembolism are also on the differential in these patients (25, 138, 139). Implications of Common Pathophysiology Shared pathophysiology in COVID-19 and cardio-oncology also have important implications. For example, ICIs and CAR-T cells used as cancer therapy can lead to excessive activation of the immune system and inflammation and subsequently autoimmune and inflammatory adverse CV effects. Despite the favorable responses from CAR-T cell and ICI therapy in cardio-oncology, we still have limited evidence and understanding of CVT from these immunotherapies or their long-term impact. We can potentially fill our knowledge gap on CVT due to CRS related to CAR-T cell therapy, or supranormal activation of the immune system related to ICIs, in cardio-oncology by pursuing a better understanding of the inflammatory pathophysiology from the ongoing COVID-19 pandemic. The reverse is also true, and long-term sequelae of CRS on the cardiovascular system should be investigated and addressed in patients who have had COVID-19 or in cancer patients who have received CAR-T cell therapy. Similarly, coagulopathy in COVID-19 is an emerging topic with the majority of evidence stemming from observational studies and autopsies (128). The hypercoagulability of cancer, which is often treated by cardio-oncologists, can be informative for COVID-19, given a role for anticoagulation to address thromboembolism in these hypercoagulable states. Additionally, the role of endothelial dysfunction can be further elucidated in both COVID-19 and cardio-oncology with anticipated shared vascular pathophysiology, albeit with different mechanisms of endothelial injury. Common Pharmacology in COVID-19 and Cardio-Oncology Corticosteroids Given the robust inflammatory response induced by COVID-19, corticosteroids are under investigation and have been demonstrating promising efficacy for treating the disease. Dexamethasone has recently garnered significant international attention for the treatment of COVID-19 with the pre-print publication (not yet peer reviewed) of the phase 3 RECOVERY trial. Patients were randomized to dexamethasone at 6 mg daily for up to 10 days vs. standard care. Dexamethasone significantly reduced deaths in patients who required supplemental oxygen or mechanical ventilation (140). Notably, the pre-print manuscript does not quantify the number of patients with cancer included in the analysis and may be difficult to generalize to an oncology population with COVID-19. Corticosteroids have been mainstays of treatment for immune-related adverse events (irAEs) induced by ICIs and CAR-T cells in cancer patients, owing to their ability to rapidly dampen inflammation and quickly reverse irAEs (141, 142). In the widely utilized, evidence-based irAE management guidelines published by the American Society of Clinical Oncology (ASCO), high-dose corticosteroids are recommended as first-line management of most grade 2 or higher irAEs (143). For cardiovascular irAEs, including myocarditis, pericarditis, heart failure, and vasculitis, high-dose corticosteroids are recommended for any grade of toxicity (141, 142, 144). Thus, steroids may be helpful to quell activated immune responses leading to CVT due to various endogenous sources, whether cancer therapy or COVID-19. Biologic Antibodies and Inhibitors Tocilizumab is an IL-6 receptor antagonist and is indicated as the first-line agent for the management of CRS in cancer patients (145–148). The use of tocilizumab in COVID-19 is an extrapolation based on the evidence of promising outcomes from using the drug to treat CRS from CAR-T cell therapy in cancer patients. Off-label use of tocilizumab is an option used in the management of severe cases of COVID-19 on compassionate grounds, supported by a case series from China (149) and a pilot open, single-arm multicenter study from Italy (150), particularly if tocilizumab is administered within 6 days of admission (HR 2.2, 95% CI 1.3–6.7, p < 0.05) (150). Additionally, a large retrospective cohort study demonstrated that tocilizumab decreased risk of death or minimized risk for invasive mechanical ventilation in patients with severe COVID-19 (adjusted HR 0.61, 95% CI 0.40–0.92; p = 0.020) (151). A smaller, retrospective cohort study demonstrated a significantly shorter need for vasopressor support in severely ill COVID-19 patients who received tocilizumab (152). Cardiac dysfunction due to CRS is largely reversible, and in severe cases mitigated by tocilizumab (153). In some severe cases not responding to tocilizumab, the corticosteroid is added. In rare cases, when the patient does not respond to tocilizumab or steroid, other agents such as anakinra (IL-1R inhibitor) and etanercept (anti-TNFα) are potential options to hinder inflammatory pathways (114, 154). Siltuximab is a chimeric monoclonal antibody that also binds IL-6; however, no studies have been published on its use in the management of CRS in cancer patients to date (96). Next generation novel immunotherapeutics could also affect COVID-19-related incidence and outcomes. For instance, AXL is a receptor tyrosine kinase which mediates tumor invasion, metastasis, and epithelial-mesenchymal transition. AXL also negatively modulates cancer immune responses through signaling pathways involving dendritic cells, natural killer cells and macrophages (155). Given its role in cancer metastasis and immune function, numerous AXL inhibitors are being used in clinical trials to treat advanced malignancies. AXL mediates viral entry into cells and modulates inflammatory responses induced by viral infections (156, 157). AXL is also overexpressed on myocardial cells in patients with heart failure and in patients who experience LV remodeling after STEMI (158). It is conceivable that through immune and cardiovascular impacts, investigational drugs that target AXL may impact outcomes of cancer patients with COVID-19 infection, and clinical trial sponsors and investigators should be encouraged to track and study COVID-19-infected trial patients to better understand these complex interactions. To this end, bemcentinib, an oral AXL inhibitor under investigation as a cancer immunotherapeutic, has recently been repurposed to combat COVID-19 as part of the Accelerating COVID-19 Research & Development (ACCORD) platform in the United Kingdom. Interestingly, human antibodies have been isolated from the convalescent serum of COVID-19 survivors and when coupled have been shown to be protective. Perhaps the use of these emerging dual antibodies may be as efficacious for COVID-19 patients as the dual antibodies trastuzumab and pertuzumab have been for breast cancer patients. Developing therapeutics from antibodies such as these may help provide safer effective options for COVID-19 patients and facilitate avoiding potential or proven drug-drug interactions. Role of CYP450 and Drug Transporters The antiviral drug remdesivir is an investigational drug being used to treat COVID-19, and concomitant use with drugs that are strong CYP3A4 inducers is not recommended (159). The CYP450 enzyme system (which includes CYP3A4) forms the backbone for metabolism of multiple drugs and plays a vital role in metabolism of numerous cardio-oncologic drugs including beta blockers, calcium channel blockers, statins, cyclophosphamide, docetaxel, cisplatin, and tyrosine kinase inhibitors (160). In particular, the antiandrogen drugs apalutamide and enzalutamide used to treat prostate cancer are strong CYP3A4 inducers (161–163). Both agents can associate with CVT, such as atrial fibrillation, hypertension, and ischemic heart disease, especially in individuals with pre-existing cardiovascular diseases (161–164). Concurrent use of remdesivir with these drugs should be avoided at the interface of COVID-19 and cardio-oncology. Of note, in cardio-oncology, the calcium channel blockers diltiazem and verapamil are moderate inhibitors of CYP3A4, which also metabolizes cancer pharmacologic drugs such as doxorubicin, imatinib, and ibrutinib (160). In vitro, remdesivir is a substrate for CYP2C8, CYP2D6, and CYP3A4, and an inhibitor of CYP3A4, as well as a substrate for p-glycoprotein and organic anion transporting polypeptides 1B1 (OATP1B1) and an inhibitor of OATP1B1 (165). P-glycoprotein and OATP1B1 are membrane transporters known to help mediate drug-drug interactions. However, remdesivir generally has a low potential for clinically significant drug-drug interactions mediated by the CYP450 system or drug transporters (165–167), since remdesivir functions as a prodrug that is rapidly metabolized to the active bioavailable form (165, 168). Anticoagulation Empiric therapeutic anticoagulation associates with better prognosis in severe COVID-19 cases, with improved in-hospital mortality in retrospective analyses (129, 169). While practice has varied across centers during the pandemic, anticoagulation should be considered based on COVID-19 patient factors and risk stratification (119). Empiric prophylactic anticoagulation also associates with better outcomes in cancer patients who are hospitalized and have reduced mobility, or are ambulatory and have (170, 171): advanced or metastatic pancreatic cancer, intermediate-high VTE risk based on cancer type or Khorana score, or treatment with immunomodulatory drugs and steroids or other systemic antineoplastic therapies. Neurohormonal Drugs: ACEIs and ARBs It has been suggested that ACE inhibitors may counteract resulting unopposed ACE-mediated effects in COVID-19 (81). Thus, the influence of these vasoactive and cardiovascular remodeling drugs on the risk and severity of COVID-19 has been under investigation, with some studies suggesting benefit, juxtaposed with initial speculations about harm (28, 172–181). It is unknown whether polymorphisms in ACE, or polymorphisms in ACE2 that may contribute to COVID-19 prognosis [see pre-prints (182, 183)], also determine the prognosis of patients in cardio-oncology treated with RAAS regulators, such as ACE inhibitors and ARBs. It is important to note that ACEIs and ARBs have established benefits in protecting the myocardium. They are among first-line therapy for various CVT (e.g., cardiomyopathy, hypertension, and myocardial infarction) in cancer patients and survivors, along with beta blockers, to mitigate symptoms and prolong survival (184). Withdrawal of these agents instigates clinical decompensation in high-risk patients, such as rapid relapse of dilated cardiomyopathy in cancer patients with CVT due to neoplastic agents (28, 172, 185). Consequently, patients receiving ACEIs or ARBs should continue ACEI/ARB therapy during the COVID-19 pandemic (172, 186, 187). Taken together, these findings suggest overlapping utility of these drugs in both cardio-oncology and COVID-19. Implications of Common Pharmacology It is also important to study shared pharmacologic management opportunities in COVID-19 and cardio-oncology. Corticosteroids and immunomodulatory drugs such as tocilizumab and bemcentinib and other analogous therapies are being used or studied in cardio-oncology and have also been repurposed during the pandemic to temper the inflammation milieu initiated by SARS-CoV-2. Further, thousands of cancer patients are currently enrolled in clinical trials combining ICIs with investigational novel therapeutics across the world, accounting for another special risk population in the COVID-19 pandemic. Ongoing clinical trials on anti-interleukins in COVID-19 patients (188, 189) (NCT04330638, NCT04317092) will also help us to elucidate benefits and outcomes. Accordingly, an algorithm has been proposed to incorporate anti-inflammatory agents such as tocilizumab, canakinumab (IL-1β monoclonal antibody), anakinra, etanercept, and infliximab (TNFα monoclonal antibody) to curb CRS in acute COVID-19 infection (190). The antiviral remdesivir carries a low risk of modulating the membrane drug transporter p-glycoprotein and the cytochrome protein 450 family of enzymes and potentially interacting with CV and cardio-oncology drugs. Nevertheless, caution is recommended with the combined use of any drugs that modulate p-glycoprotein or CYP450, due to their potential for drug-drug interactions and resultant effects on the CV system in cardio-oncology and COVID-19. Therapeutic anticoagulants are another class of medications found to be useful in both COVID-19 and cardio-oncology, due to their beneficial effects on thromboembolism. Clinical studies are being pursued to determine the impact of direct oral anticoagulants or aspirin and statin to limit arterial or venous thrombotic risk in cancer (120). Regulators of the RAAS (primarily ACEI/ARB) have also taken centerstage, as many patients are on these medications to treat hypertension or other common comorbidities that increase the risk of a more severe course in those with COVID-19. There has been debate about whether these RAAS modulator drugs augment the risk of COVID-19 infection, given the virus' use of the ACE receptor to enter host cells. ACE receptor gene polymorphisms have also been implicated in the prediction of disease severity, with questionable regulation by the ACEI/ARB drug class. Pursuit of observational studies and clinical trials continues to help elucidate the impact of ACEIs and ARBs in the pandemic (27). Further study should also define the interplay between SARS-CoV-2 and RAAS and explore any differential effects of ACEI vs. ARB therapy and tumor specific responses (91, 93, 94, 185). Future collaboration among basic and clinical scientists should focus on the biological rationale for the treatment of COVID-19 patients as well as limited understanding with respect to the interaction of RAAS inhibitors, ACE2 levels and SARS CoV-2 infectivity in humans (27). Discussion As we recover from the COVID-19 pandemic, we should not let opportunities for learning surreptitiously slip from our grasp. The myriad of overlap of CV toxicities, pathophysiology, and innovative management in COVID-19 and cardio-oncology provide multiple paths for exploration that could lead to greater understanding of both COVID-19 and CVT noted in cardio-oncology (Figure 1). It would behoove us in cardio-oncology to continue to closely study these toxicities, pathophysiology, and pharmacologic options in COVID-19 to help update our understanding in cardio-oncology. Cardio-oncology continues to expand as a relatively new medical subspecialty. Knowledge gaps in CVT toxicity, pathophysiology, and pharmacology in cardio-oncology may benefit from the application of novel concepts, paradigms, and drug use from overlapping forms of CVT in COVID-19 (Table 1). In addition to short-term morbidity and mortality, patients who recover from COVID-19 infection may be at increased risk of future incident CVD and CVD-related complications (191, 192). Severe acute respiratory syndrome coronavirus (SARS-CoV-1) and Middle East respiratory syndrome coronavirus (MERS-CoV) infection have been implicated in causing diabetes, hypertension and altered lipid metabolism (193–195). The increase in CVD risk profile combined with the possibility of viral-mediated impairment in cardiac and/or pulmonary function may combine to further increase the risk and complexity of future CVD events. Aggressive risk factor modification and prophylactic therapy may prove important in mitigating long-term CVT. Optimal prevention and management of CVT will require a multidisciplinary approach with close collaborations among various medical specialties and researchers. As our current practices change and new questions arise, future studies in cardio-oncology should focus on studying the emerging cardiovascular epidemiology of COVID-19, as well as the impact of changed practices on the health of patients with cancer and CVD. To reduce the rate of transmission while providing safe and timely care for patients with cancer and CVD, temporary recommendations favored telehealth visits in telecardio-oncology and deferral of non-urgent procedures, similar to the rest of the population (10, 196). Cardiac imaging surveillance was limited to patients who were more likely to have abnormal testing or at higher risk for cancer-related CVT, particularly if test results would guide initiation of cardioprotective medications or impact cancer therapy delivery (197). Of utmost importance is ensuring equity in our distribution of hope, health, and healing in the midst of and beyond the pandemic, as we extend lessons learned from COVID-19 to cardio-oncology. Ethnic health disparities during the pandemic have amplified a pre-existing broken healthcare structure, with disproportionate percentages of African-Americans severely and fatally affected by COVID-19 (69–73). The pandemic has been set on a backdrop of inequity, in which African-American cancer patients are known to be more susceptible to CVT following cancer therapies (64–68). The higher risk for African Americans in both COVID-19 and cardio-oncology is of multifactorial etiology, including higher rates of CVD and CVD risk factors, which are often also underdiagnosed and undertreated (57, 69, 198–206). Underlying causes of the plethora of inequalities in healthcare are largely structural and socioeconomic and reflect our imperfections as a society, with socioeconomic status being a risk factor for CVD, CVT, and COVID-19 (198, 207, 208). We must recognize the imbalance of comorbidities and sociodemographics in ethnic populations, in order to make equitable progress in the post-pandemic era. The lasting impact of COVID-19 in cardio-oncology need not be the challenges we faced while caring for our patients during the pandemic. The long-term sequelae should be steps we have taken to optimize quality and quantity of life for all. Thus, there are several areas of overlap, similarity, and interaction in the toxicity, pathophysiology, and pharmacology profiles in COVID-19 and cardio-oncology syndromes. Learning more about either will likely provide some level of insight into both, with further illumination of CVT mechanisms and new paradigms of drug utilization to help guide research and clinical practice in both COVID-19 and cardio-oncology. Such an approach can be informative peri-pandemic, and should perhaps be pursued long after the pandemic, to assess for evidence of long-term independent or synergistic CV effects in survivors of COVID-19 and cancer, with equity at the forefront of our efforts. Data Availability Statement The original contributions generated in the study are included in the article, further inquiries can be directed to the corresponding author. Author Contributions S-AB conceived, designed, and helped draft the manuscript. SZ, PM, JT, BT, DI, EW, GA, JR, JS, and DJ helped draft the manuscript. BK and MW helped design and draft the manuscript. All authors revised and approved the manuscript. Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. ==== Refs References 1. WHO WHO Coronavirus Disease (COVID-19) Dashboard . (2020 ). Available online at: https://covid19.who.int/ (accessed October 01, 2020). 2. Brown SA . Preventive cardio-oncology: the time has come . Front Cardiovasc Med . (2019 ) 6 :187 . 10.3389/fcvm.2019.00187 31998754 3. Brown SA Rhee JW Guha A Rao VU . Innovation in precision cardio-oncology during the coronavirus pandemic and into a post-pandemic world . Front Cardiovasc Med . (2020 ) 7 :145 . 10.3389/fcvm.2020.00145 32923460 4. Brown SA Sandhu N Herrmann J . Systems biology approaches to adverse drug effects: the example of cardio-oncology . Nat Rev Clin Oncol . (2015 ) 12 :718 –31 . 10.1038/nrclinonc.2015.168 26462128 5. Brown SA Nhola L Herrmann J . Cardiovascular toxicities of small molecule tyrosine kinase inhibitors: an opportunity for systems-based approaches . Clin Pharmacol Ther . (2017 ) 101 :65 –80 . 10.1002/cpt.552 27806435 6. Brown SA Ray JC Herrmann J . Precision cardio-oncology: a systems-based perspective on cardiotoxicity of tyrosine kinase inhibitors and immune checkpoint inhibitors . J Cardiovasc Transl Res . (2020 ) 13 :402 –16 . 10.1007/s12265-020-09992-5 32253744 7. Brown SA Okwuosa TM Barac A Volgman AS . The role of angiotensin-converting enzyme inhibitors and β-blockers in primary prevention of cardiac dysfunction in breast cancer patients . J Am Heart Assoc . (2020 ) 9 :e015327 . 10.1161/JAHA.119.015327 31960742 8. Guzik TJ Mohiddin SA Dimarco A Patel V Savvatis K Marelli-Berg FM . COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options . Cardiovasc Res . (2020 ) 116 :1666 –87 . 10.1093/cvr/cvaa106 32352535 9. Lang JP Wang X Moura FA Siddiqi HK Morrow DA Bohula EA . A current review of COVID-19 for the cardiovascular specialist . Am Heart J . (2020 ) 226 :29 –44 . 10.1016/j.ahj.2020.04.025 32497913 10. Ganatra S Hammond SP Nohria A . The novel coronavirus disease (COVID-19) threat for patients with cardiovascular disease and cancer . JACC CardioOncology . (2020 ) 2 :350 –5 . 10.1016/j.jaccao.2020.03.001 32292919 11. Chang HM Moudgil R Scarabelli T Okwuosa TM Yeh ETH . Cardiovascular complications of cancer therapy: best practices in diagnosis, prevention, and management: part 1 . J Am Coll Cardiol . (2017 ) 70 :2536 –51 . 10.1016/j.jacc.2017.09.1096 29145954 12. Barac A Murtagh G Carver JR Chen MH Freeman AM Herrmann J . Cardiovascular health of patients with cancer and cancer survivors: a roadmap to the next level . J Am Coll Cardiol . (2015 ) 65 :2739 –46 . 10.1016/j.jacc.2015.04.059 26112199 13. Bonaca MP Olenchock BA Salem JE Wiviott SD Ederhy S Cohen A . Myocarditis in the setting of cancer therapeutics: proposed case definitions for emerging clinical syndromes in cardio-oncology . Circulation . (2019 ) 140 :80 –91 . 10.1161/CIRCULATIONAHA.118.034497 31390169 14. Cheng P Zhu H Witteles RM Wu JC Quertermous T Wu SM . Cardiovascular risks in patients with COVID-19: potential mechanisms and areas of uncertainty . Curr Cardiol Rep . (2020 ) 22 :34 . 10.1007/s11886-020-01293-2 32350632 15. Dolhnikoff M Ferreira Ferranti J de Almeida Monteiro RA Duarte-Neto AN Soares Gomes-Gouvêa M Viu Degaspare N . SARS-CoV-2 in cardiac tissue of a child with COVID-19-related multisystem inflammatory syndrome . Lancet Child Adolesc Health . (2020 ) 4 :790 –4 . 10.1016/S2352-4642(20)30257-1 32828177 16. Inciardi RM Lupi L Zaccone G Italia L Raffo M Tomasoni D . Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19) . JAMA Cardiol . (2020 ) 5 :819 –24 . 10.1001/jamacardio.2020.1096 32219357 17. Kochav SM Coromilas E Nalbandian A Ranard LS Gupta A Chung MK . Cardiac arrhythmias in COVID-19 infection . Circ Arrhythm Electrophysiol . (2020 ) 13 :e008719 . 10.1161/CIRCEP.120.008719 32434385 18. Shi S Qin M Shen B Cai Y Liu T Yang F . Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China . JAMA Cardiol . (2020 ) 5 :802 –10 . 10.1001/jamacardio.2020.0950 32211816 19. Zeng J-H Liu Y-X Yuan J Wang F-X Wu W-B Li J-X . First case of COVID-19 complicated with fulminant myocarditis: a case report and insights . Infection . (2020 ) 48 :773 –7 . 10.1007/s15010-020-01424-5 32277408 20. Zheng YY Ma YT Zhang JY Xie X . COVID-19 and the cardiovascular system . Nat Rev Cardiol . (2020 ) 17 :259 –60 . 10.1038/s41569-020-0360-5 32139904 21. Zhu H Rhee JW Cheng P Waliany S Chang A Witteles RM Cardiovascular complications in patients with COVID-19: consequences of viral toxicities and host immune response . Curr Cardiol Rep . (2020 ) 22 :32 10.1007/s11886-020-01292-3 32318865 22. Wu Z McGoogan JM . Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese center for disease control and prevention . JAMA . (2020 ) 323 :1239 –42 . 10.1001/jama.2020.2648 32091533 23. Dabbagh MF Aurora L D'Souza P Weinmann AJ Bhargava P Basir MB Cardiac tamponade secondary to COVID-19 . JACC Case Rep . (2020 ) 2 :1326 –30 . 10.1016/j.jaccas.2020.04.009 32328588 24. Doyen D Moceri P Ducreux D Dellamonica J . Myocarditis in a patient with COVID-19: a cause of raised troponin and ECG changes . Lancet . (2020 ) 395 :1516 . 10.1016/S0140-6736(20)30912-0 32334650 25. Tavazzi G Pellegrini C Maurelli M Belliato M Sciutti F Bottazzi A . Myocardial localization of coronavirus in COVID-19 cardiogenic shock . Eur J Heart Fail . (2020 ) 22 :911 –5 . 10.1002/ejhf.1828 32275347 26. Oudit GY Kassiri Z Jiang C Liu PP Poutanen SM Penninger JM . SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS . Eur J Clin Invest . (2009 ) 39 :618 –25 . 10.1111/j.1365-2362.2009.02153.x 19453650 27. Ky B Mann DL . COVID-19 clinical trials: a primer for the cardiovascular and cardio-oncology communities . JACC CardioOncol . (2020 ) 5 :501 –17 . 10.1016/j.jacbts.2020.04.003 32309679 28. Patel AB Verma A . COVID-19 and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: what is the evidence? JAMA . (2020 ) 323 :1769 –70 . 10.1001/jama.2020.4812 32208485 29. Asokan I Rabadia SV Yang EH The COVID-19 pandemic and its impact on the cardio-oncology population . Curr Oncol Rep . (2020 ) 22 :60 10.1007/s11912-020-00945-4 32462289 30. Lee LYW Cazier JB Starkey T Turnbull CD Kerr R Middleton G COVID-19 mortality in patients with cancer on chemotherapy or other anticancer treatments: a prospective cohort study . Lancet . (2020 ) 395 :1919 –26 .32473682 31. Chang HM Okwuosa TM Scarabelli T Moudgil R Yeh ETH Cardiovascular complications of cancer therapy: best practices in diagnosis, prevention, and management: part 2 . J Am Coll Cardiol . (2017 ) 70 :2552 –65 . 10.1016/j.jacc.2017.09.1095 29145955 32. Singh D Thakur A Tang WH . Utilizing cardiac biomarkers to detect and prevent chemotherapy-induced cardiomyopathy . Curr Heart Fail Rep . (2015 ) 12 :255 –62 . 10.1007/s11897-015-0258-4 25869733 33. Meinardi MT Van Der Graaf WT Gietema JA Van Den Berg MP Sleijfer DT De Vries EG . Evaluation of long-term cardiotoxicity after epirubicin containing adjuvant chemotherapy and locoregional radiotherapy for breast cancer using various detection techniques . Heart . (2002 ) 88 :81 –2 . 10.1136/heart.88.1.81 12067953 34. Kuderer NM Choueiri TK Shah DP Shyr Y Rubinstein SM Rivera DR . Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study . Lancet . (2020 ) 395 :1907 –18 . 10.1016/S0140-6736(20)31187-9 32473681 35. Sanz J Sánchez-Quintana D Bossone E Bogaard HJ Naeije R . Anatomy, function, and dysfunction of the right ventricle: JACC state-of-the-art review . J Am Coll Cardiol . (2019 ) 73 :1463 –82 . 10.1016/j.jacc.2018.12.076 30922478 36. Zhao R Shu F Zhang C Song F Xu Y Guo Y Early detection and prediction of anthracycline-induced right ventricular cardiotoxicity by 3-dimensional echocardiography . JACC CardioOncol . (2020 ) 2 :13 –22 . 10.1016/j.jaccao.2020.01.007 37. Nagata Y Wu VC Kado Y Otani K Lin FC Otsuji Y . Prognostic value of right ventricular ejection fraction assessed by transthoracic 3D echocardiography . Circ Cardiovasc Imaging . (2017 ) 10 :e005384 . 10.1161/CIRCIMAGING.116.005384 28174197 38. Li Y Li H Zhu S Xie Y Wang B He L . Prognostic value of right ventricular longitudinal strain in patients with COVID-19 . JACC Cardiovasc Imaging . (2020 ) 13 :2287 –99 . 10.1016/j.jcmg.2020.04.014 32654963 39. Argulian E Sud K Vogel B Bohra C Garg VP Talebi S . Right ventricular dilation in hospitalized patients with COVID-19 infection . JACC Cardiovasc Imaging . (2020 ) 13 :2459 –61 . 10.1016/j.jcmg.2020.05.010 32426088 40. Mekontso Dessap A Boissier F Charron C Bégot E Repessé X Legras A . Acute cor pulmonale during protective ventilation for acute respiratory distress syndrome: prevalence, predictors, and clinical impact . Intensive Care Med . (2016 ) 42 :862 –70 . 10.1007/s00134-015-4141-2 26650055 41. Bull TM Clark B McFann K Moss M . Pulmonary vascular dysfunction is associated with poor outcomes in patients with acute lung injury . Am J Respir Crit Care Med . (2010 ) 182 :1123 –8 . 10.1164/rccm.201002-0250OC 20558628 42. Mekontso Dessap A Charron C Devaquet J Aboab J Jardin F Brochard L . Impact of acute hypercapnia and augmented positive end-expiratory pressure on right ventricle function in severe acute respiratory distress syndrome . Intensive Care Med . (2009 ) 35 :1850 –8 . 10.1007/s00134-009-1569-2 19652953 43. Zhou F Yu T Du R Fan G Liu Y Liu Z Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study . Lancet . (2020 ) 395 :1054 –62 . 10.1016/S0140-6736(20)30566-3 32171076 44. Xie Y Wang X Yang P Zhang S COVID-19 complicated by acute pulmonary embolism . Radiol Cardiothoracic Imaging . (2020 ) 2 :e200067 10.1148/ryct.2020200067 45. Rotzinger D Beigelman-Aubry C von Garnier C Qanadli S . Pulmonary embolism in patients with COVID-19: time to change the paradigm of computed tomography . Thromb Res . (2020 ) 190 :58 –9 . 10.1016/j.thromres.2020.04.011 32302782 46. Poissy J Goutay J Caplan M Parmentier E Duburcq T Lassalle F . Pulmonary embolism in COVID-19 patients: awareness of an increased prevalence . Circulation . (2020 ) 142 :184 –6 . 10.1161/CIRCULATIONAHA.120.047430 32330083 47. Network ARDS Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome . N Engl J Med . (2000 ) 342 :1301 –8 . 10.1056/NEJM200005043421801 10793162 48. Vieillard-Baron A Charron C Caille V Belliard G Page B Jardin F . Prone positioning unloads the right ventricle in severe ARDS . Chest . (2007 ) 132 :1440 –6 . 10.1378/chest.07-1013 17925425 49. Guérin C Reignier J Richard J-C Beuret P Gacouin A Boulain T . Prone positioning in severe acute respiratory distress syndrome . N Engl J Med . (2013 ) 368 :2159 –68 . 10.1056/NEJMoa1214103 23688302 50. Ghelichkhani P Esmaeili M . Prone position in management of COVID-19 patients; a commentary . Arch Acad Emerg Med . (2020 ) 8 :e48 . 32309812 51. Boczar KE Aseyev O Sulpher J Johnson C Burwash IG Turek M . Right heart function deteriorates in breast cancer patients undergoing anthracycline-based chemotherapy . Echo Res Pract . (2016 ) 3 :79 –84 . 10.1530/ERP-16-0020 27457966 52. Oliveira GH Dupont M Naftel D Myers SL Yuan Y Tang WH . Increased need for right ventricular support in patients with chemotherapy-induced cardiomyopathy undergoing mechanical circulatory support: outcomes from the INTERMACS Registry (interagency registry for mechanically assisted circulatory support) . J Am Coll Cardiol . (2014 ) 63 :240 –8 . 10.1016/j.jacc.2013.09.040 24161324 53. Vejpongsa P Yeh ET . Topoisomerase 2β: a promising molecular target for primary prevention of anthracycline-induced cardiotoxicity . Clin Pharmacol Ther . (2013 ) 95 :45 –52 . 10.1038/clpt.2013.201 24091715 54. Nebigil CG Désaubry L . Updates in anthracycline-mediated cardiotoxicity . Front Pharmacol . (2018 ) 9 :1262 . 10.3389/fphar.2018.01262 30483123 55. Moazeni S Cadeiras M Yang EH Deng MC Nguyen KL . Anthracycline induced cardiotoxicity: biomarkers and “Omics” technology in the era of patient specific care . Clin Transl Med . (2017 ) 6 :17 . 10.1186/s40169-017-0148-3 28493232 56. Price-Haywood EG Burton J Fort D Seoane L . Hospitalization and mortality among black patients and white patients with covid-19 . N Engl J Med . (2020 ) 382 :2534 –43 . 10.1056/NEJMsa2011686 32459916 57. Carnethon MR Pu J Howard G Albert MA Anderson CAM Bertoni AG . Cardiovascular health in African Americans: a scientific statement from the American Heart Association . Circulation . (2017 ) 136 :e393 –423 . 10.1161/CIR.0000000000000534 29061565 58. Ned RM Yesupriya A Imperatore G Smelser DT Moonesinghe R Chang MH . The ACE I/D polymorphism in US adults: limited evidence of association with hypertension-related traits and sex-specific effects by race/ethnicity . Am J Hypertens . (2012 ) 25 :209 –15 . 10.1038/ajh.2011.182 21993364 59. Fløe A Hoffmann HJ Nissen PH Møller HJ Hilberg O . Genotyping increases the yield of angiotensin-converting enzyme in sarcoidosis–a systematic review . Dan Med J . (2014 ) 61 :A4815 . 24814734 60. Mirsaeidi M Machado RF Schraufnagel D Sweiss NJ Baughman RP . Racial difference in sarcoidosis mortality in the United States . Chest . (2015 ) 147 :438 –49 . 10.1378/chest.14-1120 25188873 61. Trojanowicz B Ulrich C Fiedler R Martus P Storr M Boehler T . Modulation of leucocytic angiotensin-converting enzymes expression in patients maintained on high-permeable haemodialysis . Nephrol Dial Transplant . (2018 ) 33 :34 –43 . 10.1093/ndt/gfx206 28992224 62. Delanghe JR Speeckaert MM De Buyzere ML . The host's angiotensin-converting enzyme polymorphism may explain epidemiological findings in COVID-19 infections . Clin Chim Acta . (2020 ) 505 :192 –3 . 10.1016/j.cca.2020.03.031 32220422 63. Cao Y Li L Feng Z Wan S Huang P Sun X . Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations . Cell Discov . (2020 ) 6 :11 . 10.1038/s41421-020-0147-1 32133153 64. Hasan S Dinh K Lombardo F Kark J . Doxorubicin cardiotoxicity in African Americans . J Natl Med Assoc . (2004 ) 96 :196 –9 . 14977278 65. Lotrionte M Biondi-Zoccai G Abbate A Lanzetta G D'Ascenzo F Malavasi V . Review and meta-analysis of incidence and clinical predictors of anthracycline cardiotoxicity . Am J Cardiol . (2013 ) 112 :1980 –4 . 10.1016/j.amjcard.2013.08.026 24075281 66. Finkelman BS Putt M Wang T Wang L Narayan H Domchek S . Arginine-nitric oxide metabolites and cardiac dysfunction in patients with breast cancer . J Am Coll Cardiol . (2017 ) 70 :152 –62 . 10.1016/j.jacc.2017.05.019 28683962 67. Litvak A Batukbhai B Russell SD Tsai HL Rosner GL Jeter SC . Racial disparities in the rate of cardiotoxicity of HER2-targeted therapies among women with early breast cancer . Cancer . (2018 ) 124 :1904 –11 . 10.1002/cncr.31260 29381193 68. Baron KB Brown JR Heiss BL Marshall J Tait N Tkaczuk KH . Trastuzumab-induced cardiomyopathy: incidence and associated risk factors in an inner-city population . J Card Fail . (2014 ) 20 :555 –9 . 10.1016/j.cardfail.2014.05.012 24905295 69. Yancy CW . COVID-19 and African Americans . JAMA . (2020 ) 323 :1891 –2 . 10.1001/jama.2020.6548 32293639 70. Haynes N Cooper LA Albert MA Cardiologists AoB . At the heart of the matter: unmasking and addressing COVID-19's toll on diverse populations . Circulation . (2020 ) 142 :105 –7 . 10.1161/CIRCULATIONAHA.120.048126 32364762 71. Dorn AV Cooney RE Sabin ML . COVID-19 exacerbating inequalities in the US . Lancet . (2020 ) 395 :1243 –4 . 10.1016/S0140-6736(20)30893-X 32305087 72. Douglas M Katikireddi SV Taulbut M McKee M McCartney G . Mitigating the wider health effects of covid-19 pandemic response . BMJ . (2020 ) 369 :m1557 . 10.1136/bmj.m1557 32341002 73. Chung RY Dong D Li MM . Socioeconomic gradient in health and the covid-19 outbreak . BMJ . (2020 ) 369 :m1329 . 10.1136/bmj.m1329 32238351 74. Musher DM Abers MS Corrales-Medina VF . Acute infection and myocardial infarction. Reply . N Engl J Med . (2019 ) 380 :e21 . 10.1056/NEJMc1901647 30970200 75. Libby P Loscalzo J Ridker PM Farkouh ME Hsue PY Fuster V . Inflammation, immunity, and infection in atherothrombosis: JACC review topic of the week . J Am Coll Cardiol . (2018 ) 72 :2071 –81 . 10.1016/j.jacc.2018.08.1043 30336831 76. Lax SF Skok K Zechner P Kessler HH Kaufmann N Koelblinger C . Pulmonary arterial thrombosis in COVID-19 with fatal outcome: results from a prospective, single-center, clinicopathologic case series . Ann Intern Med . (2020 ) 173 :350 –61 . 10.7326/M20-2566 32422076 77. Sharma A Garcia G Arumugaswami V Svendsen CN Human iPSC-derived cardiomyocytes are susceptible to SARS-CoV-2 infection . bioRxiv . (2020 ). 10.1101/2020.04.21.051912 78. Zhu N Zhang D Wang W Li X Yang B Song J . A novel coronavirus from patients with pneumonia in China, 2019 . N Engl J Med . (2020 ) 382 :727 –33 . 10.1056/NEJMoa2001017 31978945 79. Perlot T Penninger JM . ACE2—from the renin-angiotensin system to gut microbiota and malnutrition . Microbes Infect . (2013 ) 15 :866 –73 . 10.1016/j.micinf.2013.08.003 23962453 80. Anguiano L Riera M Pascual J Valdivielso JM Barrios C Betriu A . Circulating angiotensin-converting enzyme 2 activity in patients with chronic kidney disease without previous history of cardiovascular disease . Nephrol Dial Transpl . (2015 ) 30 :1176 –85 . 10.1093/ndt/gfv025 25813276 81. South AM Diz DI Chappell MC . COVID-19, ACE2, and the cardiovascular consequences . Am J Physiol Heart Circ Physiol . (2020 ) 318 :H1084 –H90 . 10.1152/ajpheart.00217.2020 32228252 82. Arentz M Yim E Klaff L Lokhandwala S Riedo FX Chong M . Characteristics and outcomes of 21 critically ill patients with COVID-19 in Washington state . JAMA . (2020 ) 323 :1612 –4 . 10.1001/jama.2020.4326 32191259 83. Ruan Q Yang K Wang W Jiang L Song J Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China . Intensive Care Med . (2020 ) 46 :1294 –7 . 10.1007/s00134-020-06028-z 32253449 84. Zheng M Gao Y Wang G Song G Liu S Sun D . Functional exhaustion of antiviral lymphocytes in COVID-19 patients . Cell Mol Immunol . (2020 ) 17 :533 –5 . 10.1038/s41423-020-0402-2 32203188 85. Zheng HY Zhang M Yang CX Zhang N Wang XC Yang XP . Elevated exhaustion levels and reduced functional diversity of T cells in peripheral blood may predict severe progression in COVID-19 patients . Cell Mol Immunol . (2020 ) 17 :541 –3 . 10.1038/s41423-020-0401-3 32203186 86. Haslam A Prasad V . Estimation of the percentage of US patients with cancer who are eligible for and respond to checkpoint inhibitor immunotherapy drugs . JAMA Netw Open . (2019 ) 2 :e192535 . 10.1001/jamanetworkopen.2019.2535 31050774 87. Garcia-Diaz A Shin DS Moreno BH Saco J Escuin-Ordinas H Rodriguez GA . Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression . Cell Rep . (2019 ) 29 :3766 . 10.1016/j.celrep.2019.11.113 31825850 88. Robilotti EV Babady NE Mead PA Rolling T Perez-Johnston R Bernardes M . Determinants of COVID-19 disease severity in patients with cancer . Nat Med . (2020 ) 26 :1218 –23 . 10.1038/s41591-020-0979-0 32581323 89. Lee LYW Cazier JB Starkey T Turnbull CD Kerr R Middleton G COVID-19 mortality in patients with cancer on chemotherapy or other anticancer treatments: a prospective cohort study . Lancet . (2020 ) 395 :1919 –26 . 10.1016/S0140-6736(20)31173-9 32473682 90. Oren O Yang EH Molina JR Bailey KR Blumenthal RS Kopecky SL . Cardiovascular health and outcomes in cancer patients receiving immune checkpoint inhibitors . Am J Cardiol . (2020 ) 125 :1920 –6 . 10.1016/j.amjcard.2020.02.016 32312493 91. Xie G Cheng T Lin J Zhang L Zheng J Liu Y . Local angiotensin II contributes to tumor resistance to checkpoint immunotherapy . J Immunother Cancer . (2018 ) 6 :88 . 10.1186/s40425-018-0401-3 30208943 92. Pinter M Jain RK . Targeting the renin-angiotensin system to improve cancer treatment: implications for immunotherapy . Sci Transl Med . (2017 ) 9 :eaan5616 . 10.1126/scitranslmed.aan5616 28978752 93. Hicks BM Filion KB Yin H Sakr L Udell JA Azoulay L . Angiotensin converting enzyme inhibitors and risk of lung cancer: population based cohort study . BMJ . (2018 ) 363 :k4209 . 10.1136/bmj.k4209 30355745 94. Medjebar S Richard C Fumet J-D Malo J Elkrief A Blais N Angiotensin-converting enzyme inhibitor prescription is associated with decreased progression-free survival (PFS) and overall survival (OS) in patients with lung cancers treated with PD-1/PD-L1 immune checkpoint blockers . Am Soc Clin Oncol . (2019 ) 37 :e20512 10.1200/JCO.2019.37.15_suppl.e20512 95. Cascella M Rajnik M Cuomo A Dulebohn SC Di Napoli R Features, Evaluation and Treatment Coronavirus (COVID-19) . Treasure Island, FL : StatPearls Publishing Copyright, LLC (2020 ). 96. Yáñez L Sánchez-Escamilla M Perales MA . CAR T cell toxicity: current management and future directions . Hemasphere . (2019 ) 3 :e186 . 10.1097/HS9.0000000000000186 31723825 97. Neelapu SS Tummala S Kebriaei P Wierda W Gutierrez C Locke FL . Chimeric antigen receptor T-cell therapy—assessment and management of toxicities . Nat Rev Clin Oncol . (2018 ) 15 :47 –62 . 10.1038/nrclinonc.2017.148 28925994 98. Pathan N Hemingway CA Alizadeh AA Stephens AC Boldrick JC Oragui EE . Role of interleukin 6 in myocardial dysfunction of meningococcal septic shock . Lancet . (2004 ) 363 :203 –9 . 10.1016/S0140-6736(03)15326-3 14738793 99. Huang L Zhao X Qi Y Li H Ye G Liu Y . Sepsis-associated severe interleukin-6 storm in critical coronavirus disease 2019 . Cell Mol Immunol . (2020 ) 17 :1092 –4 . 10.1038/s41423-020-00522-6 32917983 100. Liu Z Li J Chen D Gao R Zeng W Chen S . Dynamic interleukin-6 level changes as a prognostic indicator in patients with COVID-19 . Front Pharmacol . (2020 ) 11 :1093 . 10.3389/fphar.2020.01093 32765283 101. Merad M Martin JC Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages . Nat Rev Immunol . (2020 ) 20 :355 –62 . 10.1038/s41577-020-0331-4 32376901 102. Liu Z Xiao X Wei X Li J Yang J Tan H . Composition and divergence of coronavirus spike proteins and host ACE2 receptors predict potential intermediate hosts of SARS-CoV-2 . J Med Virol . (2020 ) 92 :595 –601 . 10.1002/jmv.25726 32100877 103. Ratajczak MZ Kucia M . SARS-CoV-2 infection and overactivation of Nlrp3 inflammasome as a trigger of cytokine “storm” and risk factor for damage of hematopoietic stem cells . Leukemia . (2020 ) 34 :1726 –9 . 10.1038/s41375-020-0887-9 32483300 104. Kuba K Imai Y Rao S Gao H Guo F Guan B . A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury . Nat Med . (2005 ) 11 :875 –9 . 10.1038/nm1267 16007097 105. Leisman DE Deutschman CS Legrand M . Facing COVID-19 in the ICU: vascular dysfunction, thrombosis, and dysregulated inflammation . Intensive Care Med . (2020 ) 46 :1105 –8 . 10.1007/s00134-020-06059-6 32347323 106. Ren XS Tong Y Ling L Chen D Sun HJ Zhou H . NLRP3 gene deletion attenuates angiotensin II-induced phenotypic transformation of vascular smooth muscle cells and vascular remodeling . Cell Physiol Biochem . (2017 ) 44 :2269 –80 . 10.1159/000486061 29262411 107. Chen IY Moriyama M Chang MF Ichinohe T . Severe acute respiratory syndrome coronavirus viroporin 3a activates the NLRP3 inflammasome . Front Microbiol . (2019 ) 10 :50 . 10.3389/fmicb.2019.00050 30761102 108. Schieffer B Bünte C Witte J Hoeper K Böger RH Schwedhelm E . Comparative effects of AT1-antagonism and angiotensin-converting enzyme inhibition on markers of inflammation and platelet aggregation in patients with coronary artery disease . J Am Coll Cardiol . (2004 ) 44 :362 –8 . 10.1016/j.jacc.2004.03.065 15261932 109. Luther JM Gainer JV Murphey LJ Yu C Vaughan DE Morrow JD . Angiotensin II induces interleukin-6 in humans through a mineralocorticoid receptor-dependent mechanism . Hypertension . (2006 ) 48 :1050 –7 . 10.1161/01.HYP.0000248135.97380.76 17043157 110. Swanson KV Deng M Ting JP . The NLRP3 inflammasome: molecular activation and regulation to therapeutics . Nat Rev Immunol . (2019 ) 19 :477 –89 . 10.1038/s41577-019-0165-0 31036962 111. Park TS Zambidis ET . A role for the renin-angiotensin system in hematopoiesis . Haematologica . (2009 ) 94 :745 –7 . 10.3324/haematol.2009.006965 19483149 112. Ratajczak MZ Bujko K Ciechanowicz A Sielatycka K Cymer M Marlicz W . SARS-CoV-2 entry receptor ACE2 is expressed on very small CD45 . Stem Cell Rev Rep . (2020 ) 20 :1 –12 . 10.1007/s12015-020-10010-z 32691370 113. Neelapu SS Locke FL Bartlett NL Lekakis LJ Miklos DB Jacobson CA . Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma . N Engl J Med . (2017 ) 377 :2531 –44 . 10.1056/NEJMoa1707447 29226797 114. Giavridis T van der Stegen SJC Eyquem J Hamieh M Piersigilli A Sadelain M . CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade . Nat Med . (2018 ) 24 :731 –8 . 10.1038/s41591-018-0041-7 29808005 115. Shimabukuro-Vornhagen A Gödel P Subklewe M Stemmler HJ Schlößer HA Schlaak M . Cytokine release syndrome . J Immunother Cancer . (2018 ) 6 :56 . 10.1186/s40425-018-0343-9 29907163 116. Tang N Li D Wang X Sun Z . Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia . J Thromb Haemost . (2020 ) 18 :844 –7 . 10.1111/jth.14768 32073213 117. Klok FA Kruip M van der Meer NJM Arbous MS Gommers D Kant KM Incidence of thrombotic complications in critically ill ICU patients with COVID-19 . Thromb Res . (2020 ) 191 :145 –7 . 10.1016/j.thromres.2020.04.013 32291094 118. Cook D Meade M Guyatt G Walter S Heels-Ansdell D Warkentin TE . Dalteparin versus unfractionated heparin in critically ill patients . N Engl J Med . (2011 ) 364 :1305 –14 . 10.1056/NEJMoa1014475 21417952 119. Bikdeli B Madhavan MV Jimenez D Chuich T Dreyfus I Driggin E COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up . J Am Coll Cardiol . (2020 ) 75 :2950 –73 . 10.1016/j.jacc.2020.04.031 32311448 120. Navi BB Reiner AS Kamel H Iadecola C Okin PM Elkind MSV . Risk of arterial thromboembolism in patients with cancer . J Am Coll Cardiol . (2017 ) 70 :926 –38 . 10.1016/j.jacc.2017.06.047 28818202 121. Varga Z Flammer AJ Steiger P Haberecker M Andermatt R Zinkernagel AS . Endothelial cell infection and endotheliitis in COVID-19 . Lancet . 395 :1417 –8 . 10.1016/S0140-6736(20)30937-5 32325026 122. Bick RL . Cancer-associated thrombosis . N Engl J Med . (2003 ) 349 :109 –11 . 10.1056/NEJMp030086 12853582 123. Helms J Tacquard C Severac F Leonard-Lorant I Ohana M Delabranche X . High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study . Intensive Care Med . (2020 ) 46 :1089 –98 . 10.1007/s00134-020-06062-x 32367170 124. Henry BM Vikse J Benoit S Favaloro EJ Lippi G . Hyperinflammation and derangement of renin-angiotensin-aldosterone system in COVID-19: a novel hypothesis for clinically suspected hypercoagulopathy and microvascular immunothrombosis . Clin Chim Acta . (2020 ) 507 :167 –73 . 10.1016/j.cca.2020.04.027 32348783 125. Connors JM Levy JH . COVID-19 and its implications for thrombosis and anticoagulation . Blood . (2020 ) 135 :2033 –40 . 10.1182/blood.2020006000 32339221 126. Cook D Crowther M Meade M Rabbat C Griffith L Schiff D . Deep venous thrombosis in medical-surgical critically ill patients: prevalence, incidence, and risk factors . Crit Care Med . (2005 ) 33 :1565 –71 . 10.1097/01.CCM.0000171207.95319.B2 16003063 127. Zhang C Zhang Z Mi J Wang X Zou Y Chen X . The cumulative venous thromboembolism incidence and risk factors in intensive care patients receiving the guideline-recommended thromboprophylaxis . Medicine (Baltimore) . (2019 ) 98 :e15833 . 10.1097/MD.0000000000015833 31169685 128. Becker RC . COVID-19 update: covid-19-associated coagulopathy . J Thromb Thrombolysis . (2020 ) 50 :54 –67 . 10.1007/s11239-020-02134-3 32415579 129. Tang N Bai H Chen X Gong J Li D Sun Z Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy . J Thromb Haemost . (2020 ) 18 :1094 –9 . 10.1111/jth.14817 32220112 130. Iba T Levy JH . Inflammation and thrombosis: roles of neutrophils, platelets and endothelial cells and their interactions in thrombus formation during sepsis . J Thromb Haemost . (2018 ) 16 :231 –41 . 10.1111/jth.13911 29193703 131. Thachil J Falanga A Levi M Liebman H Di Nisio M Scientific and Standardization Committee of the International Society on Thrombosis and Hemostasis Management of cancer-associated disseminated intravascular coagulation: guidance from the SSC of the ISTH . J Thromb Haemost . (2015 ) 13 :671 –5 . 10.1111/jth.12838 25556711 132. Khorana AA Kuderer NM Culakova E Lyman GH Francis CW . Development and validation of a predictive model for chemotherapy-associated thrombosis . Blood . (2008 ) 111 :4902 –7 . 10.1182/blood-2007-10-116327 18216292 133. Key NS Khorana AA Kuderer NM Bohlke K Lee AYY Arcelus JI . Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update . J Clin Oncol . (2020 ) 38 :496 –520 . 10.1200/JCO.19.01461 31381464 134. Lee AY Levine MN . Venous thromboembolism and cancer: risks and outcomes . Circulation . (2003 ) 107 (Suppl. 1 ):I17 -21 . 10.1161/01.CIR.0000078466.72504.AC 12814981 135. Liu H Yang Y Jiang J Wang X Zhang C Jiang Y . Coexistence of a huge venous thromboembolism and bleeding tendency in cytokine release syndrome during CAR-T therapy . Onco Targets Ther . (2019 ) 12 :8955 –60 . 10.2147/OTT.S223697 31802905 136. Hashmi H Mirza A-S Darwin A Logothetis C Garcia F Kommalapati A Incidence and management of venous thrombo-embolism (VTE) associated with CD19-directed chimeric antigen receptor (CAR) T-cell therapy: a single institution experience . Biol Blood Marrow Transplant . (2020 ) 26 :S265 10.1016/j.bbmt.2019.12.430 137. Iliescu CA Grines CL Herrmann J Yang EH Cilingiroglu M Charitakis K SCAI Expert consensus statement: evaluation, management, and special considerations of cardio-oncology patients in the cardiac catheterization laboratory (endorsed by the cardiological society of india, and sociedad Latino Americana de Cardiologia intervencionista) . Catheter Cardiovasc Interv . (2016 ) 87 :E202 –23 . 10.1002/ccd.26379 26756277 138. Bangalore S Sharma A Slotwiner A Yatskar L Harari R Shah B . ST-segment elevation in patients with Covid-19—a case series . N Engl J Med . (2020 ) 382 :2478 –80 . 10.1056/NEJMc2009020 32302081 139. Lodigiani C Iapichino G Carenzo L Cecconi M Ferrazzi P Sebastian T . Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy . Thromb Res . (2020 ) 191 :9 –14 . 10.1016/j.thromres.2020.04.024 32353746 140. Horby P Lim WS Emberson J Mafham M Bell J Linsell L . Effect of dexamethasone in hospitalized patients with COVID-19: preliminary report . medRxiv . (2020 ) NEJMoa2021436 . 10.1101/2020.06.22.20137273 32678530 141. Ghosh AK Chen DH Guha A Mackenzie S Walker JM Roddie C CAR T cell therapy–related cardiovascular outcomes and management. Systemic disease or direct cardiotoxicity? JACC CardioOncol . (2020 ) 2 :97 –109 . 10.1016/j.jaccao.2020.02.011 142. Mahmood SS Fradley MG Cohen JV Nohria A Reynolds KL Heinzerling LM . Myocarditis in patients treated with immune checkpoint inhibitors . J Am Coll Cardiol . (2018 ) 71 :1755 –64 . 10.1016/j.jacc.2018.02.037 29567210 143. Brahmer JR Lacchetti C Thompson JA . Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American society of clinical oncology clinical practice guideline summary . J Oncol Pract . (2018 ) 14 :247 –9 . 10.1200/JOP.18.00005 29517954 144. Hu JR Florido R Lipson EJ Naidoo J Ardehali R Tocchetti CG . Cardiovascular toxicities associated with immune checkpoint inhibitors . Cardiovasc Res . (2019 ) 115 :854 –68 . 10.1093/cvr/cvz026 30715219 145. Davila ML Riviere I Wang X Bartido S Park J Curran K Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia . Sci Transl Med . (2014 ) 6 :224ra25 10.1126/scitranslmed.3008226 146. Maude SL Frey N Shaw PA Aplenc R Barrett DM Bunin NJ . Chimeric antigen receptor T cells for sustained remissions in leukemia . N Engl J Med . (2014 ) 371 :1507 –17 . 10.1056/NEJMoa1407222 25317870 147. Le RQ Li L Yuan W Shord SS Nie L Habtemariam BA FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome . Oncologist . (2018 ) 23 :943 –7 . 10.1634/theoncologist.2018-0028 29622697 148. Abboud R Keller J Slade M DiPersio JF Westervelt P Rettig MP . Severe cytokine-release syndrome after t cell-replete peripheral blood haploidentical donor transplantation is associated with poor survival and anti-IL-6 therapy is safe and well tolerated . Biol Blood Marrow Transplant . (2016 ) 22 :1851 –60 . 10.1016/j.bbmt.2016.06.010 27318038 149. Luo P Liu Y Qiu L Liu X Liu D Li J . Tocilizumab treatment in COVID-19: a single center experience . J Med Virol . (2020 ) 92 :814 –8 . 10.1002/jmv.25801 32253759 150. Sciascia S Aprà F Baffa A Baldovino S Boaro D Boero R . Pilot prospective open, single-arm multicentre study on off-label use of tocilizumab in patients with severe COVID-19 . Clin Exp Rheumatol . (2020 ) 38 :529 –32 . 32359035 151. Guaraldi G Meschiari M Cozzi-Lepri A Milic J Tonelli R Menozzi M . Tocilizumab in patients with severe COVID-19: a retrospective cohort study . Lancet Rheumatol . (2020 ) 2 :e474 –84 . 10.1016/S2665-9913(20)30173-9 32835257 152. Kewan T Covut F Al-Jaghbeer MJ Rose L Gopalakrishna KV Akbik B . Tocilizumab for treatment of patients with severe COVID-19: a retrospective cohort study . EClinicalMedicine . (2020 ) 24 :100418 . 10.1016/j.eclinm.2020.100418 32766537 153. Alvi RM Frigault MJ Fradley MG Jain MD Mahmood SS Awadalla M . Cardiovascular events among adults treated with chimeric antigen receptor T-cells (CAR-T) . J Am Coll Cardiol . (2019 ) 74 :3099 –108 . 10.1016/j.jacc.2019.10.038 31856966 154. Maude SL Barrett D Teachey DT Grupp SA . Managing cytokine release syndrome associated with novel T cell-engaging therapies . Cancer J . (2014 ) 20 :119 –22 . 10.1097/PPO.0000000000000035 24667956 155. Zhu C Wei Y Wei X . AXL receptor tyrosine kinase as a promising anti-cancer approach: functions, molecular mechanisms and clinical applications . Mol Cancer . (2019 ) 18 :153 . 10.1186/s12943-019-1090-3 31684958 156. Morizono K Xie Y Olafsen T Lee B Dasgupta A Wu AM . The soluble serum protein Gas6 bridges virion envelope phosphatidylserine to the TAM receptor tyrosine kinase Axl to mediate viral entry . Cell Host Microbe . (2011 ) 9 :286 –98 . 10.1016/j.chom.2011.03.012 21501828 157. Fujimori T Grabiec AM Kaur M Bell TJ Fujino N Cook PC . The Axl receptor tyrosine kinase is a discriminator of macrophage function in the inflamed lung . Mucosal Immunol . (2015 ) 8 :1021 –30 . 10.1038/mi.2014.129 25603826 158. Caldentey G García De Frutos P Cristóbal H Garabito M Berruezo A Bosch X . Serum levels of growth arrest-specific 6 protein and soluble AXL in patients with ST-segment elevation myocardial infarction . Eur Heart J Acute Cardiovasc Care . (2019 ) 8 :708 –16 . 10.1177/2048872617740833 29119801 159. National Institutes of Health Coronavirus Disease 2019 (COVID-19) Treatment Guidelines . (2020 ). Available online at: https://www.covid19treatmentguidelines.nih.gov/ (accessed October 01, 2020). 160. Fatunde OA Brown SA . The role of CYP450 drug metabolism in precision cardio-oncology . Int J Mol Sci . (2020 ) 21 :604 . 10.3390/ijms21020604 31963461 161. Iacovelli R Verri E Cossu Rocca M Aurilio G Cullurà D De Cobelli O . The incidence and relative risk of cardiovascular toxicity in patients treated with new hormonal agents for castration-resistant prostate cancer . Eur J Cancer . (2015 ) 51 :1970 –7 . 10.1016/j.ejca.2015.06.106 26169016 162. Lu-Yao G Nikita N Keith SW Nightingale G Gandhi K Hegarty SE . Mortality and hospitalization risk following oral androgen signaling inhibitors among men with advanced prostate cancer by pre-existing cardiovascular comorbidities . Eur Urol . (2020 ) 77 :158 –66 . 10.1016/j.eururo.2019.07.031 31420248 163. Saltalamacchia G Frascaroli M Bernardo A Quaquarini E . Renal and cardiovascular toxicities by new systemic treatments for prostate cancer . Cancers (Basel) . (2020 ) 12 :1750 . 10.3390/cancers12071750 32630204 164. Angiolillo DJ Fernández-Ortiz A Bernardo E Barrera Ramírez C Sabaté M Fernandez C . Platelet aggregation according to body mass index in patients undergoing coronary stenting: should clopidogrel loading-dose be weight adjusted? J Invasive Cardiol . (2004 ) 16 :169 –74 . 15152138 165. Yang K . What do we know about remdesivir drug interactions? Clin Transl Sci . (2020 ) 13 :842 –4 . 10.1111/cts.12815 32402130 166. Beigel JH Tomashek KM Dodd LE Mehta AK Zingman BS Kalil AC Remdesivir for the treatment of covid-19—preliminary report . N Engl J Med . (2020 ) 383 :1813 –26 . 10.1056/NEJMoa2007764 32445440 167. Wang Y Zhang D Du G Du R Zhao J Jin Y . Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial . Lancet . (2020 ) 395 :1569 –78 . 10.1016/S0140-6736(20)31022-9 32423584 168. Siegel D Hui HC Doerffler E Clarke MO Chun K Zhang L . Discovery and synthesis of a phosphoramidate prodrug of a pyrrolo[2,1-f][triazin-4-amino] adenine C-nucleoside (GS-5734) for the treatment of ebola and emerging viruses . J Med Chem . (2017 ) 60 :1648 –61 . 10.1021/acs.jmedchem.6b01594 28124907 169. Paranjpe I Fuster V Lala A Russak A Glicksberg BS Levin MA . Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with COVID-19 . J Am Coll Cardiol . (2020 ) 76 :122 –4 . 10.1016/j.jacc.2020.05.001 32387623 170. Farge D Frere C Connors JM Ay C Khorana AA Munoz A 2019 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer . Lancet Oncol . (2019 ) 20 :e566 –81 . 10.1016/S1470-2045(19)30750-8 31492632 171. Key NS Bohlke K Falanga A Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update summary . J Oncol Pract . (2019 ) 15 :661 –4 . 10.1200/JOP.19.00368 172. Vaduganathan M Vardeny O Michel T McMurray JJV Pfeffer MA Solomon SD . Renin-angiotensin-aldosterone system inhibitors in patients with covid-19 . N Engl J Med . (2020 ) 382 :1653 –9 . 10.1056/NEJMsr2005760 32227760 173. Imai Y Kuba K Rao S Huan Y Guo F Guan B . Angiotensin-converting enzyme 2 protects from severe acute lung failure . Nature . (2005 ) 436 :112 –6 . 10.1038/nature03712 16001071 174. Khan A Benthin C Zeno B Albertson TE Boyd J Christie JD . A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome . Crit Care . (2017 ) 21 :234 . 10.1186/s13054-017-1823-x 28877748 175. Zhang P Zhu L Cai J Lei F Qin JJ Xie J Association of inpatient use of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19 . Circ Res . (2020 ) 126 :1671 –81 . 10.1161/CIRCRESAHA.120.317242 32302265 176. Mehta N Kalra A Nowacki AS Anjewierden S Han Z Bhat P . Association of use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with testing positive for coronavirus disease 2019 (COVID-19) . JAMA Cardiol . (2020 ) 5 :1020 –6 . 10.1001/jamacardio.2020.1855 32936273 177. Reynolds HR Adhikari S Pulgarin C Troxel AB Iturrate E Johnson SB . Renin-angiotensin-aldosterone system inhibitors and risk of covid-19 . N Engl J Med . (2020 ) 382 :2441 –8 . 10.1056/NEJMoa2008975 32356628 178. Mancia G Rea F Ludergnani M Apolone G Corrao G . Renin-angiotensin-aldosterone system blockers and the risk of covid-19 . N Engl J Med . (2020 ) 382 :2431 –40 . 10.1056/NEJMoa2006923 32356627 179. de Abajo FJ Rodríguez-Martín S Lerma V Mejía-Abril G Aguilar M García-Luque A . Use of renin-angiotensin-aldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: a case-population study . Lancet . (2020 ) 395 :1705 –14 . 10.1016/S0140-6736(20)31030-8 32416785 180. Alashi A Lang R Seballos R Feinleib S Sukol R Cho L . Reclassification of coronary heart disease risk in a primary prevention setting: traditional risk factor assessment . Cardiovasc Diagn Ther . (2019 ) 9 :214 –20 . 10.21037/cdt.2019.04.05 31275811 181. Khera R Clark C Lu Y Guo Y Ren S Truax B . Association of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers with the risk of hospitalization and death in hypertensive patients with coronavirus disease-19 . medRxiv . (2020 ). 10.1101/2020.05.17.20104943 32511481 182. Stawiski EW Diwanji D Suryamohan K Gupta R Fellouse FA Sathirapongsasuti F Human ACE2 receptor polymorphisms predict SARS-CoV-2 susceptibility . bioRxiv . (2020 ). 10.1101/2020.04.07.024752 183. Calcagnile M Forgez P Iannelli A Bucci C Alifano M Alifano P ACE2 polymorphisms and individual susceptibility to SARS-CoV-2 infection: insights from an in silico study . bioRxiv . (2020 ). 10.1101/2020.04.23.057042 184. Gulati G Heck SL Ree AH Hoffmann P Schulz-Menger J Fagerland MW . Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 × 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol . Eur Heart J . (2016 ) 37 :1671 –80 . 10.1093/eurheartj/ehw022 26903532 185. Sommerstein R Kochen MM Messerli FH Grani C . Coronavirus disease 2019 (COVID-19): do angiotensin-converting enzyme inhibitors/angiotensin receptor blockers have a biphasic effect? J Am Heart Assoc . (2020 ) 9 :e016509 . 10.1161/JAHA.120.016509 32233753 186. Cardiology ACo . HFSA/ACC/AHA statement addresses concerns re: using RAAS antagonists in COVID-19 . J Card Fail . (2020 ) 26 :370 . 10.1016/j.cardfail.2020.04.013 32439095 187. Simone Gd Position Statement of the ESC Council on Hypertension on ACE-Inhibitors and Angiotensin Receptor Blockers . European Society of Cardiology (2020 ). 188. National Cancer Institute N COVID-19 and Its Implications for Thrombosis and Anticoagulation: ClinicalTrials.gov Identifier: NCT04317092 . (2020 ). Available online at: https://clinicaltrials.gov/ct2/show/NCT04317092 (accessed October 01, 2020). 189. Bart N Lambrecht UH, Ghent . ClinicalTrials.gov . (2020 ). Available online at: https://www.clinicaltrials.gov/ct2/show/NCT04330638 (accessed April 24, 2020). 190. Wang L Zhang Y Zhang S . Cardiovascular impairment in COVID-19: learning from current options for cardiovascular anti-inflammatory therapy . Front Cardiovasc Med . (2020 ) 7 :78 . 10.3389/fcvm.2020.00078 32426374 191. Madjid M Safavi-Naeini P Solomon SD Vardeny O . Potential effects of coronaviruses on the cardiovascular system: a review . JAMA Cardiol . (2020 ) 5 :831 –40 . 10.1001/jamacardio.2020.1286 32219363 192. Xiong TY Redwood S Prendergast B Chen M . Coronaviruses and the cardiovascular system: acute and long-term implications . Eur Heart J . (2020 ) 41 :1798 –800 . 10.1093/eurheartj/ehaa231 32186331 193. Yang JK Lin SS Ji XJ Guo LM . Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes . Acta Diabetol . (2010 ) 47 :193 –9 . 10.1007/s00592-009-0109-4 19333547 194. Zhang Z He G Filipowicz NA Randall G Belov GA Kopek BG . Host lipids in positive-strand RNA virus genome replication . Front Microbiol . (2019 ) 10 :286 . 10.3389/fmicb.2019.00286 30863375 195. Heaton NS Randall G . Dengue virus-induced autophagy regulates lipid metabolism . Cell Host Microbe . (2010 ) 8 :422 –32 . 10.1016/j.chom.2010.10.006 21075353 196. Parikh A Kumar AA Jahangir E . Cardio-oncology care in the time of COVID-19 and the role of telehealth . JACC CardioOncol . (2020 ) 2 :356 –8 . 10.1016/j.jaccao.2020.04.003 32328590 197. Calvillo-Arguelles O Abdel-Qadir H Ky B Liu JE Lopez-Mattei JC Amir E . Modified routine cardiac imaging surveillance of adult cancer patients and survivors during the COVID-19 pandemic . JACC CardioOncol . (2020 ) 2 :345 –9 . 10.1016/j.jaccao.2020.04.001 32309816 198. Karlamangla AS Merkin SS Crimmins EM Seeman TE . Socio-economic and ethnic disparities in cardiovascular risk in the United States, 2001–2006 . Ann Epidemiol . (2010 ) 20 :617 –28 . 10.1016/j.annepidem.2010.05.003 20609342 199. Rosamond WD Chambless LE Heiss G Mosley TH Coresh J Whitsel E . Twenty-two year trends in incidence of myocardial infarction, CHD mortality, and case-fatality in four US communities, 1987 to 2008 . Circulation . (2012 ) 125 :1848 –57 . 10.1161/CIRCULATIONAHA.111.047480 22420957 200. Lackland DT . Racial differences in hypertension: implications for high blood pressure management . Am J Med Sci . (2014 ) 348 :135 –8 . 10.1097/MAJ.0000000000000308 24983758 201. Braithwaite D Tammemagi CM Moore DH Ozanne EM Hiatt RA Belkora J . Hypertension is an independent predictor of survival disparity between African-American and white breast cancer patients . Int J Cancer . (2009 ) 124 :1213 –9 . 10.1002/ijc.24054 19058216 202. Breathett K Liu WG Allen LA Daugherty SL Blair IV Jones J . African Americans are less likely to receive care by a cardiologist during an intensive care unit admission for heart failure . JACC Heart Fail . (2018 ) 6 :413 –20 . 10.1016/j.jchf.2018.02.015 29724363 203. Taylor AL Ziesche S Yancy C Carson P D'Agostino R Ferdinand K . Combination of isosorbide dinitrate and hydralazine in blacks with heart failure . N Engl J Med . (2004 ) 351 :2049 –57 . 10.1056/NEJMoa042934 15533851 204. Giblin EM Adams KF JrHill L Fonarow GC Williams FB Sharma PP . Comparison of hydralazine/nitrate and angiotensin receptor neprilysin inhibitor use among black versus nonblack americans with heart failure and reduced ejection fraction (from CHAMP-HF) . Am J Cardiol . (2019 ) 124 :1900 –6 . 10.1016/j.amjcard.2019.09.020 31679641 205. Frierson GM Howard EN DeFina LE Powell-Wiley TM Willis BL . Effect of race and socioeconomic status on cardiovascular risk factor burden: the cooper center longitudinal study . Ethn Dis . (2013 ) 23 :35 –42 . 23495620 206. Liu Q Leisenring WM Ness KK Robison LL Armstrong GT Yasui Y . Racial/ethnic differences in adverse outcomes among childhood cancer survivors: the childhood cancer survivor study . J Clin Oncol . (2016 ) 34 :1634 –43 . 10.1200/JCO.2015.66.3567 27001569 207. Caplin DA Smith KR Ness KK Hanson HA Smith SM Nathan PC . Effect of population socioeconomic and health system factors on medical care of childhood cancer survivors: a report from the childhood cancer survivor study . J Adolesc Young Adult Oncol . (2017 ) 6 :74 –82 . 10.1089/jayao.2016.0016 27754726 208. Blumenthal D Fowler EJ Abrams M Collins SR . Covid-19—implications for the health care system . N Engl J Med . (2020 ) 383 :1483 –8 . 10.1056/NEJMsb2021088 32706956