Current Cardiology Reports (2020) 22:32 https://doi.org/10.1007/s11886-020-01292-3 HOT TOPIC Cardiovascular Complications in Patients with COVID-19: Consequences of Viral Toxicities and Host Immune Response Han Zhu1,2,3 & June-Wha Rhee1,2,3 & Paul Cheng1,2,3 & Sarah Waliany1 & Amy Chang1,4 & Ronald M. Witteles1,3 & Holden Maecker5,6 & Mark M. Davis5,6,7 & Patricia K. Nguyen 1,2,3 & Sean M. Wu1,2,3 # Springer Science+Business Media, LLC, part of Springer Nature 2020 Abstract Purpose of Review Coronavirus disease of 2019 (COVID-19) is a cause of significant morbidity and mortality worldwide. While cardiac injury has been demonstrated in critically ill COVID-19 patients, the mechanism of injury remains unclear. Here, we review our current knowledge of the biology of SARS-CoV-2 and the potential mechanisms of myocardial injury due to viral toxicities and host immune responses. Recent Findings A number of studies have reported an epidemiological association between history of cardiac disease and worsened outcome during COVID infection. Development of new onset myocardial injury during COVID-19 also increases mortality. While limited data exist, potential mechanisms of cardiac injury include direct viral entry through the angiotensin- converting enzyme 2 (ACE2) receptor and toxicity in host cells, hypoxia-related myocyte injury, and immune-mediated cytokine release syndrome. Potential treatments for reducing viral infection and excessive immune responses are also discussed. Summary COVID patients with cardiac disease history or acquire new cardiac injury are at an increased risk for in-hospital morbidity and mortality. More studies are needed to address the mechanism of cardiotoxicity and the treatments that can minimize permanent damage to the cardiovascular system. Keywords COVID-19 . SARS-CoV-2 . Immune response . Cardiovascular system . Cardiac injury . Cytokine storm * Sean M. Wu Mark M. Davis [email protected] [email protected] Han Zhu Patricia K. Nguyen [email protected] [email protected] June-Wha Rhee 1 Department of Medicine, Stanford University, Room G1120A, [email protected] Lokey Stem Cell Building, 265 Campus Drive, Stanford, CA 94305, Paul Cheng USA [email protected] 2 Stanford Cardiovascular Institute, Stanford, CA, USA 3 Sarah Waliany Division of Cardiovascular Medicine, Stanford University, [email protected] Stanford, CA, USA 4 Division of Infectious Disease, Stanford University, Stanford, CA, Amy Chang USA [email protected] 5 Department of Microbiology and Immunology, Stanford University, Ronald M. Witteles Stanford, CA, USA [email protected] 6 Stanford Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA Holden Maecker [email protected] 7 Howard Hughes Medical Institute, Stanford, CA, USA 32 Page 2 of 9 Curr Cardiol Rep (2020) 22:32 Introduction Biology of SARS-CoV-2 Coronavirus disease of 2019 (COVID-19), caused by in- In order to better understand the biology of viral immune fection from severe acute respiratory syndrome coronavi- response and how it impacts the heart, we explore here rus 2 (SARS-CoV-2), has spread across the world as a the basic biological mechanisms underlying viral entry serious pandemic [1, 2]. SARS-CoV-2, an enveloped virus into the host cells and the subsequent immune response. with non-segmented, single-stranded, positive-sense RNA Coronaviruses are enveloped viruses with a single-strand, genome [3], is a member of the Coronaviridae (CoV) fam- positive-sense RNA genome approximately 26–32 kilo- ily which causes a predominantly respiratory illness with a bases in size, which is the largest known genome for an wide range of clinical severity, ranging from asymptomatic RNA virus. Six coronaviruses (CoVs) are known to infect or mildly symptomatic (fever, cough, dyspnea, myalgias, humans: 229E, OC43, SARS-CoV, NL63, HKU1, and fatigue, and diarrhea) in a large proportion of patients to MERS-CoV [3]. In humans, CoV infections primarily in- severe acute respiratory distress syndrome (ARDS) and volve the upper respiratory tract and GI tract [3]. Studies fatal multi-organ failure [1, 4–6, 7••]. The disease has a have demonstrated that SARS-CoV-2, as well as other case-fatality rate that ranges from less than 0.5% to more corona viruses, requires the angiotensin-converting en- than 7% (average, ~ 3.8%) [8], with an infectivity greater zyme 2 (ACE2) for cellular entry [20]. ACE2 is a type I than that of influenza [9]. Its high transmissibility and rel- integral membrane protein that serves an important role in atively high rate of causing serious complications has led cardiorenal homeostasis. It is also highly expressed in COVID-19 to become a serious public health threat lung alveolar cells, providing the main entry site for virus worldwide. into human hosts [21]. It is plausible that the high expres- Among various physiological consequences of severe sion of ACE2 in the lung, gut, heart, and kidneys may COVID-19, cardiovascular complications have emerged as facilitate direct damage by the virus throughout the course some of the most significant and life threatening. COVID-19 of infection. One key protein on the virus—the Spike may present with respiratory failure from pneumonia and protein (S)—facilitates viral entry into the target cells by ARDS, with or without distributive ± cardiogenic shock [10, the binding of its surface unit, S1, to the ACE2 receptor 11, 12•], and severe cardiac injury manifesting as markedly on the host cell [21–23], followed by cleavage by host- elevated troponin and heart failure [12•, 13–14]. Cardiac inju- cell protease TMPRSS2 [24]. Other important SARS- ry has also been associated with increased mortality [15••]. In CoV-2 components include the hemagglutinin-esterase a cohort study of 416 patients with confirmed COVID-19, protein, the membrane (M) protein, the nucleocapsid pro- elevated troponin was present in 19.7% of patients during tein, the small envelope protein, the internal protein, and hospitalization and was found to be an independent risk factor group-specific proteins, which could become targets for for in-hospital mortality [15••]. The increased incidence of vaccines in the future [25]. Of note, SARS-CoV-2 also cardiac injury among those with severe systemic inflammato- contains an RNA-dependent RNA polymerase which is ry response syndromes (SIRS) and shock in the setting of the target of the anti-viral agent remdesivir, currently be- COVID-19 also highlights an important relationship between ing studied randomized clinical trials for use against the immune response to the virus and the cardiovascular sys- COVID-19 disease [26]. tem. In addition, a high prevalence of pre-existing cardio-met- abolic disease has been noted among those with severe COVID-19 [16, 17], and those with pre-existing cardiovascu- lar conditions suffer increased mortality during COVID-19 The Role of Host Immune Response infection [18]. In particular, the reported case fatality rates for COVID-19 are 10.5% in patients with cardiovascular dis- The host immune response to viral entry is also important ease,7.3%inpatientswithdiabetes,and6.0%inthosewith to discuss, as pathogenesis in the later stages of SARS- hypertension, higher than the case-fatality rate of 3–4% ob- CoV and SARS-CoV-2 infection results not only from served world-wide for patients without these co-morbidities direct viral toxicity but also from immune dysregulation [7••]. Last but not least, the increased frequency of adverse and hyperactivity [27, 28]. Progress in this field, however, cardiovascular events following the resolution of COVID-19, has been hindered by the failure to replicate in mice, similar to other viral infections such as influenza [19], may ferrats, or non-human primates the lethal human immune also play a role in worsening the mortality of patients with response in ARDS with the original SARS-CoV strain COVID-19. Thus, understanding the relationship between the [29, 30]. This has led to the development of mouse- or viral-host immune response and the cardiovascular system rat-adapted strains of SARS-CoV that have been able to will be critically important in our care and management of replicate the extensive and often lethal pulmonary disease patients with COVID-19 going forward. [31]. The majority of studies addressing the immune Curr Cardiol Rep (2020) 22:32 Page 3 of 9 32 response to respiratory viral infections involve mice in- CD45RO+ memory Tregs (mTregs) [41]. On recovery, there fected with a variety of natural and mouse-adapted is a rapid and significant restoration of CD3+, CD4+, and pathogens. CD8+ T cells along with B cell and NK cell counts 2– The process of respiratory viral invasion into the body be- 3 months after onset of disease [40]. Memory CD4+ T cells gins with infection of the airway epithelial cells and the acti- returned to normal 1 year after onset, whereas other cell counts vation of lung-resident dentritic cells (rDCs) via acquisition of including total T lymphocytes, CD3+, CD4+ and naïve CD4+ the invading pathogen or antigens from infected epithelial T cells were still lower than healthy controls [43•]. The mech- cells. These rDCs then become activated, process antigen anism of lymphocytopenia in peripheral blood is unclear but and migrate to the draining (mediastinal and cervical) lymph thought to be due to sequestration, with release of sequestered nodes (DLN). Naïve circulating T cells in the DLNs then cells upon recovery [21]. Taken together, these changes in recognize antigens