key: cord-0914388-kpfgg3nf
authors: Peng, Wenyi; Wu, Hao; Tan, Yan; Li, Mei; Yang, Dachun; Li, Shuang
title: Mechanisms and treatments of myocardial injury in patients with corona virus disease 2019
date: 2020-09-25
journal: Life Sci
DOI: 10.1016/j.lfs.2020.118496
sha: 7c8108e90692ea8ea79581865d1cd8b261954844
doc_id: 914388
cord_uid: kpfgg3nf

The infection epidemic event of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was formally declared a pandemic by World Health Organization on March 11th, 2020. Corona Virus Disease 2019 (COVID-19) is caused by SARS-CoV-2, a new type of coronavirus, which has high contagion and mainly causes respiratory symptoms. With the increase in confirmed cases, however, the infection symptoms turn to be diverse with secondary or first clinical symptoms relating to damage of the cardiovascular system and changes of myocardial enzyme spectrum, cardiac troponin I, electrocardiogram, cardiac function. The occurrence of extra-pulmonary manifestations, including immediately and long-term damage, means that the overall health burden caused by SARS-CoV-2 infection may be under-estimated because COVID-19 patients developed cardiovascular system injury are more likely to become serious. The factors such as directly pathogen-mediated damage to cardiomyocytes, down-regulated angiotensin-converting enzyme 2 (ACE2) expression, excessive inflammatory response, hypoxia and adverse drug reaction, are closely related to the occurrence and development of the course of COVID-19. In combination with recently published medical data of patients having SARS-CoV-2 infection and the latest studies, the manifestations of damage to cardiovascular system by COVID-19, possible pathogenic mechanisms and advances of the treatment are proposed in this article.

On February 11, 2020, the Coronaviridae Study Group of the International Committee on Taxonomy of Viruses (ICTV-CSG) announced that the novel coronavirus (2019-nCoV) had been officially classified as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The World Health Organization (WHO) declared that the novel coronavirus infection was named coronavirus disease 2019 [1]. By March 11, 2020 , more than 118,000 confirmed cases (including 4291 deaths in 114 geographical territories) had been reported, and the WHO made the assessment that the COVID-19 outbreak can be characterized as a pandemic.

SARS-CoV-2 belongs to the Betacoronavirus genus; it is an enveloped, single-stranded RNA virus with a diameter of 50-200 nm, and it is the seventh coronavirus that can infect humans to date [2] . The full genome sequences of SARS-CoV-2 share 79.6% sequence identity to SARS-CoV [3] . In a comparative analysis of genomic data between SARS-CoV-2 and other coronaviruses in nature,

In general, SARS-CoV-2 first causes pneumonia via the respiratory tract. The main symptoms are fever, dry cough, fatigue or myalgia. Chest X-ray shows extensive inflammatory infiltrates of the lungs. While most patients with COVID-19 present with respiratory symptoms as the primary clinical manifestations, some patients present with cardiovascular symptoms, including palpitations and chest tightness, as the initial symptoms. Therefore, it is essential to investigate SARS-CoV-2-related cardiovascular symptoms and potential mechanisms and search for potential treatment targets and practical treatment strategies to facilitate epidemic prevention and control.

With the increase in confirmed cases, acute cardiac injury is not rare. Early COVID-19 case reports suggested that 5 of the first 41 confirmed COVID-19 patients (12%) had acute myocardial injury, characterized by high-sensitivity cardiac troponin I (hs-cTnI) > 28 pg/mL; of these patients, 4 had severe forms of the disease [6] . Later, in another clinical cohort of COVID-19, CK and lactate dehydrogenase (LDH) were Tachycardia, bradycardia and arrhythmia are common in SARS. For example, in a study of 121 SARS patients, tachycardia was observed in 87 patients (71.9%), transient bradycardia in 18 patients (4.9%) and atrial fibrillation in 1 patient, suggesting transient heart injury [9] . It was shown that in addition to sinus tachycardia, SARS-CoV can also cause supraventricular arrhythmia, ventricular arrhythmia, first-degree atrioventricular block, and ST-T segment changes [10] . Similarly, 23 (16.7%) of 138 COVID-19 patients had arrhythmia [8] . Furthermore, Guan et al. found that severe and critical patients were more likely to present with fever-independent tachycardia, which may be associated with exacerbation [11] .

Some coronavirus infections may seriously affect the heart. For instance, in rabbits, coronavirus may induce cardiomyopathy that may result in cardiac chamber dilatation and impairment of systolic function [12] . Chen et al found that patients, even without underlying cardiovascular diseases, can also suffer from severe heart failure in the wake of SARS-CoV-2 infection and eventually die of sudden cardiac death [7] .

Likewise, Hu et al reported a case of coronavirus infection presenting fulminant myocarditis [13] , and Gnecchi et al reported a case of acute myocarditis in a subclinical left ventricular diastolic impairment in COVID-19 patients.

The clinical effects of pneumonia have been associated with an increased risk of cardiovascular disease up to a 10-year follow-up [15] . Long-term follow-up data concerning 25 recovered SARS patients showed that 68% of survivors had hyperlipidemia, 44% had cardiovascular system abnormalities and 60% had glucose metabolism disorders [16] . Among them, the most significant metabolic disruptions were the comprehensive increase in phosphatidylinositol and lysophosphatidylcholine levels. However, the mechanisms by which SARS-CoV leads to dyslipidemia and patients with previous cardiovascular diseases, such as hypertension and coronary heart disease, were at higher risk for cardiovascular system damage or mortality [11] .

Chronic cardiovascular diseases reduce the natural cardiac reserve and impair the patient's ability to fight severe pneumonia. As a result, these patients are more susceptible to acute cardiovascular events after infection. For example, the systemic inflammatory response and its procoagulant effects may lead to plaque rupture, thrombosis and myocardial infarction in patients with coronary heart disease[20]. In Shanghai, the first death related to SARS-CoV-2 pneumonia was an 88-year-old patient with severe hypertension and cardiac insufficiency. Further analysis showed that the SARS-CoV-2 infection only induced heart failure and systemic multiorgan dysfunction in the patient[21].

SARS-CoV-2 has similar gene sequences and clinical manifestations and the same cell receptor on its envelope. ACE2 is expressed in the heart, including in endothelial cells and cardiomyocytes [24] . More recently, emerging evidence has shown the presence of SARS-CoV-2 in the myocardial tissue of autopsy cadavers [25] . The virus mainly exists in endothelial cells, which may affect heart microcirculation and lead to abnormal myocardial zymograms. However, we cannot rule out the possibility of the virus directly attacking cardiomyocytes, since the expression level of ACE2 in endothelial cells is higher than that in cardiomyocytes and the patients who underwent autopsy did not show symptoms of myocarditis during the illness.

Xu et al discovered that compared with that of SARS-CoV, which emerged in 2003, the spike protein of SARS-CoV-2 has a similar structure and high affinity with ACE2, suggesting that SARS-CoV-2 may infect humans in a manner similar to SARS-CoV, in which the spike protein binds to ACE2 in the lungs, and the complex is then internalized into alveolar cells [2] . Moreover, one study found that epithelial cells infected with SARS-CoV-2 can lead to an increase in ACE2 expression on adjacent cells by activating the interferon pathway, which may provide SARS-CoV-2 with more invasive sites [26] .

ACE2 is also expressed in the heart, indicating that SARS-CoV-2 is likely to

ACE2 was identified as an angiotensin-converting enzyme (ACE) homologue in 2000, and its sequence is 42% homologous to that of ACE. It is a member of the zinc metalloprotease family and is a type I membrane protein encoded by a gene on the X chromosome. ACE2 has 805 amino acids, including an N-terminal signal peptide, a catalytic extracellular domain, a transmembrane domain, and a C-terminal intracellular domain [29] . Both ACE2 and ACE belong to the renin-angiotensin system (RAS) family, but they differ in their roles. ACE2 can hydrolyze angiotensin (Ang I) to produce Ang 1-9, which is then hydrolyzed by ACE or another peptidase to produce the vasodilator peptide Ang 1-7. ACE2 can also directly act on angiotensin II (Ang II) to produce Ang 1-7, which is far more efficient than hydrolyzing Ang I. Ang 1-7 exerts vasodilatory, antiproliferative, and antioxidative stress effects by binding to the Mas receptor [30] . It is a potent negative regulator of RAS and provides protective effects for the cardiovascular system ( Figure 1 ).

Crackower et al showed that ACE2 knockout has a severe impact on mouse cardiac contraction, increases Ang II levels and upregulates hypoxia-induced genes in the heart, indicating that ACE2 is vital for cardiac function [31] . Oudit et al showed that in mice with SARS-CoV lung infection, the expression of ACE2 mRNA and protein was downregulated in myocardial tissues [23] . In one possible pathway, a decrease in ACE2 could cause a decrease in cardioprotective Ang 1-7, probably resulting in an imbalance between the ACE/Ang II/AT 1R axis and the ACE2/Ang 1-7/Mas axis. This is followed by elevated levels of Ang II, which could accelerate the can inactivate des-Arg9-bradykinin. The decrease of ACE2 induces the increase of des-Arg9-bradykinin, which has an inflammatory effect. ACE link renin-angiotensin system and kinin-kallilrein system by cleaving bradykinin. The decrease of ACE can produce the increase of bradykinin, which exerts positive effect of vasodilation, angioedema, but also negative effect of mediating the production of interleukin-6.

J o u r n a l P r e -p r o o f

Many severe patients among the first confirmed SARS-CoV-2 patients developed cytokine storms [6, 8] . Cytokine storm, also known as cytokine release syndrome, refers to the rapid production of a large amount of various cytokines, including tumor necrosis factor-α (TNF-α), interleukin 1 (IL-1), interleukin 6 (IL-6), and interferon-γ (IFN-γ), in body fluids following microbial infection. It is an important cause of acute lung injury, acute respiratory distress syndrome (ARDS) and multiorgan disorders in patients with viral infections [33] . As mentioned above, ACE2 has an inhibitory action on the RAS. Liu et al found that the plasma Ang II level of COVID-19 patients was significantly higher than that of healthy controls [28] . Moreover, Ang II levels in COVID-19 patients are closely correlated with viral titer and lung injury, suggesting that SARS-CoV-2 may lead to acute lung injury due to an imbalance in the renin-angiotensin system in patients and that ACE2-associated pathways may be involved in the inflammatory storm.

Early studies showed that in SARS patients, elevated serum pro-inflammatory cytokines, including IL-1β, IL-6, IL-12, IFN-γ, interferon-inducible protein 10 (IP10), and monocyte chemoattractant protein 1 (MCP1), were related to pulmonary inflammation and lung injury [34] . Similarly, Huang et al analyzed 41 COVID-19 patients and found significantly elevated IL-1β, IFN-γ, IP10, and MCP1, which may lead to T helper type 1 (Th1)/Th2 imbalance and cause T cell-mediated immune injury [6] . One study indicated that SARS-CoV-2 can cause intense multifactorial immune responses, and early adaptive immune responses may be associated with J o u r n a l P r e -p r o o f better prognosis [35] . Moreover, the levels of granulocyte colony-stimulating factor (GCSF), IP10, MCP1, macrophage inflammatory protein 1 alpha (MIP1α), and TNF-α were significantly elevated in ICU patients, which suggests that cytokine storms are positively correlated with the severity of the disease [6] .

One retrospective study found that increases in COVID-19 patient serum hs-cTnI, CK-MB, IL-6, C-reactive protein, and procalcitonin were associated with a decrease in lymphocyte counts and CD4/CD8 ratios, suggesting that SARS-CoV-2 infections may lead to heart damage through excessive inflammatory responses [36] . Previous studies reported that inflammatory factors such as IL-1β, IL-6, interleukin 8 (IL-8) and TNF-α can promote coagulation and even thrombosis via multiple pathways, increasing the risk of thromboembolism [37] . Moreover, a study proposed three characteristics of poor prognosis in COVID-19 patients, including older age, higher sequential organ failure assessment (SOFA), and obviously elevated levels of D-dimer (>1 μg/L). In particular, the increase in D-dimer reflected a persistent state of inflammatory response, which may exacerbate myocardial injury [38] . The first minimally invasive autopsy of a SARS-CoV-2 patient showed markedly elevated pro-inflammatory cells, such as CC chemokine receptor 4-positive (CCR4+), CC chemokine receptor 6-positive (CCR6+) and helper T 17 (Th17) cells, which may partially explain the severe lung immune injury. Additionally, the autopsy showed inflammatory infiltration of a small number of mononuclear cells in the myocardial stroma, implying cardiac inflammation [39] . Together, these data suggest that cytokine storms may be one of the mechanisms of myocardial injury.

J o u r n a l P r e -p r o o f Journal Pre-proof 3.4 

Hypoxemia caused by viral infection is another important mechanism of cardiac damage since it can induce some adverse responses, such as mitochondrial injury and oxidative stress. Acidosis and the generation of oxygen free radicals during hypoxia and hypoxia-reperfusion can aggravate myocardial injury, while hypoxia can also induce inflammatory responses, thereby further aggravating cardiac tissue damage [40] . In addition, symptoms such as fever, inflammation, and tachycardia, etc. patients with coronary heart disease [41] . Chloroquine can cause cardiac arrhythmias and even cardiac arrest, the most serious adverse reaction [42] . For COVID-19 patients, azithromycin and hydroxychloroquine can increase the risk of different arrhythmias, such as prolonged QT intervals, torsade de pointes and sudden cardiac death [43] . In addition, Arbidol is associated with an increase in the heart failure rate when used in combination with drugs such as azithromycin and quinolones [44] .

Interferons may affect the cardiac conduction system, causing cardiac arrhythmia as well as local myocardial ischemia and cardiomyopathy [45] . [48] . Aside from antiviral drugs, a recombinant adenovirus type-5 vectored COVID-19 vaccine, a subunit vaccine created by Chen Wei et al., has been approved for clinical trials, and the data from the first phase of trials of the vaccine showed that it is safe, tolerable, and immunogenic in healthy adults [49] . However, one study found that lopinavir/ritonavir treatment is no better than standard care in hospitalized adult patients with severe COVID-19 [50] .

SARS-CoV-2 mainly invades alveolar epithelial cells via ACE2 and causes pulmonary inflammation. However, as the number of infections has increased, some patients have presented with virus-associated cardiovascular injury, which may result from direct myocardial injury via ACE2 or a range of pathophysiological changes owing to ACE2 downregulation. Thus, ACE2 can be regarded as a potential therapeutic target for SARS-CoV-2 infection. These possibilities include blocking the binding between ACE2 and SARS-CoV-2, suppressing ACE, and using recombinant human ACE2 protein for pulmonary protection.

Zhou et al found that the ACE2 expressed in mammalian cells has more glycosylation sites in its extracellular domain. They believed that these glycosylation modifications may affect the binding between the SARS-CoV-2 spike protein and J o u r n a l P r e -p r o o f Journal Pre-proof ACE2 [51] . Some researchers have investigated the structure of the SARS-CoV-2-human ACE2 complex and first revealed the interaction between the spike protein of SARS-CoV-2 and ACE2 at the molecular level [52, 53] , providing clues to guide the development of targeted drugs and vaccines. SARS-CoV-2 must bind to the ACE2 expressed on the cell surface to infect cells, so modifying the ACE2 binding site or changing its configuration may be potential approaches. Chloroquine inhibits viral infection by increasing the pH of the viral inclusion bodies required for virus-cell fusion and interfering with glycosylation at the ACE2 terminal [54] . Chloroquine phosphate has been proven to effectively inhibit SARS-CoV-2 in vitro and is scheduled for large clinical trials [55] . It was suggested that type II transmembrane serine proteases (TMSPSS2) can activate SARS-CoV-2 S proteins to bind with ACE2 and enter host cells, so TMSPSS2 inhibitors prevented the SARS-CoV-2 Spike proteins from binding to ACE2 [56] .

In addition, vaccines against SARS-CoV-2 are a classic and traditional choice. 

SARS-related studies have shown that after SARS-CoV infection, ACE2 was downregulated in the lungs, causing ACE/ACE2 imbalance. Moreover, the increase in Ang II may result in overactivation of the AT 1 receptor and acute lung injury [57] .

Decreased ACE2 combined with elevated Ang II is a potential mechanism of lung injury, which also indicates that ACEIs and angiotensin II receptor blockers (ARBs) may inhibit such injury. In animal studies, the administration of enalapril in mice with acute lung injury quickly reduced Ang II levels [58] , while the administration of captopril reduced IFN-γ, prostaglandin E2 (PGE2), and TGF-β1 levels and increased interleukin 4 (IL-4) levels, thereby regulating the Th1/Th2 balance [59] and reducing pulmonary inflammation and lung injury. A retrospective study showed that continuous in-hospital administration of ACE inhibitors can reduce mortality and intubation rates in non-SARS patients [60] .

to rats reduced blood pressure, it caused ACE2 levels to increase 4.7 times and 2.8 times, respectively [61] . The increase in ACE2 levels may make it easier for the virus to enter cells. In addition, Liu et al suggested that ACE inhibitors increase the level of bradykinin, which binds to bradykinin B2 receptor (B2R) to dilate vessels and reduce blood pressure but may also increase vascular permeability and aggravate pulmonary J o u r n a l P r e -p r o o f edema. Bradykinin also mediates IL-6 production via the B2R/Erk 1/2 pathway and thus aggravates inflammation. Therefore, Liu et al recommended that COVID-19 patients with hypertension discontinue the antihypertensive ACEIs and ARBs (if applicable) and switch to calcium channel blockers (CCBs). However, the European Society of Hypertension (ESH) emphasized that there is no evidence that ACEIs and ARBs can increase the risk of SARS-CoV-2 infection or cause deterioration of COVID-19 patients [62] , so ACEIs and ARBs should not be discontinued easily for COVID-19 patients with pre-existing cardiovascular disease. For stable patients, the use of ACEIs and ARBs should be executed according to the recommendations in the 2018 ESC/ESH guidelines 1 [63] . Currently, researchers are still debating the use of ACEIs, and further clinical data are needed to verify the conclusions.

Animal studies have shown that treating ACE2-knockout mice with rhuACE2 injections reduced acute lung injury resulting from acid aspiration or sepsis and improved pulmonary edema [57] . In a phase II clinical study, the use of rhuACE2 in 10 patients with ARDS rapidly reduced Ang II while increasing Ang 1-7, suggesting that ACE2 injections in humans may regulate the ACE2/ACE balance in the lungs and help to treat acute lung injury [64] . Recently, Monteil et al found that human recombinant soluble ACE2 can prevent SARS-CoV-2 from infecting engineered human blood vessels and kidneys [65] .

As mentioned previously, SARS-CoV-2 infection could induce overactivation of the immune system, resulting in cytokine storms, multiple organ dysfunction syndrome (MODS), and even death. Therefore, the combination of blocking cytokine storms, regulating homeostasis, and protecting organ function is a promising approach to treat SARS-CoV-2 infection and reduce mortality. Currently, most targeted drugs for COVID-19 are still being tested in preclinical studies, and symptomatic treatment remains the primary therapy. It is essential to promptly and effectively block the occurrence and development of the inflammatory response to improve patient outcomes. The expert panel of the Chinese Society of Immunology recommended the following treatments for cytokine storms: antishock therapy, supportive and symptomatic treatment, proper steroid treatment at an appropriate dose level, and neutralizing antibodies [66] .

Disease 2019 (Tentative Seventh Edition) recommends that patients with an excessive inflammatory response receive short-term (3 to 5 days) steroid therapy [46] . It should be noted that high-dose steroid therapy may delay viral clearance. Moreover, blood purification therapy may be considered if possible to remove cytokines and correct pH and electrolyte disorders [46] . In addition, melatonin, a well-known anti-inflammatory and antioxidative molecule, is protective against ALI/ARDS caused by viruses and other pathogens, which suggests avenues for new potential therapeutic targets [67] . [46] . Some researchers further proposed that in addition to tocilizumab, specific SARS-CoV-2 antibodies from convalescent patients may be added to the plasma to treat patients during the recovery stage. Zhang et al successfully isolated monoclonal antibodies from the B lymphocytes of convalescent patients and found that two of those antibodies showed a strong ability to prevent SARS-CoV-2 from binding the ACE2 receptor [71] . Recently, Cao et al identified SARS-CoV-2-neutralizing antibodies by high-throughput single B cell sequencing of antigen-enriched B cells from 60 convalescent patients, and they found that BD-368-2, the most potent one of these antibodies, showed high therapeutic and prophylactic J o u r n a l P r e -p r o o f efficacy in SARS-CoV-2-infected mice [72] . While clinical trials are ongoing, the use of plasma during the recovery stage has potential unknown risks and ethical issues. It is unlikely to be developed and mass-produced in the near future. Therefore, specific antibodies and vaccines are the main methods for treating and preventing COVID-19.

Current data show that all age groups are at risk of SARS-CoV-2 infection, and the condition is generally more severe in elderly patients and those with underlying diseases [73] . Fifty percent of COVID-19 patients had complications, of which hypertension was the most common comorbidity, followed by diabetes and coronary heart disease, that led to high mortality [38] . Therefore, COVID-19 patients with pre-existing cardiovascular disease should be closely monitored for any symptoms and signs of cardiovascular dysfunction. Recently, the American College of Cardiology (ACC) released a clinical bulletin [74] that proposed that elderly patients should be closely monitored for cough or shortness of breath and indicated that a personalized regimen that helps stabilize plaques (involving treatments such as statins, β-blockers, ACE inhibitors, aspirin) and provides additional protection for cardiovascular patients should be administered. When acute myocardial injury occurs, medication to improve myocardial energy metabolism can significantly protect and improve cardiac function, and when heart failure occurs, etiological treatment is the optimal choice. In addition to routine anti-heart failure treatment, extracorporeal membrane oxygenation (ECMO) should be implemented as early as possible. which can reflect myocardial infarction; BNP, brain natriuretic peptide, a marker of heart failure.

It is necessary and important for citizens to take precautions such as wearing a face mask or respirator, wash hands frequently and ventilating rooms regularly. After all, 86% of all infections were undocumented before the 23 January 2020 travel restrictions, and those were the major cause of the rapid spread of SARS-CoV-2 in China [75] . Therefore, increasing the identification and isolation of asymptomatic patients would be important to fully control epidemics. A new study suggested that the median duration of detoxification in COVID-19 patients is 20 days, with the shortest duration being 8 days and the longest duration being 37 days [38] . This is of vital importance for both the decision of isolation and the guidance of the duration of antiviral therapy for early and effective antiviral therapy, which may improve the prognosis of patients.

The outbreak of SARS-CoV-2 infection has been defined as a pandemic that is seriously contagious and can spread through many transmission routes. Early reports 

The authors declare that they have no conflict of interest.

[1] V. Coronaviridae Study Group of the International Committee on Taxonomy of, The species

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[2] X. Xu J o u r n a l P r e -p r o o f Highlights • The recent outbreak of coronavirus disease 2019 caused by severe acute respiratory syndrome coronavirus 2, has become a public health emergency throughout the world.

• Apart from typical respiratory syndrome, cardiovascular injury is also parallel to the confirmed cases.

• The mechanisms of myocardial injury are various, such as directly pathogen-elicited damage to cardiomyocytes, down-regulated angiotensin-converting enzyme 2 (ACE2) expression, excessively inflammatory response and hypoxia.

• Though an array of integrated therapies may be conducive to the recovery of COVID-19-induced cardiomyocyte injury, of particularly interest, ACE2 emerges as a promising target during the treatment.

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