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Coronavirus Disease 2019 (COVID-19) and Cardiovascular Disease
Kevin J. Clerkin, MD, MSc; Justin A. Fried, MD; Jayant Raikhelkar, MD; Gabriel Sayer, MD; Jan M. Griffin, MD; Amirali Masoumi, MD; Sneha S. Jain, MD, MBA; Daniel Burkhoff, MD, PhD; Deepa Kumaraiah, MD, MBA; LeRoy Rabbani, MD; Allan Schwartz, MD; Nir Uriel, MD, MSc
Summary By: Adriana C. Mares - Founder & President, The Institute of Cardiology at El Paso
Overall Study Question:
What is the association between COVID-19 and morbidity and mortality from cardiovascular disease (1)?
Background:
Coronavirus disease (COVID-19) is an infectious disease caused by a newly discovered single-stranded enveloped RNA coronavirus called Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) (2). Due to its global impact across borders and “alarming levels of spread and severity, and by the alarming levels of inaction”, on March 11, 2020, the Director-General of WHO characterized the COVID-19 outbreak as a pandemic (3). SARS-CoV-2 shares 89-96% nucleotide identity similarity with bat coronaviruses and shares 91% nucleotide identity with Malayan Pangolin coronaviruses, which is believed that SARS-CoV-2 moved from bats to an intermediate host (possibly a Malayan Pangolin) and then to humans (4-5).
Study Summary:
Role of ACE-2 and COVID-19
SARS-CoV-2 surface spike protein binds to the human angiotensin-converting enzyme 2 (ACE-2) receptor inducing activation of the spike protein by transmembrane protease serine 2 (TMPRSS2) (6). Consequently, infection that potentially causes multi-organ dysfunction as ACE-2 is expressed in intestinal epithelium, vascular endothelium, kidneys, lungs (principally Type II alveolar cells) by aiding portal of entry, although protecting against acute lung injury (7,8). As well, ACE-2 expressed in the heart by countering ACE activity by reducing Ang-II bioavailability and increasing Ang 1-7 formation, playing a key role as the central negative regulator of the renin angiotensin system (RAS) diminishing vasoconstriction. However, in patients with cardiovascular disorders (HTN, coronary artery disease, congestive heart failure, and DM) in ACE-I and ARB therapeutic regimens, ACE-2 effect has a possible effect of some unknown degree. However, infection is also known to cause ACE-2 downregulation, leading to an increase in angiotensin II and ultimately increased pulmonary vascular permeability, inducing pulmonary edema, and reduced lung function. Specifically, in this study Clerkin and colleagues focused on the impact of SARS-CoV-2 infection on the cardiovascular system. Reporting that among those with COVID-19, the SARS-CoV-2 infection leads to increased morbidity and mortality in patients with underlying cardiovascular conditions.
CVD Comorbidities and COVID-19
A number of cohort studies, meta-analysis of eight studies from China, and data from the National Health Commission (NHC) of China have reported the presence of cardiovascular comorbidities such as hypertension (HTN), diabetes mellitus (DM), and cardiovascular disease (CVD) in COVID-19 patients, especially among those with more severe disease (9-13). Potentially, these associations could be explained by factors such as age, weakened immune system, elevated levels of ACE-2, and vulnerability to COVID-19 for those with cardiovascular comorbidities (2). Not only, has cardiovascular comorbidity influenced disease severity, but early case reports have shown that elevated high sensitivity Troponin I (hs-cTnI) with other inflammatory biomarkers (D-dimer, ferritin, interleukin-6 (IL-6), lactate dehydrogenase), and echocardiographic abnormalities such as left ventricular dysfunction could be linked to myocardial injury among patients with COVID-19. The exact pathway is yet to be discovered, however in this study Clerkin and colleagues, report a potentially an ACE-2‐dependent myocardial infection pathway, a cytokine storm, mediated by an imbalanced response among subtypes of T helper cells, hypoxia induced excessive intracellular calcium leading to cardiac myocyte apoptosis, and secondary hemophagocytic lymphohistiocytosis more than isolated myocardial injury (2, 11).
Heart Transplantation and COVID-19
In the midst of these unprecedented times, a number of successful heart transplantation have been done and continue to be scheduled. It is unknown if the pool of patients that have undergone heart transplant during this COVID-19 situation may have higher risk for exposure to infection. Heart transplant donor and recipient recommendations are in question as there is an increase prevalence of COVID-19 in the donor population that may be asymptomatic or if the recipient has not tested positive for SARS-CoV-2 and has not had exposure to or symptoms of COVID-19 in the prior two to four weeks (14, 15).
COVID-19 Potential Treatment
Regarding treatment, currently, preventive measures and community mitigation strategies are most effective for COVID-19. An amplitude of eight medications were mentioned in this study all of which are under investigation for treatment of SARS-CoV-2 infection such as vaccines and monoclonal antibodies against SARS-CoV-2 (2). Secondly, camostat mesylate characterized as having TMPRSS2 blockade therapy and inhibition of SARS-CoV entry into cells (16). Thirdly, remdesevir an antiviral drug initially developed to treat Ebola, characterized to have in vitro activity against SARSCoV-2 and prevent and reduce disease severity in MERS-CoV in primates (17). Fourthly, chloroquine and hydroxychloroquine typically medications primarily used to prevent and treat malaria block SARS-CoV-2 cell entry in vitro (19, 24-27). Fifthly, lopinavir/ritonavir combination of protease inhibitors typically used in HIV have shown to have in vitro activity against SARS-CoV and improved clinical outcomes when used in combination with ribavirin for SARS (29, 30). Sixthly, oseltamivir and arbidol characterized as antiviral medications have yet to report clinical efficacy data. Seventhly, favipiravir is an antiviral drug that selectively inhibits RNA polymerase as seen in its inhibition of the RdRP of influenza virus (31). Lastly, tocilizumab and sarilumab typically used in the treatment of rheumatoid arthritis are IL-6 receptor antagonists which could are promising therapy for patients with COVID-19 related to the cytokine storm or secondary hemophagocytic lymphohistiocytosis with markedly elevated IL-6, ferritin, D-dimer, and hs-cTnI levels. So far, with reported success, tocilizumab has been used to treat patients with severe COVID-19 and ongoing clinical trials(32- 34). In addition, on March 16, 2020, a clinical program in the United States launched to evaluate sarilumab in patients hospitalized with severe COVID-19 (35, 36).
My Insights:
Looking at this study in a granular level, COVID-19 is caused by SARS-Cov-2 a newly discovered single-stranded enveloped RNA that enters cells through an ACE-2 dependent pathway that, in returns, activates the coronaviruses spike protein by TMPRSS2. In this study Clerkin and colleagues reported an abundance of information related to the impact of COVID-19 in CVD, specifically investigated the role of ACE-2 receptors that negatively regulate RSS and diminish vasoconstriction, but have unknown effect in CVD patients taking ACE-I and ARB medication. Therefore, due to this uncertainty, societies have recommended to continue clinically indicated ACE-I and ARB medications. Indeed, discontinuation of this therapeutic regimen could cause higher health risks than benefits, but further investigations are needed to confirm this information.
Interestingly, cardiovascular comorbidities such as HTN, DM, and CVD are common in patients with COVID-19. Myocardial damage including elevated cardiac biomarkers and echocardiographic abnormalities have also been shown to be present in patients with COVID-19, through possible regulatory pathways such as ACE-2‐dependent myocardial infection pathway, a cytokine storm, mediated by an imbalanced response among subtypes of T helper cells, hypoxia induced excessive intracellular calcium leading to cardiac myocyte apoptosis, and secondary hemophagocytic lymphohistiocytosis more than isolated myocardial injury. Notably, in specific to the induced cytokine storm, a cautious treatment therapy of 2 mg/kg/d glucocorticoid has shown to disrupt such pathway with possible side-effects, while monitoring Troponin I, water, electrolyte levels, oxygen saturation, vital signs, prone position, D-dimer, ECMO, and CRR.
In my view, the continuation of heart transplantation raises a lot of concerns since there is a lot of uncertainty regarding the management of transplant recipients who developed COVID-19 and donors who cannot be tested for COVID-19. Regarding treatment, I agree that preventive measures and community mitigation strategies are most effective for COVID-19. Not to mention, a rise of theoretical preventive measures that have not yet been proven effective include mouthwash and rinsing the teeth for approximately one minute while in the supine position, but at the same time being careful to avoid drinking the mouthwash. Despite theories and trials yet to be conducted are waiting to be proven, the future is bright, as there is a significant list of medications that have already been approved to treat other conditions that are under scientific investigation to further analyze their effects on SARS-CoV-2, as well trials in the U.S. evaluating new drugs such as Kevzara® (sarilumab). This type of hard work says a lot about the numerous scientific teams around the world working against time to ensuring our health and safety today and for future generations to come, in case SARS-Cov-2 acts in a cyclical manner then we should be prepared to fight it again.
Coronavirus Disease 2019 (COVID-19) and Cardiovascular Disease
Kevin J. Clerkin, MD, MSc; Justin A. Fried, MD; Jayant Raikhelkar, MD; Gabriel Sayer, MD; Jan M. Griffin, MD; Amirali Masoumi, MD; Sneha S. Jain, MD, MBA; Daniel Burkhoff, MD, PhD; Deepa Kumaraiah, MD, MBA; LeRoy Rabbani, MD; Allan Schwartz, MD; Nir Uriel, MD, MSc
Summary By: Adriana C. Mares - Founder & President, The Institute of Cardiology at El Paso
Overall Study Question:
What is the association between COVID-19 and morbidity and mortality from cardiovascular disease (1)?
Background:
Coronavirus disease (COVID-19) is an infectious disease caused by a newly discovered single-stranded enveloped RNA coronavirus called Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) (2). Due to its global impact across borders and “alarming levels of spread and severity, and by the alarming levels of inaction”, on March 11, 2020, the Director-General of WHO characterized the COVID-19 outbreak as a pandemic (3). SARS-CoV-2 shares 89-96% nucleotide identity similarity with bat coronaviruses and shares 91% nucleotide identity with Malayan Pangolin coronaviruses, which is believed that SARS-CoV-2 moved from bats to an intermediate host (possibly a Malayan Pangolin) and then to humans (4-5).
Study Summary:
Role of ACE-2 and COVID-19
SARS-CoV-2 surface spike protein binds to the human angiotensin-converting enzyme 2 (ACE-2) receptor inducing activation of the spike protein by transmembrane protease serine 2 (TMPRSS2) (6). Consequently, infection that potentially causes multi-organ dysfunction as ACE-2 is expressed in intestinal epithelium, vascular endothelium, kidneys, lungs (principally Type II alveolar cells) by aiding portal of entry, although protecting against acute lung injury (7,8). As well, ACE-2 expressed in the heart by countering ACE activity by reducing Ang-II bioavailability and increasing Ang 1-7 formation, playing a key role as the central negative regulator of the renin angiotensin system (RAS) diminishing vasoconstriction. However, in patients with cardiovascular disorders (HTN, coronary artery disease, congestive heart failure, and DM) in ACE-I and ARB therapeutic regimens, ACE-2 effect has a possible effect of some unknown degree. However, infection is also known to cause ACE-2 downregulation, leading to an increase in angiotensin II and ultimately increased pulmonary vascular permeability, inducing pulmonary edema, and reduced lung function. Specifically, in this study Clerkin and colleagues focused on the impact of SARS-CoV-2 infection on the cardiovascular system. Reporting that among those with COVID-19, the SARS-CoV-2 infection leads to increased morbidity and mortality in patients with underlying cardiovascular conditions.
CVD Comorbidities and COVID-19
A number of cohort studies, meta-analysis of eight studies from China, and data from the National Health Commission (NHC) of China have reported the presence of cardiovascular comorbidities such as hypertension (HTN), diabetes mellitus (DM), and cardiovascular disease (CVD) in COVID-19 patients, especially among those with more severe disease (9-13). Potentially, these associations could be explained by factors such as age, weakened immune system, elevated levels of ACE-2, and vulnerability to COVID-19 for those with cardiovascular comorbidities (2). Not only, has cardiovascular comorbidity influenced disease severity, but early case reports have shown that elevated high sensitivity Troponin I (hs-cTnI) with other inflammatory biomarkers (D-dimer, ferritin, interleukin-6 (IL-6), lactate dehydrogenase), and echocardiographic abnormalities such as left ventricular dysfunction could be linked to myocardial injury among patients with COVID-19. The exact pathway is yet to be discovered, however in this study Clerkin and colleagues, report a potentially an ACE-2‐dependent myocardial infection pathway, a cytokine storm, mediated by an imbalanced response among subtypes of T helper cells, hypoxia induced excessive intracellular calcium leading to cardiac myocyte apoptosis, and secondary hemophagocytic lymphohistiocytosis more than isolated myocardial injury (2, 11).
Heart Transplantation and COVID-19
In the midst of these unprecedented times, a number of successful heart transplantation have been done and continue to be scheduled. It is unknown if the pool of patients that have undergone heart transplant during this COVID-19 situation may have higher risk for exposure to infection. Heart transplant donor and recipient recommendations are in question as there is an increase prevalence of COVID-19 in the donor population that may be asymptomatic or if the recipient has not tested positive for SARS-CoV-2 and has not had exposure to or symptoms of COVID-19 in the prior two to four weeks (14, 15).
COVID-19 Potential Treatment
Regarding treatment, currently, preventive measures and community mitigation strategies are most effective for COVID-19. An amplitude of eight medications were mentioned in this study all of which are under investigation for treatment of SARS-CoV-2 infection such as vaccines and monoclonal antibodies against SARS-CoV-2 (2). Secondly, camostat mesylate characterized as having TMPRSS2 blockade therapy and inhibition of SARS-CoV entry into cells (16). Thirdly, remdesevir an antiviral drug initially developed to treat Ebola, characterized to have in vitro activity against SARSCoV-2 and prevent and reduce disease severity in MERS-CoV in primates (17). Fourthly, chloroquine and hydroxychloroquine typically medications primarily used to prevent and treat malaria block SARS-CoV-2 cell entry in vitro (19, 24-27). Fifthly, lopinavir/ritonavir combination of protease inhibitors typically used in HIV have shown to have in vitro activity against SARS-CoV and improved clinical outcomes when used in combination with ribavirin for SARS (29, 30). Sixthly, oseltamivir and arbidol characterized as antiviral medications have yet to report clinical efficacy data. Seventhly, favipiravir is an antiviral drug that selectively inhibits RNA polymerase as seen in its inhibition of the RdRP of influenza virus (31). Lastly, tocilizumab and sarilumab typically used in the treatment of rheumatoid arthritis are IL-6 receptor antagonists which could are promising therapy for patients with COVID-19 related to the cytokine storm or secondary hemophagocytic lymphohistiocytosis with markedly elevated IL-6, ferritin, D-dimer, and hs-cTnI levels. So far, with reported success, tocilizumab has been used to treat patients with severe COVID-19 and ongoing clinical trials(32- 34). In addition, on March 16, 2020, a clinical program in the United States launched to evaluate sarilumab in patients hospitalized with severe COVID-19 (35, 36).
My Insights:
Looking at this study in a granular level, COVID-19 is caused by SARS-Cov-2 a newly discovered single-stranded enveloped RNA that enters cells through an ACE-2 dependent pathway that, in returns, activates the coronaviruses spike protein by TMPRSS2. In this study Clerkin and colleagues reported an abundance of information related to the impact of COVID-19 in CVD, specifically investigated the role of ACE-2 receptors that negatively regulate RSS and diminish vasoconstriction, but have unknown effect in CVD patients taking ACE-I and ARB medication. Therefore, due to this uncertainty, societies have recommended to continue clinically indicated ACE-I and ARB medications. Indeed, discontinuation of this therapeutic regimen could cause higher health risks than benefits, but further investigations are needed to confirm this information.
Interestingly, cardiovascular comorbidities such as HTN, DM, and CVD are common in patients with COVID-19. Myocardial damage including elevated cardiac biomarkers and echocardiographic abnormalities have also been shown to be present in patients with COVID-19, through possible regulatory pathways such as ACE-2‐dependent myocardial infection pathway, a cytokine storm, mediated by an imbalanced response among subtypes of T helper cells, hypoxia induced excessive intracellular calcium leading to cardiac myocyte apoptosis, and secondary hemophagocytic lymphohistiocytosis more than isolated myocardial injury. Notably, in specific to the induced cytokine storm, a cautious treatment therapy of 2 mg/kg/d glucocorticoid has shown to disrupt such pathway with possible side-effects, while monitoring Troponin I, water, electrolyte levels, oxygen saturation, vital signs, prone position, D-dimer, ECMO, and CRR.
In my view, the continuation of heart transplantation raises a lot of concerns since there is a lot of uncertainty regarding the management of transplant recipients who developed COVID-19 and donors who cannot be tested for COVID-19. Regarding treatment, I agree that preventive measures and community mitigation strategies are most effective for COVID-19. Not to mention, a rise of theoretical preventive measures that have not yet been proven effective include mouthwash and rinsing the teeth for approximately one minute while in the supine position, but at the same time being careful to avoid drinking the mouthwash. Despite theories and trials yet to be conducted are waiting to be proven, the future is bright, as there is a significant list of medications that have already been approved to treat other conditions that are under scientific investigation to further analyze their effects on SARS-CoV-2, as well trials in the U.S. evaluating new drugs such as Kevzara® (sarilumab). This type of hard work says a lot about the numerous scientific teams around the world working against time to ensuring our health and safety today and for future generations to come, in case SARS-Cov-2 acts in a cyclical manner then we should be prepared to fight it again.
References
1 Mukherjee DP. COVID-19 and Cardiovascular Disease. American College of Cardiology. https://www.acc.org/latest-in-cardiology/journal-scans/2020/03/26/10/59/coronavirus-disease-2019-covid-19-and-cvd. Published March 26, 2020. Accessed March 27, 2020.
2 Clerkin KJ, Fried JA, Raikhelkar J, et al. Coronavirus Disease 2019 (COVID-19) and Cardiovascular Disease. Circulation. 2020. doi:10.1161/CIRCULATIONAHA.120.046941
3 WHO Director-General's opening remarks at the media briefing on COVID-19 - 11 March 2020. World Health Organization. https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020. Accessed March 29, 2020.
4 Andersen KG, Rambaut A, Lipkin WI, Holmes EC and Garry RF. The proximal origin of SARS-CoV-2. Nat Med. March 17, 2020. doi: 10.1038/s41591-020-0820-9. [epub ahead of print].
5 Zhang T WQ, Zhang Z. Probable pangolin origin of SARS-CoV-2 associated with the COVID-19 outbreak. Curr Biol. March 13, 2020. doi: 10.1016/j.cub.2020.03.022. [epub ahead of print]
6 Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Müller MA, Drosten C and Pöhlmann S. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. March 5, 2020. doi: 10.1016/j.cell.2020.02.052. [epub ahead of print].
7. Tikellis C and Thomas MC. Angiotensin-Converting Enzyme 2 (ACE2) Is a Key Modulator of the Renin Angiotensin System in Health and Disease. Int J Pept. 2012;2012:256294-256294. 9.
8. Zhang H, Penninger JM, Li Y, Zhong N and Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med. March 3, 2020. doi: 10.1007/s00134-020-05985-9. [epub ahead of print]
9. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H and Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. TheLancet. March 11, 2020. doi: 10.1016/S0140-6736(20)30566-3. [epub ahead of print].
10. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X and Peng Z. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China. JAMA. 2020;323:1061-1069. 22.
11 Zheng Y-Y, Ma Y-T, Zhang J-Y and Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol. March 5, 2020. doi: 10.1038/s41569-020-0360-5. [epub ahead of print].
12. Yang J, Zheng Y, Gou X, Pu K, Chen Z, Guo Q, Ji R, Wang H, Wang Y and Zhou Y. Prevalence of comorbidities in the novel Wuhan coronavirus (COVID-19) infection: a systematic review and meta-analysis. Int J Infect Dis. March 12, 2020. doi: 10.1016/j.ijid.2020.03.017. [epub ahead of print].
13. Guan W-j, Ni Z-y, Hu Y, Liang W-h, Ou C-q, He J-x, Liu L, Shan H, Lei C-l, Hui DSC, Du B, Li L-j, Zeng G, Yuen K-Y, Chen R-c, Tang C-l, Wang T, Chen P-y, Xiang J, Li S-y, Wang J-l, Liang Z-j, Peng Y-x, Wei L, Liu Y, Hu Y-h, Peng P, Wang J-m, Liu J-y, Chen Z, Li G, Zheng Z-j, Qiu S-q, Luo J, Ye C-j, Zhu S-y and Zhong N-s. Clinical Characteristics of Coronavirus Disease 2019 in China. New Eng J Med. February 28, 2020. doi: 10.1056/NEJMoa2002032. [epub ahead of print].
14 Guidance for Cardiothoracic Transplant and Mechanical Circulatory Support Centers
regarding SARS CoV-2 infection and COVID-19:
https://community.ishlt.org/HigherLogic/System/DownloadDocumentFile.ashx?DocumentFileK
ey=afb06f06-5d63-13d4-c107-d152a9f6cd46.
15 American Society of Transplantation. 2019-nCoV (Coronavirus): FAQs for Organ
Transplantation. Updated Feb 29, 2020.
https://www.myast.org/sites/default/files/COVID19%20FAQ%20Tx%20Centers%20030220-
1.pdf.
16 Kawase M, Shirato K, van der Hoek L, Taguchi F and Matsuyama S. Simultaneous Treatment of Human Bronchial Epithelial Cells with Serine and Cysteine Protease Inhibitors Prevents Severe Acute Respiratory Syndrome Coronavirus Entry. J Virol. 2012;86:6537-6545.
17 Gordon CJ, Tchesnokov EP, Feng JY, Porter DP and Gotte M. The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus. J Biol Chem. Feb 24, 2020. doi: 10.1074/jbc.AC120.013056 [epub ahead of print].
18 de Wit E, Feldmann F, Cronin J, Jordan R, Okumura A, Thomas T, Scott D, Cihlar T and Feldmann H. Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. PNAS. Feb 13, 2020;201922083. doi: 10.1073/pnas.1922083117. [epub ahead of print].
19. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, Shi Z, Hu Z, Zhong W and Xiao G. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019- nCoV) in vitro. Cell Res. 2020;30:269-271.
20 ClinicalTrials.gov. Severe 2019-nCoV Remdesivir RCT. Identifier: NCT04257656. Last Updated Feb 24, 2020. https://clinicaltrials.gov/ct2/show/NCT04257656.
21 ClinicalTrials.gov. Mild/Moderate 2019-nCoV Remdesivir RCT. Identifier: NCT04252664. Last Updated Feb 24, 2020. https://clinicaltrials.gov/ct2/show/NCT04252664.
22 ClinicalTrials.gov. Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734™) in Participants With Severe Coronavirus Disease (COVID-19). Identifier: NCT04292899. Updated March 19, 2020. https://clinicaltrials.gov/ct2/show/NCT04292899.
23 ClinicalTrials.gov. Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734™) in Participants With Moderate Coronavirus Disease (COVID-19) Compared to Standard of Care Treatment. Identifier: NCT04292730. Updated March 19, 2020.
https://clinicaltrials.gov/ct2/show/NCT04292730.
24 ClinicalTrials.gov. Comparison of Lopinavir/Ritonavir or Hydroxychloroquine in Patients With Mild Coronavirus Disease (COVID-19). Identifier: NCT04307693. Updated March 13, 2020. https://clinicaltrials.gov/ct2/show/NCT04307693.
25 ClinicalTrials.gov. Efficacy and Safety of Hydroxychloroquine for Treatment of Pneumonia Caused by 2019-nCoV ( HC-nCoV ). Identifier: NCT04261517. Updated March 4, 2020. https://clinicaltrials.gov/ct2/show/NCT04261517.
26 Clinical Trials.gov. Post-exposure Prophylaxis for SARS-Coronavirus-2. Identifier: NCT04308668. Updated March 19, 2020. https://clinicaltrials.gov/ct2/show/NCT04308668.
27 ClinicalTrials.gov. Chloroquine Prevention of Coronavirus Disease (COVID-19) in the Healthcare Setting (COPCOV). Identifier: NCT04303507. Updated March 11, 2020. https://clinicaltrials.gov/ct2/show/NCT04303507
28 Gao J, Tian Z and Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. BioSci Trends. 2020;14:72-73.
29 Chu CM, Cheng VC, Hung IF, Wong MM, Chan KH, Chan KS, Kao RY, Poon LL, Wong CL, Guan Y, Peiris JS and Yuen KY. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004;59:252-256.
30 Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, Ruan L, Song B, Cai Y, Wei M, Li X, Xia J, Chen N, Xiang J, Yu T, Bai T, Xie X, Zhang L, Li C, Yuan Y, Chen H, Li H, Huang H, Tu S, Gong F, Liu Y, Wei Y, Dong C, Zhou F, Gu X, Xu J, Liu Z, Zhang Y, Li H, Shang L, Wang K, Li K, Zhou X, Dong X, Qu Z, Lu S, Hu X, Ruan S, Luo S, Wu J, Peng L, Cheng F, Pan L, Zou J, Jia C, Wang J, Liu X, Wang S, Wu X, Ge Q, He J, Zhan H, Qiu F, Guo L, Huang C, Jaki T, Hayden FG, Horby PW, Zhang D and Wang C. A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19. New Eng J Med. March 18, 2020. doi: 10.1056/NEJMoa2001282. [epub ahead of print].
31 Furuta Y, Komeno T and Nakamura T. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc Jpn Acad Ser B Phys biol sci. 2017;93:449-463.
32 ClinicalTrials.gov. Tocilizumab in COVID-19 Pneumonia (TOCIVID-19) (TOCIVID19). Identifier: NCT04317092. Updated March 20, 2020. https://www.clinicaltrials.gov/ct2/show/NCT04317092.
33 ClinicalTrials.gov.Tocilizumab vs CRRT in Management of Cytokine Release Syndrome (CRS) in COVID-19 (TACOS). Identifier: NCT04306705. Updated March 17, 2020. https://clinicaltrials.gov/ct2/show/NCT04306705.
34 ClinicalTrials.gov. Tocilizumab for SARS-CoV2 Severe Pneumonitis. Identifier: NCT04315480. Updated March 19, 2020. https://clinicaltrials.gov/ct2/show/NCT04315480.
35 ClinicalTrials.gov. Evaluation of the Efficacy and Safety of Sarilumab in Hospitalized Patients With COVID-19. Identifier: NCT04315298. Updated March 19, 2020. https://www.clinicaltrials.gov/ct2/show/NCT04315298
36 Sanofi and Regeneron begin global Kevzara® (sarilumab) clinical trial program in patients with severe COVID-19 - Mar 16, 2020. http://www.news.sanofi.us/2020-03-16-Sanofi-and-Regeneron-begin-global-Kevzara-R-sarilumab-clinical-trial-program-in-patients-with-severe-COVID-19. Accessed March 29, 2020.
Back to other Article Summaries
1 Mukherjee DP. COVID-19 and Cardiovascular Disease. American College of Cardiology. https://www.acc.org/latest-in-cardiology/journal-scans/2020/03/26/10/59/coronavirus-disease-2019-covid-19-and-cvd. Published March 26, 2020. Accessed March 27, 2020.
2 Clerkin KJ, Fried JA, Raikhelkar J, et al. Coronavirus Disease 2019 (COVID-19) and Cardiovascular Disease. Circulation. 2020. doi:10.1161/CIRCULATIONAHA.120.046941
3 WHO Director-General's opening remarks at the media briefing on COVID-19 - 11 March 2020. World Health Organization. https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020. Accessed March 29, 2020.
4 Andersen KG, Rambaut A, Lipkin WI, Holmes EC and Garry RF. The proximal origin of SARS-CoV-2. Nat Med. March 17, 2020. doi: 10.1038/s41591-020-0820-9. [epub ahead of print].
5 Zhang T WQ, Zhang Z. Probable pangolin origin of SARS-CoV-2 associated with the COVID-19 outbreak. Curr Biol. March 13, 2020. doi: 10.1016/j.cub.2020.03.022. [epub ahead of print]
6 Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Müller MA, Drosten C and Pöhlmann S. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. March 5, 2020. doi: 10.1016/j.cell.2020.02.052. [epub ahead of print].
7. Tikellis C and Thomas MC. Angiotensin-Converting Enzyme 2 (ACE2) Is a Key Modulator of the Renin Angiotensin System in Health and Disease. Int J Pept. 2012;2012:256294-256294. 9.
8. Zhang H, Penninger JM, Li Y, Zhong N and Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med. March 3, 2020. doi: 10.1007/s00134-020-05985-9. [epub ahead of print]
9. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H and Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. TheLancet. March 11, 2020. doi: 10.1016/S0140-6736(20)30566-3. [epub ahead of print].
10. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X and Peng Z. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China. JAMA. 2020;323:1061-1069. 22.
11 Zheng Y-Y, Ma Y-T, Zhang J-Y and Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol. March 5, 2020. doi: 10.1038/s41569-020-0360-5. [epub ahead of print].
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