COVID-19 from a cardiovascular perspective / COVID-19 desde una perspectiva cardiovascular

Currently, myocardial injury has been reported in patients hospitalized with coronavirus disease 2019 (COVID-19). The studies also show a correlation between cardiac events and severe forms of the disease. COVID-19 begins with an early infection phase in which the virus infiltrates the lung parenchyma and proliferates. It then progresses to the pulmonary phase, where the initial inflammatory process, characterized by vasodilation, vascular permeability, and leukocyte recruitment, leads to lung damage, hypoxemia, and cardiovascular stress. The renin angiotensin aldosterone system is important in the pathophysiology of severe acute respiratory syndrome coronavirus 2 infection and in the propagation of systemic inflammation. Within this system, the pathway mediated by angiotensin-converting enzyme 2 (ACE2) produces vasodilation, cardioprotection, anti-oxidation, and anti-inflammation. Furthermore, the free form of ECA2 prevents binding of the virus to host cells and reduces its damage to the lung.

Actualmente, se ha reportado injuria miocárdica en pacientes hospitalizados por enfermedad por coronavirus 2019 (COVID-19). Los estudios, además, demuestran una correlación entre los eventos cardiacos y formas severas de la enfermedad. La COVID-19 comienza con una fase de infección temprana en la que el virus infiltra el parénquima pulmonar y prolifera. Luego progresa a la fase pulmonar, donde el proceso inflamatorio inicial, caracterizado por vasodilatación, permeabilidad vascular y reclutamiento de leucocitos, lleva a daño pulmonar, hipoxemia y estrés cardiovascular. El sistema renina angiotensina aldosterona es importante en la fisiopatología de la infección por el coronavirus 2 del síndrome respiratorio agudo grave y en la propagación de la inflamación sistémica. Dentro de este sistema, la vía mediada por la enzima convertidora de angiotensina 2 (ECA2) produce vasodilatación, cardioprotección, antioxidación y antiinflamación. Además, la forma libre de la ECA2 previene la unión del virus a las células huésped y reduce su daño al pulmón.

A close-up view of dynamic biomarkers in the setting of COVID-19: Striking focus on cardiovascular system.

Based on the recent reports, cardiovascular events encompass a large portion of the mortality caused by the COVID-19 pandemic, which drawn cardiologists into the management of the admitted ill patients. Given that common laboratory values may provide key insights into the illness caused by the life-threatening SARS-CoV-2 virus, it would be more helpful for screening, clinical management and on-time therapeutic strategies. Commensurate with these issues, this review article aimed to discuss the dynamic changes of the common laboratory parameters during COVID-19 and their association with cardiovascular diseases. Besides, the values that changed in the early stage of the disease were considered and monitored during the recovery process. The time required for returning biomarkers to basal levels was also discussed. Finally, of particular interest, we tended to abridge the latest updates regarding the cardiovascular biomarkers as prognostic and diagnostic criteria to determine the severity of COVID-19.

Aging whole blood transcriptome reveals candidate genes for SARS-CoV-2-related vascular and immune alterations.

The risk of severe COVID-19 increases with age as older patients are at highest risk. Thus, there is an urgent need to identify how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) interacts with blood components during aging. We investigated the whole blood transcriptome from the Genotype-Tissue Expression (GTEx) database to explore differentially expressed genes (DEGs) translated into proteins interacting with viral proteins during aging. From 22 DEGs in aged blood, FASLG, CTSW, CTSE, VCAM1, and BAG3 were associated with immune response, inflammation, cell component and adhesion, and platelet activation/aggregation. Males and females older than 50 years old overexpress FASLG, possibly inducing a hyperinflammatory cascade. The expression of cathepsins (CTSW and CTSE) and the anti-apoptotic co-chaperone molecule BAG3 also increased throughout aging in both genders. By exploring single-cell RNA-sequencing data from peripheral blood of SARS-CoV-2-infected patients, we found FASLG and CTSW expressed in natural killer cells and CD8 + T lymphocytes, whereas BAG3 was expressed mainly in CD4 + T cells, naive T cells, and CD14 + monocytes. In addition, T cell exhaustion was associated with increased expression of CCL4L2 and DUSP4 over blood aging. LAG3, PDCD1, TIGIT, VCAM1, HLA-DRA, and TOX also increased in individuals aged 60-69 years old; conversely, the RGS2 gene decreased with aging. We further identified a distinct gene expression profile associated with type I interferon signaling following blood aging. These results revealed changes in blood molecules potentially related to SARS-CoV-2 infection throughout aging, emphasizing them as therapeutic candidates for aggressive clinical manifestation of COVID-19. KEY MESSAGES: • Prediction of host-viral interactions in the whole blood transcriptome during aging. • Expression levels of FASLG, CTSW, CTSE, VCAM1, and BAG3 increase in aged blood. • Blood interactome reveals targets involved with immune response, inflammation, and blood clots. • SARS-CoV-2-infected patients with high viral load showed FASLG overexpression. • Gene expression profile associated with T cell exhaustion and type I interferon signaling were affected with blood aging.

Pattern Recognition Proteins: First Line of Defense Against Coronaviruses.

The rapid outbreak of COVID-19 caused by the novel coronavirus SARS-CoV-2 in Wuhan, China, has become a worldwide pandemic affecting almost 204 million people and causing more than 4.3 million deaths as of August 11 2021. This pandemic has placed a substantial burden on the global healthcare system and the global economy. Availability of novel prophylactic and therapeutic approaches are crucially needed to prevent development of severe disease leading to major complications both acutely and chronically. The success in fighting this virus results from three main achievements: (a) Direct killing of the SARS-CoV-2 virus; (b) Development of a specific vaccine, and (c) Enhancement of the host's immune system. A fundamental necessity to win the battle against the virus involves a better understanding of the host's innate and adaptive immune response to the virus. Although the role of the adaptive immune response is directly involved in the generation of a vaccine, the role of innate immunity on RNA viruses in general, and coronaviruses in particular, is mostly unknown. In this review, we will consider the structure of RNA viruses, mainly coronaviruses, and their capacity to affect the lungs and the cardiovascular system. We will also consider the effects of the pattern recognition protein (PRP) trident composed by (a) Surfactant proteins A and D, mannose-binding lectin (MBL) and complement component 1q (C1q), (b) C-reactive protein, and (c) Innate and adaptive IgM antibodies, upon clearance of viral particles and apoptotic cells in lungs and atherosclerotic lesions. We emphasize on the role of pattern recognition protein immune therapies as a combination treatment to prevent development of severe respiratory syndrome and to reduce pulmonary and cardiovascular complications in patients with SARS-CoV-2 and summarize the need of a combined therapeutic approach that takes into account all aspects of immunity against SARS-CoV-2 virus and COVID-19 disease to allow mankind to beat this pandemic killer.

Human Stem Cell Models of SARS-CoV-2 Infection in the Cardiovascular System.

The virus responsible for coronavirus disease 2019 (COVID-19), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected over 190 million people to date, causing a global pandemic. SARS-CoV-2 relies on binding of its spike glycoprotein to angiotensin-converting enzyme 2 (ACE2) for infection. In addition to fever, cough, and shortness of breath, severe cases of SARS-CoV-2 infection may result in the rapid overproduction of pro-inflammatory cytokines. This overactive immune response is known as a cytokine storm, which leads to several serious clinical manifestations such as acute respiratory distress syndrome and myocardial injury. Cardiovascular disorders such as acute coronary syndrome (ACS) and heart failure not only enhance disease progression at the onset of infection, but also arise in hospitalized patients with COVID-19. Tissue-specific differentiated cells and organoids derived from human pluripotent stem cells (hPSCs) serve as an excellent model to address how SARS-CoV-2 damages the lungs and the heart. In this review, we summarize the molecular basis of SARS-CoV-2 infection and the current clinical perspectives of the bidirectional relationship between the cardiovascular system and viral progression. Furthermore, we also address the utility of hPSCs as a dynamic model for SARS-CoV-2 research and clinical translation.

Long-term effects of coronavirus disease 2019 on the cardiovascular system, CV COVID registry: A structured summary of a study protocol.

BACKGROUND: Patients presenting with the coronavirus-2019 disease (COVID-19) may have a high risk of cardiovascular adverse events, including death from cardiovascular causes. The long-term cardiovascular outcomes of these patients are entirely unknown. We aim to perform a registry of patients who have undergone a diagnostic nasopharyngeal swab for SARS-CoV-2 and to determine their long-term cardiovascular outcomes. STUDY AND DESIGN: This is a multicenter, observational, retrospective registry to be conducted at 17 centers in Spain and Italy (ClinicalTrials.gov number: NCT04359927). Consecutive patients older than 18 years, who underwent a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) for SARS-CoV2 in the participating institutions, will be included since March 2020, to August 2020. Patients will be classified into two groups, according to the results of the RT-PCR: COVID-19 positive or negative. The primary outcome will be cardiovascular mortality at 1 year. The secondary outcomes will be acute myocardial infarction, stroke, heart failure hospitalization, pulmonary embolism, and serious cardiac arrhythmias, at 1 year. Outcomes will be compared between the two groups. Events will be adjudicated by an independent clinical event committee. CONCLUSION: The results of this registry will contribute to a better understanding of the long-term cardiovascular implications of the COVID19.

COVID-19 and cardiovascular system-a comprehensive review.

Coronavirus disease 2019 (COVID-19), a mystified cryptic virus has challenged the mankind that has brought life to a standstill. Catastrophic loss of life, perplexed healthcare system and the downfall of global economy are some of the outcomes of this pandemic. Humans are raging a war with an unknown enemy. Infections, irrespective of age and gender, and more so in comorbidities are escalating at an alarming rate. Cardiovascular diseases, are the leading cause of death globally with an estimate of 31% of deaths worldwide out of which nearly 85% are due to heart attacks and stroke. Theoretically and practically, researchers have observed that persons with pre-existing cardiovascular conditions are comparatively more vulnerable to the COVID-19 infection. Moreover, they have studied the data between less severe and more severe cases, survivors and non survivors, intensive care unit (ICU) patients and non ICU patients, to analyse the relationship and the influence of COVID-19 on cardiovascular health of an individual, further the risk of susceptibility to submit to the virus. This review aims to provide a comprehensive particular on the possible effects, either direct or indirect, of COVID-19 on the cardiovascular heath of an individual.

Covid and Cardiovascular Diseases: Direct and Indirect Damages and Future Perspective.

SARS-CoV-2 infection determines a disease that predominantly affects lungs. However the cytokines storms, determined by the huge immune response to the infection, could affect also other organs and apparatus such as heart and vessels. Beyond the acute inflammation itself also hypercoagulative status has been linked to SARSCoV-2 infection and this surely relates to the increase seen in prevalence of pulmonary embolism and myocardial infarction. A number of cardiac abnormalities and pathologies have been observed, with special attention to cardiac arrhythmias and myocardial involvement. Furthermore, indirect damages determined by the reduction in acute and chronic cardiovascular care, results in a strong mortality and morbidity outcomes in cardiological patients. In this review we will summarise current knowledge on both direct and indirect cardiovascular damages determined by the SARS-CoV-2 pandemia.

Cardiovascular RNA markers and artificial intelligence may improve COVID-19 outcome: a position paper from the EU-CardioRNA COST Action CA17129.

The coronavirus disease 2019 (COVID-19) pandemic has been as unprecedented as unexpected, affecting more than 105 million people worldwide as of 8 February 2020 and causing more than 2.3 million deaths according to the World Health Organization (WHO). Not only affecting the lungs but also provoking acute respiratory distress, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is able to infect multiple cell types including cardiac and vascular cells. Hence a significant proportion of infected patients develop cardiac events, such as arrhythmias and heart failure. Patients with cardiovascular comorbidities are at highest risk of cardiac death. To face the pandemic and limit its burden, health authorities have launched several fast-track calls for research projects aiming to develop rapid strategies to combat the disease, as well as longer-term projects to prepare for the future. Biomarkers have the possibility to aid in clinical decision-making and tailoring healthcare in order to improve patient quality of life. The biomarker potential of circulating RNAs has been recognized in several disease conditions, including cardiovascular disease. RNA biomarkers may be useful in the current COVID-19 situation. The discovery, validation, and marketing of novel biomarkers, including RNA biomarkers, require multi-centre studies by large and interdisciplinary collaborative networks, involving both the academia and the industry. Here, members of the EU-CardioRNA COST Action CA17129 summarize the current knowledge about the strain that COVID-19 places on the cardiovascular system and discuss how RNA biomarkers can aid to limit this burden. They present the benefits and challenges of the discovery of novel RNA biomarkers, the need for networking efforts, and the added value of artificial intelligence to achieve reliable advances.

Impact of COVID-19 infection on the cardiovascular system: An evidence-based analysis of risk factors and outcomes.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as COVID-19, emerged in late 2019 in Wuhan, China. The World Health Organization declared the virus a pandemic on March 11, 2020. Disease progression from COVID-19 infection has shown significant symptom manifestations within organ systems beyond the respiratory system. The literature has shown increasing evidence of cardiovascular involvement during disease course and an associated increase in mortality among infected patients. Although the understanding of this novel virus is continually evolving, it is currently proposed that the mechanism by which the SARS-CoV-2 virus contributes to cardiovascular manifestations involves the ACE2 transmembrane protein. The protein ACE2 is highly expressed in blood vessel pericytes, and infection can result in microvascular dysfunction and subsequent acute coronary syndromes. Complications involving the cardiovascular system include myocardial infarction, arrhythmias, shock, and heart failure. In this evidence-based review, we discuss risk factors of cardiovascular involvement in COVID-19 infection, pathophysiology of COVID-19-related cardiovascular infection, and injury, COVID-19 effects on the cardiovascular system and corresponding treatments, and hematologic effects of COVID-19 and COVID-19 in heart transplant patients. Clinicians managing COVID-19 patients should appreciate the potential cardiovascular effects related to the disease process.

SARS-CoV-2 Infection and Disease Modelling Using Stem Cell Technology and Organoids.

In this Review, we briefly describe the basic virology and pathogenesis of SARS-CoV-2, highlighting how stem cell technology and organoids can contribute to the understanding of SARS-CoV-2 cell tropisms and the mechanism of disease in the human host, supporting and clarifying findings from clinical studies in infected individuals. We summarize here the results of studies, which used these technologies to investigate SARS-CoV-2 pathogenesis in different organs. Studies with in vitro models of lung epithelia showed that alveolar epithelial type II cells, but not differentiated lung alveolar epithelial type I cells, are key targets of SARS-CoV-2, which triggers cell apoptosis and inflammation, while impairing surfactant production. Experiments with human small intestinal organoids and colonic organoids showed that the gastrointestinal tract is another relevant target for SARS-CoV-2. The virus can infect and replicate in enterocytes and cholangiocytes, inducing cell damage and inflammation. Direct viral damage was also demonstrated in in vitro models of human cardiomyocytes and choroid plexus epithelial cells. At variance, endothelial cells and neurons are poorly susceptible to viral infection, thus supporting the hypothesis that neurological symptoms and vascular damage result from the indirect effects of systemic inflammatory and immunological hyper-responses to SARS-CoV-2 infection.

Covid-19 and the cardiovascular system: a comprehensive review.

Cardiac injury in patients infected with the novel Coronavirus (COVID-19) seems to be associated with higher morbimortality. We provide a broad review of the clinical evolution of COVID-19, emphasizing its impact and implications on the cardiovascular system. The pathophysiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is characterized by overproduction of inflammatory cytokines (IL-6 and TNF-α) leading to systemic inflammation and multiple organ dysfunction syndrome, acutely affecting the cardiovascular system. Hypertension (56.6%) and diabetes (33.8%) are the most prevalent comorbidities among individuals with COVID-19, who require hospitalization. Furthermore, cardiac injury, defined as elevated us-troponin I, significantly relates to inflammation biomarkers (IL-6 and C-reactive protein (CRP), hyperferritinemia, and leukocytosis), portraying an important correlation between myocardial injury and inflammatory hyperactivity triggered by viral infection. Increased risk for myocardial infarction, fulminant myocarditis rapidly evolving with depressed systolic left ventricle function, arrhythmias, venous thromboembolism, and cardiomyopathies mimicking STEMI presentations are the most prevalent cardiovascular complications described in patients with COVID-19. Moreover, SARS-CoV-2 tropism and interaction with the RAAS system, through ACE2 receptor, possibly enhances inflammation response and cardiac aggression, leading to imperative concerns about the use of ACEi and ARBs in infected patients. Cardiovascular implications result in a worse prognosis in patients with COVID-19, emphasizing the importance of precocious detection and implementation of optimal therapeutic strategies.

COVID-19 and cardiovascular diseases.

The coronavirus disease 2019 (COVID-19) remains a global public health emergency. Despite being caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), besides the lung, this infectious disease also has severe implications in the cardiovascular system. In this review, we summarize diverse clinical complications of the heart and vascular system, as well as the relevant high mortality, in COVID-19 patients. Systemic inflammation and angiotensin-converting enzyme 2-involved signaling networking in SARS-CoV-2 infection and the cardiovascular system may contribute to the manifestations of cardiovascular diseases. Therefore, integration of clinical observations and experimental findings can promote our understanding of the underlying mechanisms, which would aid in identifying and treating cardiovascular injury in patients with COVID-19 appropriately.

Cardiovascular view of intermediate and high-risk COVID-19 patients: single-centre experience with low mortality and intensive care hospitalisation rates.

AIM: The purpose of this article was to report the low rates of intensive care unit admission and mortality in intermediate- and high-risk COVID-19 patients, and to share our clinical approach with other colleagues. In addition, we sought to reveal the relationship between myocardial injury and clinical outcomes such as death, intensive care unit uptake and hospital stay, and the relationship between inflammatory parameters and cardiac biomarkers in a cardiovascular perspective. METHODS: Patients admitted to the emergency department in the Department of Internal Medicine, Faculty of Medicine, Istanbul University, with laboratory or clinically and radiologically confirmed COVID-19 were included in this retrospective cross-sectional study, which was conducted from 11 March to 10 April 2020. The demographic (age and gender) and clinical (symptoms, co-morbidities, treatments, complications and outcomes) characteristics, laboratory findings, and results of cardiac examinations (cardiac biomarkers and electrocardiography) of patients during hospitalisation were collected from their medical records by two investigators. Data were analysed using SPSS version 25.0 (IBM). A two-sided p < 0.05 was considered statistically significant. Analysis began on 11 April 2020. RESULTS: Mortality and intensive care unit admission rates were statistically significantly higher in patients with cardiac injury than in those without. There was a positive correlation between levels of high-sensitivity TNT and fibrinogen, D-dimer, ferritin, procalcitonin and C-reactive protein (r = 0.24, p < 0.01; r = 0.37, p < 0.01; r = 0.25, p < 0.01, r = 0.34, p < 0.01; r = 0.31, p < 0.01). CONCLUSIONS: The first general data of our 309 patients regarding low mortality and intensive care admission rates, and particular treatment algorithms specific to our centre should be helpful in determining better treatment strategies in the future. Our study emphasises the importance and frequency of cardiovascular outcomes, and the significance of some cardiac biomarkers in predicting COVID-19 prognosis.

Prognostic Value of Troponin-T and B-Type Natriuretic Peptide in Patients Hospitalized for COVID-19. / Valor Prognóstico da Troponina T e do Peptídeo Natriurético Tipo B em Pacientes Internados por COVID-19.

BACKGROUND: COVID-19 causes severe pulmonary involvement, but the cardiovascular system can also be affected by myocarditis, heart failure and shock. The increase in cardiac biomarkers has been associated with a worse prognosis. OBJECTIVES: To evaluate the prognostic value of Troponin-T (TNT) and natriuretic peptide (BNP) in patients hospitalized for Covid-19. METHODS: This was a convenience sample of patients hospitalized for COVID-19. Data were collected from medical records to assess the association of TnT and BNP measured in the first 24 hours of hospital admission with the combined outcome (CO) of death or need for mechanical ventilation. Univariate analysis was used to compare the groups with and without the CO. Cox's multivariate model was used to determine independent predictors of the CO. RESULTS: We evaluated 183 patients (age = 66.8±17 years, 65.6% of which were males). The time of follow-up was 7 days (range 1 to 39 days). The CO occurred in 24% of the patients. The median troponin-T and BNP levels were 0.011 and 0.041ng/dL (p <0.001); 64 and 198 pg/dL (p <0.001), respectively, for the groups without and with the CO. In the univariate analysis, in addition to TnT and BNP, age, presence of coronary disease, oxygen saturation, lymphocytes, D-dimer, t-CRP and creatinine, were different between groups with and without outcomes. In the bootstrap multivariate analysis, only TnT (1.12 [95% CI 1.03-1.47]) and t-CRP (1.04 [95% CI 1.00-1.10]) were independent predictors of the CO. CONCLUSION: In the first 24h of admission, TnT, but not BNP, was an independent marker of mortality or need for invasive mechanical ventilation. This finding further reinforces the clinical importance of cardiac involvement in COVID-19. (Arq Bras Cardiol. 2020; 115(4):660-666).

FUNDAMENTO: A COVID-19 causa grave acometimento pulmonar, porém o sistema cardiovascular também pode ser afetado por miocardite, insuficiência cardíaca e choque. A elevação de biomarcadores cardíacos tem sido associada a um pior prognóstico. OBJETIVOS: Avaliar o valor prognóstico da Troponina T (TnT) e do peptídeo natriurético tipo B (BNP) em pacientes internados por Covid-19. MÉTODOS: Amostra de conveniência de pacientes hospitalizados por COVID-19. Foram coletados dados dos prontuários com o objetivo de avaliar a relação da TnT e o BNP medidos nas primeiras 24h de admissão com o desfecho combinado (DC) óbito ou necessidade de ventilação mecânica. Análise univariada comparou os grupos com e sem DC. Modelo multivariado de Cox foi utilizada para determinar preditores independentes do DC. RESULTADOS: Avaliamos 183 pacientes (idade=66,8±17 anos, sendo 65,6% do sexo masculino). Tempo de acompanhamento foi de 7 dias (1 a 39 dias). O DC ocorreu em 24% dos pacientes. As medianas de TnT e BNP foram 0,011 e 0,041 ng/dl (p<0,001); 64 e 198 pg/dl (p<0,001) respectivamente para os grupos sem e com DC. Na análise univariada, além de TnT e BNP, idade, presença de doença coronariana, saturação de oxigênio, linfócitos, dímero-D, proteína C reativa titulada (PCR-t) e creatinina, foram diferentes entre os grupos com e sem desfechos. Na análise multivariada boostraped apenas TnT (1,12[IC95%1,03-1,47]) e PCR-t (1,04[IC95%1,00-1,10]) foram preditores independentes do DC. CONCLUSÃO: Nas primeiras 24h de admissão, TnT, mas não o BNP, foi marcador independente de mortalidade ou necessidade de ventilação mecânica invasiva. Este dado reforça ainda mais a importância clínica do acometimento cardíaco da COVID-19. (AArq Bras Cardiol. 2020; 115(4):660-666).

Effects of SARS-CoV-2 and its functional receptor ACE2 on the cardiovascular system.

The clinical manifestations of COVID-19 are mainly respiratory symptoms, but some patients present with cardiovascular system disease such as palpitations and shortness of breath as the first or secondary symptoms. In this paper, we describe the characteristics of SARS-CoV­2 and its functional receptor angiotensin-converting enzyme 2 (ACE2). Furthermore, we explore the impact of virus-induced myocardial damage, decreased ACE2 activity, immune imbalance, hypoxemia, and heart damage caused by antiviral drugs.