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Open accessJournal ArticleDOI: 10.1080/00015385.2020.1846921

Endothelialitis plays a central role in the pathophysiology of severe COVID-19 and its cardiovascular complications.

04 Mar 2021-Acta Cardiologica (Taylor & Francis)-Vol. 76, Iss: 2, pp 1-16
Abstract: This clinical review paper discusses the pathophysiology of the pulmonary and cardiovascular manifestations of a SARS-CoV-2 infection and the ensuing implications on acute cardiovascular care in patients presenting with a severe COVID-19 syndrome admitted to an intensive acute cardiac care unit. The high prevalence of old age, obesity, diabetes, hypertension, heart failure, and ischaemic heart disease in patients who develop a severe to critical COVID-19 syndrome suggests shared pathophysiological mechanisms. Pre-existing endothelial dysfunction and an impaired innate immune response promote the development by the viral infection of an acute endothelialitis in the pulmonary microcirculation complicated by abnormal vasoconstrictor responses, luminal plugging by inflammatory cells, and intravascular thrombosis. This endothelialitis extends into the systemic circulation what may lead to acute myocardial injury, myocarditis, and thromboembolic complications both in the arterial and venous circulation.

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Topics: Heart failure (54%), Myocarditis (52%)
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15 results found


Open access
Fei Zhou1, Ting Yu, Ronghui Du, Guohui Fan2  +16 moreInstitutions (5)
01 Jan 2020-
Abstract: Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

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Topics: Cohort study (56%), Retrospective cohort study (56%), Odds ratio (53%) ... show more

536 Citations


Open access
15 Apr 2016-
Abstract: Heart failure (HF) remains the most common cause of death and disability, and a major economic burden, in industrialized nations. Physiological, pharmacological, and clinical studies have demonstrated that activation of the renin-angiotensin system is a key mediator of HF progression. Angiotensin-converting enzyme 2 (ACE2), a homolog of ACE, is a monocarboxypeptidase that converts angiotensin II into angiotensin 1-7 (Ang 1-7) which, by virtue of its actions on the Mas receptor, opposes the molecular and cellular effects of angiotensin II. ACE2 is widely expressed in cardiomyocytes, cardiofibroblasts, and coronary endothelial cells. Recent preclinical translational studies confirmed a critical counter-regulatory role of ACE2/Ang 1-7 axis on the activated renin-angiotensin system that results in HF with preserved ejection fraction. Although loss of ACE2 enhances susceptibility to HF, increasing ACE2 level prevents and reverses the HF phenotype. ACE2 and Ang 1-7 have emerged as a key protective pathway against HF with reduced and preserved ejection fraction. Recombinant human ACE2 has been tested in phase I and II clinical trials without adverse effects while lowering and increasing plasma angiotensin II and Ang 1-7 levels, respectively. This review discusses the transcriptional and post-transcriptional regulation of ACE2 and the role of the ACE2/Ang 1-7 axis in cardiac physiology and in the pathophysiology of HF. The pharmacological and therapeutic potential of enhancing ACE2/Ang 1-7 action as a novel therapy for HF is highlighted.

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Topics: Angiotensin II (67%), Angiotensin II receptor type 1 (62%), Angiotensin receptor (62%) ... show more

13 Citations


Open access
01 Jan 2020-
Abstract: A novel coronavirus disease (COVID-19), caused by severeacute respiratory syndrome coronavirus 2 (SARS-CoV-2) hasscourged the world since its outbreak in December 2019 atWuhan, China resulting in the World Health Organizationdeclaring it as a pandemic. As of March 22, 2020, COVID-19has affected over292,000peoplein at least 185countriesworld-wide with most of the cases being reported from China, Europeand the United States of America. The absolute number ofdeaths has already surpassed 12,750 globally and is expectedto increase further as the disease spreads rapidly. The diseasehas also infiltrated the Indian masses and is spreading fast.India being a developing nation with more than 1.3 billion peo-ple, failure to contain the virus can lead to disastrous conse-quences with death toll perhaps surpassing all other nations.Although the overall mortality rate of COVID-19 is low (1.4–2.3%), patients with comorbidities are more likely to have sev-ere disease and subsequent mortality[1,2]. Most of the avail-able studies have shown that diabetes mellitus (DM) as adistinctive comorbidity is associated with more severe dis-ease, acute respiratory distress syndrome and increased mor-tality[1,3,4]. Amongst the 32 non-survivors from a group of 52intensive care unit (ICU) patients, DM (22%) was a predomi-nant underlying comorbidity[3]. Of the 1099 confirmedCOVID-19 patients reported by Guan et al. from China, 173had severe disease; patients with severe disease had a higherprevalence of DM (16.2%) as compared to those with non-sev-ere disease (5.7%)[1]. Further, in the largest series reported bythe Chinese Center for Disease Control and Prevention com-prising of 72,314 cases of COVID-19, patients with DM hadhigher mortality (7.3% in DM vs. 2.3% overall)[2].It can be assumed that patients with DM are more likely tobe older than those without DM and advancing age has consis-tently been shown to be associated with poor prognosis inCOVID-19, however, most of the aforementioned studies didnot adjust for age. Nevertheless, diabetes has been uniformlyreported to be associated with poor prognosis in other viralinfections, notably seasonal influenza, pandemic influenza AH1N1 (2009), Severe Acute Respiratory Syndrome (SARS) andMiddle East Respiratory Syndrome (MERS)[5–8]. Multipleexplanations can be put forward for this apparent associationbetween pre-existing DM and COVID-19 severity. Innateimmunity, the first line of defense against SARS-CoV-2, isinevitably compromised in patients with uncontrolled DMthereby allowing unhindered proliferation of the pathogenwithin the host[9]. Even short-term hyperglycemia has beenshown to transiently stun the innate immune system[10].Moreover, DM is characterized by exaggerated pro-inflamma-tory cytokine response, notably interleukin (IL)-1, IL-6 andhtumor-necrosis factor (TNF)-a, in the absence of appropriateimmunostimulation; this may be further exaggerated inresponse to a stimulus as seen in patients with COVID-19 com-plicated by acute respiratory distress syndrome (ARDS)[9].The role of angiotensin-converting enzyme 2 (ACE2) in theassociation between DM and COVID-19 is plausible. ACE2 is atype 1 integral membrane glycoprotein that is constitutivelyexpressed by the epithelial cells of the lungs, kidney, intestineand blood vessels. In normal physiology, ACE2 breaks downangiotensin-II and to a lesser extent, angiotensin-I to smallerpeptides, angiotensin (1–7) and angiotensin (1–9), respectively[11]. ACE2/Ang (1–7) system plays an important anti-inflam-matory and anti-oxidant role protecting the lung againstARDS; indeed ACE2 has been shown to be protective againstlethal avian influenza A H5N1 infection[12]. ACE2 expressionis reduced in patients with DM possibly due to glycosylation;this might explain the increased predisposition to severe lunginjury and ARDS with COVID-19[4,11].Strange it might sound, even overexpression of ACE2would be counterproductive in COVID-19. SARS-CoV-2 utilizesACE2 as a receptor for entry into the host pneumocytes[13].Herein comes the confounding role of ACE inhibitors (ACEi)and angiotensin-receptor blockers (ARBs), drugs that are sowidely used in DM. The expression of ACE2 is markedlyincreased in patients with DM (and hypertension) on ACEior ARBs as an adaptive response to counteract the elevatedlevels of Ang-II and Ang-I. Thus, use of ACE2-stimulatingdrugs would facilitate the entry of SARS-CoV-2 into pneumo-cytes and consequently might result in more severe and fataldisease[14]. Amongst others, pioglitazone and liraglutidehave also been shown to be associated with ACE2 upregula-tion in animal studies[14,15]. Unfortunately, none of thestudies have taken into account the baseline treatment.Furthermore, a recently concluded study showed that severeand critically ill patients with COVID-19 had a higherprevalence of hypokalemia that resulted from renal potas-sium wasting. This can be explained by downregulation ofACE2 following viral intrusion resulting in decreased degrada-tion of angiotensin-II, increased aldosterone secretion andsubsequent increased urinary potassium loss. Infact earlynormalization of serum potassium has been proposed to bea predictor of good prognosis in COVID-19[16]. Thus, ACE2overexpression, while facilitating entry of SARS-CoV-2, isunable to protect against lung injury as the enzyme getsdegraded by the virus (see Fig. 1).Whatever may be the underlying etiology, people with DMare definitely at an increased risk of severe and fatal COVID-19 disease. The prevalence of DM in India is 7.3%[17], therebypredisposing a large section of the community to COVID-19and its complications. Hence it is advisable that commu-nity-dwelling residents having underlying DM take extra pre-cautions not to contract the virus. Social distancing, stricthand and respiratory hygiene are the need of the hour. Peoplewith DM should ensure good glucose control as improvementin glycemia does boost host immune response[9]. Althoughnot recommended due to lack of robust data, use of ACEi/ARBs/thiazolidinediones/liraglutide merits reconsiderationin patients with DM during this outbreak.

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Topics: Lung injury (53%), ARDS (51%), Diabetes mellitus (50%)

12 Citations


Open accessJournal ArticleDOI: 10.1016/J.PHARMTHERA.2020.107794
Valentin A. Pavlov1Institutions (1)
Abstract: Obesity and the metabolic syndrome (MetS), which have reached pandemic proportions significantly increase the risk for type 2 diabetes, cardiovascular disease, and other serious conditions. Recent data with COVID-19 patients indicate that obesity also is a significant risk factor for this novel viral disease and poor outcome of associated critical illness. These findings considerably change the view of obesity as a driver of serious, but slowly-progressing chronic diseases, and emphasize the urgency to explore new therapeutic approaches. Inflammation is a recognized driver of metabolic derangements in obesity and MetS, and a core feature of COVID-19 pathobiology. Recent advances in our understanding of inflammatory regulation have highlighted the role of the nervous system and the vagus nerve-based inflammatory reflex. Current bioelectronic and pharmacological therapeutic explorations centered on the inflammatory reflex offer new approaches for conditions characterized by immune and metabolic dysregulation and for ameliorating the escalating burden of obesity, MetS, and COVID-19.

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Topics: Inflammatory reflex (58%), Metabolic syndrome (51%)

10 Citations


Open accessJournal ArticleDOI: 10.1016/J.JAMCOLLSURG.2021.02.019
Abstract: The COVID-19 pandemic has introduced a global public health threat unparalleled in our history. The most severe cases are marked by ARDS attributed to microvascular thrombosis. Hypercoagulability, resulting in a profoundly prothrombotic state, is a distinct feature of COVID-19 and is accentuated by a high incidence of fibrinolysis shutdown. The aims of this review were to describe the manifestations of fibrinolysis shutdown in COVID-19 and its associated outcomes, review the molecular mechanisms of dysregulated fibrinolysis associated with COVID-19, and discuss potential implications and therapeutic targets for patients with severe COVID-19.

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Topics: Fibrinolysis (56%)

5 Citations


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147 results found


Open accessJournal ArticleDOI: 10.1016/S0140-6736(20)30183-5
Chaolin Huang1, Yeming Wang2, Xingwang Li3, Lili Ren4  +25 moreInstitutions (8)
24 Jan 2020-The Lancet
Abstract: A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not.

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26,390 Citations


Open accessJournal ArticleDOI: 10.1056/NEJMOA2002032
Wei-jie Guan1, Zhengyi Ni1, Yu Hu1, Wenhua Liang1  +33 moreInstitutions (1)
Abstract: Background Since December 2019, when coronavirus disease 2019 (Covid-19) emerged in Wuhan city and rapidly spread throughout China, data have been needed on the clinical characteristics of...

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16,855 Citations


Open accessJournal ArticleDOI: 10.1016/S0140-6736(20)30566-3
Fei Zhou1, Ting Yu, Ronghui Du, Guohui Fan2  +16 moreInstitutions (5)
28 Mar 2020-The Lancet
Abstract: Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

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Topics: Cohort study (56%), Retrospective cohort study (56%), Odds ratio (53%) ... show more

15,279 Citations


Open accessJournal ArticleDOI: 10.1001/JAMA.2020.1585
Dawei Wang1, Bo Hu1, Chang Hu1, Fangfang Zhu1  +10 moreInstitutions (1)
17 Mar 2020-JAMA
Abstract: Importance In December 2019, novel coronavirus (2019-nCoV)–infected pneumonia (NCIP) occurred in Wuhan, China. The number of cases has increased rapidly but information on the clinical characteristics of affected patients is limited. Objective To describe the epidemiological and clinical characteristics of NCIP. Design, Setting, and Participants Retrospective, single-center case series of the 138 consecutive hospitalized patients with confirmed NCIP at Zhongnan Hospital of Wuhan University in Wuhan, China, from January 1 to January 28, 2020; final date of follow-up was February 3, 2020. Exposures Documented NCIP. Main Outcomes and Measures Epidemiological, demographic, clinical, laboratory, radiological, and treatment data were collected and analyzed. Outcomes of critically ill patients and noncritically ill patients were compared. Presumed hospital-related transmission was suspected if a cluster of health professionals or hospitalized patients in the same wards became infected and a possible source of infection could be tracked. Results Of 138 hospitalized patients with NCIP, the median age was 56 years (interquartile range, 42-68; range, 22-92 years) and 75 (54.3%) were men. Hospital-associated transmission was suspected as the presumed mechanism of infection for affected health professionals (40 [29%]) and hospitalized patients (17 [12.3%]). Common symptoms included fever (136 [98.6%]), fatigue (96 [69.6%]), and dry cough (82 [59.4%]). Lymphopenia (lymphocyte count, 0.8 × 109/L [interquartile range {IQR}, 0.6-1.1]) occurred in 97 patients (70.3%), prolonged prothrombin time (13.0 seconds [IQR, 12.3-13.7]) in 80 patients (58%), and elevated lactate dehydrogenase (261 U/L [IQR, 182-403]) in 55 patients (39.9%). Chest computed tomographic scans showed bilateral patchy shadows or ground glass opacity in the lungs of all patients. Most patients received antiviral therapy (oseltamivir, 124 [89.9%]), and many received antibacterial therapy (moxifloxacin, 89 [64.4%]; ceftriaxone, 34 [24.6%]; azithromycin, 25 [18.1%]) and glucocorticoid therapy (62 [44.9%]). Thirty-six patients (26.1%) were transferred to the intensive care unit (ICU) because of complications, including acute respiratory distress syndrome (22 [61.1%]), arrhythmia (16 [44.4%]), and shock (11 [30.6%]). The median time from first symptom to dyspnea was 5.0 days, to hospital admission was 7.0 days, and to ARDS was 8.0 days. Patients treated in the ICU (n = 36), compared with patients not treated in the ICU (n = 102), were older (median age, 66 years vs 51 years), were more likely to have underlying comorbidities (26 [72.2%] vs 38 [37.3%]), and were more likely to have dyspnea (23 [63.9%] vs 20 [19.6%]), and anorexia (24 [66.7%] vs 31 [30.4%]). Of the 36 cases in the ICU, 4 (11.1%) received high-flow oxygen therapy, 15 (41.7%) received noninvasive ventilation, and 17 (47.2%) received invasive ventilation (4 were switched to extracorporeal membrane oxygenation). As of February 3, 47 patients (34.1%) were discharged and 6 died (overall mortality, 4.3%), but the remaining patients are still hospitalized. Among those discharged alive (n = 47), the median hospital stay was 10 days (IQR, 7.0-14.0). Conclusions and Relevance In this single-center case series of 138 hospitalized patients with confirmed NCIP in Wuhan, China, presumed hospital-related transmission of 2019-nCoV was suspected in 41% of patients, 26% of patients received ICU care, and mortality was 4.3%.

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Topics: Interquartile range (51%)

13,270 Citations


Open accessJournal ArticleDOI: 10.1016/S0140-6736(20)30211-7
Nanshan Chen1, Min Zhou2, Xuan Dong1, Jie-Ming Qu2  +10 moreInstitutions (3)
30 Jan 2020-The Lancet
Abstract: In December, 2019, a pneumonia associated with the 2019 novel coronavirus (2019-nCoV) emerged in Wuhan, China. We aimed to further clarify the epidemiological and clinical characteristics of 2019-nCoV pneumonia. In this retrospective, single-centre study, we included all confirmed cases of 2019-nCoV in Wuhan Jinyintan Hospital from Jan 1 to Jan 20, 2020. Cases were confirmed by real-time RT-PCR and were analysed for epidemiological, demographic, clinical, and radiological features and laboratory data. Outcomes were followed up until Jan 25, 2020.

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12,381 Citations