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2.
Viruses ; 14(2)2022 01 31.
Article in English | MEDLINE | ID: covidwho-1715767

ABSTRACT

INTRODUCTION: This study investigated the spontaneous clinical course of patients with endomyocardial biopsy (EMB)-proven lymphocytic myocarditis and cardiac human herpesvirus 6 (HHV6) DNA presence, and the effectiveness of steroid-based intervention in HHV6-positive patients. RESULTS: 756 heart failure (HF) patients underwent an EMB procedure to determine the underlying cause of unexplained HF. Low levels of HHV6 DNA, detectable by nested PCR only, were found in 10.4% of the cases (n = 79) of which 62% (n = 49) showed myocardial inflammation. The spontaneous course of patients with EMB-proven HHV6 DNA-associated lymphocytic myocarditis (n = 26) showed significant improvements in the left ventricular ejection fraction (LVEF) and clinical symptoms, respectively, in 15/26 (60%) patients, 3-12 months after disease onset. EMB mRNA expression of components of the NLRP3 inflammasome pathway and protein analysis of cardiac remodeling markers, analyzed by real-time PCR and MALDI mass spectrometry, respectively, did not differ between HHV6-positive and -negative patients. In another cohort of patients with ongoing symptoms related to lymphocytic myocarditis associated with cardiac levels of HHV6-DNA copy numbers <500 copies/µg cardiac DNA, quantified by real-time PCR, the efficacy and safety of steroid-based immunosuppression for six months was investigated. Steroid-based immunosuppression improved the LVEF (≥5%) in 8/10 patients and reduced cardiac inflammation in 7/10 patients, without an increase in cardiac HHV6 DNA levels in follow-up EMBs. CONCLUSION: Low HHV6 DNA levels are frequently detected in the myocardium, independent of inflammation. In patients with lymphocytic myocarditis with low levels of HHV6 DNA, the spontaneous clinical improvement is nearby 60%. In selected symptomatic patients with cardiac HHV6 DNA copy numbers less than 500 copies/µg cardiac DNA and without signs of an active systemic HHV6 infection, steroid-based therapy was found to be effective and safe. This finding needs to be further confirmed in large, randomized trials.


Subject(s)
Herpesvirus 6, Human/physiology , Immunosuppressive Agents/administration & dosage , Myocarditis/drug therapy , Myocarditis/virology , Roseolovirus Infections/drug therapy , Roseolovirus Infections/virology , Steroids/administration & dosage , Adult , Aged , Biopsy , Cohort Studies , DNA, Viral/genetics , Female , Gene Dosage , Herpesvirus 6, Human/genetics , Herpesvirus 6, Human/isolation & purification , Humans , Male , Middle Aged , Myocarditis/immunology , Myocarditis/physiopathology , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , Roseolovirus Infections/immunology , Roseolovirus Infections/physiopathology , Stroke Volume
3.
ESC Heart Fail ; 9(3): 1996-2002, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1704932

ABSTRACT

Acute myocarditis following mRNA COVID-19 vaccination was reported by the European Medicine Agency safety committee as a rare adverse event. We present a case series of three young male patients with suspected acute myocarditis following BNT162b2 mRNA COVID-19 vaccination including results of endomyocardial biopsies (EMB). Additionally, we analysed EMB of another 21 patients with clinically suspected acute myocarditis following vaccination to determine the pathohistological pattern. Overall, EMB revealed acute lymphocytic myocarditis in 5 (20.8%), chronic lymphocytic myocarditis in 6 (25%), cardiac sarcoidosis in 1 (4.2%), healed myocarditis in 6 (25%), and other diagnoses with cardiac damage of unclear aetiology in 6 (25%) cases. Our findings support the necessity of EMB in patients with suspected acute myocarditis following mRNA COVID-19 vaccination presenting with reduced EF to establish a correct and definite diagnosis. Concerns of these rare severe adverse events after COVID-19 immunization should not undermine its value for the global community.


Subject(s)
COVID-19 , Myocarditis , Biopsy/methods , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Humans , Male , Myocarditis/diagnosis , Myocarditis/etiology , Myocarditis/pathology , RNA, Messenger , Vaccination/adverse effects
4.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-322033

ABSTRACT

SARS-CoV-2 infection is associated with increased morbidities in men compared to women. Androgens are believed to play an important role in SARS-CoV-2 pathogenesis in men due to the postulated androgen-dependency of ACE2 and TMPRSS2. However, it is yet unclear whether the sex bias is mediated by SARS-CoV-2 infection itself or by other confounding factors. Here, using the golden hamster model, we show that SARS-CoV-2 infection attacks reproductive organs, causes massive dysregulation of sex hormones and induces elevated transcription of the androgen-to-estrogen converting enzyme aromatase CYP19A1 in the lung. In male hamsters, SARS-CoV-2 infection causes severely depleted testosterone and highly elevated estradiol levels. In female hamsters, SARS-CoV-2 infection causes reduced estradiol levels. Hormonal dysregulation in infected animals is followed by severe weight loss compared to control groups treated with poly(I:C) or PBS. Lungs of SARS-CoV-2 infected animals present abundant CYP19A1 expression in the endothelium and in macrophages, particularly in males. Prominent CYP19A1 expression in endothelial cells and macrophages was verified in lung sections of deceased Covid-19 males compared to females. Our results demonstrate that SARS-CoV-2 infection leads to massive dysregulation of sex hormones, which may increase the risk for sex-specific disease outcome particularly in combination with comorbidities. These findings provide insights into the complex metabolic cross talk between SARS-CoV-2 infection and sex hormones.

5.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-320952

ABSTRACT

BACKGROUND Male sex was repeatedly identified as a risk factor for death and intensive care admission. However, it is yet unclear whether sex hormones are associated with disease severity in COVID-19 patients. We sought to characterize sex differences in hormone levels and cytokine responses in critically ill COVID-19 patients. METHODS We performed a retrospective cohort study of critically ill COVID-19 patients. Males and females were compared. Multivariate regression was performed to assess the association between sex hormones, cytokine responses and the requirement for extracorporeal membrane oxygenation (ECMO) treatment. RESULTS We analyzed sex hormone levels (estradiol and testosterone) of n =181 male and female individuals. These consisted of n =50 critically ill COVID-19 patients ( n =39 males, n =11 females), n =42 critically ill non-COVID-19 patients ( n =27 males, n =15 females), n =39 non-COVID-19 patients with coronary heart diseases (CHD) ( n =25 males, n =14 females) and n =50 healthy individuals ( n =30 males, n =20 females). We detected highest estradiol levels in critically ill male COVID-19 patients compared to non-COVID-19 patients ( p =0.0123), patients with CHD ( p =0.0002) or healthy individuals ( p =0.0007). Lowest testosterone levels were detected in critically ill male COVID-19 patients compared to non-COVID-19 patients ( p =0.0094), patients with CHD ( p =0.0068) or healthy individuals ( p <0.0001). No statistically significant differences in sex hormone levels were detected in critically ill female COVID-19 patients, albeit similar trends in estradiol levels were observed. In critically ill male COVID-19 patients, cytokine and chemokine responses (IFN-γ, p =0.0301;IL-1RA, p =0.0160;IL-6, p =0.0145;MCP-1, p =0.0052;MIP-1α, p =0.0134) were significantly elevated in those with higher Sequential Organ Failure Assessment (SOFA) scores (8-11). Linear regression analysis revealed that herein IFN-γ levels correlate with estradiol levels in male and female COVID-19 patients (R 2 =0.216, =0.0009). Male COVID-19 patients with elevated estradiol levels were more likely to receive ECMO treatment in the course of their ICU stay ( p =0.0009). CONCLUSIONS We identified high estradiol and low testosterone levels as a hallmark of critically ill male COVID-19 patients. Elevated estradiol levels in critically ill male COVID-19 patients were positively associated with IFN-γ levels and increased risk for ECMO requirement.

6.
Front Cardiovasc Med ; 8: 737257, 2021.
Article in English | MEDLINE | ID: covidwho-1638221

ABSTRACT

Background: Despite the ongoing global pandemic, the impact of COVID-19 on cardiac structure and function is still not completely understood. Myocarditis is a rare but potentially serious complication of other viral infections with variable recovery, and is, in some cases, associated with long-term cardiac remodeling and functional impairment. Aim: To assess myocardial injury in patients who recently recovered from an acute SARS-CoV-2 infection with advanced cardiac magnetic resonance imaging (CMR) and endomyocardial biopsy (EMB). Methods: In total, 32 patients with persistent cardiac symptoms after a COVID-19 infection, 22 patients with acute classic myocarditis not related to COVID-19, and 16 healthy volunteers were included in this study and underwent a comprehensive baseline CMR scan. Of these, 10 patients post COVID-19 and 13 with non-COVID-19 myocarditis underwent a follow-up scan. In 10 of the post-COVID-19 and 15 of the non-COVID-19 patients with myocarditis endomyocardial biopsy (EMB) with histological, immunohistological, and molecular analysis was performed. Results: In total, 10 (31%) patients with COVID-19 showed evidence of myocardial injury, eight (25%) presented with myocardial oedema, eight (25%) exhibited global or regional systolic left ventricular (LV) dysfunction, and nine (28%) exhibited impaired right ventricular (RV) function. However, only three (9%) of COVID-19 patients fulfilled updated CMR-Lake Louise criteria (LLC) for acute myocarditis. Regarding EMB, none of the COVID-19 patients but 87% of the non-COVID-19 patients with myocarditis presented histological findings in keeping with acute or chronic inflammation. COVID-19 patients with severe disease on the WHO scale presented with reduced biventricular longitudinal function, increased RV mass, and longer native T1 times compared with those with only mild or moderate disease. Conclusions: In our cohort, CMR and EMB findings revealed that SARS-CoV-2 infection was associated with relatively mild but variable cardiac involvement. More symptomatic COVID-19 patients and those with higher clinical care demands were more likely to exhibit chronic inflammation and impaired cardiac function compared to patients with milder forms of the disease.

7.
Frontiers in pediatrics ; 9, 2021.
Article in English | EuropePMC | ID: covidwho-1609929

ABSTRACT

Since the beginning of the COVID-19 pandemic, in-utero transmission of SARS-CoV-2 remains a rarity and only very few cases have been proven across the world. Here we depict the clinical, laboratory and radiologic findings of preterm triplets born at 28 6/7 weeks to a mother who contracted COVID-19 just 1 week before delivery. The triplets showed SARS-CoV-2 positivity right after birth, developed significant leukopenia and early-onset pulmonary interstitial emphysema. The most severely affected triplet I required 10 days of high-frequency oscillatory ventilation due to failure of conventional invasive ventilation, and circulatory support for 4 days. Despite a severe clinical course in two triplets (triplet I and II), clinical management without experimental, targeted antiviral drugs was successful. At discharge home, the triplets showed no signs of neurologic or pulmonary sequelae. Placental immunohistology with SARS-CoV-2 N-protein localized strongly to syncytiotrophoblast cells and, to a lesser extent, to fetal Hofbauer cells, proving intrauterine virus transmission. We discuss the role of maternal viremia as a potential risk factor for vertical transmission. To the best of our knowledge, our report presents the earliest unequivocally confirmed prenatal virus transmission in long-term surviving children, i.e., at the beginning of the third trimester.

8.
EMBO Rep ; 23(2): e53865, 2022 02 03.
Article in English | MEDLINE | ID: covidwho-1579708

ABSTRACT

The ongoing COVID-19 pandemic and the emergence of new SARS-CoV-2 variants of concern (VOCs) requires continued development of effective therapeutics. Recently, we identified high-affinity neutralizing nanobodies (Nbs) specific for the receptor-binding domain (RBD) of SARS-CoV-2. Taking advantage of detailed epitope mapping, we generate two biparatopic Nbs (bipNbs) targeting a conserved epitope outside and two different epitopes inside the RBD:ACE2 interface. Both bipNbs bind all currently circulating VOCs with high affinities and are capable to neutralize cellular infection with VOC B.1.351 (Beta) and B.1.617.2 (Delta) in vitro. To assess if the bipNbs NM1267 and NM1268 confer protection against SARS-CoV-2 infection in vivo, human ACE2 transgenic mice are treated intranasally before infection with a lethal dose of SARS-CoV-2 B.1, B.1.351 (Beta) or B.1.617.2 (Delta). Nb-treated mice show significantly reduced disease progression and increased survival rates. Histopathological analyses further reveal a drastically reduced viral load and inflammatory response in lungs. These data suggest that both bipNbs are broadly active against a variety of emerging SARS-CoV-2 VOCs and represent easily applicable drug candidates.


Subject(s)
COVID-19 , Single-Domain Antibodies , Animals , Antibodies, Neutralizing , Antibodies, Viral , Humans , Mice , Mice, Transgenic , Pandemics , SARS-CoV-2 , Single-Domain Antibodies/genetics , Spike Glycoprotein, Coronavirus
9.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-297003

ABSTRACT

Male sex belongs to one of the major risk factors for severe COVID-19 outcome. However, underlying mechanisms that could affect sex dependent disease outcome are yet unknown. Here, we identified the CYP19A1 gene encoding for the testosterone-to-estradiol metabolizing enzyme CYP19A1 (alias aromatase) as a male abundant host factor that contributes to worsened disease outcome in SARS-CoV-2 infected male hamsters. Pulmonary CYP19A1 transcription is further elevated upon viral infection in males correlating with reduced testosterone and increased estradiol levels. Dysregulated circulating sex hormone levels in male golden hamsters are associated with reduced lung function compared to females. Treatment of SARS-CoV-2 infected hamsters with letrozole, a clinically approved CYP19A1 inhibitor, supported recovery of dysregulated plasma sex hormone levels and was associated with improved lung function and health in male but not female animals compared to placebo controls. Whole human exome sequencing data analysis using a Machine Learning approach revealed a CYP19A1 activity increasing mutation being associated with the development of severe COVID-19 for men. In human autopsy-derived lungs CYP19A1 was expressed to higher levels in men who died of COVID-19, at a time point when most viral RNA was cleared. Our findings highlight the role of the lung as a yet unrecognized but critical organ regulating metabolic responses upon respiratory virus infection. Furthermore, inhibition of CYP19A1 by the clinically approved drug letrozole may pose a new therapeutic strategy to reduce poor long-term COVID-19 outcome.

10.
JAMA Cardiol ; 7(3): 286-297, 2022 Mar 01.
Article in English | MEDLINE | ID: covidwho-1575887

ABSTRACT

IMPORTANCE: Myocardial injury is a common feature of patients with SARS-CoV-2 infection. However, the cardiac inflammatory processes associated with SARS-CoV-2 infection are not completely understood. OBJECTIVE: To investigate the inflammatory cardiac phenotype associated with SARS-CoV-2 infection compared with viral myocarditis, immune-mediated myocarditis, and noninflammatory cardiomyopathy by integrating histologic, transcriptomic, and proteomic profiling. DESIGN, SETTING, AND PARTICIPANTS: This case series was a cooperative study between the Ludwig Maximilian University Hospital Munich and the Cardiopathology Referral Center at the University of Tübingen in Germany. A cohort of 19 patients with suspected myocarditis was examined; of those, 5 patients were hospitalized with SARS-CoV-2 infection between March and May 2020. Cardiac tissue specimens from those 5 patients were compared with specimens from 5 patients with immune-mediated myocarditis, 4 patients with non-SARS-CoV-2 viral myocarditis, and 5 patients with noninflammatory cardiomyopathy, collected from January to August 2019. EXPOSURES: Endomyocardial biopsy. MAIN OUTCOMES AND MEASURES: The inflammatory cardiac phenotypes were measured by immunohistologic analysis, RNA exome capture sequencing, and mass spectrometry-based proteomic analysis of endomyocardial biopsy specimens. RESULTS: Among 19 participants, the median age was 58 years (range, 37-76 years), and 15 individuals (79%) were male. Data on race and ethnicity were not collected. The abundance of CD163+ macrophages was generally higher in the cardiac tissue of patients with myocarditis, whereas lymphocyte counts were lower in the tissue of patients with SARS-CoV-2 infection vs patients with non-SARS-CoV-2 virus-associated and immune-mediated myocarditis. Among those with SARS-CoV-2 infection, components of the complement cascade, including C1q subunits (transcriptomic analysis: 2.5-fold to 3.6-fold increase; proteomic analysis: 2.0-fold to 3.4-fold increase) and serine/cysteine proteinase inhibitor clade G member 1 (transcriptomic analysis: 1.7-fold increase; proteomic analysis: 2.6-fold increase), belonged to the most commonly upregulated transcripts and differentially abundant proteins. In cardiac macrophages, the abundance of C1q was highest in SARS-CoV-2 infection. Assessment of important signaling cascades identified an upregulation of the serine/threonine mitogen-activated protein kinase pathways. CONCLUSIONS AND RELEVANCE: This case series found that the cardiac immune signature varied in inflammatory conditions with different etiologic characteristics. Future studies are needed to examine the role of these immune pathways in myocardial inflammation.


Subject(s)
COVID-19 , Myocarditis , Humans , Inflammation/complications , Male , Myocarditis/etiology , Proteomics , SARS-CoV-2
11.
Viruses ; 13(12)2021 11 23.
Article in English | MEDLINE | ID: covidwho-1542791

ABSTRACT

The new WHO reference standard allows for the definition of serum antibodies against various SARS-CoV-2 antigens in terms of binding antibody units (BAU/mL) and thus to compare the results of different ELISA systems. In this study, the concentration of antibodies (ABs) against both the S- and the N-protein of SARS-CoV-2 as well as serum neutralization activity were evaluated in three patients after a mild course of COVID-19. Serum samples were collected frequently during a period of over one year. Furthermore, in two individuals, the effects of an additional vaccination with a mRNA vaccine containing the S1-RBD sequence on these antibodies were examined. After natural infection, the antibodies (IgA, IgG) against the S1-protein remained elevated above the established cut-off to positivity (S-IgA 60 BAU/mL and S-IgG 50 BAU/mL, respectively) for over a year in all patients, while this was not the case for ABs against the N-protein (cut-off N-IgG 40 BAU/mL, N-IgA 256 BAU/mL). Sera from all patients retained the ability to neutralize SARS-CoV-2 for more than a year. Vaccination resulted in a rapid boost of antibodies to S1-protein but, as expected, not to the N-protein. Most likely, the wide use of the WHO reference preparation will be very useful in determining the individual immune status of patients after an infection with SARS-CoV-2 or after vaccination.


Subject(s)
Antibodies, Viral/immunology , COVID-19 Serological Testing/standards , COVID-19/immunology , SARS-CoV-2/immunology , Adult , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , COVID-19/diagnosis , COVID-19 Vaccines/immunology , Coronavirus Nucleocapsid Proteins/immunology , Female , Humans , Immunity, Humoral , Male , Middle Aged , Phosphoproteins/immunology , Spike Glycoprotein, Coronavirus/immunology , Vaccination
12.
Front Cardiovasc Med ; 8: 716198, 2021.
Article in English | MEDLINE | ID: covidwho-1441103

ABSTRACT

Multisystem Inflammatory Syndrome (MIS) is a novel hyperinflammatory syndrome associated with SARS-CoV-2 infection. It predominantly affects children (MIS-C) a few weeks after a usually asymptomatic SARS-CoV-2 infection and is only rarely seen in adults above 21 years (MIS-A). Only scarce data on histological findings in both pediatric and adult patients has been published so far. An 18-year-old male patient was admitted to hospital in a febrile state, which progressed to severe cardiogenic shock and multi-organ failure requiring extracorporeal life support. Myocardial biopsy revealed small vessel-associated immune cell infiltrates. Diagnosis of MIS-C was made after ruling out all potential differential diagnosis. Use of immunosuppressive treatment with steroids, interleukin-1 blockade and high-dose intravenous immunoglobulins resulted in the patient's full recovery. Multisystem Inflammatory Syndrome (MIS) is a new differential diagnosis of cardiac dysfunction in pediatric and adult patients. The lack of myocardial necrosis differentiates the disease from other viral myocarditis and offers an explanation for the fast response to immunomodulatory therapy and the favorable prognosis. The preceding SARS-CoV-2 infection might only have been mildly symptomatic or even asymptomatic.

13.
Viruses ; 13(9)2021 09 21.
Article in English | MEDLINE | ID: covidwho-1430982

ABSTRACT

Evidence is emerging that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can infect various organs of the body, including cardiomyocytes and cardiac endothelial cells in the heart. This review focuses on the effects of SARS-CoV-2 in the heart after direct infection that can lead to myocarditis and an outline of potential treatment options. The main points are: (1) Viral entry: SARS-CoV-2 uses specific receptors and proteases for docking and priming in cardiac cells. Thus, different receptors or protease inhibitors might be effective in SARS-CoV-2-infected cardiac cells. (2) Viral replication: SARS-CoV-2 uses RNA-dependent RNA polymerase for replication. Drugs acting against ssRNA(+) viral replication for cardiac cells can be effective. (3) Autophagy and double-membrane vesicles: SARS-CoV-2 manipulates autophagy to inhibit viral clearance and promote SARS-CoV-2 replication by creating double-membrane vesicles as replication sites. (4) Immune response: Host immune response is manipulated to evade host cell attacks against SARS-CoV-2 and increased inflammation by dysregulating immune cells. Efficiency of immunosuppressive therapy must be elucidated. (5) Programmed cell death: SARS-CoV-2 inhibits programmed cell death in early stages and induces apoptosis, necroptosis, and pyroptosis in later stages. (6) Energy metabolism: SARS-CoV-2 infection leads to disturbed energy metabolism that in turn leads to a decrease in ATP production and ROS production. (7) Viroporins: SARS-CoV-2 creates viroporins that lead to an imbalance of ion homeostasis. This causes apoptosis, altered action potential, and arrhythmia.


Subject(s)
COVID-19/complications , COVID-19/virology , Heart Diseases/etiology , SARS-CoV-2/physiology , Apoptosis , Autophagy , Disease Management , Disease Susceptibility , Endothelial Cells/ultrastructure , Endothelial Cells/virology , Heart Diseases/diagnosis , Heart Diseases/therapy , Host-Pathogen Interactions/immunology , Humans , Myocarditis/diagnosis , Myocarditis/etiology , Myocarditis/therapy , Viroporin Proteins , Virus Replication
15.
Cardiovasc Res ; 117(1): 224-239, 2021 01 01.
Article in English | MEDLINE | ID: covidwho-1387842

ABSTRACT

AIMS: To elucidate the prognostic role of monocytes in the immune response of patients with coronary artery disease (CAD) at risk for life-threatening heart and lung injury as major complications of SARS-CoV-2 infection. METHODS AND RESULTS: From February to April 2020, we prospectively studied a cohort of 96 participants comprising 47 consecutive patients with CAD and acute SARS-CoV-2 infection (CAD + SARS-CoV-2), 19 CAD patients without infections, and 30 healthy controls. Clinical assessment included blood sampling, echocardiography, and electrocardiography within 12 h of admission. Respiratory failure was stratified by the Horovitz Index (HI) as moderately/severely impaired when HI ≤200 mmHg. The clinical endpoint (EP) was defined as HI ≤200 mmHg with subsequent mechanical ventilation within a follow-up of 30 days. The numbers of CD14dimCD16+ non-classical monocytes in peripheral blood were remarkably low in CAD + SARS-CoV-2 compared with CAD patients without infection and healthy controls (P < 0.0001). Moreover, these CD14dimCD16 monocytes showed decreased expression of established markers of adhesion, migration, and T-cell activation (CD54, CD62L, CX3CR1, CD80, and HLA-DR). Decreased numbers of CD14dimCD16+ monocytes were associated with the occurrence of EP. Kaplan-Meier curves illustrate that CAD + SARS-CoV-2 patients with numbers below the median of CD14dimCD16+ monocytes (median 1443 cells/mL) reached EP significantly more often compared to patients with numbers above the median (log-rank 5.03, P = 0.025). CONCLUSION: Decreased numbers of CD14dimCD16+ monocytes are associated with rapidly progressive respiratory failure in CAD + SARS-CoV-2 patients. Intensified risk assessments comprising monocyte sub- and phenotypes may help to identify patients at risk for respiratory failure.


Subject(s)
COVID-19/complications , Coronary Artery Disease/complications , Lipopolysaccharide Receptors/analysis , Monocytes/physiology , Receptors, IgG/analysis , SARS-CoV-2 , Aged , Aged, 80 and over , COVID-19/immunology , Coronary Artery Disease/immunology , Female , GPI-Linked Proteins/analysis , Humans , Immunohistochemistry , Male , Middle Aged , Monocytes/immunology , Phenotype , Retrospective Studies
16.
Emerg Microbes Infect ; 10(1): 1807-1818, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1360311

ABSTRACT

Male sex was repeatedly identified as a risk factor for death and intensive care admission. However, it is yet unclear whether sex hormones are associated with disease severity in COVID-19 patients. In this study, we analysed sex hormone levels (estradiol and testosterone) of male and female COVID-19 patients (n = 50) admitted to an intensive care unit (ICU) in comparison to control non-COVID-19 patients at the ICU (n = 42), non-COVID-19 patients with the most prevalent comorbidity (coronary heart diseases) present within the COVID-19 cohort (n = 39) and healthy individuals (n = 50). We detected significantly elevated estradiol levels in critically ill male COVID-19 patients compared to all control cohorts. Testosterone levels were significantly reduced in critically ill male COVID-19 patients compared to control cohorts. No statistically significant differences in sex hormone levels were detected in critically ill female COVID-19 patients, albeit similar trends towards elevated estradiol levels were observed. Linear regression analysis revealed that among a broad range of cytokines and chemokines analysed, IFN-γ levels are positively associated with estradiol levels in male and female COVID-19 patients. Furthermore, male COVID-19 patients with elevated estradiol levels were more likely to receive ECMO treatment. Thus, we herein identified that disturbance of sex hormone metabolism might present a hallmark in critically ill male COVID-19 patients.


Subject(s)
COVID-19/mortality , COVID-19/pathology , Estradiol/blood , Testosterone/blood , Aged , Aged, 80 and over , COVID-19/blood , Critical Care , Critical Illness , Extracorporeal Membrane Oxygenation , Female , Humans , Hypogonadism/pathology , Intensive Care Units , Interferon-gamma/blood , Male , Middle Aged , Retrospective Studies , Risk Factors , SARS-CoV-2 , Severity of Illness Index , Sex Distribution
17.
Hamostaseologie ; 41(5): 366-370, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1356592

ABSTRACT

Diagnosing myocarditis is still challenging due to its varying presentation ranging from none or mild symptoms to sudden cardiac death. Clinical presentation, electrocardiography, and cardiac biomarkers seem not to be sufficient for a reliable diagnosis. In fact, an unequivocal myocardial characterization is needed, applying endomyocardial biopsy (EMB) and cardiac magnetic resonance (CMR), a technique which demonstrates high accuracy to histology. Besides the assessment of functional parameters (volumes, ejection fraction), established late gadolinium enhancement and recent T1 and T2 mapping techniques including the calculation of extracellular volume fraction allow distinct myocardial tissue analysis by a noninvasive approach without the need of radiation. However, EMB is the only method which allows the identification of the underlying etiology of cardiac inflammation. Since myocardial damage and inflammation seem to be prevalent in a considerable number of patients even in the mid-term range after COVID-19, CMR and EMB seem to be adequate tools to further investigate these findings. In this article, we will (1) review current knowledge about the role of CMR in the COVID-19 pandemic and (2) report about our own EMB findings in COVID-19 patients in the Cardiopathology Center of our University Hospital.


Subject(s)
COVID-19/complications , Myocarditis/diagnosis , Myocarditis/etiology , SARS-CoV-2 , Adolescent , Adult , Aged , Aged, 80 and over , Biopsy/methods , Endocardium/pathology , Female , Heart Disease Risk Factors , Humans , Magnetic Resonance Imaging/methods , Male , Middle Aged , Myocarditis/diagnostic imaging , Myocardium/pathology , Pandemics , SARS-CoV-2/pathogenicity , Young Adult
18.
Pathologe ; 42(2): 149-154, 2021 Mar.
Article in German | MEDLINE | ID: covidwho-1235731

ABSTRACT

The worldwide novel coronavirus SARS-CoV­2 pandemic is ongoing. SARS-CoV­2 belongs to the coronavirus family, the first representatives of which have been known since the 1960s. Coronaviruses are present in animals and humans and show similarities as well as differences in their biology and pathology regarding each genus. Besides mild flu-like and gastroenterological symptoms, SARS-CoV­2 can lead to dysfunctions of the lungs and other organs including the heart as already observed during SARS and MERS infections.


Subject(s)
COVID-19 , Coronavirus Infections , Middle East Respiratory Syndrome Coronavirus , Animals , Biology , Humans , SARS-CoV-2
19.
Cardiovasc Res ; 116(14): 2207-2215, 2020 12 01.
Article in English | MEDLINE | ID: covidwho-1048209

ABSTRACT

AIMS: Coronavirus disease 2019 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has emerged as a global pandemic. SARS-CoV-2 infection can lead to elevated markers of cardiac injury associated with higher risk of mortality. It is unclear whether cardiac injury is caused by direct infection of cardiomyocytes or is mainly secondary to lung injury and inflammation. Here, we investigate whether cardiomyocytes are permissive for SARS-CoV-2 infection. METHODS AND RESULTS: Two strains of SARS-CoV-2 infected human induced pluripotent stem cell-derived cardiomyocytes as demonstrated by detection of intracellular double-stranded viral RNA and viral spike glycoprotein expression. Increasing concentrations of viral RNA are detected in supernatants of infected cardiomyocytes, which induced infections in Caco-2 cell lines, documenting productive infections. SARS-CoV-2 infection and induced cytotoxic and proapoptotic effects associated with it abolished cardiomyocyte beating. RNA sequencing confirmed a transcriptional response to viral infection as demonstrated by the up-regulation of genes associated with pathways related to viral response and interferon signalling, apoptosis, and reactive oxygen stress. SARS-CoV-2 infection and cardiotoxicity was confirmed in a 3D cardiosphere tissue model. Importantly, viral spike protein and viral particles were detected in living human heart slices after infection with SARS-CoV-2. Coronavirus particles were further observed in cardiomyocytes of a patient with coronavirus disease 2019. Infection of induced pluripotent stem cell-derived cardiomyocytes was dependent on cathepsins and angiotensin-converting enzyme 2, and was blocked by remdesivir. CONCLUSION: This study demonstrates that SARS-CoV-2 infects cardiomyocytes in vitro in an angiotensin-converting enzyme 2- and cathepsin-dependent manner. SARS-CoV-2 infection of cardiomyocytes is inhibited by the antiviral drug remdesivir.


Subject(s)
Apoptosis , COVID-19/virology , Heart Diseases/virology , Myocytes, Cardiac/virology , SARS-CoV-2/pathogenicity , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/pharmacology , Apoptosis/drug effects , COVID-19/drug therapy , COVID-19/metabolism , COVID-19/pathology , Caco-2 Cells , Cathepsins/metabolism , Heart Diseases/drug therapy , Heart Diseases/metabolism , Heart Diseases/pathology , Host-Pathogen Interactions , Humans , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Reactive Oxygen Species/metabolism , SARS-CoV-2/drug effects , Signal Transduction
20.
Circ Cardiovasc Imaging ; 14(1): e012220, 2021 01.
Article in English | MEDLINE | ID: covidwho-1035201

ABSTRACT

BACKGROUND: Myocardial injury, defined by elevated troponin levels, is associated with adverse outcome in patients with coronavirus disease 2019 (COVID-19). The frequency of cardiac injury remains highly uncertain and confounded in current publications; myocarditis is one of several mechanisms that have been proposed. METHODS: We prospectively assessed patients with myocardial injury hospitalized for COVID-19 using transthoracic echocardiography, cardiac magnetic resonance imaging, and endomyocardial biopsy. RESULTS: Eighteen patients with COVID-19 and myocardial injury were included in this study. Echocardiography revealed normal to mildly reduced left ventricular ejection fraction of 52.5% (46.5%-60.5%) but moderately to severely reduced left ventricular global longitudinal strain of -11.2% (-7.6% to -15.1%). Cardiac magnetic resonance showed any myocardial tissue injury defined by elevated T1, extracellular volume, or late gadolinium enhancement with a nonischemic pattern in 16 patients (83.3%). Seven patients (38.9%) demonstrated myocardial edema in addition to tissue injury fulfilling the Lake-Louise criteria for myocarditis. Combining cardiac magnetic resonance with speckle tracking echocardiography demonstrated functional or morphological cardiac changes in 100% of investigated patients. Endomyocardial biopsy was conducted in 5 patients and revealed enhanced macrophage numbers in all 5 patients in addition to lymphocytic myocarditis in 1 patient. SARS-CoV-2 RNA was not detected in any biopsy by quantitative real-time polymerase chain reaction. Finally, follow-up measurements of left ventricular global longitudinal strain revealed significant improvement after a median of 52.0 days (-11.2% [-9.2% to -14.7%] versus -15.6% [-12.5% to -19.6%] at follow-up; P=0.041). CONCLUSIONS: In this small cohort of COVID-19 patients with elevated troponin levels, myocardial injury was evidenced by reduced echocardiographic left ventricular strain, myocarditis patterns on cardiac magnetic resonance, and enhanced macrophage numbers but not predominantly lymphocytic myocarditis in endomyocardial biopsies.


Subject(s)
COVID-19/complications , COVID-19/pathology , Myocarditis/etiology , Myocarditis/pathology , Myocardium/pathology , Aged , Biopsy , COVID-19/blood , Cohort Studies , Echocardiography/methods , Female , Germany , Humans , Magnetic Resonance Imaging/methods , Male , Middle Aged , Myocarditis/diagnostic imaging , Prospective Studies , SARS-CoV-2 , Troponin/blood
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