Inflammation and vascular remodeling in COVID-19 hearts.

A wide range of cardiac symptoms have been observed in COVID-19 patients, often significantly influencing the clinical outcome. While the pathophysiology of pulmonary COVID-19 manifestation has been substantially unraveled, the underlying pathomechanisms of cardiac involvement in COVID-19 are largely unknown. In this multicentre study, we performed a comprehensive analysis of heart samples from 24 autopsies with confirmed SARS-CoV-2 infection and compared them to samples of age-matched Influenza H1N1 A (n = 16), lymphocytic non-influenza myocarditis cases (n = 8), and non-inflamed heart tissue (n = 9). We employed conventional histopathology, multiplexed immunohistochemistry (MPX), microvascular corrosion casting, scanning electron microscopy, X-ray phase-contrast tomography using synchrotron radiation, and direct multiplexed measurements of gene expression, to assess morphological and molecular changes holistically. Based on histopathology, none of the COVID-19 samples fulfilled the established diagnostic criteria of viral myocarditis. However, quantification via MPX showed a significant increase in perivascular CD11b/TIE2 + -macrophages in COVID-19 over time, which was not observed in influenza or non-SARS-CoV-2 viral myocarditis patients. Ultrastructurally, a significant increase in intussusceptive angiogenesis as well as multifocal thrombi, inapparent in conventional morphological analysis, could be demonstrated. In line with this, on a molecular level, COVID-19 hearts displayed a distinct expression pattern of genes primarily coding for factors involved in angiogenesis and epithelial-mesenchymal transition (EMT), changes not seen in any of the other patient groups. We conclude that cardiac involvement in COVID-19 is an angiocentric macrophage-driven inflammatory process, distinct from classical anti-viral inflammatory responses, and substantially underappreciated by conventional histopathologic analysis. For the first time, we have observed intussusceptive angiogenesis in cardiac tissue, which we previously identified as the linchpin of vascular remodeling in COVID-19 pneumonia, as a pathognomic sign in affected hearts. Moreover, we identified CD11b + /TIE2 + macrophages as the drivers of intussusceptive angiogenesis and set forward a putative model for the molecular regulation of vascular alterations.

Outcomes of patients with acute respiratory failure on veno-venous extracorporeal membrane oxygenation requiring additional circulatory support by veno-venoarterial extracorporeal membrane oxygenation.

Objective: Veno-venous (V-V) extracorporeal membrane oxygenation (ECMO) is increasingly used to support patients with severe acute respiratory distress syndrome (ARDS). In case of additional cardio-circulatory failure, some experienced centers upgrade the V-V ECMO with an additional arterial return cannula (termed V-VA ECMO). Here we analyzed short- and long-term outcome together with potential predictors of mortality. Design: Multicenter, retrospective analysis between January 2008 and September 2021. Setting: Three tertiary care ECMO centers in Germany (Hannover, Bonn) and Switzerland (Zurich). Patients: Seventy-three V-V ECMO patients with ARDS and additional acute cardio-circulatory deterioration required an upgrade to V-VA ECMO were included in this study. Measurements and main results: Fifty-three patients required an upgrade from V-V to V-VA and 20 patients were directly triple cannulated. Median (Interquartile Range) age was 49 (28-57) years and SOFA score was 14 (12-17) at V-VA ECMO upgrade. Vasoactive-inotropic score decreased from 53 (12-123) at V-VA ECMO upgrade to 9 (3-37) after 24 h of V-VA ECMO support. Weaning from V-VA and V-V ECMO was successful in 47 (64%) and 40 (55%) patients, respectively. Duration of ECMO support was 12 (6-22) days and ICU length of stay was 32 (16-46) days. Overall ICU mortality was 48% and hospital mortality 51%. Two additional patients died after hospital discharge while the remaining patients survived up to two years (with six patients being lost to follow-up). The vast majority of patients was free from higher degree persistent organ dysfunction at follow-up. A SOFA score > 14 and higher lactate concentrations at the day of V-VA upgrade were independent predictors of mortality in the multivariate regression analysis. Conclusion: In this analysis, the use of V-VA ECMO in patients with ARDS and concomitant cardiocirculatory failure was associated with a hospital survival of about 50%, and most of these patients survived up to 2 years. A SOFA score > 14 and elevated lactate levels at the day of V-VA upgrade predict unfavorable outcome.

Intramyocardial Inflammation after COVID-19 Vaccination: An Endomyocardial Biopsy-Proven Case Series.

Myocarditis in response to COVID-19 vaccination has been reported since early 2021. In particular, young male individuals have been identified to exhibit an increased risk of myocardial inflammation following the administration of mRNA-based vaccines. Even though the first epidemiological analyses and numerous case reports investigated potential relationships, endomyocardial biopsy (EMB)-proven cases are limited. Here, we present a comprehensive histopathological analysis of EMBs from 15 patients with reduced ejection fraction (LVEF = 30 (14-39)%) and the clinical suspicion of myocarditis following vaccination with Comirnaty® (Pfizer-BioNTech) (n = 11), Vaxzevria® (AstraZenica) (n = 2) and Janssen® (Johnson & Johnson) (n = 2). Immunohistochemical EMB analyses reveal myocardial inflammation in 14 of 15 patients, with the histopathological diagnosis of active myocarditis according the Dallas criteria (n = 2), severe giant cell myocarditis (n = 2) and inflammatory cardiomyopathy (n = 10). Importantly, infectious causes have been excluded in all patients. The SARS-CoV-2 spike protein has been detected sparsely on cardiomyocytes of nine patients, and differential analysis of inflammatory markers such as CD4+ and CD8+ T cells suggests that the inflammatory response triggered by the vaccine may be of autoimmunological origin. Although a definitive causal relationship between COVID-19 vaccination and the occurrence of myocardial inflammation cannot be demonstrated in this study, data suggest a temporal connection. The expression of SARS-CoV-2 spike protein within the heart and the dominance of CD4+ lymphocytic infiltrates indicate an autoimmunological response to the vaccination.

Giant cell myocarditis after first dose of BNT162b2 - a case report.

Herein we report the case of a young man, admitted to the Department of Cardiology and Angiology at Hannover Medical School with shortness of breath and elevated troponin. Few weeks earlier the patient received the first dose of BioNTech's mRNA vaccine (Comirnaty, BNT162b2). After diagnostic work-up revealed giant cell myocarditis, the patient received immunosuppressive therapy. In the present context of myocarditis after mRNA vaccination we discuss this rare aetiology and the patient's treatment strategy in the light of current recommendations.

Guía ESC/EACTS 2021 sobre el diagnóstico y tratamiento de las valvulopatías: Desarrollada por el Grupo de Trabajo de la Sociedad Europea de Cardiología (ESC) y la European Association for Cardio-Thoracic Surgery (EACTS) sobre el diagnóstico y tratamiento de las valvulopatías

The True Infection Rate (TIR) in the whole population of each country and the Infection Fatality Rate (IFR) for coronavirus disease 2019 (COVID-19) are unknown although they are important parameters. We devised a simple method to infer TIR and IFR based on the open data. The prevalence rate of the polymerase chain reaction (PCR) tests among the population (Examination Rate;ER) and the positive rate of PCR tests (Infection Rate;IR) for 66 countries were picked up at a website 5 times from April 10th to June 13th, 2020, and the trajectory of each country was drawn over the IR vs. ER plot. IR and ER showed a strong negative correlation for some countries, and TIR was estimated by extrapolating the regression line when the correlation coefficient was between -0.99 and -1. True/Identified Case Ratio (TICR) and IFR were also calculated using the estimated TIR. The estimated TIR well coincided with local antibody surveys. Estimated IFR took on a wide range of values up to 10%: generally high in the Western countries. The estimated IFR of Singapore was very low (0.018%), which may be related to the reported gene mutation causing the attenuation of the viral virulence.

Impact of COVID-19 on Medical Supply in Adults With Congenital Heart Disease.

Introduction: In March 2020, the World Health organization declared COVID-19 a global pandemic. One year later, the direct and indirect burden of the COVID-19 pandemic become more visible. In this context, there is concern about the allocation of medical resources and medical treatment of other diseases than COVID-19. Particularly, patients with chronic diseases need constant medical and pharmacological treatment. Therefore, we evaluated a large cohort of patients with adult congenital heart disease (ACHD) regarding postponed medical appointments and their possibilities to receive medical treatment during the COVID-19 pandemic. Methods: This cross-sectional study included 559 patients with ACHD (mean age 37.32 ± 11.98; 47% female). Clinical characteristics, answers to questionnaires concerning lifestyle, psychological well-being, addictive behavior and adherence were related to postponed medical appointments and limited access to medical care. Results: One hundred and nine patients (19.5%) reported problems getting necessary medical treatment or visiting a physician. Higher anxiety levels (p = 0.004) emerged as the main factor associated with medical undertreatment. The main risk factors for postponement of least one medical appointment (n = 91) were higher depression (p = 0.013) and anxiety (p = 0.05) symptoms as well as female sex (p ≤ 0.0001) and documented arrhythmias (p = 0.007) indicating a particular risk group of cardiovascular complications. In contrast, frequent physical activity identified patients at lower risk. Conclusion: In ACHD anxiety and depressive symptoms handicap patients to receive medical care. Postponement of medical appointments additionally relates to female sex and documented arrhythmias. The latter indicates that patients at high risk of adverse cardiac outcome avoid routine medical care. Our data may lead policy makers to develop strategies for the provision of medical services to particular vulnerable patient groups, and to optimize management of both future pandemics and daily routine.

Computed-Tomography as First-line Diagnostic Procedure in Patients With Out-of-Hospital Cardiac Arrest.

BACKGROUND: Mortality after out-of-hospital cardiac arrest (OHCA) with return of spontaneous circulation (ROSC) remains high despite numerous efforts to improve outcome. For patients with suspected coronary cause of arrest, coronary angiography is crucial. However, there are other causes and potentially life-threatening injuries related to cardiopulmonary resuscitation (CPR), which can be detected by routine computed tomography (CT). MATERIALS AND METHODS: At Hannover Medical School, rapid coronary angiography and CT are performed in successfully resuscitated OHCA patients as a standard of care prior to admission to intensive care. We analyzed all patients who received CT following OHCA with ROSC over a three-year period. RESULTS: There were 225 consecutive patients with return of spontaneous circulation following out-of-hospital cardiac arrest. Mean age was 64 ± 13 years, 75% were male. Of them, 174 (77%) had witnessed arrest, 145 (64%) received bystander CPR, and 123 (55%) had a primary shockable rhythm. Mean time to ROSC was 24 ± 20 min. There were no significant differences in CT pathologies in patients with or without ST-segment elevations in the initial ECG. Critical CT findings qualifying as a potential cause for cardiac arrest were intracranial bleeding (N = 6), aortic dissection (N = 5), pulmonary embolism (N = 17), pericardial tamponade (N = 3), and tension pneumothorax (N = 11). Other pathologies were regarded as consequences of CPR and relevant for further treatment: aspiration (N = 62), rib fractures (N = 161), sternal fractures (N = 50), spinal fractures (N = 11), hepatic bleeding (N = 12), and intra-abdominal air (N = 3). CONCLUSION: Early CT fallowing OHCA uncovers a high number of causes and consequences of OHCA and CPR. Those are relevant for post-arrest care and are frequently life-threatening, suggesting that CT can contribute to improving prognosis following OHCA.

The year in cardiovascular medicine 2021: heart failure and cardiomyopathies.

In the year 2021, the universal definition and classification of heart failure (HF) was published that defines HF as a clinical syndrome with symptoms and/or signs caused by a cardiac abnormality and corroborated by elevated natriuretic peptide levels or objective evidence of cardiogenic congestion. This definition and the classification of HF with reduced ejection fraction (HFrEF), mildly reduced, and HF with preserved ejection fraction (HFpEF) is consistent with the 2021 ESC Guidelines on HF. Among several other new recommendations, these guidelines give a Class I indication for the use of the sodium-glucose co-transporter 2 (SGLT2) inhibitors dapagliflozin and empagliflozin in HFrEF patients. As the first evidence-based treatment for HFpEF, in the EMPEROR-Preserved trial, empagliflozin reduced the composite endpoint of cardiovascular death and HF hospitalizations. Several reports in 2021 have provided novel and detailed analyses of device and medical therapy in HF, especially regarding sacubitril/valsartan, SGLT2 inhibitors, mineralocorticoid receptor antagonists, ferric carboxymaltose, soluble guanylate cyclase activators, and cardiac myosin activators. In patients hospitalized with COVID-19, acute HF and myocardial injury is quite frequent, whereas myocarditis and long-term damage to the heart are rather uncommon.

Immunity and inflammation: the neglected key players in congenital heart disease?

Although more than 90% of children born with congenital heart disease (CHD) survive into adulthood, patients face significantly higher and premature morbidity and mortality. Heart failure as well as non-cardiac comorbidities represent a striking and life-limiting problem with need for new treatment options. Systemic chronic inflammation and immune activation have been identified as crucial drivers of disease causes and progression in various cardiovascular disorders and are promising therapeutic targets. Accumulating evidence indicates an inflammatory state and immune alterations in children and adults with CHD. In this review, we highlight the implications of chronic inflammation, immunity, and immune senescence in CHD. In this context, we summarize the impact of infant open-heart surgery with subsequent thymectomy on the immune system later in life and discuss the potential role of comorbidities and underlying genetic alterations. How an altered immunity and chronic inflammation in CHD influence patient outcomes facing SARS-CoV-2 infection is unclear, but requires special attention, as CHD could represent a population particularly at risk during the COVID-19 pandemic. Concluding remarks address possible clinical implications of immune changes in CHD and consider future immunomodulatory therapies.

Expansion of CD10neg neutrophils and CD14+HLA-DRneg/low monocytes driving proinflammatory responses in patients with acute myocardial infarction.

Immature neutrophils and HLA-DRneg/low monocytes expand in cancer, autoimmune diseases and viral infections, but their appearance and immunoregulatory effects on T-cells after acute myocardial infarction (AMI) remain underexplored. We found an expansion of circulating immature CD16+CD66b+CD10neg neutrophils and CD14+HLA-DRneg/low monocytes in AMI patients, correlating with cardiac damage, function and levels of immune-inflammation markers. Immature CD10neg neutrophils expressed high amounts of MMP-9 and S100A9, and displayed resistance to apoptosis. Moreover, we found that increased frequency of CD10neg neutrophils and elevated circulating IFN-γ levels were linked, mainly in patients with expanded CD4+CD28null T-cells. Notably, the expansion of circulating CD4+CD28null T-cells was associated with cytomegalovirus (CMV) seropositivity. Using bioinformatic tools, we identified a tight relationship among the peripheral expansion of immature CD10neg neutrophils, CMV IgG titers, and circulating levels of IFN-γ and IL-12 in patients with AMI. At a mechanistic level, CD10neg neutrophils enhanced IFN-γ production by CD4+ T-cells through a contact-independent mechanism involving IL-12. In vitro experiments also highlighted that HLA-DRneg/low monocytes do not suppress T-cell proliferation but secrete high levels of pro-inflammatory cytokines after differentiation to macrophages and IFN-γ stimulation. Lastly, using a mouse model of AMI, we showed that immature neutrophils (CD11bposLy6GposCD101neg cells) are recruited to the injured myocardium and migrate to mediastinal lymph nodes shortly after reperfusion. In conclusion, immunoregulatory functions of CD10neg neutrophils play a dynamic role in mechanisms linking myeloid cell compartment dysregulation, Th1-type immune responses and inflammation after AMI.

Circulating cardiovascular microRNAs in critically ill COVID-19 patients.

AIMS: Coronavirus disease 2019 (COVID-19) is a still growing pandemic, causing many deaths and socio-economic damage. Elevated expression of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry receptor angiotensin-converting enzyme 2 on cardiac cells of patients with heart diseases may be related to cardiovascular burden. We have thus analysed cardiovascular and inflammatory microRNAs (miRs), sensitive markers of cardiovascular damage, in critically ill, ventilated patients with COVID-19 or influenza-associated acute respiratory distress syndrome (Influenza-ARDS) admitted to the intensive care unit and healthy controls. METHODS AND RESULTS: Circulating miRs (miR-21, miR-126, miR-155, miR-208a, and miR-499) were analysed in a discovery cohort consisting of patients with mechanically-ventilated COVID-19 (n = 18) and healthy controls (n = 15). A validation study was performed in an independent cohort of mechanically-ventilated COVID-19 patients (n = 20), Influenza-ARDS patients (n = 13) and healthy controls (n = 32). In both cohorts, RNA was isolated from serum and cardiovascular disease/inflammatory-relevant miR concentrations were measured by miR-specific TaqMan PCR analyses. In both the discovery and the validation cohort, serum concentration of miR-21, miR-155, miR-208a and miR-499 were significantly increased in COVID-19 patients compared to healthy controls. Calculating the area under the curve using receiver operating characteristic analysis miR-155, miR-208a and miR-499 showed a clear distinction between COVID-19 and Influenza-ARDS patients. CONCLUSION: In this exploratory study, inflammation and cardiac myocyte-specific miRs were upregulated in critically ill COVID-19 patients. Importantly, miR profiles were able to differentiate between severely ill, mechanically-ventilated Influenza-ARDS and COVID-19 patients, indicating a rather specific response and cardiac involvement of COVID-19.

Impact of COVID-19 outbreak on regional STEMI care in Germany.

AIMS: To assess the impact of the lockdown due to coronavirus disease 2019 (COVID-19) on key quality indicators for the treatment of ST-segment elevation myocardial infarction (STEMI) patients. METHODS: Data were obtained from 41 hospitals participating in the prospective Feedback Intervention and Treatment Times in ST-Elevation Myocardial Infarction (FITT-STEMI) study, including 15,800 patients treated for acute STEMI from January 2017 to the end of March 2020. RESULTS: There was a 12.6% decrease in the total number of STEMI patients treated at the peak of the pandemic in March 2020 as compared to the mean number treated in the March months of the preceding years. This was accompanied by a significant difference among the modes of admission to hospitals (p = 0.017) with a particular decline in intra-hospital infarctions and transfer patients from other hospitals, while the proportion of patients transported by emergency medical service (EMS) remained stable. In EMS-transported patients, predefined quality indicators, such as percentages of pre-hospital ECGs (both 97%, 95% CI = - 2.2-2.7, p = 0.846), direct transports from the scene to the catheterization laboratory bypassing the emergency department (68% vs. 66%, 95% CI = - 4.9-7.9, p = 0.641), and contact-to-balloon-times of less than or equal to 90 min (58.3% vs. 57.8%, 95%CI = - 6.2-7.2, p = 0.879) were not significantly altered during the COVID-19 crisis, as was in-hospital mortality (9.2% vs. 8.5%, 95% CI = - 3.2-4.5, p = 0.739). CONCLUSIONS: Clinically important indicators for STEMI management were unaffected at the peak of COVID-19, suggesting that the pre-existing logistic structure in the regional STEMI networks preserved high-quality standards even when challenged by a threatening pandemic. CLINICAL TRIAL REGISTRATION: NCT00794001.

Conducting clinical trials in heart failure during (and after) the COVID-19 pandemic: an Expert Consensus Position Paper from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC).

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has important implications for the safety of participants in clinical trials and the research staff caring for them and, consequently, for the trials themselves. Patients with heart failure may be at greater risk of infection with COVID-19 and the consequences might also be more serious, but they are also at risk of adverse outcomes if their clinical care is compromised. As physicians and clinical trialists, it is our responsibility to ensure safe and effective care is delivered to trial participants without affecting the integrity of the trial. The social contract with our patients demands no less. Many regulatory authorities from different world regions have issued guidance statements regarding the conduct of clinical trials during this COVID-19 crisis. However, international trials may benefit from expert guidance from a global panel of experts to supplement local advice and regulations, thereby enhancing the safety of participants and the integrity of the trial. Accordingly, the Heart Failure Association of the European Society of Cardiology on 21 and 22 March 2020 conducted web-based meetings with expert clinical trialists in Europe, North America, South America, Australia, and Asia. The main objectives of this Expert Position Paper are to highlight the challenges that this pandemic poses for the conduct of clinical trials in heart failure and to offer advice on how they might be overcome, with some practical examples. While this panel of experts are focused on heart failure clinical trials, these discussions and recommendations may apply to clinical trials in other therapeutic areas.