Long COVID and the cardiovascular system - elucidating causes and cellular mechanisms in order to develop targeted diagnostic and therapeutic strategies: A joint Scientific Statement of the ESC Working Groups on Cellular Biology of the Heart and Myocardial & Pericardial Diseases.

Long COVID has become a world-wide, non-communicable epidemic, caused by long-lasting multi-organ symptoms that endure for weeks or months after SARS-CoV-2 infection has already subsided. This scientific document aims to provide insight into the possible causes and therapeutic options available for the cardiovascular manifestations of long COVID. In addition to chronic fatigue, which is a common symptom of long COVID, patients may present with chest pain, ECG abnormalities, postural orthostatic tachycardia, or newly developed supraventricular or ventricular arrhythmias. Imaging of the heart and vessels has provided evidence of chronic, post-infectious peri-myocarditis with consequent left or right ventricular failure, arterial wall inflammation or micro-thrombosis in certain patient populations. Better understanding of the underlying cellular and molecular mechanisms of long COVID will aid in the development of effective treatment strategies for its cardiovascular manifestations. A number of mechanisms have been proposed, including those involving direct effects on the myocardium, micro-thrombotic damage to vessels or endothelium, or persistent inflammation. Unfortunately, existing circulating biomarkers, coagulation and inflammatory markers, are not highly predictive for either the presence or outcome of long COVID when measured 3 months after SARS-CoV-2 infection. Further studies are needed to understand underlying mechanisms, identify specific biomarkers and guide future preventive strategies or treatments to address long COVID and its cardiovascular sequelae.

Detection of Post-COVID-19 Lung Abnormalities: Photon-counting CT versus Same-day Energy-integrating Detector CT.

Background Photon-counting detector (PCD) CT allows ultra-high-resolution lung imaging and may shed light on morphologic correlates of persistent symptoms after COVID-19. Purpose To compare PCD CT with energy-integrating detector (EID) CT for noninvasive assessment of post-COVID-19 lung abnormalities. Materials and Methods For this prospective study, adult participants with one or more COVID-19-related persisting symptoms (resting or exertional dyspnea, cough, and fatigue) underwent same-day EID and PCD CT scans between April 2022 and June 2022. EID CT 1.0mm images and, subsequently, 1.0mm, 0.4mm, and 0.2mm PCD CT images were reviewed for the presence of lung abnormalities. Subjective and objective EID and PCD CT image quality was evaluated using a 5-point Likert scale (-2 to 2) and lung signal-to-noise ratios (SNR). Results Twenty participants (mean age, 54 years ±16 [SD], 10 men) were included. EID CT showed post-COVID-19 lung abnormalities in 15 of 20 (75%) participants with a median involvement of 10% of lung volume [IQR 0-45%], and 3.5 lobes [IQR 0-5]. Ground-glass opacities (GGO) and linear bands (both 10 of 20 participants, 50%) were the most frequent findings on EID CT. PCD CT revealed additional lung abnormalities in 10 of 20 (50%) participants, most commonly bronchiolectasis (10 of 20, 50%). Subjective image quality was improved for 1.0mm PCD vs. 1.0mm EID CT images (1 [IQR 1-2], P<.001) and 0.4mm vs. 1.0mm PCD CT images (1 [IQR 1-1], P<.001), but not for 0.4mm vs. 0.2mm PCD CT images (0 [IQR 0-0.5], P=.26). PCD CT delivered higher lung SNR vs. EID CT 1.0mm images (mean difference 0.53 ± 0.96, P=.03), but lower SNRs for 0.4mm vs. 1.0mm images, and 0.2mm vs. 0.4mm images, respectively (-1.52 ± 0.68, P<.001 and -1.15 ± 0.43, P<.001). Conclusion Photon-counting detector CT outperformed energy-integrating detector CT with regard to visualization of subtle post-COVID-19 lung abnormalities and image quality.

Long COVID – eine neue Herausforderung in der Medizin: Fokus auf Schwangerschaft und Stillzeit Long COVID—A New Challenge in Medicine: Focus on Pregnancy and Breastfeeding

Long COVID wurde als eine neue Multiorganerkrankung beschrieben, die bei Frauen häufiger auftritt als bei Männern. Schwangere und stillende Frauen sind eine spezielle Untergruppe von Patienten, die bei einer Long-COVID-Erkrankung zu berücksichtigen sind, da bisher die Datenlage nur gering ausfällt. Menstruationsveränderungen werden häufig während oder nach einer akuten Erkrankung mit dem Coronavirus-2019 (COVID-19) beobachtet. Einige Studien stellen zudem einen Zusammenhang zwischen geringen Veränderungen der Zykluslänge und einer COVID-Impfung dar. Schwangere Frauen, die eine symptomatische Infektion mit dem schweren-akuten-Atemwegssyndrom-Coronavirus Typ 2 (SARS-CoV‑2) hatten, können ein höheres Risiko für Komplikationen in der Schwangerschaft, wie Frühgeburt oder Präeklampsie, haben. Darüber hinaus sind mehr Studien notwendig, um die Auswirkungen einer vertikalen Übertragung zu beurteilen. Das wirksamste Mittel gegen die Pandemie sind die verfügbaren COVID-Impfstoffe, da sie eine Infektion verhindern, aber auch Long-COVID-Symptome lindern können. Impfstoffe haben sich sowohl bei schwangeren als auch bei stillenden Frauen als sicher und wirksam erwiesen. Ziel dieses Artikels ist es, die aktuell verfügbaren Daten zu Long COVID bei schwangeren und stillenden Frauen darzustellen und die Risikofaktoren und therapeutischen Möglichkeiten aufzuzeigen.

[Long COVID-A New Challenge in Medicine: Focus on Pregnancy and Breastfeeding]. / Long COVID ­ eine neue Herausforderung in der Medizin: Fokus auf Schwangerschaft und Stillzeit.

Long COVID (coronavirus disease) has been described as a new multi-organ disease, which appears to be more prevalent in women than in men. Pregnant and breastfeeding women are a special subgroup of patients to consider with long COVID, as only scarce data have been collected to date. Menstrual changes are commonly observed during or after COVID-19; some studies also attribute slight changes of cycle length to previous inoculation against the virus. Pregnant women who have a symptomatic infection with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) are at a higher risk for adverse outcomes and pregnancy-associated complications. Moreover, more and robust data are required to evaluate vertical transmission. COVID vaccines are the most effective tool against the pandemic, as they prevent infection, but also appear to be able to ease long COVID symptoms. Vaccines have been proven safe and effective in both pregnant and breastfeeding women. This article aims to present current data on long COVID in pregnant and breastfeeding women and elucidate risk factors and possible treatment options.

A multi-omics based anti-inflammatory immune signature characterizes long COVID-19 syndrome.

To investigate long COVID-19 syndrome (LCS) pathophysiology, we performed an exploratory study with blood plasma derived from three groups: 1) healthy vaccinated individuals without SARS-CoV-2 exposure; 2) asymptomatic recovered patients at least three months after SARS-CoV-2 infection and; 3) symptomatic patients at least 3 months after SARS-CoV-2 infection with chronic fatigue syndrome or similar symptoms, here designated as patients with long COVID-19 syndrome (LCS). Multiplex cytokine profiling indicated slightly elevated pro-inflammatory cytokine levels in recovered individuals in contrast to patients with LCS. Plasma proteomics demonstrated low levels of acute phase proteins and macrophage-derived secreted proteins in LCS. High levels of anti-inflammatory oxylipins including omega-3 fatty acids in LCS were detected by eicosadomics, whereas targeted metabolic profiling indicated high levels of anti-inflammatory osmolytes taurine and hypaphorine, but low amino acid and triglyceride levels and deregulated acylcarnitines. A model considering alternatively polarized macrophages as a major contributor to these molecular alterations is presented.

COVID-19-related cardiac complications from clinical evidences to basic mechanisms: opinion paper of the ESC Working Group on Cellular Biology of the Heart.

The pandemic of coronavirus disease (COVID)-19 is a global threat, causing high mortality, especially in the elderly. The main symptoms and the primary cause of death are related to interstitial pneumonia. Viral entry also into myocardial cells mainly via the angiotensin converting enzyme type 2 (ACE2) receptor and excessive production of pro-inflammatory cytokines, however, also make the heart susceptible to injury. In addition to the immediate damage caused by the acute inflammatory response, the heart may also suffer from long-term consequences of COVID-19, potentially causing a post-pandemic increase in cardiac complications. Although the main cause of cardiac damage in COVID-19 remains coagulopathy with micro- (and to a lesser extent macro-) vascular occlusion, open questions remain about other possible modalities of cardiac dysfunction, such as direct infection of myocardial cells, effects of cytokines storm, and mechanisms related to enhanced coagulopathy. In this opinion paper, we focus on these lesser appreciated possibilities and propose experimental approaches that could provide a more comprehensive understanding of the cellular and molecular bases of cardiac injury in COVID-19 patients. We first discuss approaches to characterize cardiac damage caused by possible direct viral infection of cardiac cells, followed by formulating hypotheses on how to reproduce and investigate the hyperinflammatory and pro-thrombotic conditions observed in the heart of COVID-19 patients using experimental in vitro systems. Finally, we elaborate on strategies to discover novel pathology biomarkers using omics platforms.

Improving translational research in sex-specific effects of comorbidities and risk factors in ischaemic heart disease and cardioprotection: position paper and recommendations of the ESC Working Group on Cellular Biology of the Heart.

Ischaemic heart disease (IHD) is a complex disorder and a leading cause of death and morbidity in both men and women. Sex, however, affects several aspects of IHD, including pathophysiology, incidence, clinical presentation, diagnosis as well as treatment and outcome. Several diseases or risk factors frequently associated with IHD can modify cellular signalling cascades, thus affecting ischaemia/reperfusion injury as well as responses to cardioprotective interventions. Importantly, the prevalence and impact of risk factors and several comorbidities differ between males and females, and their effects on IHD development and prognosis might differ according to sex. The cellular and molecular mechanisms underlying these differences are still poorly understood, and their identification might have important translational implications in the prediction or prevention of risk of IHD in men and women. Despite this, most experimental studies on IHD are still undertaken in animal models in the absence of risk factors and comorbidities, and assessment of potential sex-specific differences are largely missing. This ESC WG Position Paper will discuss: (i) the importance of sex as a biological variable in cardiovascular research, (ii) major biological mechanisms underlying sex-related differences relevant to IHD risk factors and comorbidities, (iii) prospects and pitfalls of preclinical models to investigate these associations, and finally (iv) will provide recommendations to guide future research. Although gender differences also affect IHD risk in the clinical setting, they will not be discussed in detail here.

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.