Abstract Emerging as a new epidemic, long COVID or post-acute sequelae of coronavirus disease 2019 (COVID-19), a condition characterized by the persistence of COVID-19 symptoms beyond 3 months, is anticipated to substantially alter the lives of millions of people globally. Cardiopulmonary symptoms including chest pain, shortness of breath, fatigue, and autonomic manifestations such as postural orthostatic tachycardia are common and associated with significant disability, heightened anxiety, and public awareness. A range of cardiovascular (CV) abnormalities has been reported among patients beyond the acute phase and include myocardial inflammation, myocardial infarction, right ventricular dysfunction, and arrhythmias. Pathophysiological mechanisms for delayed complications are still poorly understood, with a dissociation seen between ongoing symptoms and objective measures of cardiopulmonary health. COVID-19 is anticipated to alter the long-term trajectory of many chronic cardiac diseases which are abundant in those at risk of severe disease. In this review, we discuss the definition of long COVID and its epidemiology, with an emphasis on cardiopulmonary symptoms. We further review the pathophysiological mechanisms underlying acute and chronic CV injury, the range of post-acute CV sequelae, and impact of COVID-19 on multiorgan health. We propose a possible model for referral of post-COVID-19 patients to cardiac services and discuss future directions including research priorities and clinical trials that are currently underway to evaluate the efficacy of treatment strategies for long COVID and associated CV sequelae.

https://academic.oup.com/eurheartj/advance-article-pdf/doi/10.1093/eurheartj/ehac031/42541089/ehac031.pdf

Long COVID: post-acute sequelae of COVID-19 with a cardiovascular focus

New Findings What is the topic of this review? The emerging condition of long COVID, its epidemiology, pathophysiological impacts on patients of different backgrounds, physiological mechanisms emerging as explanations of the condition, and treatment strategies being trialled. The review leads from a Physiological Society online conference on this topic. What advances does it highlight? Progress in understanding the pathophysiology and cellular mechanisms underlying Long COVID and potential therapeutic and management strategies. Long COVID, the prolonged illness and fatigue suffered by a small proportion of those infected with SARS-CoV-2, is placing an increasing burden on individuals and society. A Physiological Society virtual meeting in February 2022 brought clinicians and researchers together to discuss the current understanding of long COVID mechanisms, risk factors and recovery. This review highlights the themes arising from that meeting. It considers the nature of long COVID, exploring its links with other post-viral illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome, and highlights how long COVID research can help us better support those suffering from all post-viral syndromes. Long COVID research started particularly swiftly in populations routinely monitoring their physical performance – namely the military and elite athletes. The review highlights how the high degree of diagnosis, intervention and monitoring of success in these active populations can suggest management strategies for the wider population. We then consider how a key component of performance monitoring in active populations, cardiopulmonary exercise training, has revealed long COVID-related changes in physiology – including alterations in peripheral muscle function, ventilatory inefficiency and autonomic dysfunction. The nature and impact of dysautonomia are further discussed in relation to postural orthostatic tachycardia syndrome, fatigue and treatment strategies that aim to combat sympathetic overactivation by stimulating the vagus nerve. We then interrogate the mechanisms that underlie long COVID symptoms, with a focus on impaired oxygen delivery due to micro-clotting and disruption of cellular energy metabolism, before considering treatment strategies that indirectly or directly tackle these mechanisms. These include remote inspiratory muscle training and integrated care pathways that combine rehabilitation and drug interventions with research into long COVID healthcare access across different populations. Overall, this review showcases how physiological research reveals the changes that occur in long COVID and how different therapeutic strategies are being developed and tested to combat this condition. 

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1113/EP090802

Long COVID: mechanisms, risk factors and recovery

Abstract Background Long-COVID is characterized by prolonged, diffuse symptoms months after acute COVID-19. Accurate diagnosis and targeted therapies for Long-COVID are lacking. We investigated vascular transformation biomarkers in Long-COVID patients. Methods A case–control study utilizing Long-COVID patients, one to six months (median 98.5 days) post-infection, with multiplex immunoassay measurement of sixteen blood biomarkers of vascular transformation, including ANG-1, P-SEL, MMP-1, VE-Cad, Syn-1, Endoglin, PECAM-1, VEGF-A, ICAM-1, VLA-4, E-SEL, thrombomodulin, VEGF-R2, VEGF-R3, VCAM-1 and VEGF-D. Results Fourteen vasculature transformation blood biomarkers were significantly elevated in Long-COVID outpatients, versus acutely ill COVID-19 inpatients and healthy controls subjects (P &lt; 0.05). A unique two biomarker profile consisting of ANG-1/P-SEL was developed with machine learning, providing a classification accuracy for Long-COVID status of 96%. Individually, ANG-1 and P-SEL had excellent sensitivity and specificity for Long-COVID status (AUC = 1.00, P &lt; 0.0001; validated in a secondary cohort). Specific to Long-COVID, ANG-1 levels were associated with female sex and a lack of disease interventions at follow-up (P &lt; 0.05). Conclusions Long-COVID patients suffer prolonged, diffuse symptoms and poorer health. Vascular transformation blood biomarkers were significantly elevated in Long-COVID, with angiogenesis markers (ANG-1/P-SEL) providing classification accuracy of 96%. Vascular transformation blood biomarkers hold potential for diagnostics, and modulators of angiogenesis may have therapeutic efficacy. 

/pdf/elevated-vascular-transformation-blood-biomarkers-in-long-1lsr9ho9.pdf

Elevated vascular transformation blood biomarkers in Long-COVID indicate angiogenesis as a key pathophysiological mechanism

Harmonizing Definitions for Diagnostic Criteria and Prognostic Assessment of Transplantation-Associated Thrombotic Microangiopathy: A Report on Behalf of the European Society for Blood and Marrow Transplantation, American Society for Transplantation and Cellular Therapy, Asia-Pacific Blood and Marrow Transplantation Group, and Center for International Blood and Marrow Transplant Research

https://doi.org/10.1016/j.blre.2023.101075

Cardiovascular and haematological pathology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): A role for viruses

To review current literature on the role of endothelial dysfunction in coronavirus disease-2019 (COVID-19) infection in terms of pathophysiology, laboratory features and markers, clinical phenotype in adults and children, as well as long COVID-19.We conducted a thorough assessment of the literature and critically analyzed current data, mostly utilizing the PubMed and Medline search engines to find original studies published in the previous decade.Accumulating evidence suggests that endothelial dysfunction may be a common denominator of severe COVID-19 in adults and children, as well as long COVID-19, implicating mutual pathophysiological pathways. This narrative review summarizes the up-to-date knowledge of endothelial dysfunction caused by COVID-19, including novel aspects of long COVID-19 and pediatric disease. This knowledge is important in order not only to understand the multisystemic attack of COVID-19, but also to improve patient management and prognosis.

/pdf/update-on-endothelial-dysfunction-in-covid-19-severe-disease-4ilx5tzsqc.pdf

Update on endothelial dysfunction in COVID-19: severe disease, long COVID-19 and pediatric characteristics

INTRODUCTION Allogeneic hematopoietic cell transplantation (alloHCT) is the standard of care for many diseases. However, survivors often present with serious complications resulting from acute and chronic toxicities and it is crucial to increase consciousness from treating physicians. AREAS COVERED We performed a comprehensive review of the literature and critically examined recent available data, mostly using the PubMed and Medline search engines for original articles published over the last decade. Better understanding of many alloHCT-related disorders has shown that endothelial injury and vascular damage plays a critical role. EXPERT OPINION The most widely studied endothelial injury syndromes (EIS) are veno-occlusive disease/sinusoidal obstruction syndrome (SOS/VOD), graft-versus-host-disease (GVHD), and transplant-associated thrombotic microangiopathy (TA-TMA). TA-TMA, frequently underdiagnosed, needs to be clarified using certain criteria and, as a life-threatening condition, requires immediate and intensive treatment. The first-in-class complement inhibitor eculizumab has significantly improved outcomes in both the pediatric and adult population. Cardiovascular (CV) events are the second major cause of morbidity and mortality of alloHCT survivors, after GVHD. Long-term monitoring and management of CV risk is expected to also incorporate patient stratification with CV risk prediction models, early markers of vascular dysfunction or procoagulant activity, subclinical target organ damage, arterial stiffness, and subclinical atherosclerosis.

Endothelial dysfunction and vascular complications after allogeneic hematopoietic cell transplantation: an expert analysis.

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Update on endothelial dysfunction in COVID-19: severe disease, long COVID-19 and pediatric characteristics

Endothelial dysfunction and vascular complications after allogeneic hematopoietic cell transplantation: an expert analysis.