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. 2023 Mar 31;119(2):336-356.
doi: 10.1093/cvr/cvac115.

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 and Pericardial Diseases

Mariann Gyöngyösi  1 , Pilar Alcaide  2 , Folkert W Asselbergs  3   4 , Bianca J J M Brundel  5 , Giovanni G Camici  6   7 , Paula da Costa Martins  8   9 , Péter Ferdinandy  10   11 , Marianna Fontana  12 , Henrique Girao  13 , Massimiliano Gnecchi  14   15 , Can Gollmann-Tepeköylü  16 , Petra Kleinbongard  17 , Thomas Krieg  18 , Rosalinda Madonna  19 , Melanie Paillard  20 , Antonis Pantazis  21   22 , Cinzia Perrino  23 , Maurizio Pesce  24 , Gabriele G Schiattarella  25   26   27   28 , Joost P G Sluijter  29   30 , Sabine Steffens  31   32 , Carsten Tschöpe  33 , Sophie Van Linthout  33 , Sean M Davidson  34
Affiliations

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 and Pericardial Diseases

Mariann Gyöngyösi et al. Cardiovasc Res. .

Abstract

Long COVID has become a world-wide, non-communicable epidemic, caused by long-lasting multiorgan 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 perimyocarditis with consequent left or right ventricular failure, arterial wall inflammation, or microthrombosis 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, microthrombotic 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.

Keywords: COVID-19; Cardiac; Cardiovascular; Long COVID; Post COVID.

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Conflict of interest statement

Conflict of interest: F.W.A., P.A., B.J.J.M.B., S.M.D., M.F., M.G., S.V.L., R.M., C.P., M.P., G.G.S., S.S., C.G.-T., T.K.: no conflicts to disclose. G.G.C. is coinventors on the International Patent WO/2020/226993 filed in April 2020. The patent relates to the use of antibodies which specifically bind IL-1α to reduce various sequelae of ischaemia-reperfusion injury to the central nervous system. G.G.C. is a consultant to Sovida solutions limited. P.F. is the founder and CEO of Pharmahungary Group, a group of R&D companies. C.T. has received speaker fees and/or contributions to congresses from Abbott, Abiomed, Astra Zeneca, Bayer, Böhringer-Ingelheim, Novartis, Pfizer, and Servier; all outside the submitted work.

Figures

Graphical Abstract
Graphical Abstract
Figure 1
Figure 1
The major cardiovascular manifestations in patients with long COVID (left side), and likely mechanistic contributing factors (right hand side).
Figure 2
Figure 2
The major mechanisms that may drive long COVID, and how they may interact. Potential cellular mechanisms may involve: T-cells (interferon-gamma, IF-beta, IF-delta1 secretion, activation of CD8+, T-cell exhaustion); B-cells (dysregulation of SARS-CoV-2-specific memory B cells); haematopoietic progenitors (epigenetic reprogramming); activated CD38 + HLA-DR+ myeloid cells; plasmacytoid dendritic cells (pDCs) expressing CD86 and CD38; mast cell activation; circulating endothelial cells; neutrophils (release of autoantigens, NETs); activated monocytes; protracted immunosuppression by latent virus reactivation. Molecular mechanisms may involve: mitochondrial dysfunction; senescence; telomere shortening of blood cells; oxidative stress. Genetic mechanisms may involve: X-chromosome-associated ACE-2 receptor; genes coding Type I interferon immunity; ABO blood group genetic locus; epigenetic mechanisms. Vascular and endothelial mechanisms may involve: endotheliopathy; deterioration of capillary integrity (capillary flow disturbance, heterogeneity of capillary transit time); vasculitis; coagulopathies or thrombosis. Persistence of viral particles may contribute to the mechanism, either in myocardial tissue or hidden reservoirs in other organs.
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