HomeCirculation ResearchVol. 132, No. 10COVID-19 and the Cardiovascular System: Requiem for a Medical Minotaur Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBCOVID-19 and the Cardiovascular System: Requiem for a Medical Minotaur Milka Koupenova, Mina K. Chung and Michael R. Bristow Milka KoupenovaMilka Koupenova Correspondence to: Milka Koupenova, PhD, Division of Cardiovascular Medicine, Department of Medicine, UMass Chan Medical School, 368 Plantation st, AS7-1041, Worcester, MA 01605. Email E-mail Address: [email protected] https://orcid.org/0000-0001-5934-8990 UMass Chan Medical School, Worcester, MA (M.K.). Search for more papers by this author , Mina K. ChungMina K. Chung https://orcid.org/0000-0002-7835-6045 Heart and Vascular Institute and Lerner Research Institute at Cleveland Clinic, Lerner College of Medicine of Case Western Reserve University, Cleveland, OH (M.K.C.). Search for more papers by this author and Michael R. BristowMichael R. Bristow https://orcid.org/0000-0002-8860-4698 University of Colorado Anschutz Medical Campus, Denver, CO (M.R.B.). Search for more papers by this author Originally published11 May 2023https://doi.org/10.1161/CIRCRESAHA.123.322935Circulation Research. 2023;132:1255–1258The world has finally emerged from the great medical, economic, and social calamity of 2020 to 2022, the COVID-19 pandemic. This Compendium of 10 articles describes various aspects of the effects of SARS-CoV-2 on the cardiovascular system, focusing on the heart. The Minotaur from Greek mythology is an apt metaphor, because this half bull/half man spike-adorned gain of function mutant slaughtered the innocent was nearly impossible to eradicate in his labyrinthian environs, inspired mass fear of the unknown, and ultimately was eliminated by resourceful, determined collaborators.1 Although SARS-CoV-2 infection has not been eliminated, it has been contained to the point of acquiring the status of a manageable infectious disease.2As we review some of the findings of the enormous, world-wide efforts to investigate the cardiovascular effects of SARS-CoV-2, it is important to reflect on the national mood of mid-March, 2020, when through reports from China, Northern Italy, and elsewhere it became apparent that a catastrophic infectious disease was on the move, and the nascent local appearance of isolated cases indicated the United States would not be spared. Shortly thereafter, it became apparent that the cardiovascular system was not going to dodge the pandemic. At this point, something remarkable in the annals of research support occurred: The American Heart Association went into emergency mode and quickly developed and disseminated a Request for Applications as part of a COVID-19 Rapid Response initiative. The Request for Applications was announced on March 26, 2020, the proposals had to be submitted by April 6, the review of 750 grants was accomplished within 10 days (by 150 reviewers), and the notices of awards of 15 grants were distributed on April 23. In other words, an emergency funding mechanism for investigating unknown mechanisms responsible for serious cardiovascular disorders tied to a burgeoning pandemic was developed and executed in under 30 days. This Compendium includes information from multiple investigations generated by the AHA’s Rapid Response funding, in addition to other contributions.The impact of COVID-19 on cardiovascular disease outcomes and treatment was profound, as detailed by Boulos et al3 in this Compendium. Reluctance of patients to seek care for serious conditions, deferral or modification of necessary procedures, an increase in thrombotic disorders related to procoagulant effects of SARS-CoV-2 and its invoked inflammatory response, led to the exacerbation of underlying conditions, such as heart failure, as well as interaction with pharmacological treatments, such as immunosuppression regimens in transplant patients.3 Others4 have described the profound impact of COVID-19 on basic and clinical cardiovascular research. Clinical trials are one example of this, as recruitment fell precipitously in many of them in 2020. In any case, during the pandemic, the adaptation and performance of cardiovascular clinical care teams as well as the professional societies charged with issuing and updating COVID-19-related guidelines was nothing short of heroic.3When it comes to the pathophysiology of COVID-19, a striking observation at the forefront of SARS-CoV-2 infection was the increased risk of thrombotic outcomes in patients. These included intravascular coagulation, macrothrombosis, organ microthrombosis, bleeding, and profound coagulopathy, and in certain cases an associated myocarditis. Despite the insult on the vasculature, antiplatelet or anticoagulant trials failed to have a uniform and beneficial outcome across all patients. Thrombotic outcomes related to classical and nonclassical platelet-mediated mechanisms are reviewed by Sciaudone et al.5 The role of SARS-CoV-2 on activating pathways related to cell death in traditional immune cells have been reviewed with respect to the release of platelet content that potentially contributes to endotheliopathy and leukocyte activation. The authors also review presence of the virus in the circulation, possible impact of Spike on platelets, challenges with methods of RNA detection, and the direct interaction of platelets with SARS-CoV-2.5 Similarly, Tsai et al6 review evidence of microthrombosis in the heart and discuss the role of endothelial cells and their interaction with other cell types and mechanisms in response to the infectious environment. Tsai et al6 describe how cell-specific techniques, such as single nuclei RNA sequencing and spatial methods, are contributing to the discovery of new mechanisms in COVID-19 cardiac pathophysiology. Recent studies highlight cardiomyocytes, fibroblasts, and pericytes, which wrap around endothelial cells, as primary targets of SARS-CoV-2 infection rather than endothelial cells, and autocrine interactions between these cell types likely contribute to the microvascular endothelial dysfunction and microthromboses evident in COVID-19 patients. The authors emphasize that the complexity of SARS-CoV-2 infection needs further investigation to delineate the many interacting mechanisms.In addition to the early reports of thrombotic outcomes in COVID-19 patients, evidence of myocardial injury, myocarditis, and pericarditis became apparent. Fairweather et al7 note that SARS-CoV-2 infection is not unique in its impact on myocarditis and that the prior coronavirus infections SARS-CoV-1 and Middle-Eastern Respiratory syndrome (MERS-CoV-1) have also been associated with myocardial inflammation. Although heightened surveillance and diagnosis relying on clinical symptoms and elevated troponins rather than endomyocardial biopsy may account for some increased incidence of myocarditis with SARS-CoV-2 infection, in some reports the incidence of myocarditis/pericarditis during the COVID-19 era is as much as 15-fold higher when compared with myocarditis in the preCOVID-19 era. Nevertheless, as noted by Fairweather et al,7 the incidence of myocarditis based on tissue diagnosis is lower than in initial reports. Regardless of the etiology of myocardial injury, its relatively common occurrence in COVID-19 may lead to long-term consequences, including a higher associations of subsequent cardiovascular events.Sex differences in COVID-19 are further highlighted by Chappell,8 relating differences in the renin-angiotensin system. Downregulation of ACE2, the receptor for SARS-CoV-2 binding and host cell internalization, may lead to a higher ratio of Ang II to Ang-(1-7) and des-Arg9 form of bradykinin due to reduced extracellular ACE2 activity. Once internalized, the viral genome can be recognized by TLR7. Both ACE2 and TLR7 can induce inflammatory responses, and interestingly, both of these receptors are encoded by the X-chromosome and may escape X-linked inactivation, thus females may have higher expression of ACE2 and TLR7. Indeed, human platelets exhibit sex-differences in TLR7 expression as women have higher transcript level than men.9 COVID-19 severity in older males may also relate to lower testosterone, resulting in exaggerated mediation of inflammation, whereas estrogen modulation of the immune response may contribute to lower circulating proinflammatory cytokines, greater vascular protection, and reduced COVID-19 severity in women compared with men.8Vaccine-associated myocarditis and sex differences associated with it are also discussed in this compendium. The higher association of infection and vaccine-associated myocarditis in males aged 12 to 40, mirrors the general increased incidence of myocarditis in males younger than 50. Similar trends are observed with pericarditis also occurring more often in males. Fairweather, et al,7 propose potential mechanisms of how sex differences might be explained using animal models, some of which may involve the TLR4 (toll-like receptor 4)/IL-1R (interleukin 1 receptor)/ST2 (Suppression Of Tumorigenicity 2) signaling axis in mast cell and macrophages. On the other hand, Altman, et al9 place the issue of mRNA vaccine-associated myocarditis and myocardial injury in the contexts of non-SARS-CoV-2-invoked myocarditis, myocardial injury associated with COVID-19 infection, and myocarditis associated with non-COVID-19 vaccines. Several points emerge from this analysis. First, only a relatively small minority of patients thought to have myocarditis presenting contemporaneously with COVID-19 infection have histological evidence of inflammation (7% in autopsy studies,4,7 and 11% by endomyocardial biopsy.5,10,11 On histopathology a low incidence of inflammatory infiltrate is also found in patients diagnosed with post mRNA vaccine myocarditis.9,10 The reasons for these differences can be many and the mechanism is reviewed by Tsai et al6 as well as in Altman et al9 in both COVID-19 and mRNA vaccine–associated injury.10,11 Second, in study designs that identify presumed myocarditis following mRNA vaccine or with COVID-19 the incidence of excess myocarditis/myocardial injury cases following the 1st course of vaccine (1.2 (BNT162b2) and1.9 (mRNA-1273) per 100,000 persons) is in the same range as for COVID-19 infection. Third, based on virtually identical patterns of altered gene expression in mRNA vaccine associated myocardial injury and COVID-19 infection, these disorders may have a common pathobiology, related to the cellular response to Spike protein-ACE2 binding and internalization.10,11The reported incidence, consequences, and pathophysiology of post-acute sequelae of SARS-CoV-2 (PASC) are reviewed by Singh et al.12 Though the COVID-19 pandemic may be sundowning, its long-term effects are persisting in up to 20-25% of patients after COVID-19 infection; the precise incidence has been limited by varying definitions of PASC. Opposite to myocarditis, PASC seems to be associated with female gender, older age, and lack of SARS-CoV-2 vaccination, but not with severity of acute infection. The multisystemic palette of symptoms spanning multiple organ systems reflects a potentially varied pathophysiologic basis and is reviewed in this contribution. Management has been largely supportive and mirroring therapies for similar cardiovascular conditions that are not related to COVID-19 infection. Preclinical data suggests that subsequent vaccination against COVID-19 may reduce symptoms of PASC. Randomized controlled trials are needed to test therapeutic strategies.The approaches for COVID-19 drug repurposing are also reviewed in this compendium. Wang and Loscalzo13 emphasize that during an unexpected pandemic featuring a novel pathogen, there is no time for standard drug development, which may take an average of 15 years from the beginning of Phase 1 clinical trials to FDA approval.14 In this situation the only viable path forward is repurposing drugs that have already been developed, allowing for trials to begin in Phase 2B or even 3. The authors summarize data from various repurposing efforts including high-throughput drug library screening in cell lines infected with virus or bearing SARS-CoV-2 targets, omics data-based drug re-positioning, and their own network module-based approach.12 Identified by these repurposing methods were the RNA dependent RNA polymerase (RdRp) inhibitor remdesivir (Veklury), the 3C-like protease inhibitor nelfinavir (Paxlovid) and the RdRp inhibitor molnupiravir (Lagevrio), which had been in development for other indications before the pandemic and eventually gained emergency use approval for COVID-19.Sophisticated imaging methodology has contributed enormously to our understanding of how a respiratory viral infection caused by SARS-CoV-2 may seriously impact cardiovascular disease. Cardiac magnetic resonance imaging is instrumental in the detection of myocardial injury and the clinical diagnosis of myocarditis in COVID-19 patients, in addition to the evaluation of coronary microvascular dysfunction particularly in patients recovered from COVID-19 infection. In this compendium, Holby et al14 provide an overview of the multimodality imaging that has been used to diagnose and evaluate COVID-19. As we dive deeper into the mechanisms of disease, murine models and mouse adaptable strains have proved valuable, which is briefly discussed by Sciaudone et al.5 However, mice including those that express human ACE2, lack a full set of sequelae presented by human COVID-19. In that sense the usefulness of iPS-derived systems, particularly cardiomyocytes, are also reviewed by Satta et al,15 including the benefits and limitations in advancements in microfluidics, organ-on-a-chip and human stem-cell derived models to study SARS-CoV-2 infection in the physiological organ microenvironment. Overall, many tools have been developed in COVID-19 investigations, and we are beginning to understand the unique roles of these model systems.Three years following the onset of the pandemic, we have gained a vast amount of knowledge as to how one virus as small as 100 µm can collapse an entire multiorgan system. We can now conclusively say that certain respiratory coronaviruses increase the risk of macrothrombotic events, organ microthrombosis, myocardial injury including myocarditis, and arrhythmias. We have learned there are factors, such as hypertension, atrial fibrillation, heart failure, diabetes and obesity, that predispose to cardiac involvement in COVID-19. We have increased our understanding of how the immune response to SARS-CoV-2 may contribute to the pathophysiology of CVD in addition to its roles in inflammation and thrombosis signaling. Nevertheless, we have just scratched the surface and many questions remain unanswered. For instance, what are the exact mechanisms that cannot be controlled by anticoagulation and antiplatelet therapy that contribute to treatment-refractory macro- and microthrombosis; what are the precise mechanisms that underline myocardial injury in cases where myocarditis is not detected, what are the factors responsible for development of prolonged fatigue and other symptoms that underlie long-COVID/PASC, and in CV research and training should there be a greater emphasis on immunology and infectious disease? History has shown that pandemics will continue to occur, and the more we understand how viruses and infections in general impact human cardiovascular pathophysiology, the better prepared we will be for the next outbreak, which may occur sooner rather than later in this age of global connectivity. Areas where we will need to do better include recognizing and preventing the consequences of cardiovascular clinical risks, understanding and avoiding postinfection sequelae, and designing better therapeutic agents and vaccines. We as a community must continue to address the remaining questions and elucidate the relevant mechanisms; only then will we be able to more effectively confront the next Minotaur of infectious impact on cardiovascular disease.Article InformationDisclosures None.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Disclosures, see page 1257.Correspondence to: Milka Koupenova, PhD, Division of Cardiovascular Medicine, Department of Medicine, UMass Chan Medical School, 368 Plantation st, AS7-1041, Worcester, MA 01605. Email Milka.[email protected]edu