SARS-CoV-2 RBD and Its Variants Can Induce Platelet Activation and Clearance: Implications for Antibody Therapy and Vaccinations against COVID-19.

The COVID-19 pandemic caused by SARS-CoV-2 virus is an ongoing global health burden. Severe cases of COVID-19 and the rare cases of COVID-19 vaccine-induced-thrombotic-thrombocytopenia (VITT) are both associated with thrombosis and thrombocytopenia; however, the underlying mechanisms remain inadequately understood. Both infection and vaccination utilize the spike protein receptor-binding domain (RBD) of SARS-CoV-2. We found that intravenous injection of recombinant RBD caused significant platelet clearance in mice. Further investigation revealed the RBD could bind platelets, cause platelet activation, and potentiate platelet aggregation, which was exacerbated in the Delta and Kappa variants. The RBD-platelet interaction was partially dependent on the ß3 integrin as binding was significantly reduced in ß3-/- mice. Furthermore, RBD binding to human and mouse platelets was significantly reduced with related αIIbß3 antagonists and mutation of the RGD (arginine-glycine-aspartate) integrin binding motif to RGE (arginine-glycine-glutamate). We developed anti-RBD polyclonal and several monoclonal antibodies (mAbs) and identified 4F2 and 4H12 for their potent dual inhibition of RBD-induced platelet activation, aggregation, and clearance in vivo, and SARS-CoV-2 infection and replication in Vero E6 cells. Our data show that the RBD can bind platelets partially though αIIbß3 and induce platelet activation and clearance, which may contribute to thrombosis and thrombocytopenia observed in COVID-19 and VITT. Our newly developed mAbs 4F2 and 4H12 have potential not only for diagnosis of SARS-CoV-2 virus antigen but also importantly for therapy against COVID-19.

Pressure overload induces ISG15 to facilitate adverse ventricular remodeling and promote heart failure.

Inflammation promotes adverse ventricular remodeling, a common antecedent of heart failure. Here, we set out to determine how inflammatory cells affect cardiomyocytes in the remodeling heart. Pathogenic cardiac macrophages induced an IFN response in cardiomyocytes, characterized by upregulation of the ubiquitin-like protein IFN-stimulated gene 15 (ISG15), which posttranslationally modifies its targets through a process termed ISGylation. Cardiac ISG15 is controlled by type I IFN signaling, and ISG15 or ISGylation is upregulated in mice with transverse aortic constriction or infused with angiotensin II; rats with uninephrectomy and DOCA-salt, or pulmonary artery banding; cardiomyocytes exposed to IFNs or CD4+ T cell-conditioned medium; and ventricular tissue of humans with nonischemic cardiomyopathy. By nanoscale liquid chromatography-tandem mass spectrometry, we identified the myofibrillar protein filamin-C as an ISGylation target. ISG15 deficiency preserved cardiac function in mice with transverse aortic constriction and led to improved recovery of mouse hearts ex vivo. Metabolomics revealed that ISG15 regulates cardiac amino acid metabolism, whereas ISG15 deficiency prevented misfolded filamin-C accumulation and induced cardiomyocyte autophagy. In sum, ISG15 upregulation is a feature of pathological ventricular remodeling, and protein ISGylation is an inflammation-induced posttranslational modification that may contribute to heart failure development by altering cardiomyocyte protein turnover.

Low Prevalence of Late Myocardial Injury on Cardiac MRI Following COVID-19 Infection.

BACKGROUND: The prevalence of abnormal cardiac magnetic resonance imaging (MRI) findings indicative of myocardial injury in patients who recovered from coronavirus disease 2019 (COVID-19) is currently unclear, with a high variability in the reported prevalence. PURPOSE: To assess the prevalence of myocardial injury after a COVID-19 infection. STUDY TYPE: Prospective, bicentric study. SUBJECTS: Seventy consecutive patients who recovered from COVID-19 and were previously hospitalized. Mean age was 57 years and 39% of the patients were female. Ten healthy controls and a comparator group of 75 nonischemic cardiomyopathy (NICM) patients were employed. FIELD STRENGTH/SEQUENCE: 1.5-T, steady-state free precession (SSFP) gradient-echo sequence, modified Look-Locker inversion recovery sequence with balanced SSFP readout, T2-prepared spiral readout sequence and a T1-weighted inversion recovery fast gradient-echo sequence was acquired ~4-5 months after recovery from COVID-19. ASSESSMENT: The SSFP sequence was utilized for the calculation of left and right ventricular volumes and ejection fractions (LVEF and RVEF) following manual endocardial contouring. T1 and T2 mapping was performed by pixel-wise exponential fitting, and T1 and T2 values were computed by manual contouring of the left ventricular endocardial and epicardial walls. Late gadolinium enhancement (LGE) images were graded qualitatively as LGE present or absent. STATISTICAL TESTS: T-tests and the χ2 or Fisher's exact tests were used to compare continuous and categorical variables respectively between the COVID-19 and NICM groups. Inter-rater agreement was evaluated by the intraclass correlation coefficient for continuous variables and Cohen's kappa test for LGE. RESULTS: Reduced RVEF occurred in 10%, LGE and elevated native T1 in 9%, reduced LVEF in 4%, and elevated T2 in 3% of COVID-19 patients, respectively. Patients with NICM had lower mean LVEF (41.6% ± 6% vs. 60% ± 7%), RVEF (46% ± 5% vs. 61% ± 9%), and a significantly higher prevalence of LGE (27% vs. 9%) when compared to those post-COVID-19. DATA CONCLUSION: Abnormal cardiac MRI findings may show a low prevalence in patients who recovered from COVID-19 and were previously hospitalized. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Suspected subclinical myocarditis detected by cardiac magnetic resonance imaging late post COVID-19 recovery.

There is growing evidence of the potential for cardiac involvement in patients who have been infected with COVID-19. In this case study, we present a patient with no history of cardiovascular disease, who was hospitalized for COVID-19 pneumonia and subsequently recovered. Despite normal serum troponin levels and left ventricular structure and function, multi-parametric cardiac magnetic resonance imaging revealed a classic myocarditis-like pattern of injury approximately 6 months after his convalescence. Physicians should be aware of the possibility of late myocardial injury/inflammation in patients with recovered COVID-19, even in the absence of elevated troponin levels and/or left ventricular dysfunction. .

Cardiovascular Physicians, Scientists, and Trainees Balancing Work and Caregiving Responsibilities in the COVID-19 Era: Sex and Race-Based Inequities.

BACKGROUND: The ongoing COVID-19 pandemic has exposed a work-life (im)balance that has been present but not openly discussed in medicine, surgery, and science for decades. The pandemic has exposed inequities in existing institutional structure and policies concerning clinical workload, research productivity, and/or teaching excellence inadvertently privileging those who do not have significant caregiving responsibilities or those who have the resources to pay for their management. METHODS: We sought to identify the challenges facing multidisciplinary faculty and trainees with dependents, and highlight a number of possible strategies to address challenges in work-life (im)balance. RESULTS: To date, there are no Canadian-based data to quantify the physical and mental effect of COVID-19 on health care workers, multidisciplinary faculty, and trainees. As the pandemic evolves, formal strategies should be discussed with an intersectional lens to promote equity in the workforce, including (but not limited to): (1) the inclusion of broad representation (including equal representation of women and other marginalized persons) in institutional-based pandemic response and recovery planning and decision-making; (2) an evaluation (eg, institutional-led survey) of the effect of the pandemic on work-life balance; (3) the establishment of formal dialogue (eg, workshops, training, and media campaigns) to normalize coexistence of work and caregiving responsibilities and to remove stigma of gender roles; (4) a reevaluation of workload and promotion reviews; and (5) the development of formal mentorship programs to support faculty and trainees. CONCLUSIONS: We believe that a multistrategy approach needs to be considered by stakeholders (including policy-makers, institutions, and individuals) to create sustainable working conditions during and beyond this pandemic.

CONTEXTE: La pandémie de COVID-19 a mis en lumière le déséquilibre entre travail et vie personnelle qui règne depuis des décennies dans les milieux de la médecine, de la chirurgie et des sciences, mais dont on ne parlait pas ouvertement. La pandémie a en effet mis au jour des iniquités dans la structure et les politiques des établissements en matière de charge de travail clinique, de productivité de la recherche et d'excellence en enseignement, qui favorisent par inadvertance les personnes qui n'ont pas de responsabilités familiales importantes ou qui ont les ressources nécessaires pour leur prise en charge. MÉTHODOLOGIE: Nous avons tenté de cerner les difficultés auxquelles font face les enseignants multidisciplinaires et les stagiaires ayant des personnes à charge, et nous proposons un certain nombre de stratégies possibles pour faciliter la conciliation travail-vie personnelle. RÉSULTATS: À ce jour, il n'existe pas de données canadiennes permettant de quantifier les répercussions physiques et mentales de la pandémie de COVID-19 sur les travailleurs de la santé, les enseignants multidisciplinaires et les stagiaires. Au fil de l'évolution de la pandémie, il conviendrait de formuler des stratégies officielles à la lumière des commentaires d'intervenants des différents secteurs concernés, afin de promouvoir l'équilibre au sein des effectifs; ces stratégies pourraient notamment inclure ce qui suit (sans toutefois s'y limiter) : 1) l'inclusion d'une vaste représentation (y compris une représentation égale des femmes et des autres personnes marginalisées) pour la réponse à la pandémie dans les établissements, la planification du rétablissement et la prise de décisions; 2) une évaluation (p. ex. au moyen d'un sondage mené sous la direction des établissements) des répercussions de la pandémie sur la conciliation travail-vie personnelle; 3) l'établissement d'un dialogue formel (p. ex. ateliers, activités de formation et campagnes dans les médias) afin de normaliser la coexistence des responsabilités professionnelles et familiales et d'éliminer la stigmatisation associée aux rôles des sexes; 4) une réévaluation de la charge de travail et des promotions; et 5) la mise sur pied de programmes formels de mentorat pour soutenir les enseignants et les stagiaires. CONCLUSIONS: Nous croyons que les intervenants (décideurs, établissements et personnes) devraient envisager une approche multistratégie afin d'instaurer des conditions de travail viables pendant la pandémie et par la suite.

COVID-19-Myocarditis and Return to Play: Reflections and Recommendations From a Canadian Working Group.

The COVID-19-related pandemic has resulted in profound health, financial, and societal impacts. Organized sporting events, from recreational to the Olympic level, have been cancelled to both mitigate the spread of COVID-19 and protect athletes and highly active individuals from potential acute and long-term infection-associated harms. COVID-19 infection has been associated with increased cardiac morbidity and mortality. Myocarditis and late gadolinium enhancement as a result of COVID-19 infection have been confirmed. Correspondingly, myocarditis has been implicated in sudden cardiac death of athletes. A pragmatic approach is required to guide those who care for athletes and highly active persons with COVID-19 infection. Members of the Community and Athletic Cardiovascular Health Network (CATCHNet) and the writing group for the Canadian Cardiovascular Society/Canadian Heart Rhythm Society Joint Position Statement on the Cardiovascular Screening of Competitive Athletes recommend that highly active persons with suspected or confirmed COVID-19 infection refrain from exercise for 7 days after resolution of viral symptoms before gradual return to exercise. We do not recommend routine troponin testing, resting 12-lead electrocardiography, echocardiography, or cardiac magnetic resonance imaging before return to play. However, medical assessment including history and physical examination with consideration of resting electrocardiography and troponin can be considered in the athlete manifesting new active cardiac symptoms or a marked reduction in fitness. If concerning abnormalities are encountered at the initial medical assessment, then referral to a cardiologist who cares for athletes is recommended.