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.

Cardiovascular signatures of COVID-19 predict mortality and identify barrier stabilizing therapies.

BACKGROUND: Endothelial cell (EC) activation, endotheliitis, vascular permeability, and thrombosis have been observed in patients with severe coronavirus disease 2019 (COVID-19), indicating that the vasculature is affected during the acute stages of SARS-CoV-2 infection. It remains unknown whether circulating vascular markers are sufficient to predict clinical outcomes, are unique to COVID-19, and if vascular permeability can be therapeutically targeted. METHODS: Prospectively evaluating the prevalence of circulating inflammatory, cardiac, and EC activation markers as well as developing a microRNA atlas in 241 unvaccinated patients with suspected SARS-CoV-2 infection allowed for prognostic value assessment using a Random Forest model machine learning approach. Subsequent ex vivo experiments assessed EC permeability responses to patient plasma and were used to uncover modulated gene regulatory networks from which rational therapeutic design was inferred. FINDINGS: Multiple inflammatory and EC activation biomarkers were associated with mortality in COVID-19 patients and in severity-matched SARS-CoV-2-negative patients, while dysregulation of specific microRNAs at presentation was specific for poor COVID-19-related outcomes and revealed disease-relevant pathways. Integrating the datasets using a machine learning approach further enhanced clinical risk prediction for in-hospital mortality. Exposure of ECs to COVID-19 patient plasma resulted in severity-specific gene expression responses and EC barrier dysfunction, which was ameliorated using angiopoietin-1 mimetic or recombinant Slit2-N. INTERPRETATION: Integration of multi-omics data identified microRNA and vascular biomarkers prognostic of in-hospital mortality in COVID-19 patients and revealed that vascular stabilizing therapies should be explored as a treatment for endothelial dysfunction in COVID-19, and other severe diseases where endothelial dysfunction has a central role in pathogenesis. FUNDING: This work was directly supported by grant funding from the Ted Rogers Center for Heart Research, Toronto, Ontario, Canada and the Peter Munk Cardiac Center, Toronto, Ontario, Canada.

Cardiovascular Collapse in COVID-19 Infection: The Role of Venoarterial Extracorporeal Membrane Oxygenation (VA-ECMO).

Coronavirus Disease 2019 (COVID-19) has been associated with cardiovascular complications, including acute cardiac injury, heart failure, and cardiogenic shock (CS). The role of venoarterial extracorporeal membrane oxygenation (VA-ECMO) in the event of COVID-19-associated cardiovascular collapse has not been established. We reviewed the existing literature surrounding the role of VA-ECMO in the treatment of coronavirus-related cardiovascular collapse. COVID-19 is associated with a higher incidence of cardiovascular complications compared with previous coronavirus outbreaks (Severe Acute Respiratory Syndrome Coronavirus and Middle East Respiratory Syndrome Coronavirus). We found only 1 case report from China in which COVID-19-associated fulminant myocarditis and CS were successfully rescued using VA-ECMO as a bridge to recovery. We identified potential clinical scenarios (cardiac injury, myocardial infarction with and without obstructive coronary artery disease, viral myocarditis, and decompensated heart failure) leading to CS and risk factors for poor/uncertain benefit (age, sepsis, mixed/predominantly vasodilatory shock, prothrombotic state or coagulopathy, severe acute respiratory distress syndrome, multiorgan failure, or high-risk prognostic scores) specific to using VA-ECMO as a bridge to recovery in COVID-19 infection. Additional considerations and proposed recommendations specific to the COVID-19 pandemic were formulated with guidance from published data and expert consensus. A small subset of patients with cardiovascular complications from COVID-19 infection may progress to refractory CS. While accepting that resource scarcity may be the overwhelming concern for healthcare systems during this pandemic, VA-ECMO can be considered in highly selected cases of refractory CS and echocardiographic evidence of biventricular failure. The decision to initiate this therapy should take into consideration the availability of resources, perceived benefit, and risks of transmitting disease.

La maladie à coronavirus 2019 (COVID-19) est associée à des complications cardiovasculaires, y compris des lésions cardiaques aiguës, l'insuffisance cardiaque et le choc cardiogénique (CC). Le rôle de l'oxygénation par membrane extracorporelle (ECMO pour extracorporeal membrane oxygenation) veino-artérielle dans les cas de collapsus cardiovasculaire associé à la COVID-19 n'a pas été établi. Nous avons passé en revue la documentation existante abordant le rôle de l'ECMO veino-artérielle dans le traitement du collapsus cardiovasculaire lié au coronavirus. La COVID-19 est associée à une incidence plus élevée de complications cardiovasculaires comparativement aux éclosions antérieures d'infections à coronavirus (syndrome respiratoire aigu sévère et syndrome respiratoire du Moyen-Orient). Nous n'avons trouvé qu'un seul cas (signalé en Chine) de myocardite fulminante et de CC associés à la COVID-19 où l'ECMO veino-artérielle a permis d'assurer la survie du patient dans l'attente d'une récupération de la fonction cardiaque. Nous avons ciblé divers scénarios cliniques (lésion cardiaque, infarctus du myocarde avec ou sans coronaropathie obstructive, myocardite virale et insuffisance cardiaque décompensée) susceptibles d'aboutir à un CC et cerné des facteurs de risque de bienfaits faibles ou incertains (âge, septicémie, choc vasodilatateur mixte ou prédominant, état prothrombotique ou coagulopathie, syndrome de détresse respiratoire aiguë sévère, défaillance multiviscérale ou scores pronostiques à haut risque) cadrant spécifiquement avec l'utilisation de l'ECMO veino-artérielle dans l'attente d'une récupération de la fonction cardiaque chez le patient atteint de COVID-19. D'autres considérations et recommandations visant spécifiquement la pandémie de COVID-19 ont été énoncées à la lumière des données publiées et d'un consensus d'experts. Au sein d'un petit sous-groupe de patients atteints de COVID-19, les complications cardiovasculaires de l'infection peuvent évoluer vers un CC réfractaire. Tout en acceptant que la pénurie de ressources puisse être la principale préoccupation des systèmes de santé pendant cette pandémie, on peut envisager de recourir à l'ECMO veino-artérielle dans des cas soigneusement sélectionnés de CC réfractaire et en présence de preuves échocardiographiques d'insuffisance biventriculaire. La décision d'instaurer ce traitement doit tenir compte de la disponibilité des ressources, des avantages perçus et des risques de transmission de la maladie.