Cardiac pathology in COVID-19: a single center autopsy experience

Sang, Charlie J.; Burkett, A.; Heindl, Brittain; Litovsky, Silvio; Prabhu, Sumanth D.; Benson, Paul; Rajapreyar, Indranee

doi:10.1016/j.carpath.2021.107370

Cited by 17 publications

(10 citation statements)

References 43 publications

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“…There was no significant difference between normalized TUNEL positivity between control and IL-1 β treated hCOs ( Fig. 2C ), consistent with minimal evidence of cardiomyocyte death in COVID-19 autopsies 37 .…”

Section: Resultssupporting

confidence: 73%

Human Cardiac Organoids to Model COVID-19 Cytokine Storm Induced Cardiac Injuries

Arhontoulis

Kerr

Richards

et al. 2022

Preprint

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Acute cardiac injuries occur in 20-25% of hospitalized COVID-19 patients. Despite urgent needs, there is a lack of 3D organotypic models of COVID-19 hearts for mechanistic studies and drug testing. Herein, we demonstrate that human cardiac organoids (hCOs) are a viable platform to model the cardiac injuries caused by COVID-19 hyperinflammation. As IL-1β is an upstream cytokine and a core COVID-19 signature cytokine, it was used to stimulate hCOs to induce the release of a milieu of proinflammatory cytokines that mirror the profile of COVID-19 cytokine storm. The IL-1β treated hCOs recapitulated transcriptomic, structural, and functional signatures of COVID-19 hearts. The comparison of IL-1β treated hCOs with cardiac tissue from COVID-19 autopsies illustrated the critical roles of hyper-inflammation in COVID-19 cardiac insults and indicated the cardioprotective effects of endothelium. The IL-1β treated hCOs also provide a viable model to assess the efficacy and potential side effects of immunomodulatory drugs, as well as the reversibility of COVID-19 cardiac injuries at baseline and simulated exercise conditions.

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Section: Resultssupporting

confidence: 73%

Human Cardiac Organoids to Model COVID-19 Cytokine Storm Induced Cardiac Injuries

Arhontoulis

Kerr

Richards

et al. 2022

Preprint

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“…Microthrombi, which arise in situ in the microvasculature of several organs, have been associated with multiorgan-injury in COVID-19 and are more frequent in patients with arterial hypertension or other comorbidities ( Parra-Medina et al, 2021 ). Several autopsy reports noted the relatively high occurrence of microvascular thrombi in lungs ( Ackermann et al, 2020 ; Carsana et al, 2020 ; Falasca et al, 2020 ; Lax et al, 2020 ; Menter et al, 2020 ; D’agnillo et al, 2021 ), heart ( Pellegrini et al, 2021 ; Sang et al, 2021 ), liver ( Rapkiewicz et al, 2020 ; Kondo et al, 2021 ), kidney ( Rapkiewicz et al, 2020 ; Akilesh et al, 2021 ) and the brain ( Bryce et al, 2021 ; Meinhardt et al, 2021 ; Pajo et al, 2021 ; Thakur et al, 2021 ). The finding that VTE, arterial thrombosis and microthrombi co-exist during COVID-19 suggests that these thrombotic events may be driven by several mechanism acting in concert ( Gu et al, 2021 ) including altered platelet function (thrombocytopathy) ( Manne et al, 2020 ; Zaid et al, 2020 ), endothelial dysfunction (endotheliopathy) ( Maruhashi and Higashi, 2021 ), altered complement function ( Stenmark et al, 2021 ), and features underlying immunothrombosis i.e., increased NET formation ( Nicolai et al, 2020 ; Bonaventura et al, 2021 ).…”

Section: Covid-19 and Vascular Cellsmentioning

confidence: 99%

COVID-19 and the Vasculature: Current Aspects and Long-Term Consequences

Martínez-Salazar

Holwerda

Stüdle

et al. 2022

Front. Cell Dev. Biol.

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Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was first identified in December 2019 as a novel respiratory pathogen and is the causative agent of Corona Virus disease 2019 (COVID-19). Early on during this pandemic, it became apparent that SARS-CoV-2 was not only restricted to infecting the respiratory tract, but the virus was also found in other tissues, including the vasculature. Individuals with underlying pre-existing co-morbidities like diabetes and hypertension have been more prone to develop severe illness and fatal outcomes during COVID-19. In addition, critical clinical observations made in COVID-19 patients include hypercoagulation, cardiomyopathy, heart arrythmia, and endothelial dysfunction, which are indicative for an involvement of the vasculature in COVID-19 pathology. Hence, this review summarizes the impact of SARS-CoV-2 infection on the vasculature and details how the virus promotes (chronic) vascular inflammation. We provide a general overview of SARS-CoV-2, its entry determinant Angiotensin-Converting Enzyme II (ACE2) and the detection of the SARS-CoV-2 in extrapulmonary tissue. Further, we describe the relation between COVID-19 and cardiovascular diseases (CVD) and their impact on the heart and vasculature. Clinical findings on endothelial changes during COVID-19 are reviewed in detail and recent evidence from in vitro studies on the susceptibility of endothelial cells to SARS-CoV-2 infection is discussed. We conclude with current notions on the contribution of cardiovascular events to long term consequences of COVID-19, also known as “Long-COVID-syndrome”. Altogether, our review provides a detailed overview of the current perspectives of COVID-19 and its influence on the vasculature.

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“…Many cardiac symptoms have been tentatively attributed to aberrant host responses to acute respiratory infection ( 7 , 8 ), but the complex mechanisms of cardiac disease are incompletely understood ( 9 ). As SARS-CoV-2 nucleic acids and proteins have been occasionally detected in cardiac tissue ( 10 – 18 ), productive SARS-CoV-2 infection of cardiomyocytes may directly injure this tissue, causing organ dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Highly Efficient SARS-CoV-2 Infection of Human Cardiomyocytes: Spike Protein-Mediated Cell Fusion and Its Inhibition

Navaratnarajah

Pease

Halfmann

et al. 2021

J Virol

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Severe cardiovascular complications can occur in coronavirus disease of 2019 (COVID-19) patients. Cardiac damage is attributed mostly to the aberrant host response to acute respiratory infection. However, direct infection of cardiac tissue by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) also occurs. We examined here the cardiac tropism of SARS-CoV-2 in spontaneously beating human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). These cardiomyocytes express the angiotensin-converting enzyme 2 (ACE2) receptor but not the transmembrane protease serine 2 (TMPRSS2) that mediates spike protein cleavage in the lungs. Nevertheless, SARS-CoV-2 infection of hiPSC-CMs was prolific: viral transcripts accounted for about 88% of total mRNA. In the cytoplasm of infected hiPSC-CMs, smooth walled exocytic vesicles contained numerous 65-90 nm particles with canonical ribonucleocapsid structures, and virus-like particles with knob-like spikes covered the cell surface. To better understand how SARS-CoV-2 spreads in hiPSC-CMs we engineered an expression vector coding for the spike protein with a monomeric emerald-green fluorescent protein fused to its cytoplasmic tail (S-mEm). Proteolytic processing of S-mEm and the parental spike were equivalent. Live cell imaging tracked spread of S-mEm cell-to-cell and documented formation of syncytia. A cell-permeable, peptide-based molecule that blocks the catalytic site of furin and furin-like proteases abolished cell fusion. A spike mutant with the single amino acid change R682S that disrupts the multibasic furin cleavage motif was fusion inactive. Thus, SARS-CoV-2 replicates efficiently in hiPSC-CMs and furin and/or furin-like-protease activation of its spike protein is required for fusion-based cytopathology. This hiPSC-CM platform enables target-based drug discovery in cardiac COVID-19. Importance Cardiac complications frequently observed in COVID-19 patients are tentatively attributed to systemic inflammation and thrombosis, but viral replication has occasionally been confirmed in cardiac tissue autopsy materials. We developed an in vitro model of SARS-CoV-2 spread in myocardium using induced pluripotent stem cell-derived cardiomyocytes. In these highly differentiated cells, viral transcription levels exceeded those previously documented in permissive transformed cell lines. To better understand the mechanisms of SARS-CoV-2 spread, we expressed a fluorescent version of its spike protein that allowed us to characterize a fusion-based cytopathic effect. A mutant of the spike protein with a single amino acid mutation in the furin/furin-like protease cleavage site lost cytopathic function. Of note, the fusion activities of the spike protein of other coronaviruses correlated with the level of cardiovascular complications observed in infections with the respective viruses. These data indicate that SARS-CoV-2 may cause cardiac damage by fusing cardiomyocytes.

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Cardiac pathology in COVID-19: a single center autopsy experience

Cited by 17 publications

References 43 publications

Human Cardiac Organoids to Model COVID-19 Cytokine Storm Induced Cardiac Injuries

Human Cardiac Organoids to Model COVID-19 Cytokine Storm Induced Cardiac Injuries

COVID-19 and the Vasculature: Current Aspects and Long-Term Consequences

Highly Efficient SARS-CoV-2 Infection of Human Cardiomyocytes: Spike Protein-Mediated Cell Fusion and Its Inhibition

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