Clinico-histopathologic and single-nuclei RNA-sequencing insights into cardiac injury and microthrombi in critical COVID-19

Brener, Michael I.; Hulke, Michelle L; Fukuma, Nobuaki; Golob, Stephanie; Zilinyi, Robert; Zhou, Zhipeng; Tzimas, Christos; Russo, Ilaria; McGroder, Claire; Pfeiffer, Ryan; Chong, Alexander M.; Zhang, Geping; Burkhoff, Daniel; Leon, Martin B.; Maurer, Mathew S.; Moses, Jeffrey W.; Uhlemann, Anne‐Catrin; Hibshoosh, Hanina; Uriel, Nir; Szabolcs, Matthias; Redfors, Björn; Marboe, Charles C.; Baldwin, Matthew R.; Tucker, Nathan R.; Tsai, Emily J.

doi:10.1172/jci.insight.154633

Cited by 19 publications

(21 citation statements)

References 67 publications

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“…Microvascular injury (Fig. 4 B) is central to the proposed mechanism of cardiac injury among patients with SARS-CoV-2 infection [ 82 , 83 ]. It is likely that the combination of NET formation and platelet activation promote coronary thrombosis to a greater degree than endothelial activation, although different factors may promote injury during various phases of disease [ 84 ].…”

Section: Cardiovascular Diseasementioning

confidence: 99%

The pathogenesis of coronavirus-19 disease

Yantiss

2022

J Biomed Sci

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Severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2) is the causal agent of coronavirus disease-2019 (COVID-19), a systemic illness characterized by variably severe pulmonary symptoms, cardiac conduction abnormalities, diarrhea, and gastrointestinal bleeding, as well as neurologic deficits, renal insufficiency, myalgias, endocrine abnormalities, and other perturbations that reflect widespread microvascular injury and a pro-inflammatory state. The mechanisms underlying the various manifestations of viral infection are incompletely understood but most data suggest that severe COVID-19 results from virus-driven perturbations in the immune system and resultant tissue injury. Aberrant interferon-related responses lead to alterations in cytokine elaboration that deplete resident immune cells while simultaneously recruiting hyperactive macrophages and functionally altered neutrophils, thereby tipping the balance from adaptive immunity to innate immunity. Disproportionate activation of these macrophages and neutrophils further depletes normal activity of B-cells, T-cells, and natural killer (NK) cells. In addition, this pro-inflammatory state stimulates uncontrolled complement activation and development of neutrophil extracellular traps (NETS), both of which promote the coagulation cascade and induce a state of “thrombo-inflammation”. These perturbations have similar manifestations in multiple organ systems, which frequently show pathologic findings related to microvascular injury and thrombosis of large and small vessels. However, the pulmonary findings in patients with severe COVID-19 are generally more pronounced than those of other organs. Not only do they feature inflammatory thromboses and endothelial injury, but much of the parenchymal damage stems from failed maturation of alveolar pneumocytes, interactions between type 2 pneumocytes and non-resident macrophages, and a greater degree of NET formation. The purpose of this review is to discuss the pathogenesis underlying organ damage that can occur in patients with SARS-CoV-2 infection. Understanding these mechanisms of injury is important to development of future therapies for patients with COVID-19, many of which will likely target specific components of the immune system, particularly NET induction, pro-inflammatory cytokines, and subpopulations of immune cells.

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Section: Cardiovascular Diseasementioning

confidence: 99%

The pathogenesis of coronavirus-19 disease

Yantiss

2022

J Biomed Sci

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“…Interestingly, none had typical evidence of myocarditis as defined by the European Society of Cardiology ( 9 ). Other recent investigations also reported the incidence of microthrombi in the autopsied hearts with COVID-19 to be high as 70% (48 out of 69 cases) ( 10 ) and 80% (12 out of 15 cases) ( 7 ). The present case adds further evidence to these observations by demonstrating the presence of microthrombosis associated with acute myocardial ischemic injury in acute phase of COVID-19 by endomyocardial biopsy prior to death.…”

Section: Discussionmentioning

confidence: 80%

Microthrombosis as a cause of fulminant myocarditis-like presentation with COVID-19 proven by endomyocardial biopsy

Nakatani

Ohta‐Ogo

Nishio

et al. 2022

Cardiovascular Pathology

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“…Local viral presence was found to be low on ultramicroscopy and on droplet digital polymerase chain reaction in heart studies (12,28). Similarly, a Brener et al (32) postmortem investigation of 69 COVID-19 decedents found, on the basis of immunohistology and single-cell nuclei RNA sequencing, that viral load was low in the myocardium but that endothelial damage and cardiac microthrombosis were common (seen in 80% of cases). Whereas inflammatory activity was greatly increased, typical myocardial ischemic necrosis (i.e., incidence of contraction-band necrosis) was rare, even in the presence of troponin leak (38).…”

Section: Pulmonary-to-myocardial Cell Invasion and Humoral Repercussionsmentioning

confidence: 93%

“…The cardiovascular system is particularly vulnerable to COVID-19 through various, primarily hematogenic, mechanisms: 2)-which can lead to spontaneous coronary spastic syndromes (7,22,26,28,(30)(31)(32)(33)(34)(35); and • Worsening of preexisting cardiovascular conditions and risk factors, including destabilization of atherosclerotic plaques with ulcerations and thrombosis, QTc interval prolongation, electrolyte imbalance, diabetes exacerbation, hypertension exacerbation, and variable levels of systemic catecholamine activation.…”

Section: The Heart In Covid-19mentioning

confidence: 99%

“…In COVID-19, both electron microscopy and molecular identification of the virus in the upper airways or lungs are done frequently and may be pathognomonic ( Figure 1B ), whereas this evidence is rarely available from postmortem cardiac studies ( 5 , 7 , 12 , 14 , 16 , 19 , 22 , 26 , 32 , 37 ). In a breakthrough pilot study by Ackermann et al ( 12 ), pulmonary autopsy tissues of patients who died from COVID-19 ( n = 7) were explored in depth by using classic histology, immunohistochemical assay, electron microscopy with microcomputer tomographic imaging, corrosion 3-dimensional casting, and direct multiplexed measurement of gene expression.…”

Section: The Heart In Covid-19mentioning

confidence: 99%

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COVID-19 and the Heart: Could Transient Takotsubo Cardiomyopathy Be Related to the Pandemic by Incidence and Mechanisms?

Angelini

Postalian²,

Hernandez-Vila³

et al. 2022

Front. Cardiovasc. Med.

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Typical emergency hospital care during the COVID-19 pandemic has centered on pulmonary-focused services. Nonetheless, patients with COVID-19 frequently develop complications associated with the dysfunction of other organs, which may greatly affect prognosis. Preliminary evidence suggests that cardiovascular involvement is relatively frequent in COVID-19 and that it correlates with significant worsening of clinical status and mortality in infected patients. In this article, we summarize current knowledge on the cardiovascular effects of COVID-19. In particular, we focus on the association between COVID-19 and transient takotsubo cardiomyopathy (TTC)—two conditions that preliminarily seem epidemiologically associated—and we highlight cardiovascular changes that may help guide future investigations toward full discovery of this new, complex disease entity. We hypothesize that coronary endothelial dysfunction, along with septic state, inflammatory storm, hypercoagulability, endothelial necrosis, and small-vessel clotting, may represent a fundamental hidden link between COVID-19 and TTC. Furthermore, given the likelihood that new genetic mutations of coronaviruses or other organisms will cause similar pandemics and endemics in the future, we must be better prepared so that a substantial complication such as TTC can be more accurately recognized, its pathophysiology better understood, and its treatment made more justifiable, timely, and effective.

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Clinico-histopathologic and single-nuclei RNA-sequencing insights into cardiac injury and microthrombi in critical COVID-19

Abstract: Order of shared first authorship was determined by the temporal order of research contribution and agreed upon by co-first authors. Each co-first author has the right to list themselves first for purposes of their curriculum vitae and biosketch.

Cited by 19 publications

References 67 publications

The pathogenesis of coronavirus-19 disease

The pathogenesis of coronavirus-19 disease

Microthrombosis as a cause of fulminant myocarditis-like presentation with COVID-19 proven by endomyocardial biopsy

COVID-19 and the Heart: Could Transient Takotsubo Cardiomyopathy Be Related to the Pandemic by Incidence and Mechanisms?

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