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COVID-19–Associated Nonocclusive Fibrin Microthrombi in the Heart
abstract
This abstract is available on the publisher's site.
Access this abstract nowBackground
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and its resultant clinical presentation, COVID-19, is an emergent cause of mortality worldwide. Cardiac complications secondary to this infection are common; however, the underlying mechanisms of such remain unclear. A detailed cardiac evaluation of a series of COVID-19 individuals undergoing postmortem evaluation is provided, with four aims: 1) describe the pathologic spectrum of the myocardium; 2) compare to an alternate viral illness; 3) investigate angiotensin converting enzyme 2 (ACE2) expression; and 4) provide the first description of the cardiac findings in patients with cleared infection.
Methods
Study cases were identified from institutional files and included COVID-19 (n=15; 12 active, 3 cleared), influenza A/B (n=6), and non-virally mediated deaths (n=6). Salient information was abstracted from the medical record. Light microscopic findings were recorded. An ACE2 immunohistochemical H-score was compared across cases. Viral detection encompassed SARS-CoV-2 immunohistochemistry, ultrastructural examination, and droplet digital polymerase chain reaction (ddPCR).
Results
Male sex was more common in the COVID-19 group (p=0.05). Non-occlusive fibrin microthrombi (without ischemic injury) were identified in 16 cases (12 COVID-19, 2 influenza, and 2 controls), and were more common in the active COVID-19 cohort (p=0.006). Four active COVID-19 cases showed focal myocarditis, while one case of cleared COVID-19 showed extensive disease. Arteriolar ACE2 endothelial expression was lower in COVID-19 cases versus controls (p=0.004). ACE2 myocardial expression did not differ by disease category, sex, age or number of patient comorbidities (p=0.69, p=1.00, p=0.46, p=0.65, respectively). SARS-CoV-2 immunohistochemistry showed non-specific staining, while ultrastructural examination and ddPCR were negative for viral presence. Four (26.7%) COVID-19 patients had underlying cardiac amyloidosis. Cases with cleared infection had variable presentations.
Conclusions
This detailed histopathologic, immunohistochemical, ultrastructural and molecular cardiac series showed no definitive evidence of direct myocardial infection. COVID-19 cases frequently have cardiac fibrin microthrombi, without universal acute ischemic injury. Moreover, myocarditis is present in 33.3% of active and cleared COVID-19 patients, but is usually limited in extent. Histologic features of resolved infection are variable. Cardiac amyloidosis may be an additional risk factor for severe disease.
Additional Info
COVID-19-Associated Non-Occlusive Fibrin Microthrombi in the Heart
Circulation 2020 Nov 16;[EPub Ahead of Print], MC Bois, NA Boire, AJ Layman, MC Aubry, MP Alexander, AC Roden, CE Hagen, RA Quinton, C Larsen, Y Erben, R Majumdar, SM Jenkins, BR Kipp, PT Lin, JJ MaleszewskiFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Cardiology
Cardiac injury as detected by blood troponin levels or wall motion abnormalities is not uncommonly seen in people with COVID-19 infection and portends poorer prognosis. Although several mechanisms, including viral myocarditis, thrombotic occlusion of epicardial coronary vessels, and microthrombotic occlusion of myocardial arterioles and capillaries have been postulated, the nature of cardiac injury in these patients remains incompletely understood but at the same time is essential to the development of therapies. Although quite a few studies have been published showing cardiac abnormalities on noninvasive imaging in patients recovering from COVID-19, specific mechanisms by which the virus causes cardiac injury cannot be easily ascertained using such techniques. Ultimately, autopsy studies are be the best avenue to learn how the virus affects the heart. In a recently published paper, Bois et al studied 15 autopsy hearts from COVID-19 victims (12 with active infection and 3 with cleared infection) and compared findings with those from individuals who died from influenza A/B (n = 6) as well as those who died non–virally mediated deaths (n = 6). Although abnormal nonocclusive fibrin microthrombi formation were detected in most of the COVID-19 hearts (12/16; 75.0%), acute ischemic injury to the myocardium was present in only 1 of these cases and troponin levels were reported in 8/15 (median [range], 19.5 [0–461] ng/L; without electrocardiographic or echocardiographic findings). The incidence of fibrin microthrombi was extremely high versus in the hearts of influenza victims (2/6; 33.3%) and control cases (2/6, 33.3%; P = .006). In addition, a relatively high number of cases was reported to have acute lymphocytic myocarditis (33.3% of COVID-19 cases). No evidence of SARS-CoV-2 virus in the heart was detected by multiple diagnostic modalities, including immunohistochemistry, electron microscopy, and droplet digital polymerase chain reaction. Although this paper suggests microthrombi as an important mechanism of cardiac injury, most cases studied did not have evidence of ischemic injury, raising the question of whether the reported findings have important clinical significance. Moreover, the rather high rate of myocarditis reported here is much higher than reported in the literature, and, in the absence of detectable virus, such findings raise the question of whether myocarditis was related to COVID-19 infection or some other cause. In the future, it will be important to determine in a systematic manner the relationship between myocardial injury as determined by blood troponin electrocardiography/ echocardiography and/ or evidence of myocyte necrosis and cardiac findings to demonstrate underlying causes responsible for myocyte injury in patients with COVID-19 infection.