SARS-CoV-2 infection causes prolonged cardiomyocyte swelling and inhibition of HIF1α translocation in an animal model COVID-19

Abstract

Recovered COVID-19 patients often display cardiac dysfunction, even after a mild infection. Most current histological results come from patients that are hospitalized and therefore represent more severe outcomes than most COVID-19 patients face. To overcome this limitation, we investigated the cardiac effects of SARS-CoV-2 infection in a hamster model. SARS-CoV-2 infected hamsters developed diastolic dysfunction after recovering from COVID-19. Histologically, increased cardiomyocyte size was present at the peak of viral load and remained at all time points investigated. As this increase is too rapid for hypertrophic remodeling, we found instead that the heart was oedemic. Moreover, cardiomyocyte swelling is associated with the presence of ischemia. Fibrin-rich microthrombi and pericyte loss were observed at the peak of viral load, resulting in increased HIF1α in cardiomyocytes. Surprisingly, SARS-CoV-2 infection inhibited the translocation of HIF1α to the nucleus both in hamster hearts, in cultured cardiomyocytes, as well as in an epithelial cell line. We propose that the observed diastolic dysfunction is the consequence of cardiac oedema, downstream of microvascular cardiac ischemia. Additionally, our data suggest that inhibition of HIF1α translocation could contribute to an exaggerated response upon SARS-CoV-2 infection.

COVID-19, Myocarditis and Pericarditis

“… 186 In a separate study using female Syrian hamsters, cardiomyocyte hypertrophy (at days 4 and 35 after infection) and cardiac fibrosis and diastolic dysfunction were observed at day 35 after SARS-CoV-2 infection using echocardiography. 187 This time course is the same as is observed with the autoimmune CVB3 and murine cytomegalovirus models of myocarditis and EAM ( Table S1 ). 35 , 124 , 170 , 188 However, they did not show a change in LV end diastolic dimension or end LV systolic dimension indicative of DCM; however, this may be because they examined females rather than males.…”

Myocardial Oedema as a Consequence of Viral Infection and Persistence – a Narrative Review with Focus on COVID-19 and Post COVID Sequelae

“…Also in the heart, SARS-COV-2 affects the microvascular barrier including pericytes, and, further, cardiomyocytes and fibroblasts [515][516][517]. In a model of COVID-19 in hamsters the occurrence of fibrin-rich microthrombi and loss of pericytes was associated with oedematous cardiomyocyte swelling [518]. In addition, the disruption of human cardiac pericytes is caused by the SARS-CoV-2 S-protein in an extracellular signal-regulated kinase 1/2 (ERK1/2) dependent manner through the CD147 receptor [519].…”

“…Though the phosphorylation of HIF-1 by ERK 1/2 promotes its nuclear accumulation and control of HIF-1 target gene expression. Surprisingly, however, SARS-CoV-2 infection inhibits HIF1α translocation in cultured cardiomyocytes, as well as in an epithelial cell line [518]. Therefore, it can be assumed that local hypoxia, which is conferred by prothrombotic and inflammatory stimuli together with impaired hypoxia resolvability is responsible for cardiomyocyte oedema formation [518].…”

“…In summary, microvascular homeostasis including glycocalyx and pericyte integrity plays a key role in maintenance of the endothelial barrier and interstitial fluid balance [80]. The impairment of the endothelial surface layer during SARS-CoV-2 infection due to inflammation and ischaemia significantly enhances vascular permeability resulting in oedema formation [64,80,84,85,518].…”

Murine studies and expressional analyses of human cardiac pericytes reveal novel trajectories of SARS-CoV-2 Spike protein-induced microvascular damage

“…Pericyte dysfunction and detachment favor the SARS-CoV-2 to spread from the bloodstream and damage the myocardium. 5 …”