SARS-CoV-2 infection causes cardiomyocyte swelling, cardiac pericyte loss, increased permeability, and diastolic dysfunction in a hamster model

ABSTRACT

Background/Introduction: Recovered COVID-19 patients often display cardiac dysfunction, even after a relatively mild infection. Purpose: We present an in-depth physiological and histological timeline of the cardiac consequences of SARS-CoV-2 infection using a hamster model. Methods: We used several methods, including transthoracic echocardiography, RNA sequencing on in vitro cultures, and in-situ hybridization techniques, complemented with histological analysis. Results: We analysed cardiac function by echocardiography over a period of 35 dpi. Already by 14 dpi and continuing at 35 dpi, infected hamsters presented with an increased E/E', decreased MV deceleration time, and an increased isovolumetric contraction time as compared to control, indicating the presence of diastolic dysfunction. Histologically, cardiomyocytes were enlarged already by 4 dpi and remained enlarged over 5 weeks. We observed the presence of fibrin-rich microthrombi at 4 dpi, which were resolved by 14 dpi. SARS-CoV-2 RNA was present in cardiac pericytes, accompanied by reduced pericyte coverage of capillaries at 4 dpi and 14 dpi, which mostly recovered by 35 dpi. At 14 dpi, the reduced pericyte coverage coincided with increased vascular permeability, suggesting that SARS-CoV-2 infection of pericytes affects microvascular integrity. SARS-CoV-2 infection of pericytes in vitro induced the expression of genes involved in viral defence, and affected genes involved in pericyte contractility and extracellular matrix proteins. Loss of cardiac pericytes was observed in cardiac biopsies from patients recovered from SARSCoV- 2 infection. Conclusion(s) Overall, our results demonstrate that SARS-CoV-2 infection causes a phenotype similar to ischemia-reperfusion, without overt ischemia. We propose that partial occlusion by microthrombi and microvascular dilation caused by pericyte loss induces regional variations in blood flow, and results in a stiffer ;swollen' heart that shows diastolic dysfunction.