A research group from Germany demonstrated a direct toxic effect of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on cardiac cells in their paper published on the bioRxiv* preprint server. The finding warrants an in-depth analysis of cardiac tissue in certain coronavirus disease (COVID-19) patients, as well as close monitoring for any direct cardiomyocyte injury.
COVID-19 pandemic has spread around the globe, putting billions of people into lockdown as health services try to cope with gravely ill individuals. Elderly and those with pre-existing medical conditions appear to be in jeopardy of serious disease outcomes.
Patients with underlying cardiovascular diseases present with an increased risk of death after SARS-CoV-2 infection. Moreover, clinical deterioration during COVID-19 is accompanied by left ventricular dysfunction in approximately 20% of patients, which is a striking number.
Nonetheless, it is not clear whether biomarkers of cardiac injury and long-term adverse effects on the cardiovascular system are caused directly by viral infection of the heart tissue, or they arise secondary to hypoxia (i.e., oxygen deprivation) and systemic inflammation during complicated COVID-19.
Previous research has hinted that human cardiomyocytes (heart cells) express the recognized SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2), most notably in patients with cardiovascular diseases, suggesting that they could be targeted by the novel coronavirus.
SARS-CoV-2 virus binding to ACE2 receptors on a human cell. Image Credit: Kateryna Kon / Shutterstock
This is why researchers from Frankfurt University, University Medical Center Hamburg-Eppendorf, German Center for Cardiovascular Research, Max Planck Institute Heart and Lung Research, Cardiopulmonary Institute, Fraunhofer Institute for Molecular Biology and Applied Ecology, German Centre for Infection Research, and several specialty clinics decided to investigate whether human cardiomyocytes are actually permissive for SARS-CoV-2 infection.
Using heart cells and living cardiac tissue slices
The researchers induced the infection by two control strains of SARS-CoV-2 (previously propagated in Caco-2 cell lines) in human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CM), as well as in two models of human cardiac tissue.
By using human cardiospheres (i.e., a cluster of endogenous heart stem cells that arises when they are cloned in suspension) generated by hiPS-cells, they aimed to determine whether SARS-CoV-2 infects cardiomyocytes in a three-dimensional tissue environment.
Finally, these scientists also addressed whether SARS-CoV-2 can infect human heart tissue by using living human cardiac tissue slices obtained from explanted hearts. All cytopathogenic effects were appraised visually 48 hours following the infection.
Cytotoxicity and lower heartbeats
The study has shown that SARS-CoV-2 can readily infect human cardiomyocytes in culture, as well as in two different models of heart tissue. The infection was demonstrated by an assortment of readouts – including the expression of intracellular viral RNA and its spike glycoprotein.
"Increasing concentrations of virus RNA are detected in supernatants of infected cardiomyocytes, which induced infections in CaCo-2 cell lines documenting productive infections", explain study authors.
The virus was further detected by in cells of the infected human heart slices by using electron microscopy, and it was also shown that it undergoes a full replication cycle. Of note, pro-apoptotic effects were also generated by SARS-CoV-2, which means it induces programmed cell death in cardiomyocytes.
In a nutshell, SARS-CoV-2 infection in this study was linked to cytotoxic changes and lower beating rate of heart cells in laboratory cultures and cardiospheres, suggesting a purported detrimental effect of the virus on the human heart.
"SARS-CoV-2 time-dependently affected beating frequency of cardiospheres with a profound inhibition at 5 days post-infection", further elucidate study authors. "At five days post-infection, cardiospheres showed a reduced size consistent with the induction of cell death," they add.
Future research and clinical practice
Although there was evidence that patients with COVID-19 had elevated cardiac injury biomarkers, as well as certain problems with left and right ventricular cardiac function, this is the first time a direct viral infection of cardiomyocytes by SARS-CoV-2 has been demonstrated convincingly.
"The used three-dimensional tissue models may serve as an experimental model for testing the effects of coronavirus infection and biology in the heart and developing therapeutic strategies," study authors explain implications of their research findings.
In any case, the significant adverse effects of SARS-CoV-2 on human cardiomyocytes – as described in this study – definitely warrants additional, continuous, and comprehensive monitoring of direct cardiac changes in COVID-19 patients.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.