Latest COVID-19 News: SARS-CoV-2 Causes Heart Muscle Cells Cardiomyocytes To Fuse And Disrupts Heart’s Electrical Rhythm
Latest COVID-19 News
: Mayo Clinic and University of Wisconsin-Madison researchers have discovered in a new study that COVID-19 can result in cardiomyocytes to fuse resulting in cardiac damage coupled with disruption of the heart electrical rhythm.
The study team made this discovery after an autopsy of a COVID-19 patient who died of sudden cardiac arrest found the virus had infected her heart in an unusual patchy pattern, with small islands of infected cells here and there.”
Dr Jay Schneider of the Mayo Clinic in Rochester, Minnesota told Thailand Medical News that upon further study in the laboratory, the study team realized the spike protein on the surface of the new coronavirus can create holes between neighboring cells, causing them to fuse together.
Dr Schneider added, "Not surprisingly, fusing beating heart cells causes problems.”
In normal circumstances as electrical signals travel through the heart, each conducting cell activates the one next to it in a domino effect to ensure smooth contractions. But in the researchers' experiments, instead of orderly electrical signal transmission and a steady heart rhythm, the signals flowed like "a tsunami tidal wave" through the fused cells.
The study team says their research may help explain the cardiac injuries often seen in COVID-19 patients without large amounts of virus in the heart or other expected findings.
The study findings were published on a preprint server but are currently being peer reviewed for publication into the journal: Nature Research. https://www.researchsquare.com/article/rs-95587/v1
Viruses spread between hosts through particles, but within hosts, viral genomes can spread from cell to cell through fusion, evading antiviral defenses and obviating costly infectious virion production.
Billions of electromechanically coupled cardiomyocytes (CMs) make myocardium inherently vulnerable to pathological electromechanical short circuits caused by intercellular viral spread. https://pubmed.ncbi.nlm.nih.gov/19357408/
Beyond respiratory illness, COVID-19 affects the heart and cardiac injury and arrhythmias are serious public health concerns.
The study team by studying myocardium of a young woman who died suddenly, diagnosed postmortem with COVID-19, discovered highly focal myocardial SARS-CoV-2 infection spreading from one CM to another through intercellular junctions identified by highly concentrated sarcolemmal t-tubule viral spike glycoprotein.
SARS-CoV-2 permissively infected beating human induced pluripotent stem cell (hiPSC)-CMs building multinucleated cardiomyotubes (CMTs) through cell type-specific fusion driven by proteolytically-activated spike glycoprotein. Recombinant spike glycoprotein, co-localizing to sarcolemma and sarcoplasmic reticulum, produced multinucleated CMTs with pathological structure, electrophysiology and Ca2+ excitation-contraction coupling. Blocking cleavage, a peptide-based protease inhibitor neutralized SARS-CoV-2 spike glycoprotein pathogenicity.
The study findings showed that the SARS-CoV-2 spike glycoprotein is a powerful fusogen of ACE2 receptor-(+) hiPSC-CMs. The study links CMT generation by cell fusion to electrical dysfunction in fatal cardiac injury associated with COVID-19. While cell-cell fusion is not immediately evident in the patient’s autopsy tissue, fusion pores may open, creating cell-cell conduits that do not extend because of cytoskeletal constraints, as characterized for other viral infections in vivo. https://pubmed.ncbi.nlm.nih.gov/31772054/
The study team suggests that SARS-CoV-2 spike glycoprotein-induced membrane changes directly injure CMs, heightening cardiac arrhythmia risk even at low viral load and in the absence of widespread lymphocytic myocarditis-mediated tissue destruction. This result explains the mismatch between cardiac injury, frequently observed in COVID-19, and lymphocytic myocarditis, which is extremely rare, an until now unsolved clinical paradox. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385689/
Cardiac damage in COVID-19 acute respiratory distress syndrome, multisystem inflammatory syndrome and shock is also caused by microthrombosis and cardiotoxic catecholamine or inflammatory-cytokine storm, but these severe conditions are uncommon.
Beyond SARS-CoV-2, its predecessors SARS-CoV and Middle East respiratory syndrome (MERS) cause cardiac injury. Moreover, coronavirus (RbCV), discovered more than three decades ago, produces sufficient cardiac injury to cause cardiomyopathy, and finally, myocardial viral nucleic acids are frequently observed in primate and murine SARS-CoV-2 infection models, but notably again without lymphocytic myocarditis. Human iPSC-CMs may have immature innate immune defenses and thus be more permissive to SARS-CoV-2 infection.
Nevertheless, virus-induced pathological modification of plasma membranes occurs even in the absence of complete viral replication. In particular, expression of spike glycoprotein alone in hiPSC-CMs induced Ca2+ sparks, tsunami-like Ca2+ waves and electromechanical abnormalities. Expression of proteolytically primed and activated spike glycoprotein at the CM surface might contribute, through cell-cell fusion, to the natural history of cardiomyopathy evolving decades after successful clearance of virus.
Sequential spike glycoprotein cleavage at two sites governs SARS-CoV-2 cell entry and pathogenesis. While cleavage by TMPRSS2 is critical for entry into lung epithelial cells, CMs do not express this protease. SARS-CoV-2 spike protein cleavage at S1/S2 site by furin contributes to cardiac pathogenicity: in hiPSC-CMs efficient spike protein proteolytic processing and CMTs formation are blocked by a furin inhibitor.
The study team analyzed the function of the spike proteins of other coronaviruses in hiPSC-CMs: while the MERS coronavirus spike glycoprotein drove CMT production with slower kinetics, the spike glycoproteins of SARS-CoV and of the common cold coronavirus HCoV-E were inactive, mirroring results in Vero cells. The protease driving S2’ cleavage of the SARS-CoV-2 spike glycoprotein in CMs and Vero cells remains to be identified. Taken together, these results demonstrate that SARS-CoV-2 spike glycoprotein, autonomously spreading from CM to CM, can directly produce cellular damage and dysfunction that may explain the cardiac injury frequently observed clinically in COVID-19 despite low myocardial viral load and absence of classic lymphocytic myocarditis or cytopathic tissue destruction.
The study team concluded that SARS-CoV-2 spike glycoprotein, efficiently primed, activated and strategically poised during biosynthesis, can exploit the CM’s inherent membranous connectivities to drive heart damage directly, uncoupling clinically common myocardial injury from lymphocytic myocarditis, often suspected but rarely confirmed in COVID-19.
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