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COVID-19 News - SARS-CoV-2 Spike Protein Mediates Cardiomyocyte Fusion   Mar 10, 2023  1 year, 1 week, 2 days, 2 hours, 14 minutes ago

COVID-19 News: Mayo Clinic Study Shows That SARS-CoV-2 Spike Protein Mediates Cardiomyocyte Fusion Leading To increased Arrhythmic Risk!

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COVID-19 News: Mayo Clinic Study Shows That SARS-CoV-2 Spike Protein Mediates Cardiomyocyte Fusion Leading To increased Arrhythmic Risk!
COVID-19 News - SARS-CoV-2 Spike Protein Mediates Cardiomyocyte Fusion   Mar 10, 2023  1 year, 1 week, 2 days, 2 hours, 14 minutes ago
COVID-19 News: A new study by researchers from Mayo Clinic, Rochester, Minnesota-USA has found that SARS-CoV-2 spike proteins are able to mediate heart muscle cells (cardiomyocytes) fusion leading to increased arrhythmic risk that can also lead to fatal outcomes!


 
Since the advent of the SARS-CoV-2 virus in the Wuhan province of China at the end of 2019, the COVID-19 disease has been responsible for the deaths of more than more 7 million worldwide and more than one million in the United States alone. Excess deaths have not been included in these figures and the actual number of COVID-19 deaths could actually be around 6 to 7-fold!
 
Most complications in patients with COVID-19 are due to pulmonary injury which leads to respiratory failure.
 
However, it is now well established that COVID-19 infections can lead to sudden cardiac death (SCD) with factors contributing to this increased risk of potentially fatal arrhythmias that include thrombosis, exaggerated immune response, and treatment with QT-prolonging drugs such as hydroxychloroquine and azithromycin.
 
Besides these risk factors is the potential for direct SARS-CoV-2 infection of the heart. Albeit rarely, this has been detected to a variable extent in numerous biopsy and autopsy studies of human myocardium from patients with COVID-19. Direct SARS-CoV-2 infection of ACE2-expressing human cardiomyocytes has also been observed in multiple in vitro cardiac cell models.
 
Most recently, a study showed that efficient and productive SARS-CoV-2 infection of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) leads to the formation of multinucleated giant cells called syncytia through cell-cell fusion which is mediated by the SARS-CoV-2 spike protein.
https://pubmed.ncbi.nlm.nih.gov/34613786/
 
This study was covered in a previous COVID-19 News coverage by Thailand Medical News.
https://www.thailandmedical.news/news/latest-covid-19-news-sars-cov-2-causes-heart-muscle-cells-cardiomyocytes-to-fuse-and-disrupts-heart-s-electrical-rhythm
 
However, despite this evidence for direct cardiac damage by SARS-CoV-2, little is known about the arrhythmic potential this may incur, and greater clarification, particularly at the level of the cardiomyocyte, is needed in order to better understand this critically important aspect of COVID-19 pathobiology.
 
Therefore, in this study, we determined the electrophysiological effects, cytosolic calcium handling, and arrhythmic potential, of direct SARS-CoV-2 infection of the heart in the ACE2-accentuated, bio-engineered hiPSC-CM model system.
 
To date, however, the intrinsic arrhythmic potential of direct SARS-CoV-2 infection of the heart remains unknown.
 
The study team aimed to determine the electrophysiological effects, cytosolic calcium handling, and arrhythmic potential, of direct SARS-CoV-2 infection of the heart in the ACE2 -accentuated, bio-engineered hiPSC-CM model system.
 
For the study, hiPSC-CMs were transfected with recombinant SARS-CoV-2 spike protein (CoV-2 S) or CoV-2 S fused to a modified Emerald fluorescence protein (CoV-2 S-mEm). Cell morphology was visualized using immunofluorescence microscopy. Action potential duration (APD) and cellular arrhythmias were measured by whole cell patch-clamp. Calcium handling was assessed using the Fluo-4 Ca2+ indicator.
 
The study findings showed that transfection of hiPSC-CMs with CoV-2 S-mEm produced multinucleated giant cells (syncytia) displaying increased cellular capacitance (75±7 pF, n = 10 vs. 26±3 pF, n = 10; P<0.0001) consistent with increased cell size. The APD90 was prolonged significantly from 419±26 ms (n = 10) in untransfected hiPSC-CMs to 590±67 ms (n = 10; P<0.05) in CoV-2 S-mEm-transfected hiPSC-CMs. CoV-2 S-induced syncytia displayed delayed afterdepolarizations, erratic beating frequency, and calcium handling abnormalities including calcium sparks, large “tsunami”-like waves, and increased calcium transient amplitude.
 
After furin protease inhibitor treatment or mutating the CoV-2 S furin cleavage site, cell-cell fusion was no longer evident and Ca2+ handling returned to normal.
 
The study findings showed that the SARS-CoV-2 spike protein can directly perturb both the cardiomyocyte’s repolarization reserve and intracellular calcium handling that may confer the intrinsic, mechanistic substrate for the increased risk of SCD observed during this COVID-19 pandemic.
 
The study findings were published in the peer reviewed journal: Plos One.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0282151
 
So far, only two other studies have assessed how SARS-CoV-2 impacts hiPSC-CM function.
https://www.jacc.org/doi/abs/10.1016/j.jacbts.2021.01.002
 
https://pubmed.ncbi.nlm.nih.gov/33657418/
 
Considering the lack of functional data, the stud team sought to better characterize the electrophysiological and arrhythmic effects of SARS-CoV-2 infection in hiPSC-CMs.
 
The study team observed that CoV-2 S-mEm (spike protein)-transfected hiPSC-CMs displayed increased cell capacitance indicating these cells had fused together to form one large syncytia, thus confirming an earlier study finding that showed expression of SARS-CoV-2 spike protein in hiPSC-CMs leads to the formation of syncytia by cell-cell fusion.
https://pubmed.ncbi.nlm.nih.gov/34613786/
 
The study tea also discovered that CoV-2 S-mEm-induced hiPSC-CMs syncytia displayed an extremely arrhythmic phenotype including erratic beating frequency and frequent DADs.
 
A potential underlying cause of these cellular arrhythmias was abnormal calcium handling. Following transfection with CoV-2 S, hiPSC-CMs displayed frequent calcium sparks. These small, spontaneous calcium release events are well known to be an underlying cause of DADs and ventricular arrhythmias in patients with underlying genetic heart disease such as catecholaminergic polymorphic ventricular tachycardia for example, and are therefore the likely cause of the DADs observed by patch clamp in CoV-2 S-mEm-induced syncytia.
 
A previous study had observed similar spontaneous calcium release events in otherwise normal hiPSC-CMs that were incubated in serum extracted from SARS-CoV-2 positive patients who were hospitalized for severe acute respiratory distress.
https://pubmed.ncbi.nlm.nih.gov/34411149/
 
Besides calcium sparks, the study team also observed a novel calcium handling phenomenon which they have termed calcium tsunamis.
 
Interestingly, this overwhelming calcium mishandling event has not been documented previously in human cardiomyocytes, likely because they only occur in large syncytia, such as those observed in this study, and not in single cells. The detailed mechanism behind these large calcium release events requires further study.
 
It is possible that calcium tsunamis are simply an extension of calcium waves which initiated by calcium sparks and propagated throughout the cell.
 
The study team speculates that calcium handling abnormalities including calcium sparks, large “tsunami”-like waves, and increased calcium transient amplitude might directly alter L-type calcium channel function in the phase 2 and indirectly modify IKr/IKs in the phase 3 of action potential resulting in delayed repolarization.
 
The study findings also showed that CoV-2 S-mEm (spike protein)-induced hiPSC-CM syncytia display a marked reduction in repolarization reserve as evidenced by APD prolongation.
 
A previous study found that SARS-CoV-2 infection of hiPSC-CMs causes field potential duration (FPD) prolongation as measured by microelectrode array.
https://pubmed.ncbi.nlm.nih.gov/33657418/
 
It should be noted that prolongation of the APD, which is a cellular surrogate for QT prolongation in patients, is well known to cause cellular arrhythmias such as early afterdepolarizations in hiPSC-CMs and can cause the potentially fatal arrhythmia torsades de pointes in humans.
https://pubmed.ncbi.nlm.nih.gov/32678103/
 
https://pubmed.ncbi.nlm.nih.gov/21240260/
 
SARS-CoV-2 infection also causes an increase in baseline QTc in patients with COVID-19.
https://pubmed.ncbi.nlm.nih.gov/33890991/
 
Numerous potential explanations exist for this change including the presence of pro-inflammatory molecules such as IL-6 which causes a down-regulation of KCNH2 expression leading to APD prolongation.
https://pubmed.ncbi.nlm.nih.gov/30521586/
 
The study findings suggest that the presence of SARS-CoV-2 spike protein following infection of the heart could contribute directly.
 
The study data points to the possibility that direct infection of the heart, along with the presence of pro-inflammatory molecules, may play a role in causing baseline QT prolongation.
 
One study has also showed that treatment with a furin protease inhibitor and mutation of the furin cleavage site of CoV-2 S both prevented spike protein cleavage and prevented cell-cell fusion.
https://pubmed.ncbi.nlm.nih.gov/34613786/
 
The study team from mayo clinic was able to confirm these findings in their study and also showed that both methods restored calcium handling. Therefore, the combination of these studies may serve as the basis for the development of potentially novel cardioprotective agents which could be used to treat patients with COVID-19.
 
The study findings show that the SARS-CoV-2 spike protein can directly produce cellular damage and electrophysiological dysfunction in hiPSC-CMs, and this may confer the intrinsic, mechanistic susceptibility for increased risk of SCD observed in patients with COVID-19.
 
Furthermore, discovery that a furin inhibitor eliminates aberrant electrophysiology and hiPSC-CM dysfunction opens a new avenue in the development of cardioprotective agents.
 
For the latest COVID-19 News, keep on logging to Thailand Medical News.
 

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