Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Wuhan in 2019, the virus has evolved into multiple variants. Among these, the World Health Organization has identified certain variants as “variants of concern” due to their enhanced infectivity, pathogenicity, and immune evasion capabilities. The Delta and Omicron variants, in particular, have led to significant waves of infection globally. Initially reported in Botswana and South Africa, the Omicron variant, with its BA.1 and BA.2 sub-lineages, quickly became the dominant strain in many regions, surpassing Delta in transmission rates. This exceptional transmissibility is largely attributed to extensive amino acid substitutions in the spike protein, which is crucial for viral entry into host cells. These changes have resulted in altered tropism for infection and increased immune evasion.
The Omicron variant’s infection mechanism diverges from earlier variants like Delta, which require the transmembrane serine protease 2 (TMPRSS2) for activation. Omicron can infect cells independently of TMPRSS2, enabling it to target cells lacking this protein. This has led to speculations about Omicron’s different tissue tropism and altered pathogenesis compared to other variants. Most research has focused on the respiratory system, but the impact of different variants on non-respiratory cells, such as cardiomyocytes (CMs), remains unclear.
Although COVID-19 is primarily a respiratory illness, cardiovascular complications are frequently observed in patients and are associated with poor outcomes. Survivors of COVID-19 face substantial risks of adverse cardiovascular disorders, including dysrhythmias, inflammatory heart disease, ischemic heart disease, and heart failure, long after the acute infection. These risks increase with the severity of the acute infection but are also evident among non-hospitalized patients with mild disease. The mechanisms behind COVID-19’s damage to the heart are not fully understood, but proposed explanations include hypoxia-induced cardiac damage, acute inflammation and myocarditis, and direct viral infection of CMs. Several studies have shown that SARS-CoV-2 can infect CMs and cause cytopathic effects, but these studies mostly involved earlier strains of the virus. The effects of different variants on CMs are not well documented.
In this study, we hypothesize that CMs, which do not express TMPRSS2, are more susceptible to Omicron variants, which do not require this protein for infection, compared to the Delta variant. Using human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs) and the Golden Syrian Hamster as models, we examined the effects of SARS-CoV-2 variants on CMs. Our results showed that SARS-CoV-2 variants have divergent effects on CMs in vitro and in vivo. Omicron BA.1 and BA.2 could efficiently infect hiPSC-CMs via endocytosis in a TMPRSS2-independent manner, while Delta minimally infected these cells. CM infection was associated with significant cytopathic damage and transcriptomic alterations, with the most severe effects observed in hiPSC-CMs infected by Omicron BA.2. Although Omicron BA.2 induces a mild phenotype in the respiratory system, it can directly injure CMs in vitro and in vivo.
The study of SARS-CoV-2 variants and their effects on different cell types is crucial for understanding the full impact of COVID-19. The Omicron variant, with its unique ability to infect cells independently of TMPRSS2, represents a significant shift in the virus’s behavior and pathogenicity. This characteristic allows Omicron to infect a broader range of cells, including those in the cardiovascular system, which could explain the higher incidence of cardiovascular complications in COVID-19 patients infected with this variant.
Cardiovascular complications in COVID-19 patients are a major concern for healthcare providers. These complications, which include dysrhythmias, inflammatory heart disease, ischemic heart disease, and heart failure, can significantly worsen patient outcomes. Understanding the mechanisms behind these complications is essential for developing effective treatments and preventive measures.
The ability of SARS-CoV-2 to directly infect CMs and cause cytopathic damage is a critical area of research. Studies have shown that the virus can induce various cytopathic effects in CMs, including cell death, inflammation, and alterations in gene expression. These effects can lead to significant damage to the heart and contribute to the development of cardiovascular complications in COVID-19 patients.
The divergence in the infectivity and pathogenicity of different SARS-CoV-2 variants highlights the importance of continuous monitoring and research. Variants like Omicron, which can infect cells independently of TMPRSS2, pose new challenges for healthcare providers and researchers. These variants require different approaches to treatment and prevention, as their unique characteristics can lead to different patterns of disease and complications.
In this study, we used hiPSC-CMs and the Golden Syrian Hamster as models to examine the effects of SARS-CoV-2 variants on CMs. These models provide valuable insights into the behavior of the virus in human cells and animal systems, helping to bridge the gap between in vitro and in vivo studies. Our findings show that Omicron variants can efficiently infect hiPSC-CMs via endocytosis in a TMPRSS2-independent manner, leading to significant cytopathic damage and transcriptomic alterations.
The ability of Omicron variants to infect CMs independently of TMPRSS2 suggests that these variants have acquired different tissue tropism and altered pathogenesis compared to earlier variants like Delta. This characteristic allows Omicron to target a broader range of cells, including those in the cardiovascular system, leading to more severe cardiovascular complications in COVID-19 patients.
Our results also show that CM infection is associated with significant cytopathic damage and transcriptomic alterations. These effects were most severe in hiPSC-CMs infected by Omicron BA.2, indicating that this variant may have a higher pathogenicity in the cardiovascular system compared to other variants. The transcriptomic alterations observed in infected CMs provide valuable insights into the molecular mechanisms behind the virus’s effects on the heart.
Understanding the full impact of SARS-CoV-2 variants on the cardiovascular system is essential for developing effective treatments and preventive measures. The findings of this study highlight the importance of continuous monitoring and research to identify and characterize new variants and their effects on different cell types. By doing so, we can develop targeted therapies and interventions to mitigate the impact of COVID-19 on the cardiovascular system and improve patient outcomes.
The emergence of new SARS-CoV-2 variants poses ongoing challenges for healthcare providers and researchers. These variants can exhibit different patterns of infectivity, pathogenicity, and immune evasion, requiring continuous monitoring and adaptation of treatment and prevention strategies. The ability of Omicron variants to infect cells independently of TMPRSS2 represents a significant shift in the virus’s behavior and highlights the need for ongoing research to understand its full impact.
In conclusion, the study of SARS-CoV-2 variants and their effects on different cell types is critical for understanding the full impact of COVID-19. The Omicron variant, with its unique ability to infect cells independently of TMPRSS2, represents a significant shift in the virus’s behavior and pathogenicity. This characteristic allows Omicron to infect a broader range of cells, including those in the cardiovascular system, leading to more severe cardiovascular complications in COVID-19 patients. Continuous monitoring and research are essential for developing effective treatments and preventive measures to mitigate the impact of COVID-19 on the cardiovascular system and improve patient outcomes.
As we move forward, it is crucial to remain vigilant in monitoring the emergence of new SARS-CoV-2 variants and their effects on different cell types. By doing so, we can develop targeted therapies and interventions to mitigate the impact of COVID-19 on the cardiovascular system and improve patient outcomes. The findings of this study provide valuable insights into the behavior of the Omicron variant and highlight the importance of continuous research in this area.
Simplified Table Outline for Key Medical Concepts
| Medical Concept | Simplified Explanation | Relevant Details | Examples |
|---|---|---|---|
| SARS-CoV-2 | The virus that causes COVID-19, a respiratory illness that started in 2019. | Part of the coronavirus family, spreads through respiratory droplets. | Symptoms include fever, cough, and shortness of breath. |
| Variants | Different versions of a virus that arise due to mutations. | Variants can have different properties, like how easily they spread or how severe the illness they cause. | Delta and Omicron are examples of SARS-CoV-2 variants. |
| Transmissibility | How easily a virus can spread from one person to another. | Higher transmissibility means the virus spreads more quickly. | Omicron has higher transmissibility compared to earlier variants. |
| Pathogenicity | The ability of a virus to cause disease. | A virus with high pathogenicity can cause more severe illness. | Delta variant is known for higher pathogenicity. |
| Cardiomyocytes (CMs) | Heart muscle cells that help the heart pump blood. | CMs are crucial for heart function and can be damaged by infections. | Damage to CMs can lead to heart problems like arrhythmias or heart failure. |
| Human Induced Pluripotent Stem Cells (hiPSCs) | Special cells created in the lab that can become almost any type of cell in the body, including heart cells. | Used in research to study how diseases affect human cells. | hiPSC-derived CMs (hiPSC-CMs) are used to study heart cell infections by viruses. |
| Endocytosis | A process by which cells take in substances from outside by engulfing them in a bubble-like structure. | Viruses can enter cells using this process. | Omicron variants use endocytosis to infect cells. |
| TMPRSS2 | A protein on the surface of some cells that helps certain viruses enter the cells. | Some variants of SARS-CoV-2 need TMPRSS2 to infect cells. | Delta variant uses TMPRSS2 for cell entry. |
| Cytopathic Effects | Visible changes in a host cell caused by viral infection, often leading to cell damage or death. | Can be used to study how harmful a virus is to cells. | SARS-CoV-2 infection can cause cell death in CMs. |
| Troponin | A protein released into the blood when heart muscle is damaged. | High levels of troponin indicate heart damage. | Elevated troponin levels are often found in COVID-19 patients with heart issues. |
| Myocardial Dysfunction | When the heart muscle doesn’t function properly, leading to poor blood circulation. | Can result from direct infection of heart cells by a virus. | Common in severe COVID-19 cases. |
| Echocardiography | A test that uses ultrasound to create images of the heart, helping to diagnose heart problems. | Non-invasive and provides detailed images of heart structure and function. | Used to detect myocardial dysfunction in COVID-19 patients. |
| Hypoxia-Induced Cardiac Damage | Heart damage caused by low oxygen levels in the blood. | Low oxygen can occur due to severe respiratory infections like COVID-19. | Leads to symptoms like chest pain and shortness of breath. |
| Acute Inflammation | The body’s immediate response to injury or infection, causing redness, heat, swelling, and pain. | Helps fight infections but can cause tissue damage if excessive. | Severe inflammation is seen in COVID-19 patients, leading to complications. |
| Myocarditis | Inflammation of the heart muscle, which can affect the heart’s ability to pump blood. | Can be caused by viral infections like SARS-CoV-2. | Symptoms include chest pain, fatigue, and shortness of breath. |
| Redox Potential | A measure of the ability of a cell to undergo chemical reactions that involve the transfer of electrons. | Important for maintaining cell health and function. | A significant decrease in redox potential indicates cell stress or damage. |
| Cell Fusion (Fusogenicity) | The merging of two or more cells into a single cell, often caused by viral infection. | Can lead to the formation of large, multinucleated cells. | Seen in SARS-CoV-2 infections and can contribute to tissue damage. |
| Transcription Factors | Proteins that help turn specific genes on or off by binding to nearby DNA. | Essential for regulating gene expression. | MEF2C, TBX5, and HAND2 are transcription factors involved in heart function. |
| Regulatory Network | A group of molecules, including proteins and RNA, that interact to control the levels of various substances within a cell. | Helps maintain normal cell function and respond to changes in the environment. | Disruption of regulatory networks can lead to diseases like heart failure. |
| Severe Disease Risk Factors | Conditions or characteristics that increase the likelihood of severe illness from infections like COVID-19. | Includes age, underlying health conditions, and vaccination status. | Elderly, unvaccinated, and individuals with comorbidities are at higher risk. |
| Echocardiographic Studies | Research using echocardiography to study heart function in various conditions. | Provides insights into how diseases like COVID-19 affect the heart. | Used to compare heart function in patients with different SARS-CoV-2 variants. |
| Transcriptomic Analysis | The study of the complete set of RNA transcripts produced by the genome under specific circumstances or in a specific cell. | Helps understand how genes are expressed and regulated in response to infections. | Used to identify changes in gene expression in CMs infected by SARS-CoV-2 variants. |
| Excess Mortality | The number of deaths during a specific period that exceeds the number expected based on historical data. | Used to measure the impact of pandemics and other health crises. | Similar excess mortality rates observed during the Omicron surge compared to early pandemic stages. |
| Metabolic Selection | A process used to promote the growth of cells with certain desired characteristics, such as adult-like traits in hiPSC-CMs. | Helps create more accurate cell models for research. | Used to make hiPSC-CMs resemble adult heart cells more closely. |
Discussion
SARS-CoV-2 variants exhibit diverse transmissibility and pathogenicity, with significant studies focusing on their effects within the respiratory system. However, their impact on extrapulmonary tissues, particularly cardiomyocytes (CMs), remains less understood. Our research utilizing human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and Golden Syrian hamsters reveals that different SARS-CoV-2 variants uniquely infect and damage CMs. Notably, Omicron BA.1 and BA.2 efficiently infect CMs through the endocytic pathway independent of TMPRSS2, whereas Delta shows minimal infection in these cells. Despite its reputation for causing mild respiratory illness, Omicron BA.2 induces severe phenotypes in both in vitro and in vivo models. This study is pioneering in comparing the effects of Delta and Omicron variants on CMs and highlights their divergent impacts.
Cardiac damage presents a severe, potentially life-threatening complication of COVID-19. Elevated biomarkers such as troponin and myocardial dysfunction assessed through echocardiography are frequently observed in COVID-19 patients and correlate with poor prognosis. The mechanisms by which SARS-CoV-2 inflicts cardiac injury remain elusive, though direct CM infection has been proposed as a pathogenic mechanism. Various studies have used hPSC-CM models to demonstrate that SARS-CoV-2 can infect CMs in vitro. Evidence of SARS-CoV-2 viral particles, RNA, protein, and signs of viral transcription have been found in CMs from endomyocardial biopsy and autopsy samples, alongside cardiac damage markers like sarcomere rupture and cell death. Conversely, some studies report the absence of CM infection in autopsy samples using single-cell RNA sequencing and dsRNA/protein analyses. Notably, most clinical studies use autopsy samples from patients long past the acute infection phase and earlier viral isolates. The extent of direct CM infection’s contribution to cardiac damage in COVID-19 patients remains controversial. Our findings indicate that different SARS-CoV-2 variants differentially infect CMs, which may explain the conflicting results in existing literature.
Our study shows that Omicron BA.1 and BA.2 variants can infect CMs via endocytosis without TMPRSS2, whereas Delta requires TMPRSS2 for cell membrane fusion. This aligns with respiratory system studies where Omicron infects cells via endocytosis independently of TMPRSS2, unlike Delta. Our hamster experiments further support these findings, demonstrating cardiac infection by Omicron BA.2 in vivo, while Delta-infected CMs were rare. Importantly, the more severe cardiac pathology induced by Omicron BA.2 was not secondary to respiratory disease severity, as lung pathology was similar or milder for this variant.
A key discovery of our report is the severe phenotype induced by Omicron BA.2 infection. In vivo experiments showed greater cardiac pathology in animals infected with Omicron BA.2 compared to Delta. In vitro, Omicron BA.2 significantly reduced redox potential and induced cell detachment in hiPSC-CMs more than other variants. We also observed rapid and dramatic morphological deterioration in hiPSC-CMs exposed to Omicron BA.2. Previous studies noted increased viral replication and fusogenicity of Delta compared to Omicron BA.1 in hPSC-CMs, with Omicron BA.2 and BA.5 being more replicative than BA.1. Discrepancies between this report and our data may stem from differences in the status and age of hPSC-CMs used, as these factors affect the expression of entry factors like TMPRSS2. Our hiPSC-CMs, cultured for over 40 days and similar to adult CMs, did not express TMPRSS2, unlike younger, immature hPSC-CMs.
Delta, Omicron BA.1, and BA.2 variants differ in pathogenicity in respiratory cells, attributed to their fusogenicity mediated by TMPRSS2. However, we observed minimal increases in cell fusion in hiPSC-CMs infected by any variants, consistent with the absence of TMPRSS2 in these cells. This suggests that fusogenicity may not play a significant role in SARS-CoV-2-induced CM damage and does not correlate with the severe phenotype induced by Omicron BA.2. Instead, our bioinformatics analysis reveals that Omicron BA.2 suppresses genes crucial to cardiac function. We identified SIX1, MEF2C, TBX5, HAND2, and SRF as key regulators of the unique transcriptomic profile of Omicron BA.2 cardiac infection. SIX1 is an interferon-stimulated transcription factor involved in SARS-CoV-2 transcription, predicted to be activated by Omicron BA.2. MEF2C, TBX5, and HAND2 regulate cardiac gene expression, with TBX5 being critical for cardiac function and dysregulated in heart failure patients. Loss of TBX5 function in adult mice leads to cardiac dysfunction, arrhythmias, and sudden cardiac death, suggesting its suppression by Omicron BA.2 may similarly damage CMs. Our analysis uncovers a previously unknown regulatory network contributing to altered cardiac gene expression and phenotype induced by Omicron BA.2.
Omicron is considered a ‘mild’ variant, with lower disease severity compared to previous variants like Delta based on hospitalization and death rates. Delta induces severe respiratory illness and inflammation, effects not fully modeled in our in vitro CM model. Additionally, our Golden Syrian Hamster model, known for developing less severe disease than humans, may underestimate systemic cardiac damage induced by Delta. While we do not claim that Omicron causes more severe cardiac illness in patients, we conclude that Omicron BA.2 damages CMs via different mechanisms compared to Delta. Vulnerable patients, such as the elderly, unvaccinated, and those with co-morbidities, remain at risk of severe disease. Recent studies show impaired right ventricular function to a lesser extent among Omicron patients compared to those infected with the wild-type variant, potentially related to attenuated pulmonary parenchymal and/or vascular disease. Another study revealed similar excess mortality due to acute myocardial infarction during the Omicron surge compared to early stages of the pandemic. Heart transplant recipients demonstrated higher disease severity among Omicron compared to Delta patients, underscoring the need for larger clinical studies to compare the pathogenesis and sequelae of cardiac injury induced by different variants.
Human iPSC-CMs have been extensively used to examine SARS-CoV-2 infection and its consequences. These cells, though developmentally immature and resembling embryonic/fetal CMs, were subjected to metabolic selection to promote more adult-like traits. Despite this, our hiPSC-CMs may not fully recapitulate the adult cardiac phenotype, posing a limitation of our in vitro study. Nonetheless, our findings provide critical insights into the mechanisms of SARS-CoV-2-induced cardiac damage and underscore the importance of continuous research to develop effective treatments and preventive measures.
In conclusion, our study highlights the divergent effects of SARS-CoV-2 variants on cardiomyocytes. Omicron BA.2, despite its mild respiratory phenotype, can directly infect and damage CMs via a TMPRSS2-independent pathway, leading to significant cytopathic effects and transcriptomic alterations. These findings emphasize the need for continuous monitoring and research on SARS-CoV-2 variants to understand their full impact on different cell types and develop targeted therapies to mitigate COVID-19-related cardiovascular complications.
reference : https://link.springer.com/article/10.1186/s13578-024-01280-y#Sec16
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