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A human cardiac tissue model demonstrated a high risk of cardiac dysfunction in heart tissues with persistent SARS-CoV-2 infection

More than 10 years before the COVID-19 pandemic, viral genomes were found in endocardial biopsies from patients with idiopathic chronic cardiomyopathy. These findings demonstrated that viral infections are deeply involved in the pathogenesis of heart diseases. In this study, the Japanese authors used a three-dimensional human heart tissue model to investigate the risk of cardiac dysfunction and heart failure progression in persistent heart infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

SARS-CoV-2 is an enveloped, positive-sense, single-stranded RNA virus. Its genome encodes four structural proteins, namely the spike (S), envelope (E), nucleocapsid (N), and membrane (M) protein. Two host-cell factors are important for SARS-CoV-2 viral entry into many cell types: angiotensin-converting enzyme 2 (ACE2), which is bound by S protein, and transmembrane serine protease 2 (TMPRSS2), which cleaves S protein, allowing this binding to take place. The authors emphasized the results of previous studies that demonstrated that ACE2 receptors are highly expressed in the heart and cardiomyocytes of patients with heart failure. They hypothesized that patients with chronic cardiomyopathy may have a persistent heart infection with SARS-CoV-2 and that conditions like heart failure may influence the severity of infection. 

About the study

The authors used a model of human cardiac microtissues (CMTs), differentiated from human iPS cells. The CMT model was composed of cardiomyocytes and other cardiac component cells (vascular endothelial cells and vascular mural cells) with a structure that morphologically and functionally mimics the human heart. The CMT model was infected with mild, moderate, and high titers of SARS-CoV-2, and the cardiac function was evaluated through tissue contractility measured by a video-based method.

 

 

 

Results

7 days after the infection with SARs-CoV-2, the results showed a deterioration of cardiac function in the CMT model infected with mild, moderate, and high titers of SARS-CoV-2 compared to those in the non-infected CMT model. A recovery trend in cardiac function was observed in the CMT model infected with mild and moderate titers, whereas the CMT model infected with high viral titers demonstrated a sustained decrease in contractility without a recovery. These results show reduced tissue contractility and the possible deterioration of cardiac function during the acute phase of COVID-19.

28 days after the SARS-CoV-2 infection, the histological and immunofluorescence analysis demonstrated that the SARS-CoV-2 S protein was co-localized with cardiomyocytes in the CMT model infected with mild titers of SARS-CoV-2. The vascular network was only slightly disrupted and the S protein was intensely co-localized with CD31, a marker for cardiac endothelial cells.

Original illustration from the study of Murata K. et al , 2023

 

 

As cardiac dysfunction and eventually heart failure may develop under additional cardiac stress, both CMT models, with and without persistent SARS-CoV-2 infection, were exposed to hypoxic stress mimicking ischemic heart disease. A hypoxic stress for 18 hours and a subsequent normoxic condition for 48 hours resulted in a further deterioration of the contractile function in the CMT model infected with SARS-CoV-2. In contrast, the CMT model without a persistent SARS-CoV-2 infection showed increased pulsating frequency and contractile functional recovery.

In the CMT model infected with SARS-CoV-2, the analysis of CD31 demonstrated that ischemia and reperfusion globally fragmented the formation of the vascular network, which was not the case in the non-infected CMT model. In addition, immunofluorescence showed that hypoxia and reperfusion upregulated the expression of ACE2 in cardiomyocytes. These results show that hypoxic conditions mimicking ischemic heart disease further deteriorated cardiac function and disrupted vascular network formation in the infected CMT model.

The scientists also investigated whether the upregulation of inflammatory cytokines plays a role in the deterioration of cardiac function under additional hypoxic stress, and found that the expression levels of interleukin (IL)-1b, IL-6, tumor necrosis factor-α, and interferon-γ did not increase under hypoxic stress in the context of persistent SARS-CoV-2 infection. These results indicate that a deterioration of cardiac function under hypoxic stress associated with a persistent SARS-CoV-2 infection was not caused by cytokines involved in inflammatory responses.

Conclusion

A human iPS cell-based cardiac tissue model demonstrated a high risk of cardiac dysfunction in heart tissues with persistent SARS-CoV-2 infection. In addition, hypoxic conditions mimicking ischemic heart disease further deteriorated cardiac function and disrupted vascular network formation in the CMT model infected with SARS-CoV-2.

The authors suggested that an explosive increase in the number of infected patients may have led to an enormous increase in the number of patients at potential risk for future heart failure. They also said that the model used in this study could be useful to investigate the mechanism of the development and progression of SARS-CoV-2 cardiomyopathy and possible therapeutic options.

 

 

This article was published in iSCIENCE.

Journal Reference

Murata K, Makino A, Tomonaga K, Masumoto H. Predicted risk of heart failure pandemic due to persistent SARS-CoV-2 infection using a three-dimensional cardiac model. iScience (2023), in press.  https://www.sciencedirect.com/science/article/pii/S2589004223027189

 

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