The emerging role of heart-on-a-chip systems in delineating mechanisms of SARS-CoV-2-induced cardiac dysfunction

Abstract

Coronavirus disease 2019 (COVID-19) has been a major global health concern since its emergence in 2019, with over 680 million confirmed cases as of April 2023. While COVID-19 has been strongly associated with the development of cardiovascular complications, the specific mechanisms by which viral infection induces myocardial dysfunction remain largely controversial as studies have shown that the severe acute respiratory syndrome coronavirus-2 can lead to heart failure both directly, by causing damage to the heart cells, and indirectly, by triggering an inflammatory response throughout the body. In this review, we summarize the current understanding of potential mechanisms that drive heart failure based on in vitro studies. We also discuss the significance of three-dimensional heart-on-a-chip technology in the context of the current and future pandemics.

Keywords: discovery and development; drug; organoids and organ‐mimetic systems; tissue engineering.

FIGURE 1

The coronavirus life cycle. The initial point of contact between SARS‐CoV‐2 and the host cell is the binding of the viral spike proteins to the ACE2 receptor, facilitating viral entry. Following the internalization, the viruses release their positive‐sense genomic RNA into the cytoplasm, which utilize the host's ribosomes to synthesize two polyproteins (pp1a and pp1ab). These polyproteins are subjected to proteolytic cleavage, giving rise to the replicase‐transcriptase complex composed of 16 nonstructural proteins. Among them, the RdRp orchestrates the generation of a complementary negative‐sense RNA strand from the viral genome. Using these negative‐sense RNA templates, the RdRp synthesize new positive‐sense genomic RNA copies, along with sub‐genomic RNAs that encode for structural proteins (S: spike, E: envelope, M: membrane, and N: nucleocapsid). Sub‐genomic RNAs are then translated into structural proteins at ribosomes located at the endoplasmic reticulum (ER). Following translation, the viral proteins are assembled within the ER‐Golgi intermediate compartment. These newly formed viral particles are transferred to the Golgi apparatus for packaging and are released from the host cell. This figure was created with the assistance of www.Biorender.com. ACE2, angiotensin‐converting enzyme‐2; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus‐2.

FIGURE 2

Key direct mechanisms of virus‐induced cardiac dysfunction. Infection by SARS‐CoV‐2 is initiated by the binding of spike proteins to ACE2 receptors and facilitated entry into the host cells by CTSL. Following internalization, the virus releases its genetic material, leading to significant transcriptional changes. These changes lead to mitochondrial damage and destruction of contractile proteins, culminating in heart dysfunction and cellular death. This figure was created with the assistance of www.Biorender.com. ACE2, angiotensin‐converting enzyme‐2; CTSL, cathepsin L; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus‐2.

FIGURE 3

Key mechanisms of inflammation‐driven virus‐associated cardiac dysfunction. Systemic inflammation induces cardiomyocyte damage, triggering the release of chemokines that recruit immune cells to the site of injury. Infiltrated monocytes can be polarized into M1‐like macrophages that release proinflammatory cytokines. These cytokines not only establish a positive feedback loop to amplify the release of cytokines and chemokines, but also contribute to a synergistic amplification of tissue inflammation. This figure was created with the assistance of www.Biorender.com.

FIGURE 4

A summary of advantages and disadvantages of various cardiac models. The classification of existing methodologies and the resultant cellular phenotype can be primarily categorized into five key parameters: interaction of cells with their microenvironment, device throughput capacity, cellular anisotropy, cellular maturity, and the incorporation of vascular structures.

FIGURE 5

Heart‐on‐a‐chip system configurations and key advantages. (a) The heart‐on‐a‐chip systems are designed to incorporate “chip” components that provide spatial confinement for the human‐derived iPSC cardiac tissues. The system is complemented with supporting structures such as thin films, micro‐pillars/posts, and polymeric wires, which facilitates the self‐assembly of cardiac tissues into an oriented structure. Vascularized heart‐on‐a‐chip system with perfusion can simulate in vivo blood flow conditions. (b) Advantages of 3D tissue models over the traditional 2D systems. Cardiac tissues grown on the heart‐on‐a‐chip models exhibit enhanced functional phenotype, permit non‐invasive functional assessment, and provide physiologically relevant microenvironment that closely mimic the human myocardium. Reproduced with permission., , , This figure was created with the assistance of www.Biorender.com. iPSC, induced pluripotent stem cell.

FIGURE 6

Current progress and opportunities in cardiac tissue engineering using heart‐on‐a‐chip systems. (a) During COVID‐19 pandemic, engineered heart tissues were exposed to SARS‐CoV‐2 or a combination of cytokines to induce disease phenotype, allowing for the investigation of underlying pathological mechanisms and drug screening. By modifying cell composition, heart‐on‐a‐chip systems can successfully model various cardiac conditions, including the generation of immune‐cardiac model for studying myocarditis within the context of viral infection. (b) A roadmap for future directions. Use of iPSC‐derived cardiomyocytes with distinct genetic mutations and sex‐specific cells to elucidate the impact of preexisting heart conditions, sex differences, and specific hormonal environment on heart failure. Advanced vascularized heart‐on‐a‐chip platforms will enable the integration of immune components and physiological dosing of viruses/drugs. Chamber‐specific cardiac tissues are vital, as ventricles and atrium exhibit distinctive drug responses. Finally, the improved scalability of these systems facilitates the use of machine learning to accelerate the drug discovery process. This figure was created with the assistance of www.Biorender.com. COVID‐19, Coronavirus disease 2019; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus‐2.