An ensemble of in vitro cardiac tissue models has been developed over the past several decades to aid our understanding of complex cardiovascular disorders using a reductionist approach. These approaches often rely on recapitulating single or multiple clinically relevant end points in a dish indicative of the cardiac pathophysiology. The possibility to generate disease-relevant and patient-specific human induced pluripotent stem cells has further leveraged the utility of the cardiac models as screening tools at a large scale. To elucidate biological mechanisms in the cardiac models, it is critical to integrate physiological cues in form of biochemical, biophysical, and electromechanical stimuli to achieve desired tissue-like maturity for a robust phenotyping. Here, we review the latest advances in the directed stem cell differentiation approaches to derive a wide gamut of cardiovascular cell types, to allow customization in cardiac model systems, and to study diseased states in multiple cell types. We also highlight the recent progress in the development of several cardiovascular models, such as cardiac organoids, microtissues, engineered heart tissues, and microphysiological systems. We further expand our discussion on defining the context of use for the selection of currently available cardiac tissue models. Last, we discuss the limitations and challenges with the current state-of-the-art cardiac models and highlight future directions.

Manifestations of cardiovascular diseases (CVDs) in a patient or a population differ based on inherent biological makeup, lifestyle, and exposure to environmental risk factors. These variables mean that therapeutic interventions may not provide the same benefit to every patient. In the context of CVDs, human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) offer an opportunity to model CVDs in a patient-specific manner. From a pharmacological perspective, iPSC-CM models can serve as go/no-go tests to evaluate drug safety. To develop personalized therapies for early diagnosis and treatment, human-relevant disease models are essential. Hence, to implement and leverage the utility of iPSC-CMs for large-scale treatment or drug discovery, it is critical to (i) carefully evaluate the relevant limitations of iPSC-CM differentiations, (ii) establish quality standards for defining the state of cell maturity, and (iii) employ techniques that allow scalability and throughput with minimal batch-to-batch variability. In this review, we briefly describe progress made with iPSC-CMs in disease modelling and pharmacological testing, as well as current iPSC-CM maturation techniques. Finally, we discuss current platforms for large-scale manufacturing of iPSC-CMs that will enable high-throughput drug screening applications.

Excessive iron accumulation in the heart causes iron overload cardiomyopathy (IOC), which initially presents as diastolic dysfunction and arrhythmia but progresses to systolic dysfunction and end-stage heart failure when left untreated. However, the mechanisms of iron-related cardiac injury and how iron accumulates in human cardiomyocytes are not well understood. Herein, using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we model IOC and screen for drugs to rescue the iron overload phenotypes. Human iPSC-CMs under excess iron exposure recapitulate early-stage IOC, including oxidative stress, arrhythmia, and contractile dysfunction. We find that iron-induced changes in calcium kinetics play a critical role in dysregulation of CM functions. We identify that ebselen, a selective divalent metal transporter 1 (DMT1) inhibitor and antioxidant, could prevent the observed iron overload phenotypes, supporting the role of DMT1 in iron uptake into the human myocardium. These results suggest that ebselen may be a potential preventive and therapeutic agent for treating patients with secondary iron overload.