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Cardiovascular diseases persist as a global health challenge that requires methodological innovation for effective drug development. Conventional pipelines relying on animal models suffer from high failure rates due to significant interspecies variation between humans and animal models. In response, the recently enacted Food and Drug Administration Modernization Act 2.0 encourages alternative approaches including induced pluripotent stem cells (iPSCs). Human iPSCs provide a patient-specific, precise, and screenable platform for drug testing, paving the way for cardiovascular precision medicine. This review discusses milestones in iPSC differentiation and their applications from disease modelling to drug discovery in cardiovascular medicine. It then explores challenges and emerging opportunities for the implementation of 'clinical trials in-a-dish'. Concluding, this review proposes a framework for future clinical trial design with strategic incorporations of iPSC technology, microphysiological systems, clinical pan-omics, and artificial intelligence to improve success rates and advance cardiovascular healthcare. [ABSTRACT FROM AUTHOR]

Acute myocardial infarction (MI) inflicts massive injury to the coronary microcirculation leading to vascular disintegration and capillary rarefication in the infarct region. Tissue repair after MI involves a robust angiogenic response that commences in the infarct border zone and extends into the necrotic infarct core. Technological advances in several areas have provided novel mechanistic understanding of postinfarction angiogenesis and how it may be targeted to improve heart function after MI. Cell lineage tracing studies indicate that new capillary structures arise by sprouting angiogenesis from pre-existing endothelial cells (ECs) in the infarct border zone with no meaningful contribution from non-EC sources. Single-cell RNA sequencing shows that ECs in infarcted hearts may be grouped into clusters with distinct gene expression signatures, likely reflecting functionally distinct cell populations. EC-specific multicolour lineage tracing reveals that EC subsets clonally expand after MI. Expanding EC clones may arise from tissue-resident ECs with stem cell characteristics that have been identified in multiple organs including the heart. Tissue repair after MI involves interactions among multiple cell types which occur, to a large extent, through secreted proteins and their cognate receptors. While we are only beginning to understand the full complexity of this intercellular communication, macrophage and fibroblast populations have emerged as major drivers of the angiogenic response after MI. Animal data support the view that the endogenous angiogenic response after MI can be boosted to reduce scarring and adverse left ventricular remodelling. The improved mechanistic understanding of infarct angiogenesis therefore creates multiple therapeutic opportunities. During preclinical development, all proangiogenic strategies should be tested in animal models that replicate both cardiovascular risk factor(s) and the pharmacotherapy typically prescribed to patients with acute MI. Considering that the majority of patients nowadays do well after MI, clinical translation will require careful selection of patients in need of proangiogenic therapies. [ABSTRACT FROM AUTHOR]

In the high-stakes arena of drug discovery, the journey from bench to bedside is hindered by a daunting 92% failure rate, primarily due to unpredicted toxicities and inadequate therapeutic efficacy in clinical trials. The FDA Modernization Act 2.0 heralds a transformative approach, advocating for the integration of alternative methods to conventional animal testing, including cell-based assays that employ human induced pluripotent stem cell (iPSC)-derived organoids, and organ-on-a-chip technologies, in conjunction with sophisticated artificial intelligence (AI) methodologies. Our review explores the innovative capacity of iPSC-derived clinical trial in a dish models designed for cardiovascular disease research. We also highlight how integrating iPSC technology with AI can accelerate the identification of viable therapeutic candidates, streamline drug screening, and pave the way toward more personalized medicine. Through this, we provide a comprehensive overview of the current landscape and future implications of iPSC and AI applications being navigated by the research community and pharmaceutical industry.