Cardiovascular diseases resulting from myocardial infarction (MI) remain a leading cause of death worldwide, imposing a substantial burden on global health systems. Current MI treatments, primarily pharmacological and surgical, do not regenerate lost myocardium, leaving patients at high risk for heart failure. Engineered heart tissue (EHT) offers a promising solution for MI and related cardiac conditions by replenishing myocardial loss. However, challenges like immune rejection, inadequate vascularization, limited mechanical strength, and incomplete tissue maturation hinder clinical application. The discovery of human-induced pluripotent stem cells (hiPSCs) has transformed the EHT field, enabling new bioengineering innovations. This review explores recent advancements and future directions in hiPSC-derived EHTs, focusing on innovative materials and fabrication methods like bioprinting and decellularization, and assessing their therapeutic potential through preclinical and clinical studies. Achieving functional integration of EHTs in the heart remains challenging due to the need for synchronized contraction, sufficient vascularization, and mechanical compatibility. Solutions such as genome editing, personalized medicine, and AI technologies offer promising strategies to address these translational barriers. Beyond MI, EHTs also show potential in treating ischemic cardiomyopathy, heart valve engineering, and drug screening, underscoring their promise in cardiovascular regenerative medicine.

Myocardial infarction-induced cardiovascular diseases remain a leading cause of mortality worldwide. Excessive post-infarct fibrosis contributes to adverse cardiac remodeling and the progression to heart failure. In vivo reprogramming strategies offer a promising avenue for heart regeneration by directly converting resident fibroblasts into cardiomyocytes through enforced expression of cardiogenic genes. This approach circumvents the need for invasive biopsies, cell expansion, induction of pluripotency, or autologous transplantation. Despite these advantages, key challenges persist, including low reprogramming efficiency and limited cellular targeting specificity. A critical factor for effective anti-fibrotic therapy is the precise and efficient delivery of reprogramming effectors specifically to fibrotic fibroblasts, while minimizing off-target effects on non-fibroblast cardiac cells and fibroblasts in non-cardiac tissues. In this review, we discuss the cellular and molecular mechanisms underlying in vivo cardiac reprogramming, with a focus on fibroblast heterogeneity, key transcriptional drivers, and relevant intercellular interactions. We also examine current advances in fibroblast-specific delivery systems employing both viral and non-viral vectors for the administration of lineage-reprogramming factors such as cDNA overexpressions or microRNAs. Finally, we underscore innovative strategies that hold promise for enhancing the precision and efficacy of cellular reprogramming, ultimately fostering translational development and paving the way for rigorous preclinical assessment.

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide, with heart failure (HF) representing a major contributor to hospitalizations, healthcare costs, and death. Effective management of HF is hindered by the limitations of current biomarkers and diagnostic tools. Conventional biomarkers, such as natriuretic peptides, primarily reflect downstream hemodynamic stress and often lack specificity, particularly in HF with preserved ejection fraction or multiple comorbidities. While imaging provides valuable structural and functional information, it is resource-intensive, costly, and unsuitable for frequent longitudinal monitoring. As a result, these conventional approaches are inadequate to capture the dynamic and heterogeneous nature of HF pathophysiology. Circulating cell-free nucleic acids (cfNAs), including cell-free DNA (cfDNA) and RNA (cfRNA), have emerged as promising noninvasive liquid biopsy biomarkers capable of providing real-time insight into upstream pathological events, such as cardiomyocyte injury, immune activation, inflammation, and maladaptive remodeling. Importantly, cfNAs also act as active mediators of CVD pathology. When released under stress or injury, cfNAs interact with pattern recognition receptors (PRRs) that trigger sterile inflammation, cardiovascular cell dysfunction, and adverse cardiac remodeling. This review summarizes the origins, mechanistic roles, and clinical significance of cfNAs in HF and related CVD, highlighting their dual roles as diagnostic biomarkers and mechanistic effectors of disease. Finally, we discuss emerging cfNA-targeted therapeutic strategies, challenges, and future opportunities for precision medicine in HF and HF-associated CVD.

Cardiac fibrosis is a major component of heart failure (HF) and develops when reparative wound healing becomes chronic, leading to excessive extracellular matrix accumulation. Cardiac fibroblasts (CFs), the main regulators of matrix remodeling, are heterogeneous in developmental origins, regional localizations, and activation states. This diversity determines whether tissue repair resolves normally or progresses into maladaptive scarring that disrupts myocardial structure and function after injuries. Recent single-cell and spatial transcriptomic studies show that CFs exist in distinct yet interrelated molecular states in murine models and human cardiac tissue with specialized roles in matrix production, angiogenesis, immune signaling, and mechanical sensing. These insights redefine cardiac fibrosis as a dynamic and context-dependent process rather than a uniform cellular response. Although CFs are promising targets for preventing HF progression and enhancing cardiac remodeling, translation into effective therapies remains limited by the unclear heterogeneity of pathological fibroblasts, the lack of distinctive CF markers, and the broad activity of fibrogenic signaling pathways. In this review, we discuss the dynamics of CF activations during the development and progression of HF and assess the underlying pathways and mechanisms contributing to cardiac dysfunction. Additionally, we highlight the potential of targeting CFs for developing therapeutic strategies. These include nonspecific suppression of fibroblast activity and targeted modulation of the signaling pathways and cell populations that sustain chronic remodeling. Furthermore, we assess regenerative approaches that can reprogram fibroblasts or modulate their paracrine functions to restore functional myocardium. Integrating antifibrotic and regenerative strategies with advances in precision drug discovery and gene delivery offers a path toward reversing established fibrosis and achieving recovery in HF.