Cardiovascular diseases (CVDs) remain the foremost cause of mortality worldwide, driven by a complex interaction of genetic, molecular, and cellular events that shape cardiac injury and repair. Recent progress in single-cell RNA sequencing (scRNA-seq), together with bulk RNA-seq and advanced in silico computational analysis, has greatly expanded our ability to characterize the cellular landscape of the heart with unprecedented resolution. This chapter examines multi-omics datasets to demonstrate how different cardiac cell populations can drive vascular dysfunction, fibrosis, inflammation, and disease progression. Our joint analysis has identified fibroblasts, endothelial cells, and macrophages as significant mediators of cardiac remodeling. Actively recruited fibroblasts mediate extracellular matrix (ECM) deposition and scarring, which facilitates further remodeling, while the endothelial-to-mesenchymal transition (EndMT) is a driver of microvascular loss and ischemia. Immune-cell profiling demonstrates a shift from pro-inflammatory (M1) to reparative (M2) macrophage phenotypes, reflecting dynamic immune adaptation during chronic injury. Pathway enrichment highlights the involvement of NFκB, PI3K–Akt, and TGF-β signaling pathways, accompanied by metabolic downregulation in more advanced disease states. Using cell–cell communication and ligand–receptor interaction modeling, we further show how cross-talk between endothelial and immune compartments drives inflammation, angiogenesis, and structural remodeling. Integrating scRNA-seq data with GTEx cardiac transcriptomics and KEGG/GSEA pathway analyses reveals several druggable molecular targets linked to fibroblast activation, cytokine regulation, and vascular inflammation. Together, these findings provide a comprehensive systems-level view of cardiac remodeling and underscore the translational value of single-cell and in silico approaches for biomarker discovery and therapeutic development in cardiovascular disease.