Abstract Body: The heart acts as a vital pump, circulating blood throughout the body. However, when subjected to various stressors stemming from genetic and environmental factors, its function can falter, leading to the development of heart failure. Through genome analysis of heart failure patients, we've pinpointed numerous genetic factors contributing to disease onset. Additionally, utilizing single-cell omics analysis of patient-derived induced pluripotent stem (iPS) cells, disease model animals, and clinical samples, we've unraveled the intricate molecular mechanisms underlying the development of heart failure. Initially, we identified a mutation in the LMNA gene linked to severe heart failure in individuals with dilated cardiomyopathy through genomic analysis, elucidated the mechanisms how this mutation traps the transcription factor TEAD1 within the nuclear membrane, and discovered that activating TEAD1 with the compound TT-10 can ameliorate the disease state. Moreover, we unveiled DNA damage occurring in severe heart failure through single-cardiomyocyte RNA-seq analysis of heart failure patients, and developed a molecular pathological analysis method targeting this damage, enabling prediction of treatment response. Furthermore, we identified various cell types contributing to heart failure pathology, including dopamine D1-positive cardiomyocytes in patients with ventricular arrhythmia, HTRA3-positive fibroblasts suppressing excessive TGF-β signaling, and senescent endothelial cells exacerbating heart failure pathology. We also developed immunological treatments targeting molecules in these tissue microenvironments, demonstrating their effectiveness in treating heart failure. Moreover, spatial omics analysis identified mechanosensing pathway-activated cardiomyocytes at the infarct border post-myocardial infarction, and lead to the development of gene therapy mimicking molecular mechanisms activated by exercise-induced cardiac rehabilitation. Additionally, through integrated multiomics analysis, we identified the transcription factor ERR-γ controlling the atrial fibrillation GWAS SNP region, and found that its dysfunction causes atrial fibrillation in humans. In summary, genome-omics analysis has elucidated the pathogenesis of cardiovascular diseases in detail and paved the way to fundamental technologies to control the disease through various intervention methods.