Myocardial ischemic injury and its resolution are the key determinants of morbidity or mortality in heart failure. The cause and duration of ischemia in patients vary. Numerous experimental models and methods have been developed to define genetic, metabolic, molecular, cellular, and pathophysiological mechanisms, in addition to defining structural and functional deterioration of cardiovascular performance. The rapid rise of big data, such as single-cell analysis techniques with bioinformatics, machine learning and neural networking, bring a new level of sophistication to our understanding of myocardial ischemia. This mini-review explores the multi-faceted nature of ischemic injury in the myocardium. We highlight recent state-of-the-art findings, and strategies to show new directions of high impact approach to understanding myocardial tissue remodeling. This next age of heart and circulatory physiology research will be more comprehensive and collaborative to uncover the origin, progression and manifestation of heart failure, while strengthening novel treatment strategies.