Heart failure is a complex syndrome responsible for high rates of death and hospitalization. Ischemic heart disease is one of the most frequent causes of heart failure and it is normally attributed to coronary artery disease, defined by the presence of one or more obstructive plaques, which determine a reduced coronary blood flow, causing myocardial ischemia and consequent heart failure. However, coronary obstruction is only an element of a complex pathophysiological process that leads to myocardial ischemia. In the literature, attention paid to the role of microcirculation, in the pathophysiology of ischemic heart disease and heart failure, is growing. Coronary microvascular dysfunction determines an inability of coronary circulation to satisfy myocardial metabolic demands, due to the imbalance of coronary blood flow regulatory mechanisms, including ion channels, leading to the development of hypoxia, fibrosis and tissue death, which may determine a loss of myocardial function, even beyond the presence of atherosclerotic epicardial plaques. For this reason, ion channels may represent the link among coronary microvascular dysfunction, ischemic heart disease and consequent heart failure.