Ischemic heart disease (IHD) remains a leading cause of death and disability globally, especially in industrialized nations. Traditionally, IHD has been linked to flow-limiting stenosis in epicardial coronary arteries caused by atherosclerotic plaque. However, recent findings suggest that many chronic IHD cases involve patients with open or non-obstructive coronary arteries, leading to the term "Open Artery Ischemia" (OAI). This new understanding has revealed diverse clinical presentations, such as ANOCA (Angina with Non-Obstructive Coronary Arteries), INOCA (Ischemia with Non-Obstructive Coronary Arteries), and MINOCA (Myocardial Infarction with Non-Obstructive Coronary Arteries).

A key mechanism of OAI is coronary microvascular dysfunction (CMD), which is thought to affect at least half of OAI patients. CMD involves endothelial or vascular smooth muscle dysfunction, leading to abnormal coronary vasoreactivity, heightened vasospasm, and reduced relaxation of vascular smooth muscle. Atherosclerosis also plays a role in OAI, as non-obstructive plaque is often present in positively remodeled epicardial arteries. Risk factors such as diabetes, hypertension, and smoking are implicated, though aging and male sex are less prominent contributors.

The overlap between OAI syndromes and heart failure with preserved ejection fraction (HFpEF) is increasingly evident, particularly in patients with CMD. These patients often show signs of left-ventricular relaxation abnormalities, preserved systolic function, and a higher likelihood of heart failure hospitalizations. Moreover, women are disproportionately affected by OAI, making up about 65% of cases, though the reasons for this gender disparity remain unclear.

Historically, OAI was considered a benign syndrome, but it is now clear that these patients face elevated risks of adverse outcomes, including recurrent angina, heart failure, and even increased mortality. Despite non-obstructive arteries, their quality of life is significantly impaired, and exercise tolerance is reduced. Additionally, signals of ischemia, such as angina, ECG abnormalities, and perfusion defects, are common but often difficult to detect due to the patchy nature of microvascular dysfunction.

Research from the Women's Ischemia Syndrome Evaluation (WISE) program has highlighted the prevalence of OAI, particularly among women, and CMD's role in predicting adverse outcomes. The need for a new taxonomy to address OAI syndromes like ANOCA, INOCA, and MINOCA has become apparent, as their clinical presentations often resemble obstructive coronary disease.

Management of OAI remains challenging, as no randomized trials have yet provided clear treatment guidelines. However, ongoing studies like the WARRIOR trial aim to evaluate the efficacy of intensive medical treatment strategies in improving outcomes for these patients. Additionally, a unifying hypothesis suggests that microvascular dysfunction may be a systemic issue affecting multiple organs, including the brain, retina, kidney, lungs, and heart, which could lead to new, holistic management approaches.

In conclusion, OAI is a prevalent and serious condition, particularly among women, and warrants further investigation. Its variable nature and the lack of correlation between ischemia severity and atherosclerotic lesions highlight the complexity of managing OAI. Future studies will be crucial in addressing these knowledge gaps and improving patient outcomes.