ANOCA/INOCA/MINOCA: Open artery ischemia

Abstract

Ischemic heart disease continues to represent a major health threat for death, disability, and poor quality of life as it also consumes enormous health-related resources. For over a century, the major clinical phenotype was taken to be obstructive atherosclerosis involving the larger coronary arteries (e.g., coronary artery disease [CAD]). However, evolving evidence now indicates that nonobstructive CAD is the predominant phenotype. Patients within this phenotype have been termed to have angina with no obstructive CAD (ANOCA), ischemia with no obstructive CAD (INOCA), or myocardial infarction with no obstructive coronary arteries (MINOCA). But as methods to assess cardiomyocyte injury evolve, these phenotypic distinctions have begun to merge, raising concern about their usefulness. Also, considerable evidence has suggested several endotypes that link to potential mechanisms. These include coronary microvascular dysfunction, augmented vasoreactivity (failure to relax appropriately, exaggerated constriction ["spasm"], etc.), nonobstructive atherosclerosis, pre-heart failure with preserved ejection fraction, hypercoagulable states, and several others, alone or in combination. This review summarizes these syndromes and their associated clinical outcomes with an emphasis on potential mechanistic signals. These involve the endothelium, the microvasculature, and cardiomyocyte function. Biomarkers of injury/dysfunction involving these structures are discussed along with a hypothetical construct for management being tested in an ongoing trial.

Keywords: ANOCA; INOCA; Ischemia; MINOCA; Mechanistic signals.

Fig. 1

Potential therapeutic targets for CMD (left to right): decreased nitric oxide (NO) bioavailability is a commonly used marker of endothelial cell (EC) dysfunction. Reduced NO produced by ECs means less is received by neighboring vascular smooth muscle cells, leading to less vasodilation. Bradykinin, an endothelium-dependent vasodilator, also increases vascular permeability, and prostacyclin (PGI2), inhibits platelet activation and vasodilates the microcirculation. Cardiac macrophages have roles in antigen presentation, phagocytosis and immunoregulation by formation of cytokines and growth factors active in tissue repair after cardiac injury. Since NO can also modify tight junction, this may cause another marker of dysfunction leading to micro bleeding during ischemic injury. Increased EC proliferation has potential to lead to aberrant angiogenesis. Endothelial cell dysfunction may result in changes in factors secreted into the circulation like endothelin-1 (ET-1), a very potent vasoconstrictor.

Fig. 2

Left coronary angiogram and left anterior descending IVUS images from a 65-year-old woman with diabetes, hypertension, dyslipidemia, and hormone replacement therapy. Note plaque in proximal left anterior descending with maintenance of lumen area.

Fig. 3

A plea for new stable ischemic heart disease taxonomy. CAD, coronary artery disease; LVH, left-ventricular hypertrophy.

Fig. 4

Multi-organ microvascular disease. Microvascular dysfunction affecting the heart, brain, retina, lung, and kidney, representing different manifestations of small vessel disease. They share pathophysiologic mechanisms and can occur concomitantly. ANOCA = angina with no obstructive coronary artery disease; HFpEF = heart failure with preserved ejection fraction; INOCA = ischemia with no obstructive coronary artery disease; MINOCA = myocardial infarction with no obstructive coronary arteries.