ANOCA/INOCA/MINOCA: Open artery ischemia

1. Introduction

Ischemic cardiovascular disease continues to be the major public health threat in the United States and most of the industrialized world. Ischemic heart disease (IHD), along with ischemic cerebrovascular disease, is responsible for most deaths and much of the disability. Together these ischemic disorders consume an enormous portion of each country’s healthcare resources.

Clinically, IHD may present as an acute coronary syndrome (e.g., unstable angina or acute myocardial infarction or as a chronic syndrome with more stable symptoms like angina pectoris. Mechanistically IHD has been traditionally linked with a flow-limiting stenosis in an epicardial coronary artery due to obstruction caused by atherosclerotic plaque.

2. What does IHD look like in 2023?

Emerging evidence indicates that many, perhaps most, chronic IHD occurs among patients with open or non-obstructed epicardial arteries. Hence, the term “open artery ischemia” (OAI) seems appropriate. Limited knowledge is available relative to its clinical phenotypes, other than the fact that they range from ANOCA (ANgina with Open Coronary Arteries), INOCA (Ischemia with NonObstructive Coronary Arteries), to MINOCA (Myocardial Infarction with Open Coronary Arteries). In my opinion studies using high sensitivity and ultra-high sensitivity biomarkers of reversible cardiomyocyte ischemic injury (cardiac troponins [cTn]) and cardiac magnetic resonance imaging (cMRI) suggest that these clinical phenotypes may overlap as HFpEF precursors. For example, prolonged angina maybe associated with cTn efflux and changes in LV strain.

Several different mechanistic endotypes have been confirmed (Table 1). These include:

Table 1. Potential mechanisms for myocardial ischemia in the absence of obstructive CAD.

1. Coronary microvascular dysfunction (CMD), estimate to be present in >50 % of cases. Defined as endothelial dysfunction, vascular smooth muscle dysfunction, or both. Physiologically, augmented coronary vascular smooth muscle activation contributing or failure to appropriately relax with either endogenous (endothelial-derived) or exogeneous vasodilator stimuli.
2. Heightened coronary vasoreactivity (vasospasm) estimated to be present in ∼20–25 % of cases at either the epicardial level or microvascular level or both. Current clinical approaches do not permit assessment of the microvasculature when epicardial vasospasm is present. Recently, acetylcholine re-challenge after intracoronary nitroglycerin has been proposed to prevent epicardial spasm and expose microvascular spasm.
3. Altered coagulation estimated to be present in ∼5 % of cases (mostly MINOCA, but estimate is likely biased by lack of testing when evidence for myocardial injury is lacking).

Coronary microvascular dysfunction (CMD), believed to be present in at least half of the cases, defined as endothelial dysfunction, vascular smooth muscle dysfunction, or both. Heightened coronary vasoreactivity (vasospasm) is estimated to occur in ∼20–25 % at the epicardial level or microvascular level. Current clinical approaches do not permit microvasculature assessment when epicardial vasospasm is present. However, a recent report suggested that adding a second acetylcholine (Ach) challenge after intracoronary nitroglycerin may have the potential to block epicardial spasm exposing only the microvascular spasm. Also, there is some mechanistic overlap between these mechanisms of heightened microvascular coronary vasoreactivity, as well as failure of the vascular smooth muscle to relax. Augmented coronary vascular smooth muscle activation may also contribute to a failure to appropriately relax with vasodilator stimuli. Finally, altered coagulation is observed in ∼5 % of the cases, mostly those with MINOCA, but this estimate is biased by lack of testing when evidence for myocardial injury was not present or not sought.

Atherosclerosis clearly plays a mechanistic role in most cases with OAI, and nonobstructive plaque with positively remodeled epicardial coronary arteries may be the rule rather than the exception. This conclusion is based on intravascular imaging studies using intravascular ultrasound (IVUS), optical coherence tomography, and multi-slice coronary computed tomographic angiography (CTA). The possibility that the atherosclerosis risk factors (e.g., diabetes/hypertension/hyperlipidemia/smoking) are involved in the mechanisms of OAI also needs to be considered. They may play a role in both atherosclerosis as well microvascular dysfunction and enhanced vasoconstriction. Against this atherosclerosis risk factor possibility, is the observation that aging and male sex are not prominently involved.

More recently, CMD with nonobstructive disease has been suggested to represent a “pre-heart failure with preserved ejection fraction” (HFpEF) endotype. Left-ventricular relaxation abnormalities have been documented in many case series; preserved systolic function is the rule, and hospitalizations for heart failure are a frequent adverse outcome. Studies with long-term follow-up of these patients with no obstructive coronary disease, who have signs and symptoms of ischemia and CMD, observed that admission for HFpEF is prevalent.

There are some other less frequently observed endotypes (cardiorenal, cardiopulmonary, retinal, cerebral microvascular disease, etc. These are reviewed in detail in [9] and Fig. 1.

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. 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.

Reprinted from: Pepine CJ. Microvascular dysfunction treatment options for coronary microvascular dysfunction. Spotlight Series. Cardiology Magazine. 2022 Dec 2.