Key result
Endothelial mitochondrial dysfunction emerges as a key driver of CMD in INOCA despite limited causal evidence.
Why the study?
INOCA and CMD cause angina and elevated cardiovascular risk, but mechanistic heterogeneity complicates diagnosis and treatment, and direct human evidence linking endothelial mitochondrial dysfunction causally to CMD remains limited.
Endothelial mitochondrial dysfunction is a mechanistically plausible amplifier of coronary microvascular dysfunction, but mitochondria-targeted strategies require prospective CMD-specific validation.
Mitochondria-targeted therapies should not yet be considered in INOCA; leaves open causal confirmation and need for prospective CMD-specific trials.
Ischemia with non-obstructive coronary arteries (INOCA) and coronary microvascular dysfunction (CMD) are increasingly recognized causes of angina, reduced quality of life, and elevated cardiovascular risk, yet mechanistic heterogeneity complicates diagnosis and treatment. This narrative review synthesizes evidence from clinical guidelines, consensus documents, landmark trials, cohorts, mechanistic studies, and high-quality reviews identified through structured, non-exhaustive searches of PubMed/MEDLINE, Google Scholar, and major cardiovascular society documents. Current evidence indicates that endothelial mitochondria function primarily as signaling organelles, regulating reactive oxygen species, nitric oxide bioavailability, endothelium-dependent hyperpolarization, calcium signaling, inflammatory activation, mitophagy, and endothelial survival. Cardiometabolic risk factors, aging, chronic kidney disease, and postmenopausal hormonal changes may converge on mitochondrial quality-control and redox pathways, contributing to CMD susceptibility and sex-specific vulnerability. However, direct human evidence linking endothelial mitochondrial dysfunction causally to CMD defined by invasive coronary function testing remains limited. Coronary physiological testing and acetylcholine provocation are validated tools for CMD endotyping, whereas mitochondrial biomarkers remain investigational. Endotype-guided diagnosis and management remain central, while mitochondria-targeted strategies require prospective CMD-specific validation.
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Šantić et al. (2026) conducted a review in Ischemia with non-obstructive coronary arteries (INOCA) and coronary microvascular dysfunction (CMD). Endothelial mitochondrial dysfunction was evaluated. Endothelial mitochondrial dysfunction acts as a mechanistic amplifier of coronary microvascular dysfunction in INOCA, though direct human evidence linking it causally to invasively defined CMD remains limited.
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