Reduced ALDH2 Activity and Cardiovascular Carbonyl Stress: From Reactive Aldehyde Networks to Coronary Microvascular Obstruction.

Abstract

Primary percutaneous coronary intervention restores epicardial flow after ST-segment elevation myocardial infarction, but tissue perfusion may remain impaired. Coronary microvascular dysfunction, angiographic no-reflow, cardiac magnetic resonance-defined microvascular obstruction, and intramyocardial hemorrhage are overlapping but non-equivalent phenotypes. This review examines reduced mitochondrial aldehyde dehydrogenase 2 (ALDH2) activity as a susceptibility amplifier rather than an established independent cause of these outcomes. Reperfusion generates reactive oxygen species that initiate lipid peroxidation and produce electrophilic aldehydes, including 4-hydroxy-2-nonenal, malondialdehyde, and acrolein. Their effects are shaped by compartmental generation, competing clearance systems, protein-adduct persistence, and positive feedback between mitochondrial injury and inflammation. Methylglyoxal is considered a parallel, glyoxalase-dominant dicarbonyl pathway rather than a principal ALDH2 substrate. The resulting network may impair endothelial nitric oxide signaling and barrier integrity, promote platelet activation and neutrophil extracellular trap formation, and increase cardiomyocyte edema and damage-associated molecular-pattern release. Pericyte constriction contributes to experimental no-reflow, whereas pericyte sensitivity to 4-hydroxy-2-nonenal remains a theoretical hypothesis awaiting direct experimental confirmation. We also assess adductomics, proteomics, lipidomics, and time-resolved sampling strategies. Free aldehydes are chemically and preanalytically unstable; protein-bound adducts provide longer detection windows but lack the clinical standardization of cardiac troponin. ALDH2 activation remains preclinical for reperfusion microvascular injury. Prospective studies should further integrate genotype, enzyme activity, local carbonyl measurements, thromboinflammatory phenotyping, invasive physiology, and cardiac magnetic resonance endpoints.