坂倉 建一

Atherosclerotic cardiovascular disease remains the leading cause of morbidity and mortality worldwide. Accumulating pathological evidence indicates that rapid plaque progression is driven not only by recurrent subclinical plaque rupture with healing but also by intraplaque hemorrhage (IPH), which can occur independently of overt luminal thrombosis. IPH is no longer regarded as a passive process that merely enlarges plaque volume through deposition of erythrocyte-derived lipids, hemoglobin, and iron. Instead, contemporary pathological studies have revealed that IPH initiates a cascade of molecular and cellular responses that actively promote plaque destabilization. Within hemorrhagic plaques, erythrocyte lysis generates oxidative stress and cholesterol crystallization, accelerating necrotic core expansion and inflammatory signaling. In parallel, hemoglobin-haptoglobin complex uptake by CD163+ macrophages induces a distinct macrophage phenotype characterized by vascular endothelial growth factor and pro-inflammatory cytokines secretion, increased microvascular permeability, and propagation of intraplaque angiogenesis. These macrophage-driven processes amplify endothelial dysfunction, promote proapoptotic endothelial-to-mesenchymal transition, impair fibrous-cap integrity, and paradoxically suppress stabilizing calcification, thereby creating a microenvironment highly susceptible to rupture. Importantly, these IPH-driven cellular responses do not act in isolation but converge to amplify plaque vulnerability through interconnected inflammatory, angiogenic, and structural pathways. Advances in vascular imaging have enabled in vivo detection of IPH-related plaque features, providing a translational bridge between pathological observations and clinical phenotyping. Across carotid and coronary arterial beds, imaging-detected IPH consistently correlates with accelerated lesion progression and adverse cardiovascular outcomes. Together, current evidence positions IPH as a central biological driver of plaque progression and destabilization rather than a secondary epiphenomenon. A deeper understanding of IPH-related cellular mechanisms may identify novel therapeutic targets beyond lipid lowering and improve identification of patients with intrinsically unstable atherosclerotic disease.

Calcified nodule (CN) is a unique calcified plaque morphology that is pathologically characterized by fibrous-cap disruption and luminal thrombus associated with eruptive, dense calcific nodules. Although CNs account for a small proportion of acute coronary syndrome, they remain challenging substrates for percutaneous coronary intervention (PCI) due to high risks of underexpansion and in-stent restenosis. To understand their unpredictable mechanical behavior, it is crucial to recognize their origin: CNs typically arise from the fragmentation of mechanically vulnerable necrotic core calcification under mechanical stress, often exacerbated by adjacent rigid sheet calcium. Crucially, while intravascular imaging typically classifies CNs into "eruptive" or "non-eruptive" forms, this binary classification alone is sometimes insufficient to predict lesion compliance or "softness." A deeper understanding of the underlying pathological evolution-from fresh, thrombus-covered nodules to mature, ossified masses-is essential to distinguish deformable lesions from rigid ones. This review bridges this gap by proposing a pathology-imaging continuum that links histological maturity to mechanical behavior, enabling more precise phenotyping beyond surface appearance. We finally discuss how this integrated approach informs contemporary PCI strategies, including atherectomy, intravascular lithotripsy, and lifetime management, to optimize clinical outcomes.