Small entities with large impact: microcalcifications and atherosclerotic plaque vulnerability

Abstract

Purpose of review: Atherosclerotic plaque rupture and subsequent acute events, such as myocardial infarction and stroke, contribute to the majority of cardiovascular-related deaths. Calcification has emerged as a significant predictor of cardiovascular morbidity and mortality, challenging previously held notions that calcifications stabilize atherosclerotic plaques. In this review, we address this discrepancy through recent findings that not all calcifications are equivalent in determining plaque stability.

Recent findings: The risk associated with calcification is inversely associated with calcification density. As opposed to large calcifications that potentially stabilize the plaque, biomechanical modeling indicates that small microcalcifications within the plaque fibrous cap can lead to sufficient stress accumulation to cause plaque rupture. Microcalcifications appear to derive from matrix vesicles enriched in calcium-binding proteins that are released by cells within the plaque. Clinical detection of microcalcifications has been hampered by the lack of imaging resolution required for in-vivo visualization; however, recent studies have demonstrated promising new techniques to predict the presence of microcalcifications.

Summary: Microcalcifications play a major role in destabilizing atherosclerotic plaques. The identification of critical characteristics that lead to instability along with new imaging modalities to detect their presence in vivo may allow early identification and prevention of acute cardiovascular events.

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FIGURE 1

Transmission electron microscopy and histology-based finite element analyses. (a) Transmission electron microscopy image of aggregated calcifying matrix vesicles forming microcalcifications in a mouse atheroma. (b) Image of a microcalcification embedded in a human fibrous cap, obtained from nondecalcified histology, and stained with von Kossa. (c and d) Stress distribution at the interface of the microcalcifications in a and b, respectively, assuming that they are embedded in fibrous caps under tension. The numbers indicate the factor by which stress is increased and concentrated at the poles of the microcalcifications. Reproduced with permission from [^▪▪].

FIGURE 2

Matrix vesicles and microcalcifications in atherosclerotic plaques. (a) Transmission electron microscopy image of matrix vesicles aggregating within a plaque in close proximity to ChC. An AB is shown for size comparison. (b) Transmission electron microscopy of aggregating matrix vesicles nucleating mineralization. (c) NIRF staining of microcalcifications within a mouse plaque. (d) NIRF staining of microcalcifications at the plaque border. AB, apoptotic body; ChC, cholesterol crystals; NIRF, near-infrared fluorescent. Reproduced with permission from [^▪▪].

FIGURE 3

Schematic of our current understanding of the vesicle-derived calcification process. (a) Typical cross section of a fibroatheroma with a thin fibrous cap and large calcification. (b) Smooth muscle cells and macrophages release vesicles that contribute to large calcifications and (c) microcalcifications within the fibrous cap. (d) Vesicles accumulating in the fibrous cap form microcalcifications creating stress concentrations as shown by finite element analysis that can lead to cap rupture.