The plaque hypothesis: understanding mechanisms of plaque progression and destabilization, and implications for clinical management

Abstract

Purpose of review: Major adverse cardiac events (MACE) typically arise from nonflow-limiting coronary artery disease and not from flow-limiting obstructions that cause ischemia. This review elaborates the current understanding of the mechanism(s) for plaque development, progression, and destabilization and how identification of these high-risk features can optimally inform clinical management.

Recent findings: Advanced invasive and noninvasive coronary imaging and computational postprocessing enhance an understanding of pathobiologic/pathophysiologic features of coronary artery plaques prone to destabilization and MACE. Early investigations of high-risk plaques focused on anatomic and biochemical characteristics (large plaque burden, severe luminal obstruction, thin cap fibroatheroma morphology, and large lipid pool), but more recent studies underscore that additional factors, particularly biomechanical factors [low endothelial shear stress (ESS), high ESS gradient, plaque structural stress, and axial plaque stress], provide the critical incremental stimulus acting on the anatomic substrate to provoke plaque destabilization. These destabilizing features are often located in areas distant from the flow-limiting obstruction or may exist in plaques without any flow limitation. Identification of these high-risk, synergistic plaque features enable identification of plaques prone to destabilize regardless of the presence or absence of a severe obstruction (Plaque Hypothesis).

Summary: Local plaque topography, hemodynamic patterns, and internal plaque constituents constitute high-risk features that may be located along the entire course of the coronary plaque, including both flow-limiting and nonflow-limiting regions. For coronary interventions to have optimal clinical impact, it will be critical to direct their application to the plaque area(s) at highest risk.

Figure 1.. Coronary Atherosclerotic Plaque as a Complex, Lengthy, and Heterogeneous Pathobiologic Lesion.

Many different constituents, morphologies, and resultant pathobiologic and biomechanical environments localize spatially distant from the minimal lumen area. ESS indicates endothelial shear stress; LCBI, lipid core burden index. Used with permission from Stone PH, et al.(6).

Figure 2.. Event rates associated with non-culprit lesions characterized by baseline low ESS, high ESSG, high PSS HI, and PB ≥ 60%.

Combined ESS, ESS gradient (ESSG) and plaque structural stress (PSS) heterogeneity index (HI), and high plaque burden, improves MACE prediction at 3 years follow-up. Abbreviations: ESS= endothelial shear stress, ESSG= ESS gradient, PSS= plaque structural stress, PSS HI= PSS heterogeneity index, PB= plaque burden. From Ahmed M, et al.(33).

Figure 3.. Pathobiologic mechanisms of plaque progression and disruption.

(A) Plaque initiation begins in areas with local low and disturbed blood flow (i.e. ESS) and can be located anywhere along the course of the plaque. Low ESS is a pro-inflammatory and pro-atherogenic stimulus, and continued exposure to low ESS can lead to plaque progression with accumulation of lipids and thinning of the fibrous cap (TCFA). (B) Plaques can progress in a stepwise manner to destabilization (rupture, superficial erosion, or calcium nodule eruption) followed by thrombosis. Repeated destabilization and the healing response to disruption including thrombus resorption can lead to progressive plaque fibrosis, constrictive remodelling, and encroachment into the lumen. (C) Plaque progression and disruption is a multifactorial process and a consequence of the local environment exerted on the plaque. 1. Non-flow limiting plaques exposed to pro-inflammatory low ESS can exhibit features of high plaque burden and elaboration of matrix-degrading metalloproteases that promotes fragility of the fibrous cap and internal plaque structures that can lead to thrombotic events. 2. Plaques that encroaches into the lumen exhibits high ESS at the throat of the obstruction and low ESS either up or downstream from the minimal luminal area, and similarly, destabilizes the plaque. 3. High ESS gradients, which represent abrupt large differences in the magnitude of ESS in immediately adjacent endothelial cells, or steep plaque upslope/downslope, with or without associated high ESS, will increase axial plaque stress and promote plaque disruption. 4. The composition and spatial proximity of internal plaque constituents of different material properties can create inhomogeneities that affect cellular function and modify the structural integrity of the plaque and foster disruption (plaque structural stress). 5. Microruptures of the plaque cap or leaking from immature and leaky vasa vasorum within an enlarging plaque, can cause intraplaque haemorrhage and drive local oxidative stress, further promoting lesion complication. Used with permission from Stone PH, et al.(6).