Fundamental Pathobiology of Coronary Atherosclerosis and Clinical Implications for Chronic Ischemic Heart Disease Management-The Plaque Hypothesis: A Narrative Review

Abstract

Importance: Recent clinical and imaging studies underscore that major adverse cardiac events (MACE) outcomes are associated not solely with severe coronary obstructions (ischemia hypothesis or stenosis hypothesis), but with the plaque burden along the entire coronary tree. New research clarifies the pathobiologic mechanisms responsible for plaque development/progression/destabilization leading to MACE (plaque hypothesis), but the translation of these insights to clinical management strategies has lagged. This narrative review elaborates the plaque hypothesis and explicates the current understanding of underlying pathobiologic mechanisms, the provocative destabilizing influences, the diagnostic and therapeutic implications, and their actionable clinical management approaches to optimize the management of patients with chronic coronary disease.

Observations: Clinical trials of management strategies for patients with chronic coronary artery disease demonstrate that while MACE rate increases progressively with the anatomic extent of coronary disease, revascularization of the ischemia-producing obstruction does not forestall MACE. Most severely obstructive coronary lesions often remain quiescent and seldom destabilize to cause a MACE. Coronary lesions that later provoke acute myocardial infarction often do not narrow the lumen critically. Invasive and noninvasive imaging can identify the plaque anatomic characteristics (plaque burden, plaque topography, lipid content) and local hemodynamic/biomechanical characteristics (endothelial shear stress, plaque structural stress, axial plaque stress) that can indicate the propensity of individual plaques to provoke a MACE.

Conclusions and relevance: The pathobiologic construct concerning the culprit region of a plaque most likely to cause a MACE (plaque hypothesis), which incorporates multiple convergent plaque features, informs the evolution of a new management strategy capable of identifying the high-risk portion of plaque wherever it is located along the course of the coronary artery. Ongoing investigations of high-risk plaque features, coupled with technical advances to enable prognostic characterization in real time and at the point of care, will soon enable evaluation of the entire length of the atheromatous coronary artery and broaden the target(s) of our therapeutic intervention to include all regions of the plaque (both flow limiting and nonflow limiting).

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.

Figure 2.. Pathobiologic Mechanisms of Plaque Progression and Disruption

Shown are the coronary plaque and arterial features that may lead to plaque progression and destabilization culminating in major adverse cardiac events in a variety of plaque scenarios involving a constellation of pathobiologic and biomechanical mechanisms, which may operate alone or in concert with other pathologic mechanisms. A, Plaque initiation and development begin in zones of low and disturbed blood flow (ie, low endothelial shear stress [ESS]), regions that typically occur on the inner aspect of an artery curve, outer waists of a bifurcation, and upstream and downstream from a luminal obstruction. Local low ESS leads endothelial cells to switch from expressing a palette of atheroprotective properties to adopt proinflammatory, pro-atherogenic, and prothrombotic functions. Ongoing exposure to low ESS leads to progressive plaque burden, lipid accumulation, and thin cap fibroatheroma (TCFA) formation. B, Plaques can progress in a stepwise manner to destabilization (rupture, superficial erosion, or calcium nodule eruption, events that can provoke thrombosis), followed by plaque healing. Repeated destabilization and the healing response to disruption including thrombus resorption can lead to progressive plaque fibrosis, constrictive remodeling, and encroachment into the lumen. C, Prominent pathobiologic mechanisms contribute to plaque destabilization and complications. (1) Regions along the course of a plaque may encounter ongoing pro-atherogenic low ESS (Figure 1) and continue to develop local progressive inflammation, lipid accumulation, and elaboration of matrix-degrading metalloproteinases that promote fragility and instability of the fibrous cap and internal plaque structures, thereby fostering plaque rupture. These events may occur in a nonobstructive plaque or in plaque portions upstream or downstream from a luminal obstruction. (2) Portions of the plaque that encroach into the lumen create local high ESS at the throat of the obstruction that may cause endothelial cell elaboration of matrix-degrading metalloproteinases, endothelial death or desquamation, and platelet activation, rendering plaques more prone to provoke thrombosis. Plaque regions immediately adjacent to the high ESS typically also exhibit sites of low and oscillatory ESS, with its attendant pro-atherogenic and proinflammatory consequences as described in scenario 1. (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. This adverse biomechanical stress operates independently of stenosis severity, drop in perfusion pressure, or local ESS. (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 or tensile stress). Computation of plaque structural stress requires accurate depiction of both atherosclerotic plaque composition and architecture. (5) Intraplaque hemorrhage may develop either as a result of microruptures of the plaque cap or leaking from immature and leaky vasa vasorum within an enlarging plaque, leading to an abrupt conformational change due to the atherogenic properties of lipids from degraded red blood cell membranes and released free hemoglobin and heme.^– Iron derived from heme can drive local oxidative stress, further promoting lesion complication.

Figure 3.. A 2-State Concept of Atherothrombosis

The classic high-risk atheroma has a thin fibrous cap overlying a large lipid core that contains tissue factor–bearing macrophages. When the fibrous cap fractures, coagulation proteins in the fluid phase of blood gain access to tissue factor–associated macrophages and tissue factor–bearing microparticles derived from apoptotic cells in the solid state of the plaque, these events trigger thrombus formation on the ruptured plaque. The clinical consequences depend on the amount of tissue factor and apoptosis in the plaque’s core and on the levels of fibrinogen and plasminogen activator inhibitor 1 (PAI-1) in the fluid phase of blood. The interaction of the fluid phase with the solid state determines whether a given plaque disruption provokes a partial or transient coronary artery occlusion (that can be clinically silent or causes an episode of unstable angina) or a persistent and occlusive thrombus that can precipitate an acute myocardial infraction. Neutrophil extracellular traps (NETs) can localize at the interface of the solid state of the intima with the fluid phase of blood. Their externalized strands of extruded nuclear DNA are decorated with mediators including tissue factor and can propagate and amplify local inflammation and thrombosis around this critical interface. SMC indicates smooth muscle cells; tPA, tissue plasminogen activator; TM, thrombomodulin; uPA, urokinase-type plasminogen activator.

Figure 4.. Heterogeneity of Local Arterial Remodeling and Endothelial Shear Stress (ESS) Within Plaques and Resultant Changes in Plaque Burden

Local patterns of arterial remodeling and ESS in 3-mm segments within individual plaques are heterogeneous (A and B) and lead to heterogeneous natural history changes of local 3-mm plaque burden along the course of the individual plaque (C) over 6 to 10 months’ follow-up. Vascular and plaque heterogeneity becomes more complex as plaques become longer. Modified from Antoniadis et al and Wentzel et al with permission.

Figure 5.. Multimodality Variables to Predict Plaque Development, Progression, Destabilization, or Quiescence

Anatomic and biomechanical pathobiologic features can be routinely characterized by invasive coronary imaging (optical coherence tomography, intravascular ultrasonography, and near-infrared spectroscopy) and noninvasive imaging (computed tomography angiography). These variables report on characteristics that foster plaque formation, progression or quiescence. Modified from Stone with permission. ESS indicates endothelial shear stress; LCBI, lipid core burden index.