Acute Coronary Syndromes: The Way Forward From Mechanisms to Precision Treatment

Abstract

Well into the 21st century, we still triage acute myocardial infarction on the basis of the presence or absence of ST-segment elevation, a century-old technology. Meanwhile, we have learned a great deal about the pathophysiology and mechanisms of acute coronary syndromes (ACS) at the clinical, pathological, cellular, and molecular levels. Contemporary imaging studies have shed new light on the mechanisms of ACS. This review discusses these advances and their implications for clinical management of the ACS for the future. Plaque rupture has dominated our thinking about ACS pathophysiology for decades. However, current evidence suggests that a sole focus on plaque rupture vastly oversimplifies this complex collection of diseases and obscures other mechanisms that may mandate different management strategies. We propose segmenting coronary artery thrombosis caused by plaque rupture into cases with or without signs of concomitant inflammation. This distinction may have substantial therapeutic implications as direct anti-inflammatory interventions for atherosclerosis emerge. Coronary artery thrombosis caused by plaque erosion may be on the rise in an era of intense lipid lowering. Identification of patients with of ACS resulting from erosion may permit a less invasive approach to management than the current standard of care. We also now recognize ACS that occur without apparent epicardial coronary artery thrombus or stenosis. Such events may arise from spasm, microvascular disease, or other pathways. Emerging management strategies may likewise apply selectively to this category of ACS. We advocate this more mechanistic approach to the categorization of ACS to provide a framework for future tailoring, triage, and therapy for patients in a more personalized and precise manner.

Keywords: erosion; inflammation; microvessels; myocardial infarction; plaque; plaque, atherosclerotic; thrombosis.

© 2017 American Heart Association, Inc.

Figures

Figure 1. Four diverse mechanisms cause acute coronary syndromes (ACS)

(A) Plaque rupture, also referred to as fissure, traditionally considered the dominant substrate for ACS, usually associates with inflammation both local (as depicted by the blue monocytes) and systemic, as indicated by the gauge showing an increased in blood C-reactive protein (measured with a high-sensitivity assay, hsCRP.) (B) In some cases, plaque rupture complicates atheromata that do not harbor large collections of intimal macrophages, as identified by optical coherence tomography (OCT) criteria, and do not associate with elevations in circulating CRP. Plaque rupture usually provokes the formation of fibrin-rich “red” thrombi. (C) Plaque erosion appears to account for a growing portion of ACS, often provoking non-ST segment elevation myocardial infarction. The thrombi overlying patches of intimal erosion generally exhibit characteristics of “white” platelet-rich structures. (D) Vasospasm can also cause ACS, long recognized as phenomenon in the epicardial arteries, but also affecting coronary microcirculation.

Figure 2. Imbalance in adaptive immune pathways can modulate atherosclerotic plaque activity

Subsets of T lymphocytes, major participants in adaptive immunity, can either promote local plaque inflammation (effector T cells), or, in the case of regulatory T cells (Treg) suppress inflammation. While many pathways regulate T cell functions, the markers and mechanisms depicted here illustrate the principle that imbalances in T cell activities can prevail in plaques. Low levels of expression of resurface marker CD 31 and high activity of PTPN22 (protein tyrosine phosphatase N22, also known as Lyp) characterize effector T cells. High levels of activation of CREB (cAMP-responsive element binding protein) characterize Treg that can dampen local adaptive immune responses in the plaque.

Figure 3. Cholesterol crystals activate local innate immune pathways in the atherosclerotic plaque

Plasma low-density lipoprotein (LDL) can enter the arterial wall and accumulate in mononuclear phagocytes via scavenger receptors. Lipid-laden macrophage foam cells can die, contributing to the accumulation of extracellular cholesteryl ester and cholesterol monohydrate crystals in the plaque’s lipid rich “necrotic” core. The dying macrophages can also release apoptotic bodies and microparticles that contain the potent procoagulant tissue factor (TF +). The cholesterol crystals can co-activate the inflammasome, an intracellular supramolecular structure, that generates the biologically active forms of the pro-inflammatory cytokines interleukin (IL)-1 beta and IL-18. Large crystals might also cause mechanical disruption of the fibrous cap.

Figure 4. Pathways implicated in arterial thrombosis due to superficial erosion

Stimuli such as disturbed flow or engagement of innate immune receptors such as toll-like receptor two (TLR2) can activate the endothelial cells that line the arterial intima. These cells can undergo cell death for example by apoptosis, depicted by the cell with the interrupted membrane an pyknotic nucleus. Injured or dying endothelial cells can desquamate uncovering the basement membrane. Neutrophils attracted by chemokines produced by activated endothelial cells can congregate on the denuded intima and can in turn gegranulate and die releasing neutrophil extracellular traps (NETs). These strands of extruded DNA can bind contents of the neutrophil granules and other proteins, for example myeloperoxidase or tissue factor. The NETs can constitute a solid-state reactor that generates oxidants such as hypochorus acid and stimulate coagulation locally. Platelets interacting with the basement membrane can activate, release their granular contents including chemokines that can recruit further leukocytes, and formed the nidus of a “white”thrombus.

Figure 5. Cellular mechanisms of arterial epicardial spasm relevant to acute coronary syndrome pathogenesis

Smooth muscle cells in the media layer of coronary arterial vessels can contract in response to stimuli from the autonomic nervous system (e.g. acetylcholine), local responses to autacoids (e.g. histamine), and to pharmacologic stimuli. Local hyper-reactivity of smooth muscle cells mainly mediated by enhanced Rho kinase activity results in spasm in response to constrictor stimuli. Normal endothelial cells produce endogenous vasodilator substances including nitric oxide. A large body of literature supports the contribution of dysfunctional endothelium to inappropriate constriction of coronary and other arteries.