Acute coronary syndromes: The way forward from mechanisms to precision treatment

Abstract

Well into the 21st century, we still triage acute myocardial infarction based on the presence or absence of ST segment elevation, a century-old technology. Meanwhile, we have learned a great deal regarding the pathophysiology and mechanisms of acute coronary syndromes (ACS) at clinical, pathological, cellular, and molecular levels. Contemporary imaging studies have shed new light into 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. Yet, 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 to segment coronary artery thrombosis due to 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 due to plaque erosion may be on the rise in an era of intense lipid lowering. Identification of patients with of ACS due to 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.

Introduction

Willem Einthoven introduced electrocardiography at the dawn of the 20th century. Well into the 21st century, we still triage acute myocardial infarction based on this venerable technology: ST segments up or not. Although this approach remains the appropriate evidence-based strategy today, aiming toward the future goal of more individualized therapy, can we apply a more pathophysiogically-based categorization of the acute coronary syndromes (ACS). Indeed, we have learned regarding the mechanisms of ACS since we last reviewed this topic in these pages.^1,2 Moreover, the human disease of atherosclerosis has evolved considerably in the interim.^3–5 This review aims to reach toward a categorization of the ACS that reaches beyond equating all ACS with plaque rupture or fissue, guided by the latest insights in the underlying mechanisms of ACS, and points a way forward toward the eventual clinical application of these considerations.

Post-mortem studies carried out in the 1980s proposed that plaque rupture (also sometimes referred to as fissure) caused most fatal myocardial infarctions⁶. These findings led to the notion of the “vulnerable” or “high-risk” plaque characterized by a large central lipid core, abundance of inflammatory cells, a paucity of smooth muscle cells, and a thin fibrous cap⁷. These observations spawned the widely accepted concept that instability of coronary atheromata resulted from fissuring of a “thin-capped fibroatheroma” or “TCFA” due to weakening of its collagen structure wrought by inflammatory mechanisms⁸.

This concept stimulated manifold attempts to develop methods to detect the “vulnerable” plaque, a quest predicated on the postulate that local interventions could preclude plaque thrombosis and possibly prevent ACS. Yet, attempts to identify vulnerable plaques proved disappointing because of the low predictive value⁹. Pathologic studies of human coronary arteries show that plaque rupture occurs commonly in individuals without symptomatic ACS¹⁰. Moreover, fewer than 5% of plaques with the features of TCFA as determined by intravascular ultrasound interrogation actually cause clinical events during 3it’s refyears of follow-up¹¹. Thus, most TCFA are clinically quite stable, a realization that renders “vulnerable plaque” a misnomer. Indeed, plaques with TCFA morphology as assessed by radiofrequency backscatter data from intravascular ultrasound (“virtual histology”) commonly convert to an apparently more “stable” character during a one year follow-up period. ¹² Such evolution in plaques may reflect mutability during the “natural history” of human atherosclerosis, but could also reflect adherence of many of these patients to a contemporary “secondary prevention” regimen including statins and agent that target the renin-angiotensin axis.

Moreover, while we have witnessed wide acceptance of the formerly controversial concept that inflammation contributes to atherogenesis ¹³, inflammation may not drive all transitions from stable atherosclerosis to acute thrombotic events. In one large study, about half of ACS occurred in the presence of normal levels of C-reactive protein (CRP), a marker of inflammation¹⁴. Another recent study using optical coherence tomography (OCT) demonstrated that among patients with ACS and plaque rupture, two-thirds of patients had imaging evidence of inflammatory cell infiltration in the region of the ruptured fibrous cap but one-third did not and the latter had lower levels of CRP¹⁵. In addition, plaque erosion causes up to a third of ACS in the current era^16,17. Finally, about one-fifth of ACS occurs in the apparent absence of coronary thrombosis, suggesting that functional alterations beyond thrombus formation can contribute to ACS pathogenesis^{18, 19}.

The ensemble of post-mortem studies and in vivo studies using intravascular imaging point to four pathologic pathways to ACS. While these mechanisms may overlap and coexist in some patients, we present them separately for heuristic simplicity: 1) plaque rupture with systemic inflammation; 2) plaque rupture without systemic inflammation; 3) plaque erosion; or 4) plaque without thrombus (Figure 1).²⁰

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.

This review considers the causes of these four predominant pathways to ACS. To strive for a more precision approach, we will explore the therapeutic implications of these distinct mechanisms that provoke ACS. Moreover, we advocate the future goal to move beyond triage of therapy based merely on electrocardiographic (ECG) current of injury by harnessing the recent advances in arterial biology, and human studies that shed new mechanistic light on ACS pathogenesis. Further improvements in the appropriate deployment of technologies and in outcomes should evolve from a more mechanistically-based classification of ACS.

Plaque rupture with systemic inflammation

Mechanisms

Several studies have implicated systemic inflammation in ACS, as assessed by the biomarker C-reactive protein (Figure 1A)²¹. Laboratory studies, as well as observations on human plaques, point to inflammatory mechanisms as key regulators of the fragility of the fibrous cap, as well as of the thrombogenic potential of the lipid core (Figure 2). Macrophages likely pave the way for the rupture of the plaque’s fibrous cap: when activated, these cells elaborate enzymes that degrade all components of the arterial extracellular matrix. These enzymes include matrix metalloproteinases (MMPs) and certain cathepsins. Multiple mechanisms regulate these matrix-degrading proteinases: transcription, translation, activation of zymogen precursors, and balance with endogenous inhibitors such as the tissue inhibitors of MMPs (TIMPS) or the cystatins. Thus, increased amounts of activated proteinases or reduced levels of their corresponding inhibitors can enhance breakdown of the plaque’s extracellular matrix²².

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 (T_reg) 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 T_reg that can dampen local adaptive immune responses in the plaque.

Adaptive immunity also appears altered in coronary plaque instability²³. Patients with ACS have an increased population of particularly pro-inflammatory CD4⁺ T-cells characterized by low cell surface expression of CD28, a co-stimulatory molecule critically involved in determining the outcome of antigen recognition by T-cells²⁴. ACS also profoundly perturb the numbers of two other circulating T-cell subsets: type 17 helper T-cells (Th17) and CD4⁺CD25⁺ regulatory T-cells (Treg). The net role of IL-17 in atherosclerosis remains controversial, however; some experimental studies in mice support a predominantly proatherogenic function for IL-17, yet Th17 cells activated in plaques promote the formation of thick collagen fibers which might increase plaque stability^{25, 26}. Treg normally help to maintain homeostasis of cells involved in adaptive immunity, including antigen-presenting cells and effector T-cells. Treg mediate these modulatory effects by contact-dependent suppression or by releasing anti-inflammatory cytokines, such IL-10 or TGF-β1²⁷. Patients with ACS have reduced number and suppressive function of circulating Treg compared to patients with stable angina and healthy controls²⁸. The molecular mechanisms responsible for the T cell dysregulation in ACS remain largely unknown. Recent work highlights the importance of the strength of the stimulation of the T cell receptor for antigen (TCR) in the differentiation of helper T-cell subsets. The altered activity observed in ACS of proteins involved in the regulation of upstream TCR signaling, such as CD31 and PTPN22, may modulate T cell functions^{29, 30}.

Therapeutic implications

Several anti-inflammatory treatments might provide benefit in this setting. Colchicine, a time-honored anti-inflammatory drug, reduced major cardiovascular events in a medium-size, unblinded randomized study in patients with stable ischemic heart disease³¹. Two trials underway are evaluating colchicine treatment in patients with coronary artery disease (CAD) – although not in the acute phase.³² A phase 3 trial is testing the potential beneficial effects of low-dose methotrexate in patients post myocardial infarction or with coronary artery disease and diabetes or elements of the metabolic syndrome³³.

Targeting proinflammatory cytokines offers another approach. Because of the potentially detrimental effects on cardiovascular risk profile and/or lack of compelling evidence of benefit in experimental atherosclerosis, monoclonal antibodies that neutralize TNF-alpha, IFN-gamma, or IL-17 may not prove appropriate for treating atherosclerosis. In a small (n=182) phase II study, the IL-1 receptor antagonist anakinra reduced the area under the curve of high sensitivity C-reactive protein (hsCRP) in patients in the 7 days following presentation with ACS. ³⁴ A large (n>10,000) phase 3 trial with clinical end-points that tested a fully humanized anti-IL-1 β monoclonal antibody, canakinumab, in patients with previous MI and CRP levels > 2 mg/L, has reportedly met its primary endpoint.³⁵

T-cell activation signaling offers possible targets. A synthetic CD31-derived peptide can suppresses immunity in vivo by restoring an inhibitory pathway to a CD31 negative T cell subset ³⁶. Moreover, the development of a novel series of inhibitors of the phosphatase PTPN22 might contribute to a better understanding of its role in immune dysregulation in ACS patients³⁷. Therapeutic strategies that target Treg include administration of low doses of IL-2 and infusion of autologous Tregs that have undergone differentiation and expansion in vitro.³⁸ Various vaccination strategies can limit experimental atherogenesis as well, and may act by augmenting the activity of Treg.³⁹

Plaque rupture without systemic inflammation

Mechanisms

When plaque rupture occurs in the absence of systemic inflammatory activation other mechanisms may contribute to pathogenesis, including extreme emotional disturbance – ranging from external events of short duration, such as earthquakes and a beloved team’s loss of a football (soccer) match, to acute manifestations of more chronic emotional disturbances (Figure 1B). Intense physical exertion, as well as local mechanical stress at the level of the artery wall – either increased circumferential stress or reduced shear stress – may also predispose to plaque rupture⁴⁰. In addition, subclinical inflammation in the microenvironment of the culprit stenosis might compound the chain of events leading to coronary instability, although the triggers for and effectors of such local inflammation may differ from those that operate in patients with systemic inflammation⁴¹. While many studies have clarified the molecular mechanisms leading to coronary instability in individuals with systemic inflammation (gauged for example by CRP elevations), patients without systemic inflammation have undergone less extensive investigation. The precise causes of instability remain poorly understood, providing a strong stimulus for further research.

The possible relationship between psychological stress and plaque rupture may relate to sympathetic nervous system activation and catecholamine release associated with increase in heart rate, blood pressure, and coronary vasoconstriction favoring plaque disruption and platelet activation, hypercoagulability, and intense coronary microvascular constriction.⁴² Morover, beta₃ adrenergic stimulation can stimulate release from the bone marrow of pro-inflammatory monocytes that can home to experimental atheromata and amplify local inflammation⁴³. Although physical or emotional stress per se may not suffice to cause coronary thrombosis, it might trigger instability in plaques already predisposed to provoke events⁴⁴.

Local changes in the equilibrium between esterified and free cholesterol might promote plaque rupture⁴⁵ (Figure 3). Cholesterol crystal formation in the lipid core could heighten risk of plaque rupture and thrombosis, and can also co-activate the inflammasome, an intracellular multimeric complex that generates active IL-1 beta and IL-18⁴⁶.

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.

Optical coherence tomography (OCT) has colocalized cholesterol crystals in human coronary arteries with thin-capped plaques⁴⁷. The development of micro-OCT with a 2μm resolution may shed new light on this potential mechanism of instability by assessing its occurrence in vivo⁴⁸. Cholesterol crystals might also theoretically resist plaque rupture by increasing the stiffness of the lipid pool, although this mechanism probably contributes little to plaque stability⁴⁹. The role of calcium mineral as causal factors in ACS remains controversial. Large collections of calcified tissue do not augment biomechanical instability of plaques or associate with lesions that provoke ACS.^50,51 Small foci of calcification within the atherosclerotic intima, some causing “spotty calcification” visible on CT, can also introduce biomechanical inhomogeneities that can favor plaque destabilization.^{3, 52, 53}

Therapeutic implications

As it is difficult to limit environmental, physical, or emotional triggers, the altered plaque characteristics produced by intensive lipid lowering treatment might protect from this form of plaque destabilization⁵⁴. In particular, statins and ezetimibe may interfere with cholesterol crystal formation^{55, 56}. Cyclodextrin can solubilize cholesterol, and limits experimental atherogenesis, and might thus provide a pharmacologic approach to combatting cholesterol crystal accumulation in plaques. ⁵⁷

Enhancement of cholesterol efflux might promote plaque stabilization, but strategies to enhance this process by manipulation of HDL concentrations or by administering apolipoprotein A-1 have generally failed to confer clinical benefit⁵⁸ A large outcome trial with anacetrapib has reportedly met its primary endpoint, but that this agent not only raises HDL, but lowers LDL, renders it difficult to attribute event reduction to raising HDL. In addition, inhibition of cholesteryl ester hydrolase, an enzyme that converts cholesteryl esters to free cholesterol might prevent cholesterol crystallization. Inhibition of ACAT-1, which in contrast promotes cholesterol crystallization, increased atheroma volume and major cardiovascular events⁵⁹.

Plaque erosion

Mechanisms

Current evidence suggests that mechanisms of plaque disruption distinct from macrophage-driven rupture of the plaque’s fibrous cap can commonly cause acute coronary syndromes. ⁶⁰ The mechanism of plaque thrombosis described by pathologists as “superficial erosion” appears not to involve inflammation mediated by macrophages, as in the case of fibrous cap fracture (Figure 1C). Superficial erosion complicates lesions with a distinct epidemiology and morphology, and involves pathophysiologic mechanisms that differ from rupture of the fibrous cap. Indeed, neutrophil activation seems to play a pivotal role in plaque erosion⁴. Patients who presented with ACS associated with plaque erosion defined by OCT had higher systemic myeloperoxidase (MPO) levels compared to concentrations in patients with plaque rupture. Moreover, in post-mortem coronary specimens, luminal thrombi superimposed on eroded plaques contain many more MPO-positive cells than thrombi associated with ruptured plaques⁶¹ (Figure 4).

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.

Autopsy studies suggest that fatal plaque erosion associates more commonly with hypertriglyceridemia, diabetes mellitus, female sex, and elderly⁶². The morphology of lesions that produce thrombosis due to superficial erosion differs radically from the features associated with fibrous cap rupture. Superficially eroded lesions contain few macrophages or T lymphocytes, inflammatory cells considered pathogenic in plaque rupture. Rather than depleted collagen, the lesions associated with superficial erosion contain abundant proteoglycan and glycosaminoglycans. Instead of a paucity of smooth muscle cells, eroded lesions can contain abundant arterial smooth muscle cells. Plaques complicated by fibrous cap fracture typically harbour large necrotic, lipid-rich cores. In contrast, the more fibrous lesions associated with superficial erosion generally lack prominent central lipid cores⁶³. A loss of intimal endothelial cells defines lesions that provoke thrombosis by the mechanism denoted superficial erosion.

Recent work has implicated engagement of the innate immune receptor Toll-like receptor 2 (TLR2) in promoting the susceptibility of endothelial cells to apoptotic stimuli. Hyaluronic acid, a prominent constituent of the extracellular matrix of eroded lesions, could serve as an endogenous ligand of TLR2, implicated in promoting endothelial cell apoptosis.⁶⁴ Experiments that have evaluated gain and loss of TLR2 function in mice support these observations.⁶⁵ Indeed, hyaluronan and its receptor, CD44, co-localize along the plaque/thrombus interface in eroded plaque but not in ruptured or stable plaque⁶⁶. Accumulation of hyaluronan and expression of CD44 along the plaque/thrombus interface of eroded plaques may promote de-endothelization, resulting in CD44-dependent platelet adhesion and subsequent thrombus formation, in part mediated by a direct action of hyaluronan on fibrin polymerization^{67, 68}.

We have hypothesized that thrombosis due to superficial erosion occurs in two phases. The first “hit,” mediated for example by TLR2, would jeopardize endothelial viability or adherence, leading to a breach in the integrity of the endothelial monolayer overlying the atherosclerotic plaque. The denuded patch on the intimal surface would then attract platelets that could undergo activation by contact with collagen and other components of the arterial extracellular matrix usually protected from the blood compartment by the endothelial lining of the intima. The second “hit,” mediated by the release of granular contents from activated platelets and the local production of chemoattractants for polymorphonuclear leukocytes (PMN), would beckon these granulocytes to join the platelets at local sites of endothelial denudation. In turn, the activation of PMN could generate structures known as neutrophil extracellular traps (NETs), comprised of strands of unwound DNA released by the dying granulocytes.⁶⁹ This uncoiled DNA becomes decorated with proteases, tissue factor, and pro-oxidant enzymes that could propagate local amplification of an innate immune response, thrombin activation, fibrin generation, and entrap further platelets and fibrin strands in an evolving thrombus⁴⁹.

This hypothetical scenario posits a mechanism of thrombosis independent of the chronic inflammatory cells typically implicated in fibrous cap rupture: macrophages and T lymphocytes. Rather, this schema implicates different arms of innate immunity in thrombus initiation, propagation, and stabilization. These mechanistic differences with fibrous cap fracture have potential therapeutic implications.

Therapeutic implications

As statins alter the lipid profile primarily by lowering LDL rather than triglycerides, therapies that address triglyceride-rich lipoproteins may address the residual risk of events due to erosion that persists in the statin era, more effectively than more intense LDL lowering therapies⁷⁰. Moreover, therapies that destabilize neutrophil extracellular traps such as deoxyribonuclease (DNAase) administration might limit the propagation of thrombi resulting from superficial erosion⁷¹. Receptors such as CD44 expressed by neutrophils may bind hyaluronan and glycosaminoglycan enriched in plaques complicated by erosion, and furnish a potential therapeutic target⁷².

Jia et al. recently reported a series of patients with ACS with OCT-defined erosion and treated with anti-coagulant/anti-platelet therapy rather that mechanical revascularization. About 80% of the patients showed a > 50% reduction of thrombus volume after 1 month. More than a third of patients lacked detectable thrombus after 1 month. This study suggests that pharmacologic rather than interventional treatment can effectively manage ACS due to superficial erosion, a proposition that merits and requires rigorous testing in outcome trials^{73, 74}.

Plaque without thrombus

Mechanisms

In patients with ACS without plaque thrombus, a functional alteration of coronary circulation likely causes the acute ischemia involving large epicardial coronary arteries or the coronary microcirculation (Figure 1D). Epicardial coronary vasospasm may occur in patients in whom coronary angiography does not demonstrate an obstructive atherosclerotic plaque⁷⁵. In the CASPAR study, coronary angiography failed to show “culprit lesions” in about 30% of patients with suspected ACS^76. Intracoronary acetylcholine (ACh) administration elicited coronary spasm in nearly 50% of these patients. Similar findings pertained to a Japanese population⁷⁷. Coronary artery spasm may cause coronary instability also in patients with obstructive atherosclerosis. Indeed, in a classical study Bertrand et al. found that ergonovine induced spasm in 20% of patients with recent myocardial infarction and in 40% of patients with unstable angina⁷⁸. In a more recent study ACh induced spasm in 20% of Caucasian patients and in 60% of patients with MI within the previous 14 days⁷⁹. Japanese people have a higher prevalence of coronary spasm than Caucasians for unknown reasons.

Microvascular spasm also can cause myocardial ischemia⁸⁰. This mechanism likely operates in patients with Takotsubo cardiomyopathy⁸¹, which frequently occurs in the absence of obstructive atherosclerosis, although about 15% of these patients exhibit concomitant obstructive atheroslerosis⁸². Microvascular spasm can also contribute to ischemia in the face of angiographically normal appearing epicardial coronary arteries. Microvascular ischemia often manifests as angina pectoris, but can also cause non-ST segment elevation ACS as defined by EKG alterations and biomarker evidence of myocyte injury⁸³. Coronary spasm can also contribute to plaque instability by causing endothelial damage as shown in an infarction-prone strain of the Watanabe heritable hyperlipidemic rabbits.⁴²

Either macro- or microvascular spasm can result from impaired vasodilatation and/or from vasoconstrictor stimuli acting on hyperreactive vascular SMC (Figure 5)^{84, 85}. Shimokawa et al. demonstrated SMC hyperreactivity in a coronary segment in pigs following adventitial exposure of a coronary segment to an inflammatory stimulus (IL-1β)⁸⁶. Subsequent experimental and clinical data suggested that an increase in Rho-kinase activity comprised a major mechanisms of SMC hyperreactivity^87–89. Perivascular fibrosis in the coronary microvasculature can contribute to myocardial ischemia. ⁹⁰ This observation highlights the potential contribution of fixed structural changes in coronary arterioles beyond impaired endothelial vasodilator function as a contributor to myocardial ischemia in the absence of obstructive disease of the epicardial coronary arteries.

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.

Therapeutic implications

Several vasoconstrictor substances implicated as triggers of epicardial coronary spasm may cause ischemia in the same patient under different conditions⁹¹. Accordingly, the vasoactive substances themselves may not respond to therapeutic targeting. The current treatment of epicardial spasm uses non-specific vasodilators such as long-acting nitrates and calcium-channel blockers⁹². Nitrates and calcium channel antagonists may alleviate ischemia due to vasospasm. Yet, we need to identify the molecular alterations responsible for SMC hyperreactivity, as many patients do not respond satisfactorily to standard doses of vasodilators⁹³. Knowledge of the post-receptor mechanisms responsible for SMC hyperreactivity and epicardial coronary spasm might enable the development of new therapeutic options for patients who present poor clinical response to nonspecific vasodilator therapy. Fasudil, a rho kinase inhibitor, reduces the rate of coronary spasm episodes in patients with vasospastic angina^94. Similarly, further efforts are warranted to unravel the molecular mechanisms responsible for coronary microvascular dysfunction in Takotsubo cardiomyopathy and in ischemia with normal coronary arteries.²⁰ The observation that Takotsubo cardiomyopathy may have worse outcomes than previously considered, and the challenges of managing patients with episodic ischemia due to microvascular dysfunction render this quest urgent⁸². Preventing or reversing perivascular fibrosis in the coronary arterial microvasculature represents another novel target beyond traditional anti-atherosclerotic therapies.

Conclusions and perspectives

A dichotomous approach based on the EKG has traditionally dominated our clinical management of ACS: STEMI vs. NSTEMI. Our thinking regarding the pathophysiologic bases of the ACS has also evolved separately and in parallel, dominated by the concept of the “vulnerable plaque” as a substrate for fibrous cap rupture, or of a “minority” mechanism: superficial erosion. We and others have championed and explored the role of inflammation as a pathway to the ACS.

Yet, we now have a greater appreciation that not all cases of ACS fit this mold. To move forward we need to remain vigilant not to cling to our cherished notions and remain open to shifts in the nature of the diseases we treat, and to new vistas opened by scientific advances. As discussed here, we need to consider more deeply in the current era arterial spasm, rupture without inflammation, and distinct aspects of innate immunity or dyslipidemia as an instigators of plaque erosion. The complexity of clinical ACS surpasses our traditional categorization of this condition we should evolve beyond the current constrained concepts by expanding our understanding.

We have achieved considerable mastery of plaque rupture with inflammation from a mechanistic and therapeutic viewpoint. Control of traditional risk factors such as hypercholesterolemia, hypertension, and smoking address the pathophysiology of this mechanism of ACS. The other categories that we discuss here may account for an increasing proportion of ACS, now that we are addressing more effectively the traditional risk factors.⁵ We should remain open to the possibility – even likelihood – that tailored therapeutic approaches may apply to the prevention and treatment of the less well recognized pathways to acute myocardial ischemia discussed here.

We must aim to link the clinical presentation of ACS more tightly to pathophysiologic mechanisms. More than a century after the introduction of EKG we still triage our ACS patients on the basis of this mature technology. To move forward in management of ACS, we should strive for a more personalized approach to therapy based on criteria more tightly linked to the diverse pathophysiologic mechanisms than EKG repolarization abnormalities. We need to develop and validate soluble and imaging biomarkers that reflect the underlying mechanism that yields acute ischemia. Point-of-care assessment of such biomarkers would help render their use clinically practical in the triage of patients who present with ACS, with the goal of sparing some the need for urgent invasive diagnostic or therapeutic measures^{64, 95}. We then need rigorous clinical evaluation of targeted therapies guided by a more precise pathophysiologic classification of ACS that reach beyond our current dichotomous approach based on the EKG. If these ventures succeed, we may one day look back on today’s treatment of ACS as oversimplified and rather primitive. We should strive as a community not to be satisfied with our current approach to ACS management but reach to realize the promise of a more personalized precision deployment of treatment strategies including new ones based on greater mechanistic understanding of the diverse underlying causes of acute myocardial ischemia.