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Available online at www.sciencedirect.com
www.elsevier.com/locate/tcm
Review article
Mechanisms of myocardial infarction without obstructive coronary artery disease Harmony R. Reynoldsn Cardiovascular Clinical Research Center, Leon H. Charney Division of Cardiology, Department of Medicine, NYU Langone Medical Center, 530 First Ave, Skirball 9R, New York, NY 10016, USA
article info
abstract
Article history:
Angiography in patients with myocardial infarction (MI) most commonly reveals one or
Received 16 October 2013
more significantly narrowed coronary arteries, but a substantial minority of patients with
Received in revised form
spontaneous MI have no obstructive coronary artery disease (CAD) at angiography. This
3 December 2013
review summarizes evidence for the most commonly hypothesized mechanisms, including
Accepted 4 December 2013
plaque disruption, plaque erosion, vasospasm, embolism, and spontaneous coronary
Available online 14 December 2013
dissection. In addition, tako-tsubo syndrome and myocarditis are discussed. The best treatment of MI without obstructive CAD is likely to differ substantially based on the underlying cause. Additional mechanistic research is needed to facilitate the design of research studies aimed at documenting the best treatments for these patients, numbering as many as 225,000 per year in the US. & 2014 Elsevier Inc. All rights reserved.
Introduction The universal definition of myocardial infarction indicates that MI is diagnosed when there is a rise and fall of cardiac biomarkers such as troponin in combination with ischemic symptoms, ischemic ECG changes, imaging evidence of loss of viable myocardium, or identification of an intracoronary thrombus (Thygesen et al., 2012). Coronary obstruction is not required according to this definition. Angiography in patients with myocardial infarction (MI) most commonly reveals one or more significantly narrowed coronary arteries, but a substantial minority of patients with spontaneous MI have no obstructive CAD at angiography (Berger et al., 2009; Chokshi et al., 2010; Gehrie et al., 2009; Hochman et al., 1999). “Significant” narrowing is usually defined as Z50% stenosis, though it must be recognized that a considerable degree of atherosclerosis may be present in cases without at least 50% narrowing on an angiogram and that diffuse lesions may in n
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fact limit flow (Gould et al., 2000). The prevalence of nonobstructive CAD or “open arteries,” terms which in this review will encompass both visible atherosclerosis and angiographically normal coronary arteries, is higher among women regardless of ECG presentation (Berger et al., 2009; Chokshi et al., 2010; Gehrie et al., 2009; Hochman et al., 1999; Smilowitz et al., 2011) (Table). The absence of obstructive CAD at angiography is also more common among younger individuals and those of black race (Chokshi et al., 2010; Larsen et al., 2013; Shaw et al., 2008). The timing of angiography relative to symptom onset does not appear to alter the prevalence of “open arteries” at angiography (Thiele et al., 2012). MI without obstructive CAD is a common problem. Based on the US incidence of MI and published ranges of prevalence of no obstructive CAD at angiography, incidence is estimated at 56,000–225,000 people annually in the US (Berger et al., 2009; Chokshi et al., 2010; Gehrie et al., 2009; Go et al., 2013;
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Table – Prevalence of no obstructive CAD at angiography in MI by sex. Study title
ECG type
n
Prevalence of no obstructive CAD (%) Men
Meta-analysis (Berger et al., 2009) GUSTO IIb (Hochman et al., 1999) CRUSADE (Gehrie et al., 2009)
STEMI NSTEMI STEMI NSTEMI NSTEMI
Hochman et al., 1999). The prognosis of MI without obstructive CAD is 2–3 times better than that of typical MI with obstructive CAD but is not completely benign (Berger et al., 2009; Larsen et al., 2013; Patel et al., 2006; Roe et al., 2000). Risk of death and MI is approximately 2% per year (Bugiardini et al., 2006; Dey et al., 2009; Diver et al., 1994; Gehrie et al., 2009; Larsen et al., 2013; Patel et al., 2006; Roe et al., 2000; Rossini et al., 2013), although this may be an underestimate considering that 17% of decedents with pathologic confirmation of MI had no obstructive CAD in a large series of NYC medical examiner cases (Smilowitz et al., 2011). The relationship between prognosis and the presence or complete absence of angiographic evidence of atherosclerosis has varied across reports in MI patients with open arteries; in stable patients with symptoms and open arteries, there is a clear increase in risk associated with angiographic detection and increasing severity of atherosclerosis (Bugiardini et al., 2006; Roe et al., 2000; Rossini et al., 2013; Sedlak et al., 2013; Sharaf et al., 2013). The TIMI risk score does discriminate risk over 1 year in patients with open arteries (Bugiardini et al., 2006). MI without obstructive CAD has been reported to be due to plaque disruption, plaque erosion, vasospasm, embolism, spontaneous coronary dissection, and other causes. In addition, transient left ventricular dysfunction syndrome (a.k.a., tako-tsubo syndrome) is a form of MI without obstructive CAD and may be due to plaque disruption, vasospasm, catecholamine toxicity, autonomic dysfunction, or a combination of these or other causes (Bybee and Prasad, 2008). Furthermore, myocarditis can present clinically as a syndrome meeting the universal definition of MI, with symptoms potentially attributable to ischemia, ECG changes, and biomarker elevation (Baccouche et al., 2009). Secondary prevention measures recommended according to the current ACC/AHA guidelines for post-MI patients include aspirin, beta blockade, statin, and ACE inhibition; no distinction is made regarding severity of atherosclerosis (O0 Gara et al., 2013). However, observational studies show that physicians are less likely to prescribe these medications to patients without obstructive CAD at angiography (Dey et al., 2009; Maddox et al., 2010). For example, patients admitted for acute coronary syndrome (ACS) and found to have no obstructive CAD were less frequently prescribed aspirin (78.6% vs. 93.5%), statins (64.9% vs. 83.4%), and β-blockers (64.4% vs. 84.4%) after angiography in the ACCNCDR registry (n ¼ 1,489,745) (Maddox et al., 2010). Medication use rates were lower at discharge than in hospital, reflecting provider reaction to the finding of open arteries. Whether the rates of use of these medications are appropriate depends on the underlying mechanism(s) of MI in these patients.
20,352 6743 2251 1749 51,608
7.6 4.8 6.8 4.2 6.3
Women 8.8 10 10.2 9.1 14.7
Advanced imaging techniques such as intravascular ultrasound, intracoronary optical coherence tomography, coronary CT angiography, and cardiac magnetic resonance imaging (CMR) can identify mechanisms in individual patients but are not routinely employed at all centers. To date, no diagnostic algorithm has been routinely employed in these patients, and these imaging techniques have only been used in small cohorts. This review will summarize evidence for the most commonly hypothesized mechanisms of MI without angiographically obstructive CAD. Each has been recognized as a cause of MI in at least some patients, but the relative proportion of patients with MI due to each mechanism is unknown at this time due to a paucity of data in patients surviving to hospital. Multiple mechanisms may exist in combination.
Mechanisms Plaque disruption Plaque rupture or ulceration Atherosclerotic plaque rupture has long been hypothesized as a cause of MI without angiographically obstructive CAD as it causes a majority of fatal coronary thromboses (Falk et al., 2013) and nonfatal spontaneous MIs (Hong et al., 2004), and it is well known that angiography can underestimate the degree of atherosclerosis as compared to histology (Silvanto et al, 2012). In the case of MI without obstructive CAD at angiography, it has been hypothesized that transient occlusive thrombosis may occur with spontaneous thrombolysis or that superimposed vasospasm and/or embolization of atherothrombotic material may cause infarction. In support of this hypothesis is the well-known limitation of conventional angiography: this technique only demonstrates plaque that encroaches on the lumen. More extensive atherosclerosis can be demonstrated in many clinical scenarios using intravascular imaging techniques such as intravascular ultrasound (IVUS) or optical coherence tomography (OCT), or on pathologic evaluation (Stone et al., 2011); see Figs. 1 and 2 for examples of plaque rupture as imaged by IVUS and OCT. We identified atherosclerotic plaque rupture and/or ulceration in 38% of patients undergoing IVUS (n ¼ 42) in a single center study of MI patients without obstructive CAD at NYU Langone Medical Center and Bellevue Hospital who were referred for angiography for the clinical diagnosis of MI (Reynolds et al., 2011). Multiple disrupted plaques were identified in 3 patients (16% of those with disruption). The
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Fig. 1 – Representative IVUS image showing plaque rupture in a normal segment. The site of plaque rupture is marked with an arrow on the angiogram. The middle panel shows the outline of the lumina border (yellow) and external elastic lamina (red) corresponding to the IVUS image in the right panel. (Adapted with permission from Reynolds et al., 2011.) finding of plaque rupture in MI with open arteries was subsequently verified in another single center study including women and men, with a similar prevalence on IVUS, 37% (Ouldzein et al., 2012). In each of these studies, imaging was limited to 1–2 coronary arteries and therefore it remains possible that the prevalence was actually higher. Contrary to expectations, disrupted plaques were rarely located within the angiographically worst plaque in the vessel in our study (Fig. 1). This study also included cardiac magnetic resonance imaging (CMR) with late gadoliniumenhanced imaging (LGE) for infarction and T2-weighted imaging for edema. LGE was present in only 1 patient with plaque disruption but T2 signal hyperintensity was common (75% of 8 such patients who had T2-weighted imaging) and was typically located in the territory of the disrupted plaque (83%). The CMR finding of myocardial edema in the territory subtended by disrupted plaque suggests that disruption was etiologic but requires confirmation, particularly when considering that plaque rupture also occurs in patients with stable angina (Hong et al., 2005; Maehara et al., 2002a). However, reports including “stable” patients with plaque rupture enrolled patients at the time of clinically indicated cardiac catheterization (cath), and it remains possible that these patients had changing symptom patterns that prompted cath and reflected plaque rupture. Notably, case series reporting the use of IVUS in patients with stable chest pain and without obstructive CAD reported no ruptured plaques (Ge et al., 1994; Khuddus et al., 2010). A larger study investigating all 3 coronary arteries in combination with
myocardial imaging in patients with MI without obstructive CAD is needed to improve our understanding of these findings in the context of the literature.
Plaque erosion On pathologic review, a ruptured plaque is not always found beneath fatal coronary thrombosis (Falk et al., 2013). Plaque erosion is defined as coronary thrombosis at a site for which careful sectioning does not reveal plaque rupture. The typical pathologic appearance includes denuded endothelium over a pathologically thickened intima composed of smooth muscle cells and proteoglycans, rather than atherosclerosis. Plaque erosion is more common in women than in men, especially younger women (Farb et al., 1996). This is of particular interest given that MI without obstructive CAD is more common at younger ages and among women. With the advent of OCT, a newer intravascular imaging technique using light rather than ultrasound for imaging and with up to ten-fold better resolution than IVUS (Maehara et al., 2009), plaque erosion has been characterized in living patients with STEMI (Prati et al., 2013) and non-ST-elevation ACS (Jia et al., 2013) after thrombus aspiration (see Fig. 2 for example). Plaque erosion accounted for 31% of non-ST-elevation ACS in a recent series (Jia et al., 2013). Plaque erosion has not to date been investigated in patients with ACS without obstructive CAD.
Calcified nodule A minority of plaques with thrombosis exhibit nodular calcification that protrudes into the lumen (Falk et al., 2013).
Fig. 2 – Representative OCT images of (A) Plaque rupture. Yellow arrow, broken fibrous cap. White arrow, cavity. (Adapted with permission from Tearney et al., 2012.) (B) Plaque erosion. White thrombus (arrow) is on an irregular luminal surface; no evidence of rupture. (Adapted with permission from Tearney et al., 2012.) (C) Calcified nodule; protrudes into lumen through a disrupted fibrous cap overlying superficial calcification with red thrombus attached to the disrupted site in a different frame. (n) guide wire. (Adapted with permission from Jia et al., 2013.) (D) Intramural hematoma from SCAD (2 o0 clock to 7 o0 clock). Adapted from Saw et al. (2012). (E) Normal artery. (Adapted with permission from Tearney et al., 2012.)
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Fig. 3 – CMR images showing LGE with corresponding end-diastolic cine image in two patients with a clinical diagnosis of MI without obstructive CAD. (right most panel for each of A þ B). (A) Myocardial infarction: small, nearly transmural LGE involving mid-inferior wall (arrows). (B) Myocarditis: patchy areas of LGE, primarily midwall, with some septal areas extending to the right ventricular subendo cardium (white arrows) and a nearly transmural area in the apical lateral wall (black arrow). (Adapted with permission from Reynolds et al., 2011.)
This type of plaque can also be identified using IVUS and OCT and may cause ACS (Jia et al., 2013; Stone et al., 2011) (see Fig. 2 for example).
Vasospasm Vasospasm may contribute to MI whether or not there is coronary atherosclerosis. Although this diagnosis has potential therapeutic implications, it is difficult to prove. Vasospasm may be evident spontaneously on diagnostic angiography with relief by administration of intracoronary nitroglycerin. It may occur with or without associated atherosclerosis, which may or may not be obstructive in nature. Thrombosis may play a role in MI pathogenesis when spasm is present. However, catheter manipulation may also cause spasm, and unless symptoms and ECG changes are recapitulated with spontaneous vasospasm in the cath lab, it may not be clear that vasospasm was the cause of MI. Provocative testing with ergonovine or acetylcholine in the cath lab may induce vasospasm in up to half of the cases but this does not prove that spasm was the inciting event for MI (Ong et al., 2008). In the abovementioned study using IVUS and CMR, some patients had an ischemic pattern of LGE without demonstration of plaque disruption on IVUS; these patients may have had vasospasm or experienced embolism or another ischemic MI etiology, or this could represent limited sensitivity of IVUS for plaque disruption, as above. Recent reports using OCT have suggested there may be characteristic findings (intimal thickening and/or intima– media separation) in patients with vasospasm (Kobayashi et al., 2010).
Spontaneous coronary artery dissection Dissection may occur spontaneously in coronary arteries, typically without an intimal tear. Spontaneous coronary artery dissection (SCAD) is a rare but increasingly recognized cause of MI that preferentially affects young women (Tweet et al., 2012). SCAD may occur in a location affected by atherosclerosis or without atherosclerosis. In the latter case, it has been associated with fibromuscular dysplasia of the coronary and other arteries (Saw et al., 2013; Tweet et al., 2012). The diagnosis of SCAD may be made angiographically but IVUS and OCT are more sensitive (Alfonso et al., 2012; Maehara et al., 2002a, 2002b) (see Fig. 2 for example).
Myocarditis Myocarditis may mimic MI in terms of symptoms, ECG changes, and new wall motion abnormalities. Thus, in the absence of specific diagnostic techniques such as CMR or biopsy, patients with myocarditis may meet the criteria for MI, typically without obstructive CAD at angiography. Several groups have investigated the role of CMR in making this diagnosis in patients without obstructive CAD. The prevalence of a non-ischemic appearance of LGE consistent with myocarditis has ranged from 4% to 63%, depending on the cohort investigated (Assomull et al., 2007; Baccouche et al., 2009; Christiansen et al., 2006; Collste et al., 2013; Reynolds et al., 2011; Stensaeth et al., 2011; Laraudogoitia Zaldumbide et al., 2009). Of note, studies including more men report higher prevalence of myocarditis in these series. See Figure 3 for a representative example of myocarditis on CMR.
Tako-tsubo syndrome This syndrome is defined by the characteristic left ventricular wall motion abnormality, which is transient and not due to angiographic obstructive CAD or plaque disruption, pheochromocytoma, or myocarditis (Prasad et al., 2008). Interestingly, the requirement for exclusion of myocarditis could be taken to suggest that MRI is required for diagnosis. Patients with tako-tsubo syndrome comprise 2% of patients with STEMI and 1.2% of all ACS patients and they frequently have 430% stenosis on angiography (Kurowski et al., 2007; Prasad et al., 2011). Several mechanisms have been hypothesized for tako-tsubo cardiomyopathy, including plaque disruption, multivessel spasm, baroreflex abnormalities, and catecholamine toxicity (Bybee and Prasad, 2008; Norcliffe-Kaufmann and Reynolds, 2011; Reynolds et al., 2011). It is likely that tako-tsubo syndrome is a disorder with heterogeneous etiology.
Potential for sex differences in mechanisms of MI without obstructive CAD As noted, the finding of no obstructive CAD at angiography is more common in women than in men in numerous published series. However, outcomes for men and women with this problem are similar, suggesting similar mechanisms
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(Dey et al., 2009; Gehrie et al., 2009). Plaque erosion and SCAD are each more common among women, while the incidence of myocarditis is higher among men (Kyto et al., 2007; Tweet et al., 2012). In patients with obstructive CAD undergoing intracoronary imaging, plaque disruption rates appear to be similar for men and women (Chia et al., 2007), but men have a greater amount of plaque and different plaque composition, while women have smaller vessel size (Kruk et al., 2007; Qian et al., 2009; Sheifer et al., 2001). In addition, age may play a role. For example, though men and women both have increasing amounts of plaque with age, plaque rupture is more common at younger ages (Hong et al., 2008).
The importance of elucidating mechanisms of MI with “open arteries” Future clinical research and interim recommendations for treatment require an understanding of mechanisms. The treatment of MI without obstructive CAD is likely to differ substantially based on mechanism. For example, the best treatment of MI with open arteries due to disrupted plaque is likely to be the same as typical spontaneous MI due to disrupted plaque. The best treatment of plaque erosion remains unknown but would likely include antiplatelet agents and possibly statins, depending on the composition of the underlying plaque. The best treatment of vasospasm may be different, perhaps including calcium channel blockers and nitrates. SCAD is frequently not due to atherosclerosis and therefore treatment might not include statins. Myocarditis is not true MI and therefore treatment with secondary prevention measures is not appropriate, though some medications might be considered for primary prevention. Thus, a rational approach to treatment cannot be undertaken without knowledge of the mechanism or mechanisms of MI without obstructive CAD. Clinical trials are needed to establish the role of different treatments for patients with MI and open arteries. It is not currently possible to carry out such a clinical trial because causes are so variable, and therefore, it is difficult to design a therapeutic strategy for testing. Mechanistic studies have been small, with most only utilizing a single diagnostic technique in a study cohort. The study using both IVUS and CMR demonstrated feasibility of making several different diagnoses in a cohort, but was small and restricted to women. OCT would likely improve accuracy of the diagnosis of plaque disruption. Furthermore, the event rate is relatively low among patients with MI without obstructive CAD, which poses a limitation to clinical trial design. Identification of a higher risk subset, e.g., those with plaque disruption, would facilitate the design of research studies aimed at documenting the best treatments for these patients, numbering as many as 225,000 per year in the US.
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Available online at www.sciencedirect.com
www.elsevier.com/locate/tcm
Review article
Mechanisms of myocardial infarction without obstructive coronary artery disease Harmony R. Reynoldsn Cardiovascular Clinical Research Center, Leon H. Charney Division of Cardiology, Department of Medicine, NYU Langone Medical Center, 530 First Ave, Skirball 9R, New York, NY 10016, USA
article info
abstract
Article history:
Angiography in patients with myocardial infarction (MI) most commonly reveals one or
Received 16 October 2013
more significantly narrowed coronary arteries, but a substantial minority of patients with
Received in revised form
spontaneous MI have no obstructive coronary artery disease (CAD) at angiography. This
3 December 2013
review summarizes evidence for the most commonly hypothesized mechanisms, including
Accepted 4 December 2013
plaque disruption, plaque erosion, vasospasm, embolism, and spontaneous coronary
Available online 14 December 2013
dissection. In addition, tako-tsubo syndrome and myocarditis are discussed. The best treatment of MI without obstructive CAD is likely to differ substantially based on the underlying cause. Additional mechanistic research is needed to facilitate the design of research studies aimed at documenting the best treatments for these patients, numbering as many as 225,000 per year in the US. & 2014 Elsevier Inc. All rights reserved.
Introduction The universal definition of myocardial infarction indicates that MI is diagnosed when there is a rise and fall of cardiac biomarkers such as troponin in combination with ischemic symptoms, ischemic ECG changes, imaging evidence of loss of viable myocardium, or identification of an intracoronary thrombus (Thygesen et al., 2012). Coronary obstruction is not required according to this definition. Angiography in patients with myocardial infarction (MI) most commonly reveals one or more significantly narrowed coronary arteries, but a substantial minority of patients with spontaneous MI have no obstructive CAD at angiography (Berger et al., 2009; Chokshi et al., 2010; Gehrie et al., 2009; Hochman et al., 1999). “Significant” narrowing is usually defined as Z50% stenosis, though it must be recognized that a considerable degree of atherosclerosis may be present in cases without at least 50% narrowing on an angiogram and that diffuse lesions may in n
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fact limit flow (Gould et al., 2000). The prevalence of nonobstructive CAD or “open arteries,” terms which in this review will encompass both visible atherosclerosis and angiographically normal coronary arteries, is higher among women regardless of ECG presentation (Berger et al., 2009; Chokshi et al., 2010; Gehrie et al., 2009; Hochman et al., 1999; Smilowitz et al., 2011) (Table). The absence of obstructive CAD at angiography is also more common among younger individuals and those of black race (Chokshi et al., 2010; Larsen et al., 2013; Shaw et al., 2008). The timing of angiography relative to symptom onset does not appear to alter the prevalence of “open arteries” at angiography (Thiele et al., 2012). MI without obstructive CAD is a common problem. Based on the US incidence of MI and published ranges of prevalence of no obstructive CAD at angiography, incidence is estimated at 56,000–225,000 people annually in the US (Berger et al., 2009; Chokshi et al., 2010; Gehrie et al., 2009; Go et al., 2013;
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Table – Prevalence of no obstructive CAD at angiography in MI by sex. Study title
ECG type
n
Prevalence of no obstructive CAD (%) Men
Meta-analysis (Berger et al., 2009) GUSTO IIb (Hochman et al., 1999) CRUSADE (Gehrie et al., 2009)
STEMI NSTEMI STEMI NSTEMI NSTEMI
Hochman et al., 1999). The prognosis of MI without obstructive CAD is 2–3 times better than that of typical MI with obstructive CAD but is not completely benign (Berger et al., 2009; Larsen et al., 2013; Patel et al., 2006; Roe et al., 2000). Risk of death and MI is approximately 2% per year (Bugiardini et al., 2006; Dey et al., 2009; Diver et al., 1994; Gehrie et al., 2009; Larsen et al., 2013; Patel et al., 2006; Roe et al., 2000; Rossini et al., 2013), although this may be an underestimate considering that 17% of decedents with pathologic confirmation of MI had no obstructive CAD in a large series of NYC medical examiner cases (Smilowitz et al., 2011). The relationship between prognosis and the presence or complete absence of angiographic evidence of atherosclerosis has varied across reports in MI patients with open arteries; in stable patients with symptoms and open arteries, there is a clear increase in risk associated with angiographic detection and increasing severity of atherosclerosis (Bugiardini et al., 2006; Roe et al., 2000; Rossini et al., 2013; Sedlak et al., 2013; Sharaf et al., 2013). The TIMI risk score does discriminate risk over 1 year in patients with open arteries (Bugiardini et al., 2006). MI without obstructive CAD has been reported to be due to plaque disruption, plaque erosion, vasospasm, embolism, spontaneous coronary dissection, and other causes. In addition, transient left ventricular dysfunction syndrome (a.k.a., tako-tsubo syndrome) is a form of MI without obstructive CAD and may be due to plaque disruption, vasospasm, catecholamine toxicity, autonomic dysfunction, or a combination of these or other causes (Bybee and Prasad, 2008). Furthermore, myocarditis can present clinically as a syndrome meeting the universal definition of MI, with symptoms potentially attributable to ischemia, ECG changes, and biomarker elevation (Baccouche et al., 2009). Secondary prevention measures recommended according to the current ACC/AHA guidelines for post-MI patients include aspirin, beta blockade, statin, and ACE inhibition; no distinction is made regarding severity of atherosclerosis (O0 Gara et al., 2013). However, observational studies show that physicians are less likely to prescribe these medications to patients without obstructive CAD at angiography (Dey et al., 2009; Maddox et al., 2010). For example, patients admitted for acute coronary syndrome (ACS) and found to have no obstructive CAD were less frequently prescribed aspirin (78.6% vs. 93.5%), statins (64.9% vs. 83.4%), and β-blockers (64.4% vs. 84.4%) after angiography in the ACCNCDR registry (n ¼ 1,489,745) (Maddox et al., 2010). Medication use rates were lower at discharge than in hospital, reflecting provider reaction to the finding of open arteries. Whether the rates of use of these medications are appropriate depends on the underlying mechanism(s) of MI in these patients.
20,352 6743 2251 1749 51,608
7.6 4.8 6.8 4.2 6.3
Women 8.8 10 10.2 9.1 14.7
Advanced imaging techniques such as intravascular ultrasound, intracoronary optical coherence tomography, coronary CT angiography, and cardiac magnetic resonance imaging (CMR) can identify mechanisms in individual patients but are not routinely employed at all centers. To date, no diagnostic algorithm has been routinely employed in these patients, and these imaging techniques have only been used in small cohorts. This review will summarize evidence for the most commonly hypothesized mechanisms of MI without angiographically obstructive CAD. Each has been recognized as a cause of MI in at least some patients, but the relative proportion of patients with MI due to each mechanism is unknown at this time due to a paucity of data in patients surviving to hospital. Multiple mechanisms may exist in combination.
Mechanisms Plaque disruption Plaque rupture or ulceration Atherosclerotic plaque rupture has long been hypothesized as a cause of MI without angiographically obstructive CAD as it causes a majority of fatal coronary thromboses (Falk et al., 2013) and nonfatal spontaneous MIs (Hong et al., 2004), and it is well known that angiography can underestimate the degree of atherosclerosis as compared to histology (Silvanto et al, 2012). In the case of MI without obstructive CAD at angiography, it has been hypothesized that transient occlusive thrombosis may occur with spontaneous thrombolysis or that superimposed vasospasm and/or embolization of atherothrombotic material may cause infarction. In support of this hypothesis is the well-known limitation of conventional angiography: this technique only demonstrates plaque that encroaches on the lumen. More extensive atherosclerosis can be demonstrated in many clinical scenarios using intravascular imaging techniques such as intravascular ultrasound (IVUS) or optical coherence tomography (OCT), or on pathologic evaluation (Stone et al., 2011); see Figs. 1 and 2 for examples of plaque rupture as imaged by IVUS and OCT. We identified atherosclerotic plaque rupture and/or ulceration in 38% of patients undergoing IVUS (n ¼ 42) in a single center study of MI patients without obstructive CAD at NYU Langone Medical Center and Bellevue Hospital who were referred for angiography for the clinical diagnosis of MI (Reynolds et al., 2011). Multiple disrupted plaques were identified in 3 patients (16% of those with disruption). The
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Fig. 1 – Representative IVUS image showing plaque rupture in a normal segment. The site of plaque rupture is marked with an arrow on the angiogram. The middle panel shows the outline of the lumina border (yellow) and external elastic lamina (red) corresponding to the IVUS image in the right panel. (Adapted with permission from Reynolds et al., 2011.) finding of plaque rupture in MI with open arteries was subsequently verified in another single center study including women and men, with a similar prevalence on IVUS, 37% (Ouldzein et al., 2012). In each of these studies, imaging was limited to 1–2 coronary arteries and therefore it remains possible that the prevalence was actually higher. Contrary to expectations, disrupted plaques were rarely located within the angiographically worst plaque in the vessel in our study (Fig. 1). This study also included cardiac magnetic resonance imaging (CMR) with late gadoliniumenhanced imaging (LGE) for infarction and T2-weighted imaging for edema. LGE was present in only 1 patient with plaque disruption but T2 signal hyperintensity was common (75% of 8 such patients who had T2-weighted imaging) and was typically located in the territory of the disrupted plaque (83%). The CMR finding of myocardial edema in the territory subtended by disrupted plaque suggests that disruption was etiologic but requires confirmation, particularly when considering that plaque rupture also occurs in patients with stable angina (Hong et al., 2005; Maehara et al., 2002a). However, reports including “stable” patients with plaque rupture enrolled patients at the time of clinically indicated cardiac catheterization (cath), and it remains possible that these patients had changing symptom patterns that prompted cath and reflected plaque rupture. Notably, case series reporting the use of IVUS in patients with stable chest pain and without obstructive CAD reported no ruptured plaques (Ge et al., 1994; Khuddus et al., 2010). A larger study investigating all 3 coronary arteries in combination with
myocardial imaging in patients with MI without obstructive CAD is needed to improve our understanding of these findings in the context of the literature.
Plaque erosion On pathologic review, a ruptured plaque is not always found beneath fatal coronary thrombosis (Falk et al., 2013). Plaque erosion is defined as coronary thrombosis at a site for which careful sectioning does not reveal plaque rupture. The typical pathologic appearance includes denuded endothelium over a pathologically thickened intima composed of smooth muscle cells and proteoglycans, rather than atherosclerosis. Plaque erosion is more common in women than in men, especially younger women (Farb et al., 1996). This is of particular interest given that MI without obstructive CAD is more common at younger ages and among women. With the advent of OCT, a newer intravascular imaging technique using light rather than ultrasound for imaging and with up to ten-fold better resolution than IVUS (Maehara et al., 2009), plaque erosion has been characterized in living patients with STEMI (Prati et al., 2013) and non-ST-elevation ACS (Jia et al., 2013) after thrombus aspiration (see Fig. 2 for example). Plaque erosion accounted for 31% of non-ST-elevation ACS in a recent series (Jia et al., 2013). Plaque erosion has not to date been investigated in patients with ACS without obstructive CAD.
Calcified nodule A minority of plaques with thrombosis exhibit nodular calcification that protrudes into the lumen (Falk et al., 2013).
Fig. 2 – Representative OCT images of (A) Plaque rupture. Yellow arrow, broken fibrous cap. White arrow, cavity. (Adapted with permission from Tearney et al., 2012.) (B) Plaque erosion. White thrombus (arrow) is on an irregular luminal surface; no evidence of rupture. (Adapted with permission from Tearney et al., 2012.) (C) Calcified nodule; protrudes into lumen through a disrupted fibrous cap overlying superficial calcification with red thrombus attached to the disrupted site in a different frame. (n) guide wire. (Adapted with permission from Jia et al., 2013.) (D) Intramural hematoma from SCAD (2 o0 clock to 7 o0 clock). Adapted from Saw et al. (2012). (E) Normal artery. (Adapted with permission from Tearney et al., 2012.)
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Fig. 3 – CMR images showing LGE with corresponding end-diastolic cine image in two patients with a clinical diagnosis of MI without obstructive CAD. (right most panel for each of A þ B). (A) Myocardial infarction: small, nearly transmural LGE involving mid-inferior wall (arrows). (B) Myocarditis: patchy areas of LGE, primarily midwall, with some septal areas extending to the right ventricular subendo cardium (white arrows) and a nearly transmural area in the apical lateral wall (black arrow). (Adapted with permission from Reynolds et al., 2011.)
This type of plaque can also be identified using IVUS and OCT and may cause ACS (Jia et al., 2013; Stone et al., 2011) (see Fig. 2 for example).
Vasospasm Vasospasm may contribute to MI whether or not there is coronary atherosclerosis. Although this diagnosis has potential therapeutic implications, it is difficult to prove. Vasospasm may be evident spontaneously on diagnostic angiography with relief by administration of intracoronary nitroglycerin. It may occur with or without associated atherosclerosis, which may or may not be obstructive in nature. Thrombosis may play a role in MI pathogenesis when spasm is present. However, catheter manipulation may also cause spasm, and unless symptoms and ECG changes are recapitulated with spontaneous vasospasm in the cath lab, it may not be clear that vasospasm was the cause of MI. Provocative testing with ergonovine or acetylcholine in the cath lab may induce vasospasm in up to half of the cases but this does not prove that spasm was the inciting event for MI (Ong et al., 2008). In the abovementioned study using IVUS and CMR, some patients had an ischemic pattern of LGE without demonstration of plaque disruption on IVUS; these patients may have had vasospasm or experienced embolism or another ischemic MI etiology, or this could represent limited sensitivity of IVUS for plaque disruption, as above. Recent reports using OCT have suggested there may be characteristic findings (intimal thickening and/or intima– media separation) in patients with vasospasm (Kobayashi et al., 2010).
Spontaneous coronary artery dissection Dissection may occur spontaneously in coronary arteries, typically without an intimal tear. Spontaneous coronary artery dissection (SCAD) is a rare but increasingly recognized cause of MI that preferentially affects young women (Tweet et al., 2012). SCAD may occur in a location affected by atherosclerosis or without atherosclerosis. In the latter case, it has been associated with fibromuscular dysplasia of the coronary and other arteries (Saw et al., 2013; Tweet et al., 2012). The diagnosis of SCAD may be made angiographically but IVUS and OCT are more sensitive (Alfonso et al., 2012; Maehara et al., 2002a, 2002b) (see Fig. 2 for example).
Myocarditis Myocarditis may mimic MI in terms of symptoms, ECG changes, and new wall motion abnormalities. Thus, in the absence of specific diagnostic techniques such as CMR or biopsy, patients with myocarditis may meet the criteria for MI, typically without obstructive CAD at angiography. Several groups have investigated the role of CMR in making this diagnosis in patients without obstructive CAD. The prevalence of a non-ischemic appearance of LGE consistent with myocarditis has ranged from 4% to 63%, depending on the cohort investigated (Assomull et al., 2007; Baccouche et al., 2009; Christiansen et al., 2006; Collste et al., 2013; Reynolds et al., 2011; Stensaeth et al., 2011; Laraudogoitia Zaldumbide et al., 2009). Of note, studies including more men report higher prevalence of myocarditis in these series. See Figure 3 for a representative example of myocarditis on CMR.
Tako-tsubo syndrome This syndrome is defined by the characteristic left ventricular wall motion abnormality, which is transient and not due to angiographic obstructive CAD or plaque disruption, pheochromocytoma, or myocarditis (Prasad et al., 2008). Interestingly, the requirement for exclusion of myocarditis could be taken to suggest that MRI is required for diagnosis. Patients with tako-tsubo syndrome comprise 2% of patients with STEMI and 1.2% of all ACS patients and they frequently have 430% stenosis on angiography (Kurowski et al., 2007; Prasad et al., 2011). Several mechanisms have been hypothesized for tako-tsubo cardiomyopathy, including plaque disruption, multivessel spasm, baroreflex abnormalities, and catecholamine toxicity (Bybee and Prasad, 2008; Norcliffe-Kaufmann and Reynolds, 2011; Reynolds et al., 2011). It is likely that tako-tsubo syndrome is a disorder with heterogeneous etiology.
Potential for sex differences in mechanisms of MI without obstructive CAD As noted, the finding of no obstructive CAD at angiography is more common in women than in men in numerous published series. However, outcomes for men and women with this problem are similar, suggesting similar mechanisms
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(Dey et al., 2009; Gehrie et al., 2009). Plaque erosion and SCAD are each more common among women, while the incidence of myocarditis is higher among men (Kyto et al., 2007; Tweet et al., 2012). In patients with obstructive CAD undergoing intracoronary imaging, plaque disruption rates appear to be similar for men and women (Chia et al., 2007), but men have a greater amount of plaque and different plaque composition, while women have smaller vessel size (Kruk et al., 2007; Qian et al., 2009; Sheifer et al., 2001). In addition, age may play a role. For example, though men and women both have increasing amounts of plaque with age, plaque rupture is more common at younger ages (Hong et al., 2008).
The importance of elucidating mechanisms of MI with “open arteries” Future clinical research and interim recommendations for treatment require an understanding of mechanisms. The treatment of MI without obstructive CAD is likely to differ substantially based on mechanism. For example, the best treatment of MI with open arteries due to disrupted plaque is likely to be the same as typical spontaneous MI due to disrupted plaque. The best treatment of plaque erosion remains unknown but would likely include antiplatelet agents and possibly statins, depending on the composition of the underlying plaque. The best treatment of vasospasm may be different, perhaps including calcium channel blockers and nitrates. SCAD is frequently not due to atherosclerosis and therefore treatment might not include statins. Myocarditis is not true MI and therefore treatment with secondary prevention measures is not appropriate, though some medications might be considered for primary prevention. Thus, a rational approach to treatment cannot be undertaken without knowledge of the mechanism or mechanisms of MI without obstructive CAD. Clinical trials are needed to establish the role of different treatments for patients with MI and open arteries. It is not currently possible to carry out such a clinical trial because causes are so variable, and therefore, it is difficult to design a therapeutic strategy for testing. Mechanistic studies have been small, with most only utilizing a single diagnostic technique in a study cohort. The study using both IVUS and CMR demonstrated feasibility of making several different diagnoses in a cohort, but was small and restricted to women. OCT would likely improve accuracy of the diagnosis of plaque disruption. Furthermore, the event rate is relatively low among patients with MI without obstructive CAD, which poses a limitation to clinical trial design. Identification of a higher risk subset, e.g., those with plaque disruption, would facilitate the design of research studies aimed at documenting the best treatments for these patients, numbering as many as 225,000 per year in the US.
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