Spontaneous Coronary Artery Dissection Daniele Giacoppo, Davide Capodanno, George Dangas, Corrado Tamburino PII: DOI: Reference:
S0167-5273(14)00860-2 doi: 10.1016/j.ijcard.2014.04.178 IJCA 18079
To appear in:
International Journal of Cardiology
Received date: Revised date: Accepted date:
13 August 2013 19 February 2014 17 April 2014
Please cite this article as: Giacoppo Daniele, Capodanno Davide, Dangas George, Tamburino Corrado, Spontaneous Coronary Artery Dissection, International Journal of Cardiology (2014), doi: 10.1016/j.ijcard.2014.04.178
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ACCEPTED MANUSCRIPT Spontaneous Coronary Artery Dissection
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Tamburino, MD, PhD*†
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Daniele Giacoppo, MD, Davide Capodanno MD, PhD*†, George Dangas, MD, PhD‡§, Corrado
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Institute of Cardiology, Ferrarotto Hospital, University of Catania, Catania, Italy (D.G., D.C.,
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C.T.), ETNA Foundation, Catania, Italy (D.C., C.T.), Department of Cardiology, Mount Sinai Medical Center, New York, United States (G.D.), Cardiovascular Research Foundation, New
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York, United States (G.D.)
Address for correspondence:
Davide Capodanno, MD, PhD. Cardiothoracic-vascular Department, Ferrarotto Hospital, University of Catania, via Citelli 6, 95124, Catania, Sicily, Italy; Phone: +39 0957436202; Fax: +39 0957436202; e-mail: [email protected]
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ACCEPTED MANUSCRIPT ABSTRACT Spontaneous Coronary Artery Dissection (SCAD) is a relatively rare and unexplored type
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of coronary disease. Although atherosclerosis, hormonal changes during pregnancy and
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connective tissue disorders might represent a sufficiently convincing explanation for some patients with SCAD, the many remaining cases display only a weak relationship with these
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causes. While on one side the clinical heterogeneity of SCAD masks a full understanding of their
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underlying pathophysiologic process, paucity of data and misleading presentations on the other side hamper the quick diagnosis and optimal management of this condition. A definite diagnosis
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of SCAD can be significantly facilitated by endovascular imaging techniques. In fact, intravascular ultrasound and optical coherence tomography overcome the limitations of coronary
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angiography providing detailed endovascular morphologic information. In contrast, optimal
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treatment strategies for SCAD still represent a burning controversial question. Herein, we review
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the published data examining possible causes and investigating the best therapy for SCAD in different clinical scenarios.
Key Words:
SCAD, Spontaneous Coronary Artery Dissection, Dissection.
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ACCEPTED MANUSCRIPT Spontaneous coronary artery dissection (SCAD) is a vessel wall lesion characterized by an intramural hematoma (ie., false lumen) flattening the lumen (ie., true lumen) through the shift of
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the inner media against the opposite wall, which by definition requires the absence of a iatrogenic, non-coronary or traumatic etiology [1,2]. According to the underlying
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pathophysiology, SCAD has been also named “primary” coronary artery dissection, in contrast to
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the definitely more common “secondary” coronary artery dissection, which in contrast is
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explained by known factors, such as coronary catheterization, percutaneous coronary intervention (PCI), cardiac surgery, extended aortic root dissection or chest trauma (Figure 1) [3-6].
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SCADs generally present an intimal-media tear producing a communication between the vessel lumen and the intramural hematoma (“SCAD with entry door”) (Figure 2, left). Blood
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coming into the false lumen clots and spreads the flap of detached tissue. The dissection plane,
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located between the intima and the media or more commonly in the outer media, delimits a new
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hollow (false lumen) causing usually severe luminal narrowing and distortion [1,2,7]. However, several SCADs at least initially are only intramural hematomas that compress the lumen from outside reducing the blood flow (“angiographically-invisible SCAD). Subsequently some of these hematomas can evolve as result of continuous intramural bleeding and/or structural abnormalities (ie., inflammatory infiltrates, cystic medial necrosis) with the final intimal-media disruption promoting suddenly a further path of growth [1,2,7-9] (Figure 2, right). The typical angiographic sign of coronary dissection is a radiolucent intimal-media flap (double lumen), frequently associated with persistent extra-luminal filling and/or delayed clearance of contrast media from the lumen, detected in at least 2 orthogonal projections [1,2,10] (Figure 3A). However, as mentioned above, SCAD without luminal entry door frequently determines exclusively a smooth and regular coronary narrowing due to intramural hematoma eversion into the lumen [11,12]. These lesions not fulfilling the classical angiographic pattern of 3
ACCEPTED MANUSCRIPT coronary dissection can be detected with tomographic imaging techniques, such as intravascular ultrasound (IVUS) and optical coherence tomography (OCT) (Figure 3B, 3C) [11,12].
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The aim of this article is to provide a comprehensive description of SCADs, review their
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presentation and outcomes from the available literature, and critically appraise current diagnostic
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and therapeutic options.
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EPIDEMIOLOGY OF SCAD
SCAD is a relatively rare presentation of coronary disease with an estimated prevalence of 0.07-
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0.28% [12-17] and an annual incidence of 0.26 cases per 100,000 persons (0.33 in women, 0.18 in men) among US subjects [18]. Since the first case described by Pretty in 1931 [19], a total of
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only ~ 1125 SCADs (Appendix) have been reported in literature consisting largely of individual
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cases or case series and rarely of small single-center registries (< 90 patients).
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Patients with SCAD generally present without cardiovascular risk factors or history of coronary events [13-17] and are typically female (58-79%) [1,12,13,20] and young, with a mean age of 41 ± 10.6 years in women and of 45.4 ± 14.4 years in men [21]. SCAD may account for more than 10% of STEMI in women < 50 years of age [14]. Recently, SCAD presentations have been documented also in adolescents and in elderly [12,22-26]. The early assumption of a gender-specific location of SCAD, characterized by more frequent left coronary artery involvement in women (84-88%) and right coronary artery involvement in men (67-73%) [3,27], has been recently rejected, since left anterior descending represents the most frequent site of SCAD both in males and in females (69% vs 72%; p = 0.81) [12,13,18]. Regardless of the coronary involved, the mid segment appears the preferential site [12,26]. Combining data extracted from existing small registries and case series (Table 1, see the Online Appendix for a description of the adopted methodology), the left anterior descending 4
ACCEPTED MANUSCRIPT artery results the most commonly involved vessel (63.9% of patients) followed by the right coronary artery (26.5% of patients), the left circumflex (19.4% of patients) and the left main
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coronary artery (6.5% of patients) (Figure 4, upper; Table 1). Multi-vessel SCAD is near three
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times less common than single-vessel SCAD (26.4% vs 76.3%; p < 0.01) [21]. Comparing multivessel involvement frequency in female and male, the prevalence of SCAD results higher in
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women both in two-vessels (17.5% vs 12.9%; p = 0.022) and in three-vessels SCAD
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presentations (12.3% vs 5.3%; p = 0.029) (Figure 4, mid). Conversely, men more often present with single-vessel SCAD (81.8% vs 70.1%; p = 0.011) (Figure 4, mid) [21]. Reports of SCAD
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simultaneously involving all the three major epicardial arteries are anecdotal [28,29]. The prevalence of SCAD increases significantly in acute coronary syndromes (ACS) because the
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dissection is frequently responsible for an abrupt and severe flow limitation. However, there is a
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substantial discordance among reports in the frequency of each type of ACS. For instance,
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Mortensen et al. found almost invariably a ST-Elevation Myocardial Infarction (STEMI) at admission (84%), Tweet et al. indicated similar rates of STEMI (49%) and Non-ST Elevation Myocardial Infarction (NSTEMI) (44%), and Kansara et al. concluded that NSTEMI was the usual presentation of SCAD (85%) [13,18,30]. Aggregating the available evidence (Table 1), STEMI is diagnosed in 48.0% followed by NSTEMI in 36.3% and unstable angina (UA) in 6.5% (Figure 4, lower). In 5.5% of cases the admission diagnosis is stable angina, chronic heart failure symptoms or ventricular arrhythmias (Figure 4, lower). Ultimately, the true incidence of SCAD may be underestimated because of the frequent association between SCAD and sudden coronary death (SCD) [18]. Additional potential causes of SCAD under-reporting are “angiographically-invisible SCADs”, which are commonly misdiagnosed as atherosclerotic plaques or coronary spasms, and the general perception that coronary disease cannot involve young and otherwise healthy subjects. 5
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CLASSIFICATION
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Patients with SCAD are traditionally grouped into three subsets: those affected by coronary
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atherosclerotic disease (CAD), young women in the peripartum period and patients without known underlying coronary disease (idiopathic SCAD) [27] (Figure 1).
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Atherosclerotic SCAD: In earlier and recent SCAD registries, CAD accounts for not
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more than 24-28% [13,27]. Notably, in a retrospective study on gender difference in SCAD, female patients were found to be associated less frequently with a concurrent CAD (3.7% vs
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20.6%; p = 0.01) [30] and this is consistent with a contemporary registry reporting 83% of men in the group with atherosclerosis (p < 0.001) [12].
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Peripartum SCAD: SCAD is responsible for 27% of acute myocardial infarctions during
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pregnancy [32]; this rate increases to 50% in the peripartum period, representing the main cause
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of acute myocardial infarction [32]. Traditionally, SCAD presents a striking association with the peripartum period (more than 25%) [15,21,30], especially within the 2-3 weeks after the delivery [20,32,33]. Latest reports, however, show definitely lower percentages (3.8-5.3%) indicating that the actual prevalence may be lower [12,25]. Antepartum SCAD, both single-vessel and multivessel, occurs almost invariably in the last weeks of pregnancy and is definitely less common then the postpartum variant [34]. Idiopathic SCAD: Idiopathic SCAD, by definition, does not present with a clear etiology (Figure 5). The relationship between some idiopathic cases and connective tissue (Marfan, Ehlers-Danlos) and inflammatory disorders (rheumatoid arthritis, systemic lupus erythematosus) has been highlighted [2].
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ACCEPTED MANUSCRIPT Recurrent SCAD Recurrent SCAD is defined as an unexpected ACS due to the development of a new dissection in
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a different coronary segment. The first report of recurrent SCAD was a post-mortem case
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described by van der Bel-Kahn in 1982 [35]. Recurrent SCAD involves women in almost all cases and has a strong correlation with the peripartum period and Ehlers-Danlos syndrome
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[15,36,37]. After the primary SCAD event, the 10-year recurrence rate is 29.4% [15]. The
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second event may occur between 3 days and 12 years, but approximately 50% of patients
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develops a recurrent SCAD within the first 2 weeks [31].
PATHOPHYSIOLOGY AND RISK FACTORS OF SCAD
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The aetiology of SCAD is still unknown but certainly multi-factorial and complex (Figure 6).
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Recurrent and multi-vessel SCADs might suggest a pathologic condition involving all coronary
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segments but the superimposed mechanism that allows explaining why some patients experienced SCAD differently compared with others with equivalent baseline conditions is generally lacking. Atherosclerosis: Clinical features of this subgroup of SCAD patients are driven by the underlying CAD. These patients are frequently male (78-83%) with typical coronary risk factors (diabetes, hypertension, hypercholesterolemia, smoke habit) [12,38]. Coronary plaque rupture might create a deep fissure into the artery wall and bleeding of plaque-induced vasa vasorum might progressively detach the wall tissues [38-42]. Peri-partum period: Pregnancy-related SCAD could be related to an excess of sexual hormones leading to vessel wall biochemical and structural changes [32,34,43]. Pathological signs consist of loss of normal corrugation of elastic fibers, fragmentation of reticular fibers, collagen degeneration and deficient production, hypertrophy of the smooth muscle cells, decrement in acid mucopolysaccharides and changes in protein and composition of the media 7
ACCEPTED MANUSCRIPT [43-46]. Moreover, the physiologic increase in blood volume and cardiac output observed in pregnancy may magnify shear forces of the blood column, resulting in a greater propensity for
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artery dissections [32,34]. The postabortion period should be considered at risk for SCAD
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because of hormonal influences [47].
Multiparity and menopausal period: These conditions may increase the risk for SCAD
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and the cause should be ascribed to hormonal factors similarly to typical neoplasms of elder
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female [33,48]. Recently it has been described that 26-45% of SCAD female patients are postmenopausal [25,49].
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Oral contraceptive: Oral contraceptive use (5.8%) has been correlated to SCAD in nonpregnant women [18,21,44,50-52]. The altered levels of sexual female hormones might impact on
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the risk for SCAD. The analogies among peripartum, menopausal and oral contraceptive SCAD
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variants could imply a common pathologic mechanism.
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Connective disorders: The Ehlers-Danlos syndrome consists of a heterogeneous group of inherited connective tissue disorders. The vascular type (type IV), resulting from mutations in the gene for type III procollagen (COL3A1), is the most severe because its complications are vascular fistula, artery dissection, aneurysm or perforation, and hollow organ (uterus, intestine) rupture [53]. SCAD in the Ehlers-Danlos syndrome is frequently associated with spontaneous dissections either of carotid/vertebral and/or principal thoracic and/or abdominal arteries [54,55]. The Marfan syndrome is an inherited autosomal dominant connective-tissue disease mainly caused by mutations in the gene encoding for the fibrillin-1 (FBN1), the primary constituent of extracellular matrix microfibrils [56]. Cystic medial necrosis, the common histologic sign of Marfan syndrome, is represented by focal fragmentation of elastic fibers, loss of media smooth muscle cells, and increased deposits of mucopolysaccharides [57,58]. Although up to 80% of patients with a Marfan syndrome have coronary cystic medial necrosis, coronary dissections are 8
ACCEPTED MANUSCRIPT more frequently due to extension of an aortic dissection [59,60]. Cystic medial necrosis has been described in 38% of SCAD, but only exceptionally a true pattern in non-Marfan patients has been
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associated to SCAD [7,61-64]. Loeys-Dietz syndrome and Neurofibromatosis type I are
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autosomal dominant disorders characterized by early mortality for dissection/rupture of aorta and renal arteries, respectively. Recent isolated reports of SCAD in patients with these syndromes
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strengthen the plausible association between some idiopathic SCADs and connective disorders
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[65,66].
Psycophysical stress: Several circumstances (strenuous physical exercise, emotional
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stress, sexual intercourse, protracted forceful retching or sneezing, prolonged sleep deprivation) may exceptionally determine SCAD but it is clear that the prerequisite is the presence of yet
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unknown common pathologic baseline conditions [67-82]. Strenuous exercise (increase in blood
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pressure and aorta/coronary flow, coronary vessel systolic mechanical stress) during athletic
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activity (cycling, soccer, running, swimming) [10,67-72] or weightlifting [73-76] is a frequent (up to 28%) SCAD trigger condition in athletes or trained subjects without SCAD risk factors [25,42]. Intense emotional stress (death of family member, arguments, divorce) was identified even in 17-26% of women just before SCAD [25,33]. Cocaine: The etiology of cocaine-induced myocardial ischemia appears to be the result of coronary artery vasoconstriction, thrombosis, and accelerated atherosclerosis [83-86]. The anomalous vessel regulation is probably related to marked media infiltration of chronic inflammatory cells, adventitial accumulation of activated mast cells, and critical hypertensive endothelial injury for increased sympathetic output [86-88]. Vascular inherited malformations: Osler-Rendu-Weber disease is a rare hereditary haemorrhagic disease characterized by abnormal telangiectasias and arterovenous malformations [89]. One case of SCAD is documented but this association could be a chance finding [90]. 9
ACCEPTED MANUSCRIPT Physical forces: Myocardial bridges are relatively common in the general population with an attested frequency > 1% [91]. Recently, myocardial bridge has been considered as a
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potential SCAD risk factor, but there is no strong evidence [92]. Sometime, coronary ecstasia and
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aneurysms are observed near or within SCAD [93-96]. The causal relationship might be bidirectional, since on one side aneurysms could be the long-term result of unsuccessful
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dissection healing processes, while on the other SCAD could be promoted by ectasia/aneurysm
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itself for the superficial tension produced on the parietal surface of the false lumen. This physical model has not been proved and appears unable in explaining the many remaining SCAD cases
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not associated with coronary ectasia/aneurysm. Finally, hypertensive crisis [97,98] and severe coronary spasm [99,100] have been uncommonly advocated as first step of SCAD process.
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Vasculitis and inflammatory disorders: The underlying inflammatory process has been
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frequently used to explain SCAD because of the frequent observation of inflammatory infiltrates,
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predominantly eosinophil granulocytes but also macrophages and histiocytic multinucleated giant cells, in the adventitia of dissected arteries [101-103]. Parietal damage may be due to the lytic action of proteases released from eosinophil cells, but this finding could be more probably a reactive process than expression of primary vasculitis [103-105]. When observed, however, inflammatory abnormalities may predict early SCAD recurrence [30]. Polyarteritis nodosa and Takayasu’s arteritis have been exceptionally related to SCAD ascertainment of SCAD [106-108]. Laboratory test and renal biopsies showeing a coexisting systemic lupus erythematosus and the reported concurrence of HCV-related mixed cryoglobulinaemia in one case also suggesst a possible role of cryoprecipitable circulating immune complexes [109-111]. Occasionally, inflammatory bowel disease has been found in patients with SCAD [25,30]. Fibromuscular dysplasia: Fibromuscular dysplasia (FMD) is an emerging hypothesis. FMD is a segmental idiopathic, non-atherosclerotic, non-inflammatory vasculopathy typically 10
ACCEPTED MANUSCRIPT affecting small-medium muscular arteries [112]. Renal (60-80%) and cervical arteries (20-30%) are the most commonly involved, while coronary FMD is very rare [113,114]. A recent registry
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of 50 patients experiencing SCAD, who were screened for peripheral FMD (cerebrovascular,
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carotid, renal, iliac) provided an unexpected potential explanation for idiopathic SCAD [25]. The "string of beads pattern" typical of FMD in peripheral vessels was disclosed with invasive
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angiography or multi-detector computed tomography (MDCT) or magnetic resonance imaging
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(MRI) in 86% of patients [25]. However, a recent case series of 12 patients with SCAD who underwent MRI reported a significantly lower prevalence (17%) and exclusive renal arteries
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localization [81]. Some reports tried to supply additional information on this association using also endovascular imaging [115-118]. SCAD associated with coronary FMD seems to be less
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common [25]. These interesting results deserve further investigation.
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Polycystic Kidney Disease: Autosomal dominant polycystic kidney disease is a
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monogenic disorder characterized by the formation of cysts in both kidneys. Vascular abnormalities include intracranial aneurysms, aortic aneurysm and dissection, and cervicocephalic arteries dissections. In the last years SCAD has also been described in patients suffering from polycystic kidney disease [119]. Drugs: Administration of antineoplastic (cyclosporine, 5-fluorouracil), antipsychotic (fenfluramine) and antimigraine (ergotamine) drugs has been associated with SCAD [120-123] and drug hypersensivity reactions can produce angiitis of vasa vasorum [124]. Recently a patient who underwent nonmyeloablative (Fludarabine and 400 cGy)-matched unrelated donor bone marrow transplant experienced SCAD [125]. Whether all these findings are associated with SCAD occurrence and whether they are sufficient to produce the lesion is unclear.
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ACCEPTED MANUSCRIPT CLINICAL PRESENTATION AND LABORATORY FINDINGS OF SCAD SCAD presentation encompasses the entire spectrum of coronary syndromes, ranging
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from asymptomatic patients, across those presenting stable angina, NSTEMI, STEMI, to SCD.
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Regardless of the type and cause, SCAD impairs myocardial perfusion reducing vessel lumen area similarly to atherosclerotic stenoses; therefore symptoms usually do not differ from those
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observed in ACS for CAD, but sometimes the clinical setting can be atypical and even
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misleading. Chest pain is the main symptom (91%) followed by syncope (23%), dyspnea, diaphoresis, and nausea [13,18]. Rarely dizziness and pre-syncope are the leading symptoms at
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presentation [126]. In other cases clinical manifestation can be only represented by dyspnoea [25,127], which in the most dramatic cases can evolve rapidly in cardiogenic shock due to severe
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global systolic dysfunction [128,129]. Life-threating arrhythmia requiring emergent defibrillation
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(high-frequency ventricular tachycardia, ventricular fibrillation) at admission has been
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documented in 8-14% [13,18,30,130], while an atrio-ventricular block is particularly uncommon [13]. Finally, SCAD can be also completely asymptomatic [131]. Blood cells, hemoglobin, coagulation, acute phase reactants, hormones and antibodies are within normal range in almost all SCAD patients. Sometimes unspecific increases upon the normal range in erythrocyte sedimentation rate, C-reactive protein, fibrinogen, leukocytes, rheumatoid factor, homocysteine, IgA, IgG, anticardiolipin IgM and phospholipid antibodies were noted, but these findings did not imply a clear causal relationship with SCAD [12,13,30,108,132,133].
DIAGNOSIS OF SCAD The diagnosis of SCAD is almost exclusively incidental during coronary angiography following STEMI or UA/NSTEMI. Coronary angiography represents the first line exam because it can rule 12
ACCEPTED MANUSCRIPT out the suspicion of SCAD. The angiographic pattern, however, is highly variable ranging from long and multiple dissections in an otherwise physiologic coronary tree to a single short
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dissection in atherosclerotic and calcific coronary vessels. Coronary angiography becomes less sensible in specific conditions such as extensive thrombosis, when luminal material masks the
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dissected segment or completely fills the false lumen, in the “angiographically-invisible” pattern,
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when a radiolucent flap is not detectable and the smooth narrowing is due to spasm.
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Intracoronary injection of nitroglycerin can facilitate the differential diagnosis between SCAD and spasm [134].
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Sometimes the dissection can progress under the action of blood flow or contrast media [33,135,136]. A pre-discharge second-look coronary angiography during index hospitalization
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could be considered in potentially dangerous anatomic patterns (large amount of downstream
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jeopardized myocardium) or when symptoms could indicate the potential worsening of dissection
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extent. Routine coronary angiography control should be avoided since contrast media can favor SCAD progression. During coronary angiography for SCAD, after the initial angiograms, an extension of the lesion is displayed in 17% of cases and a new dissection in another coronary vessel is observable in 26% [33].
Saw proposed an angiographic classification of SCAD [134]. This classification is essentially based on three distinct angiographic appearances: type 1 (“evident arterial wall stain”), characterized by contrast dye staining of arterial wall with multiple radiolucent filling defects; type 2 (“diffuse stenosis of varying severity”), namely misleading/unapparent angiographic features characterized by abrupt changes from normal vessel diameter to diffuse narrowing (generally > 20 mm) and frequent involvement of the mid-distal segments; type 3 (“mimic atherosclerosis”) characterized by absent atherosclerotic changes in other coronary arteries, long lesions (11–20 mm), and hazy or linear stenosis. 13
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Endovascular Imaging Techniques
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Maehara et al. firstly described with IVUS the presence of two morphologic patterns of
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SCAD: the SCAD provided with intimal flap, usually identifiable with coronary angiography alone, characterized by an intimal tear and the ability to propagate for blood inflow into the false
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lumen, and the “angiographically-invisible” SCAD, characterized by intramural hematoma but no
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intimal entry site, having enlargement potentiality after continuous bleeding into the new virtual cavity [137] (Figure 2, Figure 3B). According to OCT results, SCADs associated with one or,
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very rarely, double rupture site account for 74% of SCADs [138]. Invasive coronary imaging techniques result irreplaceable in the “angiographically-invisible” pattern.
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IVUS can define with high precision the magnitude of true lumen impairment as well as
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the spatial distribution and the heterogeneity degree of the false lumen [13,139,140] (Figure 3A,
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3B). IVUS, however, do not display accurately the endothelial surface and smaller intramural hematomas. OCT overcomes these limitations by means of its higher resolution (150 µm vs 15 µm) and, comparing the two techniques, OCT is able to disclose an intimal entry site whereas IVUS detects only the intramural hematoma [141-143]. OCT is the gold standard technique to evaluate the double-lumen morphology characteristics, to identify the entry tear, to measure with high accuracy the circumferential and longitudinal extent of the lesion, to define the involvement of side branches and finally to detect any associated intraluminal thrombus [138,144,145] (Figure 3C). The most important characteristic of OCT is the ability in ruling out almost all doubtful angiograms. In 35% of confined angiographic lumen narrowing or linear filling defect diagnosed as SCAD, OCT reveals only a luminal red thrombus inducing partial dorsal shadowing or an ulcerated severe atherosclerotic coronary artery disease [138]. However, OCT requires more caution than IVUS 14
ACCEPTED MANUSCRIPT since contrast media injection during image acquisition requires greater volumes and sometimes higher flow velocity and/or pressure. These factors can be dangerous in hemodynamically
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unstable conditions and entail in every clinical presentation a minimal risk of dissection
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progression.
Alfonso et al. described in vivo the micr-oanatomic characteristics of SCAD in a case
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series of 11 patients evaluated with OCT [138]. All patients had a partial or complete thrombosis
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of false lumen (mean area 5.9 ± 2.1 mm2) determining a critical reduction of the true lumen (mean area 1.1 ± 0.5 mm2) [138]. The length of the diseased segment was high (32 ± 12 mm) and
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greater than with angiography measurements (double lumen, 8.4 ± 6.7 mm; intramural hematoma, 21.9 ± 15 mm) [138]. Even though the intimal-media membrane was relatively thick
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(348 ± 84 µm), the edges of the intimal rupture site were particularly thin (99 ± 66 µm) [138].
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This interesting finding should be integrated with the documented presence of superficial lipid
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plaque nearby the coronary dissection entry point, which might explain the focal fragility of the arterial wall and the subsequent development of a “SCAD with entry door” pattern [146]. OCT/IVUS-guided PCI for SCAD is strongly recommended to prevent inadequate or excessive stent coverage, displaying precisely the effective measures of dissection, and to reduce the risk of progression following stenting [138,142,143]. Three-dimensional OCT has been shown to be able to elaborate extremely reliable images but its effective usefulness compared to standard OCT is unclear [147].
Non-invasive Imaging Techniques MDCT has been proven to be superior to coronary angiography in showing the subadventitial hematoma in “angiographically-invisible SCAD” [140,148]. SCAD generate a low-intermediate density signal surrounding the diseased vessel segment and a double lumen 15
ACCEPTED MANUSCRIPT aspect [149,150]. Obviously MDCT is recommended only when the patient is stable and asymptomatic and when there is a reasonably low probability of PCI necessity. Information
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regarding cardiac MRI in SCAD diagnosis are insufficient. In a recent case of SCAD detected
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with coronary angiography implemented by IVUS, subsequent MRI showed the coronary
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intramural hematoma as a hyperintense region on non-contrast T1-weighted imaging [151].
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TREATMENT OF SCAD
The lack of consensus surrounding the treatment of SCAD stems from its clinical
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heterogeneity and the evidence of different successful therapeutic strategies. In non-lifethreatening SCAD, long-term benefits of invasive revascularization compared to medical
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treatment are uncertain. Management decision should be made case-by-case, integrating clinical
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conditions and echocardiographic parameters with angiography and endovascular imaging to
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recognize SCAD location, extent and characteristics as well as the degree of flow impairment or luminal area reduction. In highly unstable ACS the preferential therapy is PCI. Shamloo et al., aggregating data and comparing retrospectively different treatment modalities, showed that patients undergoing coronary artery bypass grafting (CABG) or PCI had a statistically significant longer symptom-free period and lower mortality rates compared to those who were managed with medical therapy alone [21]. However, registries prevalently consisting of stable patients showed excellent long-term results with conservative treatment [25,152].
Medical management A conservative management may be the optimal initial treatment in SCAD ≤ 50% and TIMI flow 3 or asymptomatic patients (Figure 7). In stable clinical conditions and reassuring hemodynamic status the watchful waiting approach is recommendable since the lesion can meet 16
ACCEPTED MANUSCRIPT an autonomous resolution. This has been proven not only with coronary angiography but also with IVUS [153-156]. However, whether medical management alone is an acceptable strategy in
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SCAD causing a lumen diameter limitation > 70% and/or TIMI flow < 3 and/or presenting
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proximal location is controversial. In these conditions the evidence of myocardial ischemia and the potential inefficacy of medical treatment could imply a considerable risk. Presently it is not
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available an imaging sign or a laboratory marker anticipating the natural evolution of SCAD.
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Dual antiplatelet therapy with acetylsalicylic acid and a platelet P2Y12 receptor inhibitor, initially combined with heparin, either unfractioned and low weight molecular, could reduce the risk of
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thrombus formation/propagation [12,13,15,18,21,49,69]. These medications do not act on vessel wall healing, which remains an autonomous process, but could theoretically reduce true lumen
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compression interrupting false lumen thrombosis. The role of new P2Y12 adenosine diphosphate
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platelet receptor inhibitors, prasugrel and ticagrelor, for patients with SCAD is undefined.
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Chronic management with acetylsalicylic acid could be required for secondary prevention of recurrent SCAD. Following SCAD responsible for ACS, regardless stenting, 1-year DAPT should be recommended. Oral anticoagulation was sometimes indicated as adjunctive medication to acetylsalicylic acid and/or thienopyridine but its superiority or inefficacy compared with dual antiplatelet therapy is completely unexplored [12,13,19,157]. These therapeutic options are empirical and essentially based on the potential association between SCAD and thrombotic pseudoaneurysms [157,158]. Similarly, results of thrombolysis in SCAD are extremely controversial. Although thrombolysis can be effective [18,79,81,159], there are also data showing a systematic inefficacy to meet reperfusion criteria [160,161]. Thrombolysis is probably frequently ineffective because the vessel flow limitation is mostly due to mechanical luminal restriction (intimal-media membrane) rather than a true lumen thrombotic burden. Conversely, when thrombolytic agents are effective probably they lyse the thrombus into the false lumen 17
ACCEPTED MANUSCRIPT thereby enabling the improvement of coronary flow in the true lumen, but at the price of a serious risk of intramural hematoma propagation presumably due to exacerbated bleeding from vasa
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vasorum and subadventitial microvasculature surrounding the false lumen [162]. A single case of
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complete healing after treatment with tirofiban has been reported [163] and abciximab administration during PCI seems safe but its real efficacy is unknown [12].
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Beta-blockers can play a role in improving myocardial distress by lowering the heart rate
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and reducing oxygen consumption [13,15,69,138]. Calcium-blockers may be used to treat the possible vasospastic component associated to SCAD [12,120]. The eosinophilic periadventitial
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inflammation observed in some SCADs has suggested the adoption of an aggressive immunosuppressive therapy (prednisone and cytoxan) resulting in angiographic healing of
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SCAD, but it is very uncertain if the resolution was really attributable to immune-suppressive
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drugs more than to a spontaneous process [37]. Anti-inflammatory properties of statin could aid
AC CE P
the healing process but the efficacy of this treatment in SCAD remains speculative [18]. SCADs managed conservatively do not always meet a resolution and sometimes can even worsen [157,158,164,165]. In the retrospective study of Shamloo et al. these unfavourable results amounted to 60% of SCADs treated conservatively [21]. More recent data reported that in 4750% of SCADs treated with medical therapy the lesion worsens or remains unchanged and in 2529% PCI is required in the following weeks/months [12,18]. Studies supporting the excellent long-term outcome of patients receiving conservative treatment are hampered by a significant incidence of subsequent PCI during the index hospitalization or at follow up due to persisting symptoms or hemodynamic instability [12,18]. For these reasons, although an initial conservative strategy is reasonable in many SCAD, PCI remains a valid treatment in a certain amount of these patients. The physiologic healing process of SCAD generally leads to the almost complete disappearance of the intramural hematoma within 1-3 months [153,156]. This time limit could be 18
ACCEPTED MANUSCRIPT adopted as a cut-off to define, according to hemodynamic status, lesion site, and clinical
PT
condition, the need for subsequent PCI or CABG.
RI
Percutaneous management
PCI with stent deployment should be performed in dissections having reasonable
SC
extension, causing severe narrowing (70-99%) and/or vessel occlusion (TIMI flow 0 or 1), and
NU
associated with an unstable condition (Figure 7). After the first case of PCI with stent implantation reported by Stone et al. more than 15 years ago [166], many other successful
MA
procedures have been described [12,14,18,167-169]. In the last years drug eluting stents (DES) have been used frequently with good angiographic and clinical results [12,13,169].
D
Stent act not only providing the scaffolding that assures vessel canalization but also
TE
sealing the entry tear of dissection. After stenting, OCT generally discloses an adequate stent
AC CE P
coverage, expansion, and apposition, but frequently also a slight persistent intramural hematoma at the stented site (abluminal) and at the distal stent edge (75%) [138]. However, these residual findings observed in the early phase following stenting do not invalidate an optimal coronary flow and usually disappear in the long-term follow-up [138]. Residual hematoma might persist or worsen when imaging techniques are performed immediately after the implantation, showing the presence of a significant distance between stent and adventitia, a significant length of noncovered hematoma, and an enlargement of the false lumen in non-covered vessel segments adjacent to the stent, despite sealing of the entry door [69,170]. The clinical rate of successful PCI for SCAD is extremely variable (65-90%) according to the different reports [2,18] and, although stent implantation has been proven effective also in cases of multi-vessel involvement and in case of left main coronary artery location [171,172], PCI in these patients may be challenging and associated with dangerous complications. First, the 19
ACCEPTED MANUSCRIPT presence of a dissected segment entails the risk of lesion extension in case of guide-wire anterograde advancing within the subintimal space. On one side PCI of SCAD determining
PT
critical luminal reduction can save a greater amount of myocardium than medical therapy, but on
RI
the other side in 11.6% it causes intra-procedural propagation of the lesion worsening perfusion, temporarily or permanently [18]. Second, stent implantation may cause retrograde and/or
SC
anterograde propagation of the dissection toward unaffected coronary segments due to false
NU
lumen pressure-driven thrombus extrusion during inflation with further separation of dissected parietal layers [13,137,69,173]. In 16.3% of PCI for SCAD, while ultimately successful, an
MA
unanticipated propagation of the dissection flap or intramural hematoma requires placement of ≥ 2 further stents [18]. Paradoxically, SCAD propagation occurs more easily in normal arteries than
TE
D
in atherosclerotic ones. Atherosclerosis leads to medial atrophy and scarring that result in a lower propensity to media detachment while in normal artery the hallmark of dissection remains
AC CE P
separation of the vessel wall layers in segments free from disease [137]. The medium length of SCAD with associated CAD is significantly lower than that of SCAD without CAD (37 ± 26 mm vs 23 ± 16; p = 0.052) [13]. In pregnancy or in the postpartum period, SCAD propagation following stenting seems higher just because the young patients have not atherosclerotic coronaries and it has been described that in this subset up to 50% of PCI requires the implantation of additional stent for retrograde or anterograde extension of the lesion [33]. Direct stenting should be the preferred technique in SCAD non-associated with atherosclerosis, because the absence of complex fibrotic and calcific composition of the lesion does not require a preparatory pre-dilatation. Presently, however, no comparisons in SCAD between direct and secondary stenting are available. Third, regardless of dissection propagation, as described by Alfonso et al. by angiography and OCT [13,138], the lesion extent is generally very long. Since
20
ACCEPTED MANUSCRIPT the mean length of SCAD amounts generally to 30% of total coronary length [69], the total length of implanted stents is frequently consistent, up to 100-120 mm (7 stents) [13]. Although
PT
multiple stent implantation allows for an optimal early result, a “full-metal jacket” procedure may
RI
be complicated, even in DES era, by a high long-term risk of restenosis and target lesion revascularization (23.4%) [174]. In addition, long multiple stents can be subjected to fracture
SC
[175,176]. Finally, an extensive and unplanned stent implantation on the distal coronary may
NU
limit a subsequent surgical revascularization.
Stent implantation in SCAD should be performed selecting the most accurate diameter
MA
size. The thrombotic burden into the false lumen and the prolapsing intimal-media membrane of dissection can be responsible for a possible mismatch between the true reference vessel diameter
D
and the selected stent size with final late stent malapposition after wall healing [170]. Similarly,
TE
stent oversizing and high pressures should be avoided for the risk of SCAD propagation [69,170].
AC CE P
In conclusion, stent implantation should be recommended recommended in unstable patients requiring an urgent revascularization and in suitable clinical and anatomic conditions. PCI with balloon alone may be not enough to maintain the vessel permanently open [22].
Surgical management
Surgery is probably the most preferred treatment in stable patients with left main coronary artery bifurcation involvement, extensive multi-vessel presentation, failed medical therapy or ineffective PCI with evolving lesions [14,18,33,177,178] (Figure 7). SCAD of the left main coronary artery can be dangerous for the usual unstable presentation but emergency CABG has been proven to be feasible and effective [14,179-181]. Although CABG for SCAD generally showed favourable results and a good safety profile there are some considerable limitations. First, in some patients CABG is not feasible when SCAD 21
ACCEPTED MANUSCRIPT has extended into the periphery of coronary tree [3,14,18]. Second, in a consistent proportion of patients with SCAD the unstable hemodynamic status requires emergency PCI and in acute
PT
STEMI with involvement of a main coronary branch PCI has more chances to save vital
RI
myocardium. Third, up to 73% of grafts can be occluded at follow up for competitive flow after SCAD autonomous healing [18].
SC
SCAD can cause coronary pseudoaneurysm, when the healing process is unsuccessful, or
NU
left ventricular aneurysm, when the myocardial necrosis is extensive. Surgical repair in both these conditions has been proven effective [182,183]. Additionally, cardiac transplantation has been
MA
successfully performed in rare cases of young patients with persistent dramatic left ventricular
TE
Recurrent SCAD
D
dysfunction after SCAD [184-186].
AC CE P
Although long-term survival after SCAD appears favourable, the high rate of recurrent SCAD (17-46%) is of note [18,30,81]. Recurrent SCAD treatment is challenging and could invalidate the results of a successful first strategy. Even though in many cases recurrent SCAD can be due to the progression of SCAD in other vessel for unknown reasons rather than to first strategy failure, the treatment of the new episodes is generally more aggressive with PCI and CABG when the previous SCAD had been treated with medical therapy and PCI respectively. However there is no evidence that a more aggressive approach leads to superior results [30,34].
PROGNOSIS OF SCAD Early analyses defined SCAD as a rare coronary disease, diagnosed in 69% of cases only post-mortem, characterized by a poor prognosis and a strong association with SCD (75%) [3,20]. Furthermore a twenty-year post-mortem registry classified SCAD as the second most common 22
ACCEPTED MANUSCRIPT cause of non-atherosclerotic SCD [187]. Later, a comprehensive review reported an approximate mortality of 50%; patients who survived the main episode presented a survival probability of
PT
80% which decreased approximately to 50% in case of recurrent SCAD within 2 months [100].
RI
For the first time Jorgensen et al. demonstrated that a prompt and aggressive therapy could drastically improve SCAD survival rates [3]. SCAD is a dangerous coronary disease which, when
SC
immediately recognized and adequately treated, does not preclude a favourable long-term
NU
outcome. Although SCAD recurrence is relatively common, after the acute phase SCAD presents generally with a benign course. Data from the largest SCAD registry (87 patients) defines a
MA
98.9% 1-year survival rate and a 93.3% 10-year survival rate [18]. Long-term deaths were not commonly related to SCAD but to concurrent pathologies [18]. Since SCAD patients are
D
frequently not affected by CAD, when they are compared with matched atherosclerotic controls,
TE
the long term follow-up indicated significantly more favorable survival in the SCAD group (p =
AC CE P
0.02) [18].
CONCLUSION
SCAD is a relatively rare type of coronary artery disease. The available information derives from case report, case series and small retrospective mono-center registries. The optimal management of SCAD is uncertain because of the little amount of data in literature and the heterogeneous presentation. According to clinical conditions and lesion characteristics, a casespecific treatment seems the most reasonable strategy. Prospective multicenter registry involving a larger number of patients might help to elucidate the best treatment modality for SCAD.
23
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AC CE P
61.
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AC CE P
80.
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147. 148.
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tomography appearance and insights from intravascular ultrasound examination. Circulation 2006;113:e403-5. Alfonso F, Paulo M, Dutary J. Endovascular imaging of angiographically invisible spontaneous coronary artery dissection. JACC: Cardiovasc Interv 2012;5:452-3. Paulo M, Sandoval J, Lennie V, Dutary J, Medina M, Gonzalo N, Jimenez-Quevedo P, Escaned J, Bañuelos C, Hernandez R, Macaya C, Alfonso F. Combined Use of OCT and IVUS in Spontaneous Coronary Artery Dissection. JACC Cardiovasc Imaging 2013;6:8302. Poon K, Bell B, Raffel OC, Walters DL, Jang IK. Spontaneous coronary artery dissection. Utility of intravascular ultrasound and optical coherence tomography during percutaneous coronary intervention. Circ Cardiovasc Interv 2011;4:e5-7. Ishibashi K, Kitabata H, Akasaka T. Intracoronary optical coherence tomography assessment of spontaneous coronary artery dissection. Heart 2009;95:818. Alfonso F, Canales E, Aleong G. Spontaneous coronary artery dissection: diagnosis by optical coherence tomography. Eur Heart J 2009;30:385. Hoshi T, Sato A, Hiraya D, Kimura T, Aonuma K. Multimodality intracoronary imaging in spontaneous coronary artery dissection: Impacts of intravascular ultrasound, optical coherence tomography, and coronary angioscopy. Catheter Cardiovasc Interv 2013;81:E151-4. Cordone S, Ghione M, Foin N, et al. Endovascular imaging and 3-dimensional reconstruction of spontaneous coronary artery dissection. J Am Coll Cardiol 2013;62:350. Lubarsky L, Jelnin V, Roubin GS, Hecht HS. Spontaneous right coronary artery dissection: evaluation by 64-slice multidetector computed tomographic angiography. J Invasive Cardiol 2007;19:280-1. Park SM, Koh KK, Kim JH, Yoon KH, Chung WJ, Kang WC. Myocardial infarction with huge mural thrombus due to spontaneous coronary artery dissection detected by 64multidetector computed tomography. Int J Cardiol 2008;127:e73-5. Satoda M, Takagi K, Uesugi M, et al. Acute myocardial infarction caused by spontaneous postpartum coronary artery dissection. Nat Clin Pract Cardiovasc Med 2007; 4: 688-92. Nakashima T, Noguchi T, Morita Y, et al. Detection of intramural hematoma and serial non-contrast T1-weighted magnetic resonance imaging findings in a female patient with spontaneous coronary artery dissection. Circ J 2013;77:2844-5. Alfonso F, Paulo M, Lennie V, Das-Neves B, Echavarría-Pinto M. Fibromuscular dysplasia and spontaneous coronary artery dissection: coincidental association or causality? JACC Cardiovasc Interv 2013;6:638. Fujikura H, Hata Y, Morino Y, Matsuzaki A, Oikawa K, Ikari Y, Taguchi J. Acute Coronary Syndrome due to Intramural Hematoma. Circulation 2006;114:e644-5. Himbert D, Makowski S, Laperche T, Steg G, Juliard JM, Gourgon R. Left main coronary spontaneous dissection: progressive healing without surgery. Am Heart J 1991;122:1757-9. Sarmento-Leite R, Machado PR, Garcia SL. Spontaneous coronary artery dissection: stent it or wait for healing? Heart 2003;89:164. Porto I, Aurigemma C, Pennestrì F, Rebuzzi AG. Intravascular ultrasound-documented healing of spontaneous coronary artery dissection. Circ Cardiovasc Interv 2010;3:519-22. Furuichi S, Montorfano M, Godino C, Murino M, Sangiorgi GM, Colombo A. How should I treat a long and huge coronary pseudoaneurysm after spontaneous coronary artery dissection? EuroIntervention 2011;6:1131-1136. 31
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158. Boyer WB, Atalay MK, Sharaf BL. Left Main Pseudoaneurysm After Postpartum Coronary Dissection. Circ Cardiovasc Interv 2011;4:303-305. 159. Leclercq F, Messner-Pellenc P, Carabasse D, Lucke N, Rivalland F, Grolleau R. Successful thrombolysis treatment of a spontaneous left main coronary artery dissection without subsequent surgery. Eur Heart J 1996;17:320-1. 160. Banning AP. Salvage angioplasty and stenting following spontaneous dissection of the left anterior descending coronary artery. Heart 1999;82:e6. 161. Roig S, Gómez JA, Fiol M, Guindo J, Perez J, Carrillo A, Esplugas E, Bayes de Luna A. Spontaneous coronary artery dissection causing acute coronary syndrome: an early diagnosis implies a good prognosis. Am J Emerg Med 2003;21:549-51. 162. Zupan I, Noc M, Trinkaus D, Popovic M. Double vessel extension of spontaneous left main coronary artery dissection in young women treated with thrombolytics. Catheter Cardiovasc Interv 2001;52:226-30. 163. Cheung S, Mithani V, Watson RM. Healing of spontaneous coronary dissection in the context of glycoprotein IIB/IIIA inhibitor therapy: a case report. Catheter Cardiovasc Interv 2000;51:95-100. 164. Frimerman A, Meisel SR. Peripartum dissection of the right coronary artery. N Engl J Med 2004;351:e18. 165. Dhakam S, Ahmed H, Jafferani A. Percutaneous coronary intervention of left main pseudoaneurysm with customized covered stents. Catheter Cardiovasc Interv 2011;77:1033-5. 166. Stone GW, St Goar FG. Spontaneous coronary dissection resulting in acute myocardial infarction: successful treatment with primary angioplasty. Cathet Cardiovasc Diagn 1996;38:62-6. 167. Hanratty CG, McKeown PP, O'Keeffe DB. Coronary stenting in the setting of spontaneous coronary artery dissection. Int J Cardiol 1998;67:197-199 168. Vale PR, Baron DW. Coronary artery stenting for spontaneous coronary artery dissection: a case report and review of the literature. Cathet Cardiovasc Diagn 1998;45:280-6. 169. Datta G. Primary percutaneous coronary intervention in a case of idiopathic spontaneous coronary artery dissection. J Invasive Cardiol 2012;24:E84-6. 170. Sanchez-Recalde A, Moreno R, Jiménez-Valero S. Stenting of spontaneous intramural coronary haematoma: long-term consequences. Eur Heart J 2008;29:1593. 171. Azzarelli S, Fiscella D, Amico F, Giacoppo M, Argentino V, Fiscella A. Multivessel spontaneous coronary artery dissection in a postpartum woman treated with multiple drugeluting stents. J Cardiovasc Med (Hagerstown) 2009;10:340-343. 172. Le MQ, Ling FS. Spontaneous dissection of the left main coronary artery treated with percutaneous coronary stenting. J Invasive Cardiol 2007;19:E218-21. 173. Kang WC, Oh KJ, Han SH, Ahn TH, Shin EK. Progression of dissection due to residual dissection after intracoronary stenting for spontaneous coronary dissection at bifurcation site of LAD and diagonal artery. Int J Cardiol 2008;125:e40-3. 174. Sharp AS, Latib A, Ielasi A, Larosa C, Godino C, Saolini M, Magni V, Gerber RT, Montorfano M, Carlino M, Michev I, Chieffo A, Colombo A. Long-term follow-up on a large cohort of "full-metal jacket" percutaneous coronary intervention procedures. Circ Cardiovasc Interv 2009;2:416-22. 175. Sanchez-Recalde A, Guzmán G, Armada E, Moreno R. Multiple spontaneous coronary artery dissection associated with a left main coronary artery lesion treated by stenting. Late multiple stent fractures detected by multislice CT. Rev Esp Cardiol 2009;62:225-6. 32
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176. Canan T, Lee MS. Drug-eluting stent fracture: incidence, contributing factors, and clinical implications. Catheter Cardiovasc Interv 2010;75:237-45. 177. Unal M, Korkut AK, Kosem M, Ertunc V, Ozcan M, Caglar N. Surgical management of spontaneous coronary artery dissection. Tex Heart Inst J 2008;35:402-5. 178. Jobic Y, Avinée P, Boschat J, et al. Spontaneous and isolated dissection of the coronary arteries, apropos of 8 cases with favorable outcome. Arch Mal Coeur Vaiss 1993;86:173946. 179. Badmanaban B, McCarty D, Mole DJ, McKeown PP, Sarsam MA. Spontaneous coronary artery dissection presenting as cardiac tamponade. Ann Thorac Surg 2002;73:1324-6. 180. Thistlethwaite PA, Tarazi RY, Giordano FJ, Jamieson SW. Surgical management of spontaneous left main coronary artery dissection. Ann Thorac Surg 1998;66:258-60. 181. Goland S, Schwarz ER, Siegel RJ, Czer LS. Pregnancy-associated spontaneous coronary artery dissection. Am J Obstet Gynecol 2007;197:e11-3. 182. Pande AK, Kasliwal RR, Trehan N. Spontaneous primary coronary artery dissection leading to pseudoaneurysm. Int J Cardiol 1993;42:97-9. 183. Takaseya T, Nishimi M, Kawara T, Tayama E, Fukunaga S, Yokose S, Chihara S, Hayashida N, Aoyagi S. Spontaneous coronary artery dissection causing myocardial infarction and left ventricular aneurysm. Circ J 2002;66:972-3. 184. Ferrari E, Tozzi P, von Segesser LK. Spontaneous coronary artery dissection in a young woman: from emergency coronary artery bypass grafting to heart transplantation. Eur J Cardiothorac Surg 2005;28:349-51. 185. Ceresa F, Sansone F, Attisani M, Rinaldi M. Spontaneous coronary dissection due to isolated eosinophilic arteritis as a cause of urgent heart transplantation. Eur J Cardiothorac Surg 2009;36:767. 186. Appleby CE, Barolet A, Ing D, et al. Contemporary management of pregnancy-related coronary artery dissection: A single-centre experience and literature review. Exp Clin Cardiol 2009;14:e8-e16. 187. Hill SF, Sheppard MN. Non-atherosclerotic coronary artery disease associated with sudden cardiac death. Heart 2010;96:1119-25.
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Figure 1: Coronary Artery Dissections Classification – Coronary artery dissections can be classified as “Primary”, or spontaneous coronary artery dissections (SCAD), and “Secondary”.
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By definition, SCAD requires the absence of a traumatic, iatrogenic and non-coronary process
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(aortic dissection). Secondary dissections are generally consequent to coronary angioplasty
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(wiring, balloon dilatation, stenting), coronary angiography (coronary catheterization), cardiac
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surgery, ascending aortic dissection and thoracic trauma.
Figure 2: Morphologic Patterns – SCAD presents two patterns, one (“SCAD with entry door”,
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left) characterized by a luminal entry door and a detached intimal-media membrane (radiolucent
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flap at angiography), the other (SCAD without entry door or “angiographically-invisible SCAD”,
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right) characterized by an intramural hematoma without communication with coronary lumen. Probably most SCAD are at least initially SCAD without luminal entry door that subsequently break suddenly following the progressive enlargement of the intramural hematoma. The sudden blood inflow into the false lumen causes generally an abrupt vessel flow limitation and represents a further path of growth.
Figure 3: A) Angiography and Spontaneous Coronary Artery Dissection ˗ The radiolucent intimal-media flap (double lumen) is generally associated with persistent extra-luminal filling and/or delayed clearance of contrast media from lumen; B) Intravascular Ultrasound Imaging and Spontaneous Coronary Artery Dissection – IVUS can display not only the intimal-media membrane, but also the false lumen composition. Arrows: Organized thrombotic material; *: False lumen. Adapted from Maehara et al. [137]. C) Optical Coherence Tomography and 34
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identify the entry tear. OCT is the gold standard for the diagnosis of “angiographically-invisible
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SCAD”. Adapted from Alfonso et al. [138] and Cordone et al. [147].
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Figure 4: [Top panel] Spontaneous Coronary Artery Dissection Distribution in the
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Coronary Tree – Aggregating the prior reports of case series of at least 5 patients and small single-center registries, the left anterior descending is the more frequently involved coronary
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vessel. LMCA: Left Main Coronary Artery; LAD: Left Anterior Descending; LCX: Left Circumflex; RCA: Right Coronary Artery. [Center Panel]:
Spontaneous Coronary
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Dissections Vessel Distribution in Male and Female – Single-vessel (1) involvement is the
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most common presentation both in male and in female. Two-vessel (2) and three-vessel (3)
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presentations are significantly more frequent in female. Data from Shamloo et al. [21]. [Bottom Panel] Spontaneous Coronary Dissection Clinical Presentation – Aggregating the data deriving from case series of at least 5 patients and small single-center registries, STEMI resulted the most frequent clinical presentation. STEMI: ST segment Elevation Myocardial Infarction; NSTEMI: Non-ST segment Elevation Myocardial Infarction; UA: Unstable Angina; OTHERS: Stable Angina, Chronic Heart Failure symptoms or Ventricular Tachyarrhythmias.
Figure 5: A) Idiopathic Spontaneous Coronary Artery Dissection ˗ Macroscopic postmortem examination of a SCAD of left main coronary artery; B) Microscopic Appearance of Spontaneous Coronary Artery Dissection ˗ Intramural hematoma occupies a new virtual cavity between adventitia (outer) and intimal-media membrane (inner). *Indicates coronary lumen. Image modified from Adkins [61]. 35
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Figure 6: Spontaneous Coronary Dissection Physiopathology – Schematic representation of
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the processes potentially implicated in SCAD development. According to the site of action, it is
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possible to distinguish three groups of factors: 1) Vascular factors: mechanical and physical processes involving either the endothelium surface or the coronary vascular function; 2) Systemic
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factors: biochemical systemic dysfunction concerning inflammatory signalling, anomalous vessel
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response to endocrine stimulation, and immune-mediate lesions; 3) Parietal factors: abnormalities of media/subadventitia tissue layer characterized by connective tissue defects, vasa vasorum
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haemorrhage and microvascular anomalies. SCAD: Spontaneous Coronary Artery Dissection.
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Figure 7: Diagnostic and Therapeutic Algorithm – Proposed diagnostic and therapeutic
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algorithm for SCAD..*Whether hemodynamic condition allows the use of OCT or IVUS;
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†Unstable condition is defined by systolic blood pressure 30 minutes or catecholamines administration to maintain a systolic pressure >90 mmHg plus clinical signs of pulmonary congestion (dyspnea, pulmonary rales) or signs of impaired organ perfusion (mental status, hypoperfusion of extremities, oliguria with urine output 2.0 mmol/L);‡In unprotected left main coronary artery LMCA, SCAD without bifurcation involvement or without complex and extensive multi-vessel pattern could be considered for PCI. §Whether the vessel anatomy e SCAD complexity of distribution does not allow a percutaneous coronary artery intervention, urgent surgical revascularization is recommended. OCT: Optical Coherence Tomography; IVUS: IntraVascular UltraSound; Left Main Coronary Artery: LMCA; PCI: Percutaneous Coronary Intervention; CABG: Coronary Artery Bypass Grafting.
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Table 1: Most Relevant Data on Spontaneous Coronary Artery Dissection – The table table displays the most relevant data deriving from
LMCA
LAD
LCX
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published case series of at least 5 patients and small mono-center registries on Spontaneous Coronary Artery Dissection (SCAD).
RCA
PCI
N (%)
N (%)
N (%)
N (%)
N (%)
Women
N (%)
N (%)
N
Years
NR
11*
6 (54.5)
9
0 (0)
10 9852
0 (0)
2 (25)
CE
8
Basso et al.1
2,241
5 (0.22)
NR
8
2,225
5 (0.22)
N (%)
N (%)
N (%) (%)
3
2
8
0 (0) (27.3)
NR NR
(19.2)
(72.7)
3 (30)
7 (70)
3
5
(37.5)
(62.5)
NR
NR
0 (0)
4 (40)
1
4 (40)
5 (50)
1
3
6 (75) (12.5)
AC
(10.7)
Pasalodos Pita et al.16
N (%)
0 (0)
9 (90)**
1 (10)
(13.2) 44.1
NR
N (%)
46.1 8 (80)
(0.10) Jobic et al.178
UA N
0 (0)
(81.8)
PT ED
(11.8) Jorgensen et al.3
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43.1 DeMaio et al.27
Other CABG Medical STEMI NSTEMI
NU
(SD)
SC
Age SCAD
1 (20)
0 (0) (12.5)
(37.5)
4 (50)
4 (50)
52.0 (8.9) 1 (20)
2 (40)
0 (0)
3 (60)
0 (0)
2 (40)
3 (60)
3 (60)
0 (0)
2 (40) 0 (0)
8 (100) 43.2 (7.4) 2 (25)
5 (62)
1 (12)
1 (12)
NR
NR
NR
NR
NR
NR
3 (60)
2 (40)
1 (20)
3 (60)
0 (0)
0 (0)
5 (100)
3 (60)
0 (0)
0 (0)
NR 2
Zampieri et al.10
44.8 (14)
0 (0)
(40) 42 Hering et al.42
3,803
19 16 (38)
59 (12)
0 (0)
(1.10) Celik et al.38
3,750
9 (0.24)
15
(45) 2 (29)
55.8 (8.4) 2 (22)
31
8 (19)
5 (56)
44
0 (0)
8 (19) (36)
(74)
2 (22)
1 (11)
7 (78)
3 (7)
1 (11)
21
8
(50)
(19)
7 (78)
2
13 (31)
0 (0)
0 (0)
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(22) 15,000 5 (0.03)
4 (80)
42.8 (7.4) 1 (20)
3 (60)
0 (0)
2 (40)
1 (20)
0 (0)
4 (80)*
1 (20) 0 (0)
1 (14)
5 (71)
1 (14)
1 (14)
2 (33)
3 (50)
1 (17)
4 (57)*
3 (43)
44 (8.7)
0 (0)
3 (60)
2 (40)
0 (0)
1 (20)
1 (20)
3 (60)
4 (80)*
1 (20) 0 (0)
44 (NR)
2 (15)
5 (31)
4 (38)
9 (82)
2 (18)
NR
13 (100)*
2 (33)
3 (17)
3 (50)
1 (17)
1 (17)
4 (67)
5 (83)
1 (17)
0 (0)
0 (0)
0 (0)
1 (17)
0 (0)
0 (0)
5 (83)
0 (0)
1 (17)
3 (60)
2 (40)
0 (0)
7 (30)
0 (0)
NR
7
5 (71)
Maeder et al.15
5,054
5 (0.09) 5 (100)
NR
13
11 (85)
NU
12 Butler et al.69
SC
(12.2)
RI
40.6 Roig et al.161
4 (80)
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Maehara et al.135
0 (0)
0 (0) 0 (0)
1100† 6 (0.54)
1 (17)
Unal et al.177
5,000
4 (67)
Appleby et al.186
NR
Vanzetto et al.14
11,605
6 (0.12)
5
Motreff et al.48
1,780#
13 12
Ito et al.33
NR
CE
(100)
4 (80)
1 (20)
1 (20)
3 (60)
1 (10)
1 (10)
5 (22)
3 (13)
8 (35)
5 (22)
10 (43)
12
14
(52)
(60)
(10)
0 (0)
9 (69)
3 (23)
2 (18)
3 (23)
2 (15)
8 (62)
43.8 (9.0) 5 (42)
9 (75)
3 (25)
2 (17)
8 (67)
2 (17)
2 (17)
NR
NR
NR
16
7 (35)
6 (26)
3 (13)
6 (26)
14 (61)
11
11 (48)
1 (4)
19
13 1 (5)
3 (14)
(86)
16 2 (9)
7 (32)
(59)
1 (5) 4 (18)
1 (5)
(72) 13 (100)*
0 (0)
12 (100)
23
23
0 (0) 2
11 (85) 40.7 (6.7)
(0.67)
0 (0) 0 (0)
2 (9)
18 (82) 48.7 (8.9) (0.07)
6
AC
22 32,869
NR
48.0 (9.3) 5 (83)
17 (74) 46.3 (9.7) 3 (13) (0.20)
Kansara et al.30
0 (0)
5 (100) 30.8 (3.1) 1 (20)
23
Mortensen et al.13
38 (NR)
PT ED
Hendiri et al.82
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(92)
0 (0) 0(0)
44.8
5 (22)
45
0 (0)
ACCEPTED MANUSCRIPT
al.80 Toggweiler et al.81
47.7 15 (79)
(0.20) 3,428
12 0 (0)
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7
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(10.1) 45 Alfonso et al.12
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53 (11)
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(71) 24
26 (58) (0.27)
Saw et al.25
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(48)
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9,502†
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Romero-Rodríguez et
(10.7)
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Buja et al.49
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0 (0)
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(17.2)
*DeMaio et al. study consists of 94 patients but only 11 were antemortem and collected in the same institution; **Unspecified type of acute myocardial infarction; †Acute coronary syndromes; ‡Only 12 patients were reported (Magnetic Resonance Imaging study). CABG: coronary artery bypass grafting; LAD: left anterior descending; LCX: left circumflex; LMCA: left main coronary artery; NSTEMI: non ST-segment elevation myocardial infarction; PCI: percutaneous coronary intervention; RCA: right coronary artery; STEMI: ST-segment elevation myocardial infraction; NR: not reported or not retrievable; UA: unstable angina; Others: stable angina, silent ischemia, ventricular arrhythmias alone, heart failure. The case series of Alfonso et al.136 and Saw et al.117 are not showed in the table because included in their larger registries12,25. 46
S0167-5273(14)00860-2 doi: 10.1016/j.ijcard.2014.04.178 IJCA 18079
To appear in:
International Journal of Cardiology
Received date: Revised date: Accepted date:
13 August 2013 19 February 2014 17 April 2014
Please cite this article as: Giacoppo Daniele, Capodanno Davide, Dangas George, Tamburino Corrado, Spontaneous Coronary Artery Dissection, International Journal of Cardiology (2014), doi: 10.1016/j.ijcard.2014.04.178
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Spontaneous Coronary Artery Dissection
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Tamburino, MD, PhD*†
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Daniele Giacoppo, MD, Davide Capodanno MD, PhD*†, George Dangas, MD, PhD‡§, Corrado
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Institute of Cardiology, Ferrarotto Hospital, University of Catania, Catania, Italy (D.G., D.C.,
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C.T.), ETNA Foundation, Catania, Italy (D.C., C.T.), Department of Cardiology, Mount Sinai Medical Center, New York, United States (G.D.), Cardiovascular Research Foundation, New
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York, United States (G.D.)
Address for correspondence:
Davide Capodanno, MD, PhD. Cardiothoracic-vascular Department, Ferrarotto Hospital, University of Catania, via Citelli 6, 95124, Catania, Sicily, Italy; Phone: +39 0957436202; Fax: +39 0957436202; e-mail: [email protected]
1
ACCEPTED MANUSCRIPT ABSTRACT Spontaneous Coronary Artery Dissection (SCAD) is a relatively rare and unexplored type
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of coronary disease. Although atherosclerosis, hormonal changes during pregnancy and
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connective tissue disorders might represent a sufficiently convincing explanation for some patients with SCAD, the many remaining cases display only a weak relationship with these
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causes. While on one side the clinical heterogeneity of SCAD masks a full understanding of their
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underlying pathophysiologic process, paucity of data and misleading presentations on the other side hamper the quick diagnosis and optimal management of this condition. A definite diagnosis
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of SCAD can be significantly facilitated by endovascular imaging techniques. In fact, intravascular ultrasound and optical coherence tomography overcome the limitations of coronary
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angiography providing detailed endovascular morphologic information. In contrast, optimal
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treatment strategies for SCAD still represent a burning controversial question. Herein, we review
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the published data examining possible causes and investigating the best therapy for SCAD in different clinical scenarios.
Key Words:
SCAD, Spontaneous Coronary Artery Dissection, Dissection.
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ACCEPTED MANUSCRIPT Spontaneous coronary artery dissection (SCAD) is a vessel wall lesion characterized by an intramural hematoma (ie., false lumen) flattening the lumen (ie., true lumen) through the shift of
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the inner media against the opposite wall, which by definition requires the absence of a iatrogenic, non-coronary or traumatic etiology [1,2]. According to the underlying
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pathophysiology, SCAD has been also named “primary” coronary artery dissection, in contrast to
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the definitely more common “secondary” coronary artery dissection, which in contrast is
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explained by known factors, such as coronary catheterization, percutaneous coronary intervention (PCI), cardiac surgery, extended aortic root dissection or chest trauma (Figure 1) [3-6].
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SCADs generally present an intimal-media tear producing a communication between the vessel lumen and the intramural hematoma (“SCAD with entry door”) (Figure 2, left). Blood
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coming into the false lumen clots and spreads the flap of detached tissue. The dissection plane,
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located between the intima and the media or more commonly in the outer media, delimits a new
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hollow (false lumen) causing usually severe luminal narrowing and distortion [1,2,7]. However, several SCADs at least initially are only intramural hematomas that compress the lumen from outside reducing the blood flow (“angiographically-invisible SCAD). Subsequently some of these hematomas can evolve as result of continuous intramural bleeding and/or structural abnormalities (ie., inflammatory infiltrates, cystic medial necrosis) with the final intimal-media disruption promoting suddenly a further path of growth [1,2,7-9] (Figure 2, right). The typical angiographic sign of coronary dissection is a radiolucent intimal-media flap (double lumen), frequently associated with persistent extra-luminal filling and/or delayed clearance of contrast media from the lumen, detected in at least 2 orthogonal projections [1,2,10] (Figure 3A). However, as mentioned above, SCAD without luminal entry door frequently determines exclusively a smooth and regular coronary narrowing due to intramural hematoma eversion into the lumen [11,12]. These lesions not fulfilling the classical angiographic pattern of 3
ACCEPTED MANUSCRIPT coronary dissection can be detected with tomographic imaging techniques, such as intravascular ultrasound (IVUS) and optical coherence tomography (OCT) (Figure 3B, 3C) [11,12].
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The aim of this article is to provide a comprehensive description of SCADs, review their
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presentation and outcomes from the available literature, and critically appraise current diagnostic
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and therapeutic options.
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EPIDEMIOLOGY OF SCAD
SCAD is a relatively rare presentation of coronary disease with an estimated prevalence of 0.07-
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0.28% [12-17] and an annual incidence of 0.26 cases per 100,000 persons (0.33 in women, 0.18 in men) among US subjects [18]. Since the first case described by Pretty in 1931 [19], a total of
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only ~ 1125 SCADs (Appendix) have been reported in literature consisting largely of individual
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cases or case series and rarely of small single-center registries (< 90 patients).
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Patients with SCAD generally present without cardiovascular risk factors or history of coronary events [13-17] and are typically female (58-79%) [1,12,13,20] and young, with a mean age of 41 ± 10.6 years in women and of 45.4 ± 14.4 years in men [21]. SCAD may account for more than 10% of STEMI in women < 50 years of age [14]. Recently, SCAD presentations have been documented also in adolescents and in elderly [12,22-26]. The early assumption of a gender-specific location of SCAD, characterized by more frequent left coronary artery involvement in women (84-88%) and right coronary artery involvement in men (67-73%) [3,27], has been recently rejected, since left anterior descending represents the most frequent site of SCAD both in males and in females (69% vs 72%; p = 0.81) [12,13,18]. Regardless of the coronary involved, the mid segment appears the preferential site [12,26]. Combining data extracted from existing small registries and case series (Table 1, see the Online Appendix for a description of the adopted methodology), the left anterior descending 4
ACCEPTED MANUSCRIPT artery results the most commonly involved vessel (63.9% of patients) followed by the right coronary artery (26.5% of patients), the left circumflex (19.4% of patients) and the left main
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coronary artery (6.5% of patients) (Figure 4, upper; Table 1). Multi-vessel SCAD is near three
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times less common than single-vessel SCAD (26.4% vs 76.3%; p < 0.01) [21]. Comparing multivessel involvement frequency in female and male, the prevalence of SCAD results higher in
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women both in two-vessels (17.5% vs 12.9%; p = 0.022) and in three-vessels SCAD
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presentations (12.3% vs 5.3%; p = 0.029) (Figure 4, mid). Conversely, men more often present with single-vessel SCAD (81.8% vs 70.1%; p = 0.011) (Figure 4, mid) [21]. Reports of SCAD
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simultaneously involving all the three major epicardial arteries are anecdotal [28,29]. The prevalence of SCAD increases significantly in acute coronary syndromes (ACS) because the
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dissection is frequently responsible for an abrupt and severe flow limitation. However, there is a
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substantial discordance among reports in the frequency of each type of ACS. For instance,
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Mortensen et al. found almost invariably a ST-Elevation Myocardial Infarction (STEMI) at admission (84%), Tweet et al. indicated similar rates of STEMI (49%) and Non-ST Elevation Myocardial Infarction (NSTEMI) (44%), and Kansara et al. concluded that NSTEMI was the usual presentation of SCAD (85%) [13,18,30]. Aggregating the available evidence (Table 1), STEMI is diagnosed in 48.0% followed by NSTEMI in 36.3% and unstable angina (UA) in 6.5% (Figure 4, lower). In 5.5% of cases the admission diagnosis is stable angina, chronic heart failure symptoms or ventricular arrhythmias (Figure 4, lower). Ultimately, the true incidence of SCAD may be underestimated because of the frequent association between SCAD and sudden coronary death (SCD) [18]. Additional potential causes of SCAD under-reporting are “angiographically-invisible SCADs”, which are commonly misdiagnosed as atherosclerotic plaques or coronary spasms, and the general perception that coronary disease cannot involve young and otherwise healthy subjects. 5
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CLASSIFICATION
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Patients with SCAD are traditionally grouped into three subsets: those affected by coronary
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atherosclerotic disease (CAD), young women in the peripartum period and patients without known underlying coronary disease (idiopathic SCAD) [27] (Figure 1).
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Atherosclerotic SCAD: In earlier and recent SCAD registries, CAD accounts for not
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more than 24-28% [13,27]. Notably, in a retrospective study on gender difference in SCAD, female patients were found to be associated less frequently with a concurrent CAD (3.7% vs
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20.6%; p = 0.01) [30] and this is consistent with a contemporary registry reporting 83% of men in the group with atherosclerosis (p < 0.001) [12].
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Peripartum SCAD: SCAD is responsible for 27% of acute myocardial infarctions during
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pregnancy [32]; this rate increases to 50% in the peripartum period, representing the main cause
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of acute myocardial infarction [32]. Traditionally, SCAD presents a striking association with the peripartum period (more than 25%) [15,21,30], especially within the 2-3 weeks after the delivery [20,32,33]. Latest reports, however, show definitely lower percentages (3.8-5.3%) indicating that the actual prevalence may be lower [12,25]. Antepartum SCAD, both single-vessel and multivessel, occurs almost invariably in the last weeks of pregnancy and is definitely less common then the postpartum variant [34]. Idiopathic SCAD: Idiopathic SCAD, by definition, does not present with a clear etiology (Figure 5). The relationship between some idiopathic cases and connective tissue (Marfan, Ehlers-Danlos) and inflammatory disorders (rheumatoid arthritis, systemic lupus erythematosus) has been highlighted [2].
6
ACCEPTED MANUSCRIPT Recurrent SCAD Recurrent SCAD is defined as an unexpected ACS due to the development of a new dissection in
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a different coronary segment. The first report of recurrent SCAD was a post-mortem case
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described by van der Bel-Kahn in 1982 [35]. Recurrent SCAD involves women in almost all cases and has a strong correlation with the peripartum period and Ehlers-Danlos syndrome
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[15,36,37]. After the primary SCAD event, the 10-year recurrence rate is 29.4% [15]. The
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second event may occur between 3 days and 12 years, but approximately 50% of patients
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develops a recurrent SCAD within the first 2 weeks [31].
PATHOPHYSIOLOGY AND RISK FACTORS OF SCAD
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The aetiology of SCAD is still unknown but certainly multi-factorial and complex (Figure 6).
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Recurrent and multi-vessel SCADs might suggest a pathologic condition involving all coronary
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segments but the superimposed mechanism that allows explaining why some patients experienced SCAD differently compared with others with equivalent baseline conditions is generally lacking. Atherosclerosis: Clinical features of this subgroup of SCAD patients are driven by the underlying CAD. These patients are frequently male (78-83%) with typical coronary risk factors (diabetes, hypertension, hypercholesterolemia, smoke habit) [12,38]. Coronary plaque rupture might create a deep fissure into the artery wall and bleeding of plaque-induced vasa vasorum might progressively detach the wall tissues [38-42]. Peri-partum period: Pregnancy-related SCAD could be related to an excess of sexual hormones leading to vessel wall biochemical and structural changes [32,34,43]. Pathological signs consist of loss of normal corrugation of elastic fibers, fragmentation of reticular fibers, collagen degeneration and deficient production, hypertrophy of the smooth muscle cells, decrement in acid mucopolysaccharides and changes in protein and composition of the media 7
ACCEPTED MANUSCRIPT [43-46]. Moreover, the physiologic increase in blood volume and cardiac output observed in pregnancy may magnify shear forces of the blood column, resulting in a greater propensity for
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artery dissections [32,34]. The postabortion period should be considered at risk for SCAD
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because of hormonal influences [47].
Multiparity and menopausal period: These conditions may increase the risk for SCAD
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and the cause should be ascribed to hormonal factors similarly to typical neoplasms of elder
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female [33,48]. Recently it has been described that 26-45% of SCAD female patients are postmenopausal [25,49].
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Oral contraceptive: Oral contraceptive use (5.8%) has been correlated to SCAD in nonpregnant women [18,21,44,50-52]. The altered levels of sexual female hormones might impact on
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the risk for SCAD. The analogies among peripartum, menopausal and oral contraceptive SCAD
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variants could imply a common pathologic mechanism.
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Connective disorders: The Ehlers-Danlos syndrome consists of a heterogeneous group of inherited connective tissue disorders. The vascular type (type IV), resulting from mutations in the gene for type III procollagen (COL3A1), is the most severe because its complications are vascular fistula, artery dissection, aneurysm or perforation, and hollow organ (uterus, intestine) rupture [53]. SCAD in the Ehlers-Danlos syndrome is frequently associated with spontaneous dissections either of carotid/vertebral and/or principal thoracic and/or abdominal arteries [54,55]. The Marfan syndrome is an inherited autosomal dominant connective-tissue disease mainly caused by mutations in the gene encoding for the fibrillin-1 (FBN1), the primary constituent of extracellular matrix microfibrils [56]. Cystic medial necrosis, the common histologic sign of Marfan syndrome, is represented by focal fragmentation of elastic fibers, loss of media smooth muscle cells, and increased deposits of mucopolysaccharides [57,58]. Although up to 80% of patients with a Marfan syndrome have coronary cystic medial necrosis, coronary dissections are 8
ACCEPTED MANUSCRIPT more frequently due to extension of an aortic dissection [59,60]. Cystic medial necrosis has been described in 38% of SCAD, but only exceptionally a true pattern in non-Marfan patients has been
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associated to SCAD [7,61-64]. Loeys-Dietz syndrome and Neurofibromatosis type I are
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autosomal dominant disorders characterized by early mortality for dissection/rupture of aorta and renal arteries, respectively. Recent isolated reports of SCAD in patients with these syndromes
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strengthen the plausible association between some idiopathic SCADs and connective disorders
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[65,66].
Psycophysical stress: Several circumstances (strenuous physical exercise, emotional
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stress, sexual intercourse, protracted forceful retching or sneezing, prolonged sleep deprivation) may exceptionally determine SCAD but it is clear that the prerequisite is the presence of yet
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unknown common pathologic baseline conditions [67-82]. Strenuous exercise (increase in blood
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pressure and aorta/coronary flow, coronary vessel systolic mechanical stress) during athletic
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activity (cycling, soccer, running, swimming) [10,67-72] or weightlifting [73-76] is a frequent (up to 28%) SCAD trigger condition in athletes or trained subjects without SCAD risk factors [25,42]. Intense emotional stress (death of family member, arguments, divorce) was identified even in 17-26% of women just before SCAD [25,33]. Cocaine: The etiology of cocaine-induced myocardial ischemia appears to be the result of coronary artery vasoconstriction, thrombosis, and accelerated atherosclerosis [83-86]. The anomalous vessel regulation is probably related to marked media infiltration of chronic inflammatory cells, adventitial accumulation of activated mast cells, and critical hypertensive endothelial injury for increased sympathetic output [86-88]. Vascular inherited malformations: Osler-Rendu-Weber disease is a rare hereditary haemorrhagic disease characterized by abnormal telangiectasias and arterovenous malformations [89]. One case of SCAD is documented but this association could be a chance finding [90]. 9
ACCEPTED MANUSCRIPT Physical forces: Myocardial bridges are relatively common in the general population with an attested frequency > 1% [91]. Recently, myocardial bridge has been considered as a
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potential SCAD risk factor, but there is no strong evidence [92]. Sometime, coronary ecstasia and
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aneurysms are observed near or within SCAD [93-96]. The causal relationship might be bidirectional, since on one side aneurysms could be the long-term result of unsuccessful
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dissection healing processes, while on the other SCAD could be promoted by ectasia/aneurysm
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itself for the superficial tension produced on the parietal surface of the false lumen. This physical model has not been proved and appears unable in explaining the many remaining SCAD cases
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not associated with coronary ectasia/aneurysm. Finally, hypertensive crisis [97,98] and severe coronary spasm [99,100] have been uncommonly advocated as first step of SCAD process.
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Vasculitis and inflammatory disorders: The underlying inflammatory process has been
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frequently used to explain SCAD because of the frequent observation of inflammatory infiltrates,
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predominantly eosinophil granulocytes but also macrophages and histiocytic multinucleated giant cells, in the adventitia of dissected arteries [101-103]. Parietal damage may be due to the lytic action of proteases released from eosinophil cells, but this finding could be more probably a reactive process than expression of primary vasculitis [103-105]. When observed, however, inflammatory abnormalities may predict early SCAD recurrence [30]. Polyarteritis nodosa and Takayasu’s arteritis have been exceptionally related to SCAD ascertainment of SCAD [106-108]. Laboratory test and renal biopsies showeing a coexisting systemic lupus erythematosus and the reported concurrence of HCV-related mixed cryoglobulinaemia in one case also suggesst a possible role of cryoprecipitable circulating immune complexes [109-111]. Occasionally, inflammatory bowel disease has been found in patients with SCAD [25,30]. Fibromuscular dysplasia: Fibromuscular dysplasia (FMD) is an emerging hypothesis. FMD is a segmental idiopathic, non-atherosclerotic, non-inflammatory vasculopathy typically 10
ACCEPTED MANUSCRIPT affecting small-medium muscular arteries [112]. Renal (60-80%) and cervical arteries (20-30%) are the most commonly involved, while coronary FMD is very rare [113,114]. A recent registry
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of 50 patients experiencing SCAD, who were screened for peripheral FMD (cerebrovascular,
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carotid, renal, iliac) provided an unexpected potential explanation for idiopathic SCAD [25]. The "string of beads pattern" typical of FMD in peripheral vessels was disclosed with invasive
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angiography or multi-detector computed tomography (MDCT) or magnetic resonance imaging
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(MRI) in 86% of patients [25]. However, a recent case series of 12 patients with SCAD who underwent MRI reported a significantly lower prevalence (17%) and exclusive renal arteries
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localization [81]. Some reports tried to supply additional information on this association using also endovascular imaging [115-118]. SCAD associated with coronary FMD seems to be less
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common [25]. These interesting results deserve further investigation.
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Polycystic Kidney Disease: Autosomal dominant polycystic kidney disease is a
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monogenic disorder characterized by the formation of cysts in both kidneys. Vascular abnormalities include intracranial aneurysms, aortic aneurysm and dissection, and cervicocephalic arteries dissections. In the last years SCAD has also been described in patients suffering from polycystic kidney disease [119]. Drugs: Administration of antineoplastic (cyclosporine, 5-fluorouracil), antipsychotic (fenfluramine) and antimigraine (ergotamine) drugs has been associated with SCAD [120-123] and drug hypersensivity reactions can produce angiitis of vasa vasorum [124]. Recently a patient who underwent nonmyeloablative (Fludarabine and 400 cGy)-matched unrelated donor bone marrow transplant experienced SCAD [125]. Whether all these findings are associated with SCAD occurrence and whether they are sufficient to produce the lesion is unclear.
11
ACCEPTED MANUSCRIPT CLINICAL PRESENTATION AND LABORATORY FINDINGS OF SCAD SCAD presentation encompasses the entire spectrum of coronary syndromes, ranging
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from asymptomatic patients, across those presenting stable angina, NSTEMI, STEMI, to SCD.
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Regardless of the type and cause, SCAD impairs myocardial perfusion reducing vessel lumen area similarly to atherosclerotic stenoses; therefore symptoms usually do not differ from those
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observed in ACS for CAD, but sometimes the clinical setting can be atypical and even
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misleading. Chest pain is the main symptom (91%) followed by syncope (23%), dyspnea, diaphoresis, and nausea [13,18]. Rarely dizziness and pre-syncope are the leading symptoms at
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presentation [126]. In other cases clinical manifestation can be only represented by dyspnoea [25,127], which in the most dramatic cases can evolve rapidly in cardiogenic shock due to severe
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global systolic dysfunction [128,129]. Life-threating arrhythmia requiring emergent defibrillation
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(high-frequency ventricular tachycardia, ventricular fibrillation) at admission has been
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documented in 8-14% [13,18,30,130], while an atrio-ventricular block is particularly uncommon [13]. Finally, SCAD can be also completely asymptomatic [131]. Blood cells, hemoglobin, coagulation, acute phase reactants, hormones and antibodies are within normal range in almost all SCAD patients. Sometimes unspecific increases upon the normal range in erythrocyte sedimentation rate, C-reactive protein, fibrinogen, leukocytes, rheumatoid factor, homocysteine, IgA, IgG, anticardiolipin IgM and phospholipid antibodies were noted, but these findings did not imply a clear causal relationship with SCAD [12,13,30,108,132,133].
DIAGNOSIS OF SCAD The diagnosis of SCAD is almost exclusively incidental during coronary angiography following STEMI or UA/NSTEMI. Coronary angiography represents the first line exam because it can rule 12
ACCEPTED MANUSCRIPT out the suspicion of SCAD. The angiographic pattern, however, is highly variable ranging from long and multiple dissections in an otherwise physiologic coronary tree to a single short
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dissection in atherosclerotic and calcific coronary vessels. Coronary angiography becomes less sensible in specific conditions such as extensive thrombosis, when luminal material masks the
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dissected segment or completely fills the false lumen, in the “angiographically-invisible” pattern,
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when a radiolucent flap is not detectable and the smooth narrowing is due to spasm.
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Intracoronary injection of nitroglycerin can facilitate the differential diagnosis between SCAD and spasm [134].
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Sometimes the dissection can progress under the action of blood flow or contrast media [33,135,136]. A pre-discharge second-look coronary angiography during index hospitalization
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could be considered in potentially dangerous anatomic patterns (large amount of downstream
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jeopardized myocardium) or when symptoms could indicate the potential worsening of dissection
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extent. Routine coronary angiography control should be avoided since contrast media can favor SCAD progression. During coronary angiography for SCAD, after the initial angiograms, an extension of the lesion is displayed in 17% of cases and a new dissection in another coronary vessel is observable in 26% [33].
Saw proposed an angiographic classification of SCAD [134]. This classification is essentially based on three distinct angiographic appearances: type 1 (“evident arterial wall stain”), characterized by contrast dye staining of arterial wall with multiple radiolucent filling defects; type 2 (“diffuse stenosis of varying severity”), namely misleading/unapparent angiographic features characterized by abrupt changes from normal vessel diameter to diffuse narrowing (generally > 20 mm) and frequent involvement of the mid-distal segments; type 3 (“mimic atherosclerosis”) characterized by absent atherosclerotic changes in other coronary arteries, long lesions (11–20 mm), and hazy or linear stenosis. 13
ACCEPTED MANUSCRIPT
Endovascular Imaging Techniques
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Maehara et al. firstly described with IVUS the presence of two morphologic patterns of
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SCAD: the SCAD provided with intimal flap, usually identifiable with coronary angiography alone, characterized by an intimal tear and the ability to propagate for blood inflow into the false
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lumen, and the “angiographically-invisible” SCAD, characterized by intramural hematoma but no
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intimal entry site, having enlargement potentiality after continuous bleeding into the new virtual cavity [137] (Figure 2, Figure 3B). According to OCT results, SCADs associated with one or,
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very rarely, double rupture site account for 74% of SCADs [138]. Invasive coronary imaging techniques result irreplaceable in the “angiographically-invisible” pattern.
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IVUS can define with high precision the magnitude of true lumen impairment as well as
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the spatial distribution and the heterogeneity degree of the false lumen [13,139,140] (Figure 3A,
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3B). IVUS, however, do not display accurately the endothelial surface and smaller intramural hematomas. OCT overcomes these limitations by means of its higher resolution (150 µm vs 15 µm) and, comparing the two techniques, OCT is able to disclose an intimal entry site whereas IVUS detects only the intramural hematoma [141-143]. OCT is the gold standard technique to evaluate the double-lumen morphology characteristics, to identify the entry tear, to measure with high accuracy the circumferential and longitudinal extent of the lesion, to define the involvement of side branches and finally to detect any associated intraluminal thrombus [138,144,145] (Figure 3C). The most important characteristic of OCT is the ability in ruling out almost all doubtful angiograms. In 35% of confined angiographic lumen narrowing or linear filling defect diagnosed as SCAD, OCT reveals only a luminal red thrombus inducing partial dorsal shadowing or an ulcerated severe atherosclerotic coronary artery disease [138]. However, OCT requires more caution than IVUS 14
ACCEPTED MANUSCRIPT since contrast media injection during image acquisition requires greater volumes and sometimes higher flow velocity and/or pressure. These factors can be dangerous in hemodynamically
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unstable conditions and entail in every clinical presentation a minimal risk of dissection
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progression.
Alfonso et al. described in vivo the micr-oanatomic characteristics of SCAD in a case
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series of 11 patients evaluated with OCT [138]. All patients had a partial or complete thrombosis
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of false lumen (mean area 5.9 ± 2.1 mm2) determining a critical reduction of the true lumen (mean area 1.1 ± 0.5 mm2) [138]. The length of the diseased segment was high (32 ± 12 mm) and
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greater than with angiography measurements (double lumen, 8.4 ± 6.7 mm; intramural hematoma, 21.9 ± 15 mm) [138]. Even though the intimal-media membrane was relatively thick
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(348 ± 84 µm), the edges of the intimal rupture site were particularly thin (99 ± 66 µm) [138].
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This interesting finding should be integrated with the documented presence of superficial lipid
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plaque nearby the coronary dissection entry point, which might explain the focal fragility of the arterial wall and the subsequent development of a “SCAD with entry door” pattern [146]. OCT/IVUS-guided PCI for SCAD is strongly recommended to prevent inadequate or excessive stent coverage, displaying precisely the effective measures of dissection, and to reduce the risk of progression following stenting [138,142,143]. Three-dimensional OCT has been shown to be able to elaborate extremely reliable images but its effective usefulness compared to standard OCT is unclear [147].
Non-invasive Imaging Techniques MDCT has been proven to be superior to coronary angiography in showing the subadventitial hematoma in “angiographically-invisible SCAD” [140,148]. SCAD generate a low-intermediate density signal surrounding the diseased vessel segment and a double lumen 15
ACCEPTED MANUSCRIPT aspect [149,150]. Obviously MDCT is recommended only when the patient is stable and asymptomatic and when there is a reasonably low probability of PCI necessity. Information
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regarding cardiac MRI in SCAD diagnosis are insufficient. In a recent case of SCAD detected
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with coronary angiography implemented by IVUS, subsequent MRI showed the coronary
SC
intramural hematoma as a hyperintense region on non-contrast T1-weighted imaging [151].
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TREATMENT OF SCAD
The lack of consensus surrounding the treatment of SCAD stems from its clinical
MA
heterogeneity and the evidence of different successful therapeutic strategies. In non-lifethreatening SCAD, long-term benefits of invasive revascularization compared to medical
D
treatment are uncertain. Management decision should be made case-by-case, integrating clinical
TE
conditions and echocardiographic parameters with angiography and endovascular imaging to
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recognize SCAD location, extent and characteristics as well as the degree of flow impairment or luminal area reduction. In highly unstable ACS the preferential therapy is PCI. Shamloo et al., aggregating data and comparing retrospectively different treatment modalities, showed that patients undergoing coronary artery bypass grafting (CABG) or PCI had a statistically significant longer symptom-free period and lower mortality rates compared to those who were managed with medical therapy alone [21]. However, registries prevalently consisting of stable patients showed excellent long-term results with conservative treatment [25,152].
Medical management A conservative management may be the optimal initial treatment in SCAD ≤ 50% and TIMI flow 3 or asymptomatic patients (Figure 7). In stable clinical conditions and reassuring hemodynamic status the watchful waiting approach is recommendable since the lesion can meet 16
ACCEPTED MANUSCRIPT an autonomous resolution. This has been proven not only with coronary angiography but also with IVUS [153-156]. However, whether medical management alone is an acceptable strategy in
PT
SCAD causing a lumen diameter limitation > 70% and/or TIMI flow < 3 and/or presenting
RI
proximal location is controversial. In these conditions the evidence of myocardial ischemia and the potential inefficacy of medical treatment could imply a considerable risk. Presently it is not
SC
available an imaging sign or a laboratory marker anticipating the natural evolution of SCAD.
NU
Dual antiplatelet therapy with acetylsalicylic acid and a platelet P2Y12 receptor inhibitor, initially combined with heparin, either unfractioned and low weight molecular, could reduce the risk of
MA
thrombus formation/propagation [12,13,15,18,21,49,69]. These medications do not act on vessel wall healing, which remains an autonomous process, but could theoretically reduce true lumen
D
compression interrupting false lumen thrombosis. The role of new P2Y12 adenosine diphosphate
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platelet receptor inhibitors, prasugrel and ticagrelor, for patients with SCAD is undefined.
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Chronic management with acetylsalicylic acid could be required for secondary prevention of recurrent SCAD. Following SCAD responsible for ACS, regardless stenting, 1-year DAPT should be recommended. Oral anticoagulation was sometimes indicated as adjunctive medication to acetylsalicylic acid and/or thienopyridine but its superiority or inefficacy compared with dual antiplatelet therapy is completely unexplored [12,13,19,157]. These therapeutic options are empirical and essentially based on the potential association between SCAD and thrombotic pseudoaneurysms [157,158]. Similarly, results of thrombolysis in SCAD are extremely controversial. Although thrombolysis can be effective [18,79,81,159], there are also data showing a systematic inefficacy to meet reperfusion criteria [160,161]. Thrombolysis is probably frequently ineffective because the vessel flow limitation is mostly due to mechanical luminal restriction (intimal-media membrane) rather than a true lumen thrombotic burden. Conversely, when thrombolytic agents are effective probably they lyse the thrombus into the false lumen 17
ACCEPTED MANUSCRIPT thereby enabling the improvement of coronary flow in the true lumen, but at the price of a serious risk of intramural hematoma propagation presumably due to exacerbated bleeding from vasa
PT
vasorum and subadventitial microvasculature surrounding the false lumen [162]. A single case of
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complete healing after treatment with tirofiban has been reported [163] and abciximab administration during PCI seems safe but its real efficacy is unknown [12].
SC
Beta-blockers can play a role in improving myocardial distress by lowering the heart rate
NU
and reducing oxygen consumption [13,15,69,138]. Calcium-blockers may be used to treat the possible vasospastic component associated to SCAD [12,120]. The eosinophilic periadventitial
MA
inflammation observed in some SCADs has suggested the adoption of an aggressive immunosuppressive therapy (prednisone and cytoxan) resulting in angiographic healing of
D
SCAD, but it is very uncertain if the resolution was really attributable to immune-suppressive
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drugs more than to a spontaneous process [37]. Anti-inflammatory properties of statin could aid
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the healing process but the efficacy of this treatment in SCAD remains speculative [18]. SCADs managed conservatively do not always meet a resolution and sometimes can even worsen [157,158,164,165]. In the retrospective study of Shamloo et al. these unfavourable results amounted to 60% of SCADs treated conservatively [21]. More recent data reported that in 4750% of SCADs treated with medical therapy the lesion worsens or remains unchanged and in 2529% PCI is required in the following weeks/months [12,18]. Studies supporting the excellent long-term outcome of patients receiving conservative treatment are hampered by a significant incidence of subsequent PCI during the index hospitalization or at follow up due to persisting symptoms or hemodynamic instability [12,18]. For these reasons, although an initial conservative strategy is reasonable in many SCAD, PCI remains a valid treatment in a certain amount of these patients. The physiologic healing process of SCAD generally leads to the almost complete disappearance of the intramural hematoma within 1-3 months [153,156]. This time limit could be 18
ACCEPTED MANUSCRIPT adopted as a cut-off to define, according to hemodynamic status, lesion site, and clinical
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condition, the need for subsequent PCI or CABG.
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Percutaneous management
PCI with stent deployment should be performed in dissections having reasonable
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extension, causing severe narrowing (70-99%) and/or vessel occlusion (TIMI flow 0 or 1), and
NU
associated with an unstable condition (Figure 7). After the first case of PCI with stent implantation reported by Stone et al. more than 15 years ago [166], many other successful
MA
procedures have been described [12,14,18,167-169]. In the last years drug eluting stents (DES) have been used frequently with good angiographic and clinical results [12,13,169].
D
Stent act not only providing the scaffolding that assures vessel canalization but also
TE
sealing the entry tear of dissection. After stenting, OCT generally discloses an adequate stent
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coverage, expansion, and apposition, but frequently also a slight persistent intramural hematoma at the stented site (abluminal) and at the distal stent edge (75%) [138]. However, these residual findings observed in the early phase following stenting do not invalidate an optimal coronary flow and usually disappear in the long-term follow-up [138]. Residual hematoma might persist or worsen when imaging techniques are performed immediately after the implantation, showing the presence of a significant distance between stent and adventitia, a significant length of noncovered hematoma, and an enlargement of the false lumen in non-covered vessel segments adjacent to the stent, despite sealing of the entry door [69,170]. The clinical rate of successful PCI for SCAD is extremely variable (65-90%) according to the different reports [2,18] and, although stent implantation has been proven effective also in cases of multi-vessel involvement and in case of left main coronary artery location [171,172], PCI in these patients may be challenging and associated with dangerous complications. First, the 19
ACCEPTED MANUSCRIPT presence of a dissected segment entails the risk of lesion extension in case of guide-wire anterograde advancing within the subintimal space. On one side PCI of SCAD determining
PT
critical luminal reduction can save a greater amount of myocardium than medical therapy, but on
RI
the other side in 11.6% it causes intra-procedural propagation of the lesion worsening perfusion, temporarily or permanently [18]. Second, stent implantation may cause retrograde and/or
SC
anterograde propagation of the dissection toward unaffected coronary segments due to false
NU
lumen pressure-driven thrombus extrusion during inflation with further separation of dissected parietal layers [13,137,69,173]. In 16.3% of PCI for SCAD, while ultimately successful, an
MA
unanticipated propagation of the dissection flap or intramural hematoma requires placement of ≥ 2 further stents [18]. Paradoxically, SCAD propagation occurs more easily in normal arteries than
TE
D
in atherosclerotic ones. Atherosclerosis leads to medial atrophy and scarring that result in a lower propensity to media detachment while in normal artery the hallmark of dissection remains
AC CE P
separation of the vessel wall layers in segments free from disease [137]. The medium length of SCAD with associated CAD is significantly lower than that of SCAD without CAD (37 ± 26 mm vs 23 ± 16; p = 0.052) [13]. In pregnancy or in the postpartum period, SCAD propagation following stenting seems higher just because the young patients have not atherosclerotic coronaries and it has been described that in this subset up to 50% of PCI requires the implantation of additional stent for retrograde or anterograde extension of the lesion [33]. Direct stenting should be the preferred technique in SCAD non-associated with atherosclerosis, because the absence of complex fibrotic and calcific composition of the lesion does not require a preparatory pre-dilatation. Presently, however, no comparisons in SCAD between direct and secondary stenting are available. Third, regardless of dissection propagation, as described by Alfonso et al. by angiography and OCT [13,138], the lesion extent is generally very long. Since
20
ACCEPTED MANUSCRIPT the mean length of SCAD amounts generally to 30% of total coronary length [69], the total length of implanted stents is frequently consistent, up to 100-120 mm (7 stents) [13]. Although
PT
multiple stent implantation allows for an optimal early result, a “full-metal jacket” procedure may
RI
be complicated, even in DES era, by a high long-term risk of restenosis and target lesion revascularization (23.4%) [174]. In addition, long multiple stents can be subjected to fracture
SC
[175,176]. Finally, an extensive and unplanned stent implantation on the distal coronary may
NU
limit a subsequent surgical revascularization.
Stent implantation in SCAD should be performed selecting the most accurate diameter
MA
size. The thrombotic burden into the false lumen and the prolapsing intimal-media membrane of dissection can be responsible for a possible mismatch between the true reference vessel diameter
D
and the selected stent size with final late stent malapposition after wall healing [170]. Similarly,
TE
stent oversizing and high pressures should be avoided for the risk of SCAD propagation [69,170].
AC CE P
In conclusion, stent implantation should be recommended recommended in unstable patients requiring an urgent revascularization and in suitable clinical and anatomic conditions. PCI with balloon alone may be not enough to maintain the vessel permanently open [22].
Surgical management
Surgery is probably the most preferred treatment in stable patients with left main coronary artery bifurcation involvement, extensive multi-vessel presentation, failed medical therapy or ineffective PCI with evolving lesions [14,18,33,177,178] (Figure 7). SCAD of the left main coronary artery can be dangerous for the usual unstable presentation but emergency CABG has been proven to be feasible and effective [14,179-181]. Although CABG for SCAD generally showed favourable results and a good safety profile there are some considerable limitations. First, in some patients CABG is not feasible when SCAD 21
ACCEPTED MANUSCRIPT has extended into the periphery of coronary tree [3,14,18]. Second, in a consistent proportion of patients with SCAD the unstable hemodynamic status requires emergency PCI and in acute
PT
STEMI with involvement of a main coronary branch PCI has more chances to save vital
RI
myocardium. Third, up to 73% of grafts can be occluded at follow up for competitive flow after SCAD autonomous healing [18].
SC
SCAD can cause coronary pseudoaneurysm, when the healing process is unsuccessful, or
NU
left ventricular aneurysm, when the myocardial necrosis is extensive. Surgical repair in both these conditions has been proven effective [182,183]. Additionally, cardiac transplantation has been
MA
successfully performed in rare cases of young patients with persistent dramatic left ventricular
TE
Recurrent SCAD
D
dysfunction after SCAD [184-186].
AC CE P
Although long-term survival after SCAD appears favourable, the high rate of recurrent SCAD (17-46%) is of note [18,30,81]. Recurrent SCAD treatment is challenging and could invalidate the results of a successful first strategy. Even though in many cases recurrent SCAD can be due to the progression of SCAD in other vessel for unknown reasons rather than to first strategy failure, the treatment of the new episodes is generally more aggressive with PCI and CABG when the previous SCAD had been treated with medical therapy and PCI respectively. However there is no evidence that a more aggressive approach leads to superior results [30,34].
PROGNOSIS OF SCAD Early analyses defined SCAD as a rare coronary disease, diagnosed in 69% of cases only post-mortem, characterized by a poor prognosis and a strong association with SCD (75%) [3,20]. Furthermore a twenty-year post-mortem registry classified SCAD as the second most common 22
ACCEPTED MANUSCRIPT cause of non-atherosclerotic SCD [187]. Later, a comprehensive review reported an approximate mortality of 50%; patients who survived the main episode presented a survival probability of
PT
80% which decreased approximately to 50% in case of recurrent SCAD within 2 months [100].
RI
For the first time Jorgensen et al. demonstrated that a prompt and aggressive therapy could drastically improve SCAD survival rates [3]. SCAD is a dangerous coronary disease which, when
SC
immediately recognized and adequately treated, does not preclude a favourable long-term
NU
outcome. Although SCAD recurrence is relatively common, after the acute phase SCAD presents generally with a benign course. Data from the largest SCAD registry (87 patients) defines a
MA
98.9% 1-year survival rate and a 93.3% 10-year survival rate [18]. Long-term deaths were not commonly related to SCAD but to concurrent pathologies [18]. Since SCAD patients are
D
frequently not affected by CAD, when they are compared with matched atherosclerotic controls,
TE
the long term follow-up indicated significantly more favorable survival in the SCAD group (p =
AC CE P
0.02) [18].
CONCLUSION
SCAD is a relatively rare type of coronary artery disease. The available information derives from case report, case series and small retrospective mono-center registries. The optimal management of SCAD is uncertain because of the little amount of data in literature and the heterogeneous presentation. According to clinical conditions and lesion characteristics, a casespecific treatment seems the most reasonable strategy. Prospective multicenter registry involving a larger number of patients might help to elucidate the best treatment modality for SCAD.
23
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41.
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67.
68.
69. 70. 71.
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73. 74.
75. 76.
77. 78.
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62.
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AC CE P
61.
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86. 87.
88. 89. 90. 91. 92.
93.
94. 95. 96. 97.
98.
99.
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84.
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83.
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82.
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158. Boyer WB, Atalay MK, Sharaf BL. Left Main Pseudoaneurysm After Postpartum Coronary Dissection. Circ Cardiovasc Interv 2011;4:303-305. 159. Leclercq F, Messner-Pellenc P, Carabasse D, Lucke N, Rivalland F, Grolleau R. Successful thrombolysis treatment of a spontaneous left main coronary artery dissection without subsequent surgery. Eur Heart J 1996;17:320-1. 160. Banning AP. Salvage angioplasty and stenting following spontaneous dissection of the left anterior descending coronary artery. Heart 1999;82:e6. 161. Roig S, Gómez JA, Fiol M, Guindo J, Perez J, Carrillo A, Esplugas E, Bayes de Luna A. Spontaneous coronary artery dissection causing acute coronary syndrome: an early diagnosis implies a good prognosis. Am J Emerg Med 2003;21:549-51. 162. Zupan I, Noc M, Trinkaus D, Popovic M. Double vessel extension of spontaneous left main coronary artery dissection in young women treated with thrombolytics. Catheter Cardiovasc Interv 2001;52:226-30. 163. Cheung S, Mithani V, Watson RM. Healing of spontaneous coronary dissection in the context of glycoprotein IIB/IIIA inhibitor therapy: a case report. Catheter Cardiovasc Interv 2000;51:95-100. 164. Frimerman A, Meisel SR. Peripartum dissection of the right coronary artery. N Engl J Med 2004;351:e18. 165. Dhakam S, Ahmed H, Jafferani A. Percutaneous coronary intervention of left main pseudoaneurysm with customized covered stents. Catheter Cardiovasc Interv 2011;77:1033-5. 166. Stone GW, St Goar FG. Spontaneous coronary dissection resulting in acute myocardial infarction: successful treatment with primary angioplasty. Cathet Cardiovasc Diagn 1996;38:62-6. 167. Hanratty CG, McKeown PP, O'Keeffe DB. Coronary stenting in the setting of spontaneous coronary artery dissection. Int J Cardiol 1998;67:197-199 168. Vale PR, Baron DW. Coronary artery stenting for spontaneous coronary artery dissection: a case report and review of the literature. Cathet Cardiovasc Diagn 1998;45:280-6. 169. Datta G. Primary percutaneous coronary intervention in a case of idiopathic spontaneous coronary artery dissection. J Invasive Cardiol 2012;24:E84-6. 170. Sanchez-Recalde A, Moreno R, Jiménez-Valero S. Stenting of spontaneous intramural coronary haematoma: long-term consequences. Eur Heart J 2008;29:1593. 171. Azzarelli S, Fiscella D, Amico F, Giacoppo M, Argentino V, Fiscella A. Multivessel spontaneous coronary artery dissection in a postpartum woman treated with multiple drugeluting stents. J Cardiovasc Med (Hagerstown) 2009;10:340-343. 172. Le MQ, Ling FS. Spontaneous dissection of the left main coronary artery treated with percutaneous coronary stenting. J Invasive Cardiol 2007;19:E218-21. 173. Kang WC, Oh KJ, Han SH, Ahn TH, Shin EK. Progression of dissection due to residual dissection after intracoronary stenting for spontaneous coronary dissection at bifurcation site of LAD and diagonal artery. Int J Cardiol 2008;125:e40-3. 174. Sharp AS, Latib A, Ielasi A, Larosa C, Godino C, Saolini M, Magni V, Gerber RT, Montorfano M, Carlino M, Michev I, Chieffo A, Colombo A. Long-term follow-up on a large cohort of "full-metal jacket" percutaneous coronary intervention procedures. Circ Cardiovasc Interv 2009;2:416-22. 175. Sanchez-Recalde A, Guzmán G, Armada E, Moreno R. Multiple spontaneous coronary artery dissection associated with a left main coronary artery lesion treated by stenting. Late multiple stent fractures detected by multislice CT. Rev Esp Cardiol 2009;62:225-6. 32
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Figure 1: Coronary Artery Dissections Classification – Coronary artery dissections can be classified as “Primary”, or spontaneous coronary artery dissections (SCAD), and “Secondary”.
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By definition, SCAD requires the absence of a traumatic, iatrogenic and non-coronary process
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(aortic dissection). Secondary dissections are generally consequent to coronary angioplasty
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(wiring, balloon dilatation, stenting), coronary angiography (coronary catheterization), cardiac
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surgery, ascending aortic dissection and thoracic trauma.
Figure 2: Morphologic Patterns – SCAD presents two patterns, one (“SCAD with entry door”,
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left) characterized by a luminal entry door and a detached intimal-media membrane (radiolucent
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flap at angiography), the other (SCAD without entry door or “angiographically-invisible SCAD”,
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right) characterized by an intramural hematoma without communication with coronary lumen. Probably most SCAD are at least initially SCAD without luminal entry door that subsequently break suddenly following the progressive enlargement of the intramural hematoma. The sudden blood inflow into the false lumen causes generally an abrupt vessel flow limitation and represents a further path of growth.
Figure 3: A) Angiography and Spontaneous Coronary Artery Dissection ˗ The radiolucent intimal-media flap (double lumen) is generally associated with persistent extra-luminal filling and/or delayed clearance of contrast media from lumen; B) Intravascular Ultrasound Imaging and Spontaneous Coronary Artery Dissection – IVUS can display not only the intimal-media membrane, but also the false lumen composition. Arrows: Organized thrombotic material; *: False lumen. Adapted from Maehara et al. [137]. C) Optical Coherence Tomography and 34
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identify the entry tear. OCT is the gold standard for the diagnosis of “angiographically-invisible
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SCAD”. Adapted from Alfonso et al. [138] and Cordone et al. [147].
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Figure 4: [Top panel] Spontaneous Coronary Artery Dissection Distribution in the
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Coronary Tree – Aggregating the prior reports of case series of at least 5 patients and small single-center registries, the left anterior descending is the more frequently involved coronary
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vessel. LMCA: Left Main Coronary Artery; LAD: Left Anterior Descending; LCX: Left Circumflex; RCA: Right Coronary Artery. [Center Panel]:
Spontaneous Coronary
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Dissections Vessel Distribution in Male and Female – Single-vessel (1) involvement is the
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most common presentation both in male and in female. Two-vessel (2) and three-vessel (3)
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presentations are significantly more frequent in female. Data from Shamloo et al. [21]. [Bottom Panel] Spontaneous Coronary Dissection Clinical Presentation – Aggregating the data deriving from case series of at least 5 patients and small single-center registries, STEMI resulted the most frequent clinical presentation. STEMI: ST segment Elevation Myocardial Infarction; NSTEMI: Non-ST segment Elevation Myocardial Infarction; UA: Unstable Angina; OTHERS: Stable Angina, Chronic Heart Failure symptoms or Ventricular Tachyarrhythmias.
Figure 5: A) Idiopathic Spontaneous Coronary Artery Dissection ˗ Macroscopic postmortem examination of a SCAD of left main coronary artery; B) Microscopic Appearance of Spontaneous Coronary Artery Dissection ˗ Intramural hematoma occupies a new virtual cavity between adventitia (outer) and intimal-media membrane (inner). *Indicates coronary lumen. Image modified from Adkins [61]. 35
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Figure 6: Spontaneous Coronary Dissection Physiopathology – Schematic representation of
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the processes potentially implicated in SCAD development. According to the site of action, it is
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possible to distinguish three groups of factors: 1) Vascular factors: mechanical and physical processes involving either the endothelium surface or the coronary vascular function; 2) Systemic
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factors: biochemical systemic dysfunction concerning inflammatory signalling, anomalous vessel
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response to endocrine stimulation, and immune-mediate lesions; 3) Parietal factors: abnormalities of media/subadventitia tissue layer characterized by connective tissue defects, vasa vasorum
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haemorrhage and microvascular anomalies. SCAD: Spontaneous Coronary Artery Dissection.
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Figure 7: Diagnostic and Therapeutic Algorithm – Proposed diagnostic and therapeutic
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algorithm for SCAD..*Whether hemodynamic condition allows the use of OCT or IVUS;
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†Unstable condition is defined by systolic blood pressure 30 minutes or catecholamines administration to maintain a systolic pressure >90 mmHg plus clinical signs of pulmonary congestion (dyspnea, pulmonary rales) or signs of impaired organ perfusion (mental status, hypoperfusion of extremities, oliguria with urine output 2.0 mmol/L);‡In unprotected left main coronary artery LMCA, SCAD without bifurcation involvement or without complex and extensive multi-vessel pattern could be considered for PCI. §Whether the vessel anatomy e SCAD complexity of distribution does not allow a percutaneous coronary artery intervention, urgent surgical revascularization is recommended. OCT: Optical Coherence Tomography; IVUS: IntraVascular UltraSound; Left Main Coronary Artery: LMCA; PCI: Percutaneous Coronary Intervention; CABG: Coronary Artery Bypass Grafting.
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Table 1: Most Relevant Data on Spontaneous Coronary Artery Dissection – The table table displays the most relevant data deriving from
LMCA
LAD
LCX
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published case series of at least 5 patients and small mono-center registries on Spontaneous Coronary Artery Dissection (SCAD).
RCA
PCI
N (%)
N (%)
N (%)
N (%)
N (%)
Women
N (%)
N (%)
N
Years
NR
11*
6 (54.5)
9
0 (0)
10 9852
0 (0)
2 (25)
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8
Basso et al.1
2,241
5 (0.22)
NR
8
2,225
5 (0.22)
N (%)
N (%)
N (%) (%)
3
2
8
0 (0) (27.3)
NR NR
(19.2)
(72.7)
3 (30)
7 (70)
3
5
(37.5)
(62.5)
NR
NR
0 (0)
4 (40)
1
4 (40)
5 (50)
1
3
6 (75) (12.5)
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(10.7)
Pasalodos Pita et al.16
N (%)
0 (0)
9 (90)**
1 (10)
(13.2) 44.1
NR
N (%)
46.1 8 (80)
(0.10) Jobic et al.178
UA N
0 (0)
(81.8)
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(11.8) Jorgensen et al.3
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43.1 DeMaio et al.27
Other CABG Medical STEMI NSTEMI
NU
(SD)
SC
Age SCAD
1 (20)
0 (0) (12.5)
(37.5)
4 (50)
4 (50)
52.0 (8.9) 1 (20)
2 (40)
0 (0)
3 (60)
0 (0)
2 (40)
3 (60)
3 (60)
0 (0)
2 (40) 0 (0)
8 (100) 43.2 (7.4) 2 (25)
5 (62)
1 (12)
1 (12)
NR
NR
NR
NR
NR
NR
3 (60)
2 (40)
1 (20)
3 (60)
0 (0)
0 (0)
5 (100)
3 (60)
0 (0)
0 (0)
NR 2
Zampieri et al.10
44.8 (14)
0 (0)
(40) 42 Hering et al.42
3,803
19 16 (38)
59 (12)
0 (0)
(1.10) Celik et al.38
3,750
9 (0.24)
15
(45) 2 (29)
55.8 (8.4) 2 (22)
31
8 (19)
5 (56)
44
0 (0)
8 (19) (36)
(74)
2 (22)
1 (11)
7 (78)
3 (7)
1 (11)
21
8
(50)
(19)
7 (78)
2
13 (31)
0 (0)
0 (0)
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(22) 15,000 5 (0.03)
4 (80)
42.8 (7.4) 1 (20)
3 (60)
0 (0)
2 (40)
1 (20)
0 (0)
4 (80)*
1 (20) 0 (0)
1 (14)
5 (71)
1 (14)
1 (14)
2 (33)
3 (50)
1 (17)
4 (57)*
3 (43)
44 (8.7)
0 (0)
3 (60)
2 (40)
0 (0)
1 (20)
1 (20)
3 (60)
4 (80)*
1 (20) 0 (0)
44 (NR)
2 (15)
5 (31)
4 (38)
9 (82)
2 (18)
NR
13 (100)*
2 (33)
3 (17)
3 (50)
1 (17)
1 (17)
4 (67)
5 (83)
1 (17)
0 (0)
0 (0)
0 (0)
1 (17)
0 (0)
0 (0)
5 (83)
0 (0)
1 (17)
3 (60)
2 (40)
0 (0)
7 (30)
0 (0)
NR
7
5 (71)
Maeder et al.15
5,054
5 (0.09) 5 (100)
NR
13
11 (85)
NU
12 Butler et al.69
SC
(12.2)
RI
40.6 Roig et al.161
4 (80)
PT
Maehara et al.135
0 (0)
0 (0) 0 (0)
1100† 6 (0.54)
1 (17)
Unal et al.177
5,000
4 (67)
Appleby et al.186
NR
Vanzetto et al.14
11,605
6 (0.12)
5
Motreff et al.48
1,780#
13 12
Ito et al.33
NR
CE
(100)
4 (80)
1 (20)
1 (20)
3 (60)
1 (10)
1 (10)
5 (22)
3 (13)
8 (35)
5 (22)
10 (43)
12
14
(52)
(60)
(10)
0 (0)
9 (69)
3 (23)
2 (18)
3 (23)
2 (15)
8 (62)
43.8 (9.0) 5 (42)
9 (75)
3 (25)
2 (17)
8 (67)
2 (17)
2 (17)
NR
NR
NR
16
7 (35)
6 (26)
3 (13)
6 (26)
14 (61)
11
11 (48)
1 (4)
19
13 1 (5)
3 (14)
(86)
16 2 (9)
7 (32)
(59)
1 (5) 4 (18)
1 (5)
(72) 13 (100)*
0 (0)
12 (100)
23
23
0 (0) 2
11 (85) 40.7 (6.7)
(0.67)
0 (0) 0 (0)
2 (9)
18 (82) 48.7 (8.9) (0.07)
6
AC
22 32,869
NR
48.0 (9.3) 5 (83)
17 (74) 46.3 (9.7) 3 (13) (0.20)
Kansara et al.30
0 (0)
5 (100) 30.8 (3.1) 1 (20)
23
Mortensen et al.13
38 (NR)
PT ED
Hendiri et al.82
MA
(92)
0 (0) 0(0)
44.8
5 (22)
45
0 (0)
ACCEPTED MANUSCRIPT
al.80 Toggweiler et al.81
47.7 15 (79)
(0.20) 3,428
12 0 (0)
48.2
1 (8)‡
7
62 8 (9)
(10.1) 45 Alfonso et al.12
16,813
50
(18)
53 (11)
1 (2)
7 (16)
(53)
PT ED
NR
(71) 24
26 (58) (0.27)
Saw et al.25
16
NU
71 (82)
MA
87
1 (8)‡
(58)‡
42.6 NR
49 (98) 51.0 (9.6)
2 (11)
0 (0)
2
5
0 (0)‡
(17)‡
(42)‡
27
27
(63)
(9.8)‡ Tweet et al.18
13 5 (26)
(10.4)
24 (0.7) 9 (75)‡
(48)
PT
9,502†
(70)
RI
19
Romero-Rodríguez et
(10.7)
SC
(100)
0 (0)
5 (26)
14 (76) (68) 7 (58)‡
8
(31)
13
12
12
(29) 7 (14)
20
17
16
(40)
(34)
(32)
29 (69)
41 (82)
15
42.2 (3.9)
0 (0)
2 (40)
2 (40)
2 (40)
3 (60)
1 (20)
2 (40)
3 (60)
Buja et al.49
NR
38
32 (84)
51.4
5 (13)
31
5 (13)
6 (16)
17
3 (9)
18 (47)
19
AC
CE
3 (60)
1,159†
10 (0.86)
9 (90)
46.8
0 (0)
4 (40)
(45) 1 (10)
6 (60)
6 (7)
16 (36)
0 (0)
11 (24) 35 (70)
0 (0)
0 (0)
(30)
5
Tokura et al.22
0 (0) 38 (44)
(40)
NR
(82)
(0)‡
18
2 (4)
0
(49)
Pfeiffer et al.93
(11.6)
0 (0)‡
43
(14)
1 (2) (29)
4 (33)‡
(67)‡
47 (55) (31)
0 (0) 6 (32)
9 (90)
0 (0)
11 (29)
(50) 0 (0)
1 (10)
9 (90)
2 (40) 0 (0) 8 (21)
0 (0)
1 (10) 0 (0)
(17.2)
*DeMaio et al. study consists of 94 patients but only 11 were antemortem and collected in the same institution; **Unspecified type of acute myocardial infarction; †Acute coronary syndromes; ‡Only 12 patients were reported (Magnetic Resonance Imaging study). CABG: coronary artery bypass grafting; LAD: left anterior descending; LCX: left circumflex; LMCA: left main coronary artery; NSTEMI: non ST-segment elevation myocardial infarction; PCI: percutaneous coronary intervention; RCA: right coronary artery; STEMI: ST-segment elevation myocardial infraction; NR: not reported or not retrievable; UA: unstable angina; Others: stable angina, silent ischemia, ventricular arrhythmias alone, heart failure. The case series of Alfonso et al.136 and Saw et al.117 are not showed in the table because included in their larger registries12,25. 46
