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Contents lists available at ScienceDirect

Trends in Cardiovascular Medicine

journal homepage: www.elsevier.com/locate/tcm

Spontaneous coronary artery dissection: Overview of pathophysiology

Stefania Angela Di Fusco a,1,∗, Roberta Rossini b,2, Filippo Zilio c,1, Luigi Pollarolo d,1,
Fortunato Scotto di Uccio e,4, Annamaria Iorio f,1, Fabiana Lucà g,3,
Michele Massimo Gulizia h,i, Domenico Gabrielli j,4, Furio Colivicchi a,4
a
U.O.C. Cardiologia Clinica e Riabilitativa, San Filippo Neri Hospital, ASL Roma 1, via Martinotti 20, 00135 Rome, Italy
b
U.O.C. Cardiologia, Azienda Ospedaliera Santa Croce e Carle, Cuneo, Italy
c
U.O.C. Cardiologia, Ospedale Santa Chiara, Trento, Italy
d
U.O.C Cardiologia, Ospedale Santo Spirito, Casale Monferrato (AL), Italy
e
Cardiologia UTIC-Emodinamica, Ospedale del Mare, ASL NA1, Napoli, Italy
f
U.S.C. Cardiologia 2, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy
g
U.O.C. Cardiologia, Grande Ospedale Metropolitano, Reggio Calabria, Italy
h
U.O.C. Cardiologia, Ospedale Garibaldi-Nesima, Azienda di Rilievo Nazionale e Alta Specializzazione "Garibaldi", Catania, Italy
i
Fondazione per il Tuo cuore, Firenze - Heart Care Foundation Onlus, Italy
j
U.O.C Cardiologia, Ospedale Civile Augusto Murri, Area Vasta 4 Fermo, ASUR Marche (AN), Italy

a r t i c l e i n f o a b s t r a c t

Keywords: The growing use of imaging examinations has led to increased detection of spontaneous coronary artery
Spontaneous coronary artery dissection dissection (SCAD) as a non-atherosclerotic cause of acute coronary syndrome (ACS). Since a greater aware-
Acute coronary syndrome
ness of pathophysiologic mechanisms has relevant implications in clinical practice, we aim to provide an
Pathophysiology
update to current knowledge of SCAD pathophysiology. We discuss the most common conditions associ-
Genetics
Intracoronary imaging examinations ated with SCAD, including predisposing factors and triggers, and focus on potential mechanisms leading
to SCAD development. Furthermore, we report the main genetic research findings that have shed fur-
ther light on SCAD pathophysiology. Finally, we summarize practical considerations in SCAD management
based on pathophysiologic insights.
© 2021 Elsevier Inc. All rights reserved.

Introduction
In patients with acute coronary syndrome (ACS), the growing
use of diagnostic imaging examinations, such as coronary angiog-
raphy and intracoronary imaging, has led to increased diagnosis of
spontaneous coronary artery dissection (SCAD). SCAD is currently
recognized as a non-negligible cause of ACS, especially in young
or middle-aged females. The estimated prevalence of SCAD among
patients with ACS ranges between 1.7% and 4% [1], increasing to
43% among young women with peripartum ACS [2]. According to
expert consensus, the term SCAD refers to an acute separation
of the wall of epicardial coronary arteries that is not associated
with recent trauma or atherosclerotic plaque and is non-iatrogenic
[1,3,4]. The underlying mechanism is the development of intramu-
∗
Corresponding author.
E-mail address: stefaniaa.difusco@aslroma1.it (S.A. Di Fusco).
1
Italian National Association of Hospital Cardiologists (ANMCO) Young working
group.
2
ANMCO Emergency working group.
4
ANMCO Executive Board.
3
ANMCO Management and Quality working group.
ral hematoma and/or intimal tearing that leads to the obstruction
of the true artery lumen, compromising arterial flow. Several sci-
entific publications have focused on SCAD epidemiology, clinical
characterization, imaging appearance, management, and progno-
sis [1–4]. Identifying SCAD is important due to the specific man-
agement approach needed for this condition, which differs from
that needed for atherosclerotic ACS. However, there is limited un-
derstanding of the exact pathophysiologic mechanisms underlying
SCAD. With the present review, we aimed to provide an overview
of available knowledge on SCAD pathophysiology and highlight re-
cent insights from advanced intracoronary imaging techniques and
genetic research findings. Predisposing conditions and trigger fac-
tors and their possible mechanisms leading to SCAD is also ad-
dressed. A greater awareness of these mechanisms has relevant im-
plications in clinical practice. Finally, we summarize practical con-
siderations for patient management.
Epidemiology
In the last years, the greater and earlier use of coronary
angiography and advanced intracoronary imaging examinations
in ACS has led to increased detection of SCAD. In the general

https://doi.org/10.1016/j.tcm.2021.01.002
1050-1738/© 2021 Elsevier Inc. All rights reserved.

Please cite this article as: S.A. Di Fusco, R. Rossini, F. Zilio et al., Spontaneous coronary artery dissection: Overview of pathophysiology,
Trends in Cardiovascular Medicine, https://doi.org/10.1016/j.tcm.2021.01.002
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Table 1
Demographic characteristics and cardiovascular risk factors in SCAD patients.

Author [Country, year (ref.)] N Age (y)∗ Female (%) BMI Hypertension (%) Diabetes (%) Dyslipidemia (%) Smoking (%) P-SCAD (%)

Saw [CA, 2019 [6]] 750 52±10 88 26 [23-31]§ 32 5 20 12 5

Eleid [US, 2014(9)] 246 45±9 96 26± 5∗ 34 2 27 2 9
Clare [US, 2019 [8]] 208 49±12 89 29 ± 7∗ 31 8 28 NA NA
Smaardijk [NL, 2021 [10]] 172 52±8 100 25 ± 4∗ 31 1 9 54 NA
Al-Hussaini [UK, 2020 [11]] 158 45±8 98 26±6∗ 19 1 8 28 10
Lettieri [IT, 2015 [12]] 134 52±1 81 24±3∗ 51 2 32 34 NA
Camacho Freire [ES, 2019 [13]] 73 55±12 77 NA 48 8 41 36 3
Rogowsky [CH, 2017 [14]] 64 53±11 94 25±5∗ 45 0 52 28 5
Nakashima [JP, 2016 (15] 63 46±10 94 NA 33 0 23 32 8
Motreff [FR, 2017 [16]] 55 50±10 100 24±5∗ 27 4 11 22 4

Data from case series including more than 50 patients. In studies with overlapping cohorts, the study with the largest cohort was reported.
Data are reported as percentages, ∗ mean± standard deviation, or § median (interquartile range).
BMI indicates body mass index; Y, year; N, number of cases; NA, not available; P-SCAD, pregnancy-associated spontaneous coronary artery dissection; SCAD, spontaneous
coronary artery dissection.

population SCAD may account for up to 4% of ACS cases, with a
higher rate among women aged <50 years (35%) [5]. Large contem-
porary series have shown that peripartum events account for only
a small portion (<5%) of the overall SCAD population [1,6]. How-
ever, since SCAD is often undetected in clinical practice, its true
prevalence in the general population remains to be established [4].
A recent meta-analysis including 2172 patients with SCAD showed
that 84% were female, with a mean age of 51 years [7]. Although
the majority of patients included in the case series are Caucasian,
this finding may not be due to a lower risk of SCAD in other
ethnicities but to referral bias in recruiting centers [4]. Although
atherosclerosis is usually absent at angiography in SCAD patients,
the prevalence of atherosclerotic risk factors is non-negligible [8].
Hypertension has been found to be the most common cardiovas-
cular risk factor, being reported in 45% of patients [7]. In a co-
hort study of patients with ACS undergoing coronary angiography,
no differences in atherosclerotic risk factor prevalence or mortality
rate were found between SCAD and non-SCAD patients when us-
ing propensity score matching for age, sex, and ethnicity [8]. De-
mographic characteristics and cardiovascular risk factors in SCAD
patients included in the larger US/Canadian and European case se-
ries are summarized in Table 1 [6,8–16]. Various clinical conditions
have been reported to be associated with SCAD (Supplemental
Table 1) [3,4,6,9,13–23] and seem to augment patient susceptibility
to SCAD occurrence.
Pathophysiology
SCAD is defined as a non-atherosclerotic coronary artery dis-
ease characterized by the development of a false lumen within
the coronary artery wall that compresses the true lumen. SCAD
is emerging as an important possible cause of ACS, with patho-
physiological mechanisms that differ from atherosclerosis. In SCAD,
histopathological findings and coronary imaging have shown that
arterial wall separation can occur between any of the three arterial
layers: intima, media, or adventitia. Two models have been pro-
posed to explain the inciting process underlying the separation of
arterial wall layers [24]. The first, the so-called inside-out model,
suggests that coronary arterial wall separation is due to a tear in
the intima layer (Figs. 1a, 2). Intimal discontinuation permits blood
flow propagation inside the vessel wall, creating a false lumen that
can compress the true lumen and compromise myocardial perfu-
sion, resulting in ischemia. This theory is supported by imaging
studies demonstrating a pathognomonic angiographic presence of
intimal fenestration with evidence of communication between the
true and false lumens [25,26].
However, an intimal discontinuation may be absent in SCAD
[26,27]. This finding has led to the hypothesis of a different mech-
anism known as the outside-in hypothesis, which suggests that a
spontaneous hemorrhage within the arterial wall could be the pri-
mary pathological event (Fig. 1b). According to this hypothesis, the
causal mechanism could be vasa vasorum disruption that results
in the formation of an intramural hematoma, with the accumula-
tion of blood creating a false lumen. The presence of a true lumen
smaller than the false lumen and the elliptical morphology of the
true lumen, as observed with intracoronary image studies, are sug-
gestive of extrinsic compression due to intramural hematoma [26].
If pressure exerted by the intramural hematoma exceeds intraves-
sel blood pressure, a reverse intimal rupture from the false lumen
to the true lumen may occur [1]. Therefore, intimal rupture may
represent an epiphenomenon rather than a primary event of coro-
nary dissection. Indeed, the outside-in model has been proposed as
a unifying theory for the development of both fenestrated-type and
non-fenestrated-type SCAD (Fig. 3) [28]. A study that performed
repeat angiographic examinations in conservatively managed SCAD
patients showed that the progression of intramural hematomas to
intimal disruption was associated with reduced vessel obstruction
[29]. This finding supports the theory of intimal tearing as a sec-
ondary event leading to decompression in the vessel lumen [30].
SCAD angiographic appearance may provide important informa-
tion regarding the SCAD underlying mechanism in the individual
patient. Four main types of SCAD angiographic presentation have
been reported [3,31,32]. Type 1 has the pathognomonic appearance
of multiple radiolucent lumens with arterial wall contrast stain-
ing, suggesting a slowed flow in the false lumen. This angiographic
feature is consistent with the presence of an intimal tear that al-
lows contrast dye to enter into the false lumen and may be vis-
ible as a radiolucent “flap” that separates the true and false lu-
mens. Type 2, the most common angiographic pattern ([20,33]),
is characterized by a diffuse and smooth stenosis that commonly
involves mid-distal segments. Furthermore, type 2 SCAD has been
divided into variants 2A and 2B depending on the presence or ab-
sence of a normal caliber distal vessel, respectively [1,4]. Type 3
is a focal stenosis mimicking atherosclerotic stenosis that often re-
quires intravascular imaging to confirm SCAD diagnosis. In type 2
and type 3 SCAD luminal narrowing is due to external compression
consistent with the presence of an intramural hematoma. Type 4
presents with total vessel occlusion, usually involving a distal seg-
ment, and requires the exclusion of embolic causes and subsequent
evidence of re-established coronary flow due to vessel wall healing
[32,34]. Intravascular ultrasound and OCT clearly displaying dou-
ble lumen and intramural hematoma may help confirm diagnosis
(Figs. 4 and 5) [1,26].
Advanced intracoronary imaging techniques has provided fur-
ther insight into the understanding of SCAD pathophysiology. Jack-
son et al. [28] using 3D OCT with novel imaging analysis meth-
ods demonstrated an association between the lack of fenestration
and features suggestive of increased false lumen pressure that can

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Fig. 1. Illustration of the “inside-out” (1a) and “outside-in” (1b) mechanisms leading to the development of a false lumen and external compression of the true lumen.
occlude the true lumen [28]. Abnormal vessel wall features found
in segments remote from the dissection site support the presence
of a diffuse vasculopathy that is not limited to the dissected site
[28]. No significant differences between vasa vasorum density in
SCAD patients in the acute phase and vasorum density in control
subjects have been found. The neovascularization of the remnant
false lumen observed in convalescent SCAD patients can be con-
sidered a possible epiphenomenon of vascular healing.
The potential role of coronary artery wall functional abnormal-
ities in SCAD pathophysiology has also been investigated. Poorer
endothelium-mediated vasomotion in the peripheral arteries has
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been reported in SCAD patients as compared with matched con-
trols [35]. In patients with previous SCAD and recurrent angina,
coronary microvascular dysfunction has been found in both the
previously affected SCAD coronary artery and in non-SCAD coro-
nary arteries, suggesting that microvascular dysfunction may be
due to underlying microvascular abnormalities and not to SCAD it-
self or the subsequent healing process [36]. These findings support
the possible role of impaired coronary vasomotion in SCAD patho-
genesis.
Histopathological studies have found a periadventitial inflam-
matory infiltrate rich in eosinophils and mast cells, which could
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Fig. 3. Fenestrated and nonfenestrated dissections

OCT cross-sectional images (A to D) and 3D segmentation (E, F) of SCAD showing
sites of communication between the TL and FL “fenestrations” (arrows) with either
extensive (A) or limited (B) localized contrast penetration of the FL. Examples of
nonfenestrated dissection show either incomplete (C) or complete (D) dehiscence
of the TL from the vessel wall. Examples of 3D segmented SCAD show relationships
between the FL and side branches (E, F). ∗ Wire artifact. FL indicates false lumen;
OCT, optical coherence tomography; SCAD, spontaneous coronary artery dissection;
TL, true lumen. (Reprinted from Jackson et al. [28] with permission from Elsevier.).

have a pathogenic role [37,38]. Cytotoxic and collagenolytic sub-

stances released by eosinophils may cause medial disruption, pre-
disposing to arterial dissection. This infiltrate has been considered
as a pathognomonic histopathologic finding in SCAD [4]. However,
it has not been established whether eosinophilic infiltrate causes
SCAD or is a reactive response to vascular injury [39]. Circulat-
ing fibrillin-1, a component of microfibrils in elastic tissues of the
coronary medial layer, has been found in higher concentrations in
SCAD patients, and its levels seem to correlate with adverse cardio-
vascular events [40]. Based on these observations, the assessment
of plasma fibrillin-1 concentration has been proposed to differen-
tiate SCAD from non-SCAD ACS and aid in prognostic evaluation.

Fig. 2. Coronary angiography and IVUS images in a female with SCAD lesions
In Fig. 2a, the white arrow indicates an intimal tear. In Fig. 2b, the white arrow
Female sex and the role of hormones
indicates an intramural hematoma. In Fig. 2c, the yellow arrow indicates the tunica
intima, and the white stars indicate an intramural hematoma. Female patients represent the large majority (> 90%) of pa-
IVUS indicates intravascular ultrasound; SCAD, spontaneous coronary artery dissec- tients affected by SCAD [3] and are more likely to have recurrent
tion.
SCAD. SCAD is commonly recognized as the mechanism underlying

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Fig. 4. Combined intravascular imaging in a patient with suspected SCAD

(A) Angiographic image of a long lesion in the left anterior descending coronary artery suggestive of spontaneous coronary artery dissection (SCAD). The proximal aspect of
the diseased segment shows an intimomedial membrane and a double lumen appearance by optical coherence tomography (OCT) (B) and intravascular ultrasound (IVUS)
(B’). At this site, the complete vessel is visualized by both techniques, although the thrombus in the false lumen is more clearly depicted by IVUS. (C) More distally, OCT
detects a severely narrowed lumen and a side branch exit from the true lumen (4 o’clock position). The thickness of the intimomedial membrane is well visualized (5 to
11 o’clock position), but severe attenuation prevents visualization of dorsal structures. (C’) IVUS displays the false lumen content better and detects the side branch take off
from the true lumen (3 o’clock position). ∗ Denotes wire artifact. (Reprinted from Paulo et al. [26] with permission from Elsevier.).

demonstrating the effects of sex hormones on vessel wall architec-

Fig. 5. Angiographic classification of SCAD
(A) Type 1 spontaneous coronary artery dissection (SCAD) of distal left anterior de-
scending (LAD) artery with staining of artery wall (asterisk). (B) Type 2A SCAD of
mid-distal LAD (between arrows). (C) Type 2B SCAD of diagonal branch (asterisk),
which healed 1 year later (asterisk in D). (E) Type 3 SCAD of mid-circumflex artery
(asterisk), with corresponding optical coherence tomography showing intramural
hematoma in (F). (Reprinted from Saw et al. [1] with permission from Elsevier.).
peripartum ACS, accounting for up to 43% of pregnancy-related
ACS [2]. SCAD has also been found to be associated with hormone
replacement therapy [18]. These observations suggest that female
hormones may have a pathogenic role in SCAD. Although their
precise biological mechanisms still need to be defined, evidence
ture and function supports this hypothesis.
Estrogen increases endothelial-mediated vasodilatation through
a nitric oxide synthase-dependent mechanism, suppresses the
cyclooxygenase-dependent vasoconstriction pathway, promotes an-
giogenesis, reduces mitochondrial reactive oxygen species pro-
duction, and modulates nervous autonomic system function [41].
In the arterial walls of pregnant women, histopathological stud-
ies have found structural changes compared with non-pregnant
women, including fragmentation of elastic and collagen fibers
and the loss of mucopolysaccharides [42]. Furthermore, in preg-
nant women with SCAD, vessels involved often show eosinophilic
adventitial inflammatory infiltration and focal areas with muci-
nous microcystic changes within the media [43]. These structural
changes weaken arterial walls and, together with the hemody-
namic changes of pregnancy and labor, may result in vasa vasorum
rupture or intimal tears. Pregnancy-related SCAD presents more of-
ten as a severe clinical event [44] and may have worse outcomes.
It is more common in patients with a history of multiparity and in-
fertility treatment. Pregnancy-related SCAD was also reported dur-
ing/after cesarian sections. In these cases, SCAD occurrence may be
due to predisposing arterial wall structural changes due to preg-
nancy hormone effects and precipitated by hemodynamic fluctua-
tions induced by delivery and potentiated by pharmacological in-
terventions with vasoactive drugs during spinal anesthesia or in
the failed attempt to induce spontaneous vaginal delivery [44].
Patients on hormonal therapy seem to have higher SCAD recur-
rence [19]. In women with a history of SCAD, cyclic recurrence of
chest pain during the late luteal phase of the menstrual cycle has
also been reported [45]. In these patients, chest pain occurrence
coincided with the menstrual cycle phase with the lowest circulat-
ing estrogen levels. Some case reports with SCAD occurrence dur-
ing the menstrual phase have also been described, leading to the

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definition of the menstrual phase as a vulnerable period in sus-
ceptible females [46]. Overall, several studies support the possi-
ble contribution of hormonal fluctuations to SCAD development in
women.
Predisposing diseases: fibromuscular dysplasia, connective
tissue disorders, and chronic inflammatory conditions
Several diseases causing arterial wall injury can result in SCAD,
including fibromuscular dysplasia (FMD), connective tissue disor-
ders, and chronic systemic inflammatory diseases.
The most common association concerns FMD, an arteriopathy
that can cause stenosis, dissection, and aneurysm in small and
medium-sized arteries. FMD histopathological characteristics in-
clude anomalous cell proliferation and aberrant connective ma-
trix architecture with loose collagen and deteriorated elastic fibrils,
which may weaken the arterial wall [47]. These histopathological
findings support the hypothesis that FMD may cause SCAD. Among
SCAD patients, FMD prevalence ranges from 16 to 70% [17]. The
wide range reported is due to the different examination protocols
used to screen for FMD in the different studies. An even higher
rate of SCAD patients with FMD is expected to be found with more
appropriate FMD screenings [20]. Even if SCAD events are not fre-
quent in the FMD population (less than 3% in the U.S. Registry for
FMD) [48], ACS caused by SCAD may be the first manifestation
of FMD. FMD pathogenesis has been ascribed to multiple factors,
including environmental (i.e., smoking), endocrines, and genetics.
However, no definite etiology has been established. High levels of
circulating TGFβ have been found in FMD patients [49]. Abnormal
TGFβ activity may have a pathogenic role by enhancing collagen
production and leading to an altered elastin/collagen ratio in the
vascular wall. The consequent reduced arterial wall elasticity may
predispose patients to SCAD. However, clear evidence on the local
effects of abnormal TGFβ levels in FMD is lacking.
Several connective tissue disorders have been observed in SCAD
patients. However, the overall prevalence reported is low, being ob-
served in less than 4% of SCAD cases in most studies ([6,9,20]).
Some of these heritable conditions, including vascular Ehlers-
Danlos syndrome, Marfan syndrome, and Loeys-Dietz syndrome,
are associated with gene mutations that are known to weaken
the arterial wall by altering components of extracellular microfib-
rils. The mechanism responsible for SCAD seems to be related to
fibrillin-1 defects and the abnormal activity of matrix metallopro-
teinases and TGFβ -signaling pathways [50].
Although pathological evidence of a causal role has never been
reported, some inflammatory conditions have also been associ-
ated with SCAD. In these conditions, systemic inflammation and
coronary vasculitis may predispose patients to SCAD development.
Systemic inflammatory diseases that have been observed in asso-
ciation with SCAD include lupus erythematosus, polyarteritis no-
dosa, celiac disease, inflammatory bowel disease, sarcoidosis, and
Takayasu arteritis, many of them reported as single case studies
[4,51]. However, it should be emphasized that SCAD development
in these patients may be associated with the use of corticosteroids
and/or immunosuppressants that could contribute to SCAD. Indeed,
a recent case-control study showed that SCAD patients did not
have a higher prevalence of autoimmune disease [21].
Genetics
The common occurrence of SCAD in young patients without
risk factors for atherosclerosis and the identification of cases with
familial association [52] have led to the hypothesis of possible
genetically-mediated pathophysiologic mechanisms. Some inherita-
ble connective tissue diseases characterized by multivessel fragility
have been reported to be associated with SCAD. However, genetic
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evaluation for known pathogenetic connective tissue gene muta-
tions seems to have a low yield in SCAD patients [53].
Genetic testing performed in patients enrolled in a prospective
SCAD registry has made it possible to identify pathogenic variants
known to be associated with vascular disease in 8.2% of SCAD pa-
tients [54]. The most common pathogenic variants were found in
COL3A1, the causative gene of vascular Ehlers–Danlos syndrome,
which leads to abnormalities in collagen type III alpha-1 chain
structure causing vascular wall fragility. Pathogenetic mutations
have been identified involving the SMAD3 gene encoding trans-
forming growth factor β (TGFβ ) receptors in individual/familial
SCAD cases with Loeys–Dietz syndrome [54,55]. A recent study
found a higher frequency of variants in Loeys–Dietz syndrome
genes (TGFBR1/2, SMAD2/3, TGFB 2/3) in a cohort of SCAD patients
compared with controls [56].
The FBN1 gene mutation, which causes Marfan syndrome, en-
codes a defective fibrillin protein with altered mechanical propri-
eties and regulatory activities. It may predispose patients to SCAD
and has been detected with molecular evaluation in a single case
in the Mayo Clinic SCAD Registry [53].
On the basis of the strong epidemiological association between
FMD and SCAD, Adlam et al. studied genetic variants associated
with FMD risk in the SCAD population and found a genetic link be-
tween SCAD and FMD [57]. The genetic locus PHACTR1/EDN1, par-
ticularly the common allele rs9349379-A, was the first detected ge-
netic variant significantly associated with a 60% increased SCAD
risk [57]. This allele was also associated with a lower risk of
atherosclerotic coronary artery disease. This observation may be
explained by the role of rs9349379 in regulating endothelin-1 ex-
pression. This modulation may promote vasodilatation, and thus
dissection, and simultaneously hinder vasoconstriction, thus pro-
tecting against atherosclerosis [58] .
Whole-exome sequencing (WES) has enabled further examina-
tion of the genetics that underpin some SCAD cases. The WES
study in the Chinese Han population found TSR1 as a further
potential causal gene of SCAD [59]. The TSR1 gene encodes the
TSR1 ribosome maturation factor, which may be involved in SCAD
pathogenesis, although its mechanisms have not yet been defined
[60]. WES performed in a family with three individuals affected
by SCAD and in a cohort of sporadic SCAD patients found TLN1,
which encodes the cytoskeletal protein talin-1, to be a further dis-
ease gene [61]. This gene is expressed mostly in vascular tissue and
has been associated with arterial disease.
Genome sequencing in a large UK cohort has shown that only
3.6% of SCAD patients have pathogenic variants that may con-
tribute to SCAD. In the same cohort study, gene-set enrichment
analysis suggested a pathogenic role of genes involved in renal dis-
ease [62]. A recent genome-wide association study identified 5 ge-
netic risk loci associated with SCAD. These loci contain genes that
encode proteins or regulate the expression of proteins involved in
arterial wall structure and/or function [63]. Genetic studies also
seem to support an inverse relationship between SCAD and coro-
nary atherosclerotic disease risk [64]. These findings further con-
firm that different pathogenetic mechanisms underlie SCAD events
and atherosclerotic ACS.
Although no genetic tests specific for SCAD are currently avail-
able and the yield from routine clinical genetic screening currently
seems to be low, genetic evaluation may be considered for some
SCAD patients, especially younger patients or those with familial
occurrence or recurrent SCAD.
Medications and recreational drugs as potential predisposing
factors
Some medications have been associated with SCAD and may
be considered possible predisposing factors. Female hormones are
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Table 2
Clinical, anatomopathological, and genetic features and trigger factors associated with SCAD.

Clinical Anatomopathological Genetic Triggers

• ACS at young age • Intramural hematoma • COL3A1 in Ehlers–Danlos S. (collagen α 1 chain)∗ • Intense emotional stress
• Familial cases • False lumen • SMAD3 in Loeys–Dietz S. (TGF β receptor)∗ • Intense Valsalva-type straining
• ACS recurrence • Intimal disruption • FBN1 in Marfan S. (fibrillin)∗ • Heavy isometric activity
• Gonadal hormone fluctuations • Eosinophilic infiltrates • PHACTR1/EDN1 in FMD (endotelin-1)∗ • Labor/delivery
• Pregnancy • TSR1 (ribosome maturation factor)∗ • Recreational drugs
• Arteriopathies • TLN1 (talin 1)∗
• Connective disorders
• Systemic inflammatory diseases

∗
Potential structural proteins or biological pathways implicated in the development of spontaneous coronary artery dissection are reported in parentheses.ACS indicates
acute coronary syndrome.

possible mediators of connective matrix changes that may promote

arterial wall vulnerability to dissection. Besides exogenous sex hor-
mones [20], other medications have been associated with SCAD in
registries and case reports.
SCAD events have been documented in patients treated with
immunosuppressants, such as the calcineurin inhibitors ciclosporin
and tacrolimus [65]. The vascular toxicity of calcineurin inhibitors
mediated by inflammatory cytokines, apoptosis, and oxidative
stress may contribute to arterial wall vulnerability. Corticosteroids
in high doses may also be further predisposing factors [66] by in-
ducing vessel wall architectural changes and hemodynamic over-
load [1].
Cancer treatment with cisplatin and 5-fluoruracil [67] was also
associated with SCAD. Possible pathomechanisms underlying SCAD
development during chemotherapy include vascular toxicity due
to an impaired vasoreactivity signaling pathway. The association
between 5-fluoruracil and SCAD is a controversial issue since 5-
fluoruracil may cause several vascular effects, including significant
coronary spasm that may mimic SCAD angiographic appearance.
Anecdotal case reports of SCAD have been described in patients
taking cabergoline [68], a dopamine agonist used as prolactinoma
treatment, and in patients taking ergotamine [69], an ergot alka-
Fig. 6. Practical considerations in long-term SCAD management.
loid used to treat migraines. In these cases, the presumptive mech-
anism predisposing patients to SCAD is drug-induced arterial va-
sospasm that causes an acute increase in arterial wall stress. How- weights, has been reported [22]. Less commonly, Valsalva-type
ever, in a small cohort of patients with previous SCAD studied with efforts, such as retching/vomiting, vigorous coughing, and force-
ergonovine testing, a low prevalence of coronary vasospasm was ful bowel movements, have been found to be precipitating fac-
reported [70]. tors by causing transient abrupt increases in intrathoracoabdomi-
Recreational drugs are also potential precipitating factors of nal pressure. Bereavement, arguments, and job stress are examples
ACS due to SCAD [71]. Amphetamine and cocaine-related SCAD of emotional stressors reported as precipitating factors [22]. A sin-
cases have been reported [6]. SCAD associated with these drugs gle SCAD event could also be triggered by the concurrence of dif-
is ascribed to the induced catecholaminergic surge that causes en- ferent mechanisms, including hormonal changes, emotional stres-
dothelial dysfunction and acute hemodynamic changes, elevating sors, and Valsalva-like efforts, such as in cases of labor- or sexual
shear forces on the coronary artery wall. intercourse-related SCAD.
Overall, the observed association between drugs and SCAD de-
rives from a small number of cases that often do not report the ex- Practical considerations: insights from pathophysiology
tent of drug exposure and may be impacted by recall bias. There-
fore, available data are too weak to determine a cause/effect re- SCAD seems to be the result of predisposing arteriopathies
lationship. The precipitants of SCAD events associated with these combined with precipitating triggers that induce arterial wall dis-
medications could be physical and/or emotional triggers [30]. ruption. Knowledge of the main clinical, anatomopathological, and
genetic characteristics and potential trigger factors of SCAD, as
Triggers: physical and emotional stressors summarized in Table 2, may help identify and manage this con-
dition.
Acute precipitating stressors preceding SCAD events have been Furthermore, insight into pathophysiologic mechanisms sup-
identified in most cases [6,20,22]. A higher frequency of mechani- ports some key practical considerations in SCAD management
cal stress has been reported in men, whereas a higher frequency (Fig. 6) [1,3,12,28]. In acute management, due to the sponta-
of emotional stress has been reported in women [22]. The pos- neous vessel healing observed over time in most cases [34], a
tulated mechanisms of induced SCAD are the hypercatecholamin- conservative approach is generally preferred [3]. However, ongo-
ergic state, due to physical or emotional stressors, and Valsalva- ing symptoms and hemodynamic instability prompt revasculariza-
like maneuvers that increase shear forces on the arterial wall, pre- tion [3,4,33]. Several intraprocedural challenges should be consid-
cipitating vascular damage. Among mechanical stressors, unusu- ered, including the risk of wiring into the false lumen, hematoma
ally intense isometric activity, such as lifting and/or pulling heavy migration during stent deployment and consequent dissection

7
JID: TCM
ARTICLE IN PRESS
S.A. Di Fusco, R. Rossini, F. Zilio et al.
propagation, and stent malapposition due to stent undersizing or
inadequate stent expansion due to a wide intramural hematoma.
Specific interventional approaches have been proposed for the dif-
ferent challenges [3]. Coronary artery bypass grafting, usually re-
served as a rescue strategy, may also be challenging due to coro-
nary artery wall frailty, and long-term artery bypass patency may
be undermined by dissection healing that may cause a competitive
flow and bypass conduit failure [3,30].
Considering the high prevalence of extracoronary vascular dis-
ease, especially FMD, assessment for extracoronary arteriopathies
is advised in SCAD patients (Supplemental Table 2) [1,3,4,5,72].
Understanding the pathophysiologic mechanisms underlying
SCAD also influences long-term management. Due to the theo-
retical risk of inducing increased intramural bleeding and a con-
sequent dissection extension, antithrombotic treatment is contro-
versial. After percutaneous coronary intervention, dual antiplatelet
therapy should follow ACS guidelines. In conservatively managed
SCAD, evidence of a thrombus in the true lumen [26,28] may jus-
tify antiplatelet therapy in the acute phase [3], whereas lifelong
antiplatelet use remains questionable. In the absence of other indi-
cations for anticoagulation, there is a consensus on limited antico-
agulation during revascularization procedures and its discontinu-
ation after SCAD detection [3]. In light of the controversial find-
ings regarding statin treatment and SCAD recurrence risk [8,19],
statin use should be limited to preexisting indications [3]. By re-
ducing heart rate, blood pressure, myocardial contractility, and ar-
terial wall shear stress beta-blockers may confer specific benefits.
Indeed, although beta-blocker use has been associated with a re-
duced SCAD recurrence risk [73], the protective effects of beta-
blockers need to be confirmed by randomized clinical trials.
Due to the recognized role of some physical activities and
emotional stressors in precipitating SCAD, a rehabilitative pro-
gram including tailored exercises and psychosocial support should
be implemented. Patients should be advised against lifting heavy
weights, extreme endurance training, or activities that require in-
tense Valsalva-like maneuvers, whereas moderate aerobic exercise
is encouraged [74].
A psychoeducational approach [75] that provides patients with
useful tools to take control of their health is advised. Due to the
poor outcomes of pregnancy-associated SCAD, dedicated counsel-
ing is recommended to review pregnancy risk. However, after SCAD
events women seem to tolerate pregnancies, with the majority ex-
periencing uncomplicated pregnancies [76].
Currently, therapeutic management remains a challenge and is
mainly based on expert consensus [3,4,30].
Conclusion
Despite growing research aimed at characterizing SCAD events,
many aspects of SCAD remain enigmatic. The presence of a po-
tential systemic disease predisposing patients to SCAD, which has
been reported in several cases, does not establish a causative
mechanism. Further genetic and imaging studies may elucidate
the complex etiopathogenesis and help refine SCAD diagnosis and
risk prediction. Overall, insight into SCAD pathophysiologic mech-
anisms may pave the way for tailored management.
Declaration of Competing Interest
None.
Supplementary materials
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.tcm.2021.01.002.
8
[m5G;January 22, 2021;9:47]
Trends in Cardiovascular Medicine xxx (xxxx) xxx
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