A breakthrough in spontaneous coronary artery dissection pathogenesis: is it an inherited condition?

KEYWORDS:

• Spontaneous coronary artery dissection
• genetics
• acute coronary syndrome
• atherosclerosis
• fibromuscular dysplasia

Spontaneous coronary artery dissection (SCAD) is an infrequent cause of acute coronary syndrome (ACS), typically affecting younger women [1–3]. The condition differs from atherosclerosis. Both the underlying cause and precipitating mechanism of the majority of SCAD events remain uncertain. However, recent observations of the occurrence of SCAD within families have raised the potential of inherited vulnerability and/or a genetic predisposition.

The clinical spectrum of SCAD ranges from ACS to sudden cardiac death. Female gender, absence of atherosclerotic risk factors, presence of unique angiographic signs, characteristic findings on intravascular ultrasound (IVUS) or optical coherence tomography (OCT) [4], and presence of concomitant fibromuscular dysplasia (FMD) in non-coronary vascular beds [5–7] may help establish the diagnosis. Traditionally, the diagnosis of SCAD is made by coronary angiography and/or intravascular imaging [1]. Three distinct angiographic patterns have been characterized, Type 1 with arterial wall stain, Type 2 with diffuse stenosis, and Type 3 that resembles an atherosclerosis pattern [8,9].

Two types of SCAD are also described by IVUS, stratified by presence or absence of intimal tear [10]. Besides medial disruption, pathological findings may also include cystic medial necrosis and eosinophilic infiltration. Similar to IVUS, OCT has identified two distinct morphologies in SCAD [11]. First, an ‘entry door’ type, in which a false lumen between the media and adventitia is associated with an intimal tear, and second, the ‘false lumen thrombosis’ type, in which separation between media and adventitia with intramural hematoma could be identified regardless of the presence of intimal tear. The true incidence of SCAD is unknown. Prior estimates have reported prevalence ranging 0.07–1.1% [1,12], but these are likely underestimates. The incidence is likely much higher in postpartum females and in premenopausal women without traditional cardiovascular risk factors [13].

The evidence of genetic susceptibility in patients with SCAD was recently evaluated by our group in five pairs of relatives with angiographically confirmed SCAD: three pairs of first-degree relatives, including mother–daughter, identical twin sisters, and sisters, and two pairs of second-degree relatives, including aunt–niece and first cousins [13]. These familial patterns suggest both recessive and dominant mode of inheritance with incomplete penetrance and variable expression. It is of interest to note that several conditions associated with SCAD, such as FMD, Marfan, and Ehler–Danlos syndromes, have some genetic predisposition. Rushton et al. performed a formal pedigree analysis and suggested that FMD may be transmitted as an autosomal dominant disease with incomplete penetrance [14]. The limitation of this study was that the authors included patients with atherosclerosis (coronary and peripheral arterial disease) and the conclusions were drawn from interviews of relatives with suspicion of FMD and therefore were subject to recall and other biases. Familial occurrence of FMD was noted in a study of 104 patients in which 11% of patients with renal multifocal FMD had at least one sibling with angiographic evidence of renal artery FMD [15]. The true prevalence of FMD in first-degree relatives could not be determined as not all relatives were systematically studied for FMD. Marfan’s syndrome and certain Ehlers–Danlos syndrome subtypes, which have an autosomal dominant inheritance pattern, have also been found to be associated with SCAD, albeit at low levels of frequency. With the improvement in recognition and awareness of SCAD, it is quite conceivable that detection of relatives with this disease will increase and that the inheritance pattern will be better delineated.

The clinical implications of the recent case series of SCAD affecting family members [13] are as follows: (1) genetic transmission of this important cause of ACS is a novel finding which may help target future research and therapy and (2) careful screening of relatives for SCAD, connective tissue disorders, and FMD is needed to help further characterize inheritance.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Funding

This paper was not funded.