Is there more than meets the eye? Spontaneous coronary artery dissection and sudden cardiac death

This editorial refers to ‘Vascular histopathology and connective tissue ultrastructure in spontaneous coronary artery dissection: pathophysiological and clinical implications’ by M. Margaritis et al., https://doi.org/10.1093/cvr/cvab183.

Spontaneous coronary artery dissection (SCAD) is an important but under-appreciated cause of acute coronary syndrome (ACS) that occurs in the absence of clinically meaningful atherosclerosis, trauma, or iatrogenesis. Although SCAD accounts for no more than 4% of all ACS cases, it underlies up to 35% of ACS occurring in women ≤ 50 years of age and represents the most common cause of ACS in pregnancy.¹ Tragically, ventricular arrhythmia and sudden cardiac death (SCD) are the sentinel clinical manifestation of SCAD in up to 10% of cases.¹

Mechanistically, SCAD is likely a heterogeneous and multifactorial disorder that arises secondary to the collision of multiple risk factors that include acquired and inherited predisposing disorder(s) [arteriopathies such as fibromuscular dysplasia (FMD), connective tissue disorders such as vascular Ehlers–Danlos, common and rare genetic variants in genes that regulate cell–cell adhesion/extracellular matrix function, etc.], hormonal shifts (e.g. pregnancy, exogenous, etc.), hypertension, and environmental (e.g. emotional and physical stress, etc.) precipitants.¹ Whether secondary to the development of an intimal tear (i.e. the ‘inside out’ hypothesis) or more likely the de novo formation of a haematoma within the vessel media (i.e. the ‘outside in’ hypothesis), this perfect storm of genetic, hormonal, and acquired/environmental risk factors leads to the formation of an intramural haematoma capable of obstructing the true coronary lumen.

At present, serial angiographic² and optical coherence tomography³ data support the ‘outside in’ hypothesis. However, the degree to which underlying connective tissue abnormalities, peri-coronary inflammation/vasculitis, and FMD/systemic arteriopathies contribute to spontaneous intramural haematoma formation at the histopathologic and ultrastructural level remains uncertain.

Given the relative paucity of clinicopathologic correlations in SCAD, the study by Margaritis et al.⁴ sought to (i) characterize the spectrum of coronary histopathological findings observed among SCD decedents with an autopsy-rendered SCAD diagnosis and (ii) ascertain if ultrastructural differences exist within the skin biopsies of SCAD survivors and otherwise healthy volunteers by transmission electron microscopy (TEM).

Unfortunately, due to the invariably poor quality of TEM images obtained from paraffin-embedded tissue, the authors were forced to use two separate SCAD cohorts to address these lines of inquiry. Nevertheless, with the use of the largest post-mortem SCAD cohort (n = 36) assembled to date and the only published collection of SCAD dermal skin biopsies (n = 31), the authors provide convincing data arguing against a substantive causative role for several commonly hypothesized and debated mechanisms for SCAD including a pre-existing autoimmune or vasculitic process, intimal injury, coronary FMD, increased vaso vasorum density, or systemic alterations to collagen architecture.⁴

Although Margaritis et al.⁴ provide important histopathological evidence in support of the prevailing ‘outside-in’ hypothesis, few novel mechanistic insights were unearthed. As the authors suggest, the paucity of histopathological clues combined with an apparent predisposition towards elastin instability observed in the dermal biopsies of SCAD patients suggests that subtle functional alterations in extracellular matrix, cell–cell adhesion, or actin cytoskeleton may contribute to SCAD pathogenesis. This is consistent, at least in part, with recent unbiased SCAD genome-wide association and exome sequencing studies that identified common risk loci near (e.g. PHACTR1-encoded phosphatase and actin regulator 1)^5,6 or putative disease-causative rare variants within (e.g. TLN1-encoded talin 1)⁷ genes that regulate cell adhesion and actin cytoskeleton remodelling. Future meta-analyses of existing SCAD genome-wide association studies and functional characterization of SCAD-associated risk loci, and rare variants are needed to further explore this hypothesis and allow us to better understand the role of underlying genetic susceptibility in SCAD.

Potential mechanistic insights aside, perhaps the most important takeaway from this work is the observation that no macroscopic or microscopic evidence of myocardial necrosis was appreciated in the majority (66%) of SCAD decedents, indicative of an arrhythmic cause of death. Practically, this finding suggests that SCAD, particularly when shorter or more distal arterial segments are involved, has the potential to go unrecognized if the post-mortem examination is limited to a standard death scene investigation and conventional autopsy (Figure 1).

Figure 1

Generalized approach to the investigation of sudden unexplained death. Boxes correspond to the strength of recommendation according to the American Heart Association/American College of Cardiology recommendation system. COR, class of recommendation; GHD, genetic heart disease; SCAD, spontaneous coronary artery dissection. Adapted from Stiles et al.⁸ with permission. Copyright © 2021, Elsevier.

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Additionally, the SCAD autopsy cases have several notable differences that contrast with prospective and retrospective registry reports.¹ The proportion of men in the SCAD autopsy series is higher than contemporary registries, including the UK Spontaneous Coronary Artery Dissection Study comparator.⁴ Whether this observation reflects that sentinel SCD is more common in male SCAD patients, or if other factors, such as sex differences in diagnostic testing, accuracy, or autopsy rates influenced this finding, is of interest. Furthermore, none of the autopsy SCAD cases were diagnosed prior to death, whereas SCAD virtually always present with typical signs and symptoms of ACS, albeit not always initially recognized as such. It is not stated if ACS was suspected or diagnosed prior to death or if any decedent’s presenting symptoms were known, so it remains uncertain if SCAD patients presenting with SCD may have a different symptom complex, or just one that was not recognized in time to seek and receive appropriate care. The true prevalence of SCAD in either sex remains impossible to assess since the case counts do not include those who survive without ever seeking care, those who seek care without the diagnosis ever considered or confirmed, or those who do not survive to diagnostic coronary imaging and have no or inadequate post-mortem evaluation.

Nevertheless, the potential contribution of SCAD is not addressed in the recent Heart Rhythm Society/Asia Pacific Heart Rhythm Society consensus statement on the investigation of decedents with unexplained SCD.⁸ In the light of the current findings,⁴ one could make a strong argument for the inclusion of a systematic microscopic assessment of the entire coronary tree, similar to the use of a molecular autopsy to assess for pathologically silent cardiac channelopathies,⁹ to exclude shorter/distal segment SCAD in all ‘autopsy-negative’ decedents in which an SCD root cause remains elusive following conventional investigations (Figure 1).

In addition, the incorporation of a systematic coronary pathology assessment and exome/genome-based molecular autopsy into population-based, prospective SCD registries has the potential to allow for (i) the determination of the true prevalence of SCAD among SCD decedents and (ii) enhance our understanding of the molecular underpinnings and pathologic hallmarks of this still enigmatic condition.

Conflict of interest: none declared.

References

Author notes