Vascular histopathology and connective tissue ultrastructure in spontaneous coronary artery dissection: pathophysiological and clinical implications

Abstract

Aims Spontaneous coronary artery dissection (SCAD) is a cause of acute coronary syndromes and in rare cases sudden cardiac death (SCD). Connective tissue abnormalities, coronary inflammation, increased coronary vasa vasorum density and coronary fibromuscular dysplasia have all been implicated in the pathophysiology of SCAD but have not previously been systematically assessed. We designed a study to investigate the coronary histological and dermal collagen ultrastructural findings in SCAD. Methods and Results 36 autopsy SCAD cases were compared with 359 SCAD survivors. Coronary and myocardial histology and immunohistochemistry were undertaken. Transmission electron microscopy (TEM) of dermal extracellular matrix components (ECM) of n = 31 SCAD survivors and n = 16 healthy volunteers were compared. Autopsy cases were more likely male (19% versus 5%; p = 0.0004) with greater proximal left coronary involvement (56% versus 18%; p < 0.0001) compared to SCAD survivors. N = 24 (66%) of cases showed no myocardial infarction on macro- or microscopic examination consistent with arrhythmogenic death. There was significantly (p < 0.001) higher inflammation in cases with delayed-onset death vs sudden death and significantly more inflammation surrounding the dissected vs. non-dissected vessel segments. N = 17 (47%) cases showed limited intimal fibro-elastic thickening but no features of fibromuscular dysplasia and no endothelial or internal elastic lamina abnormalities. There were no differences in vasa vasorum density between SCAD and control cases. TEM revealed no general ultrastructural differences in ECM components or markers of fibroblast metabolic activity. Conclusions Assessment of SCD requires careful exclusion of SCAD, particularly in cases without myocardial necrosis. Peri-coronary inflammation in SCAD is distinct from vasculitides and likely a reaction to, rather than a cause for SCAD. Coronary fibromuscular dysplasia or increased vasa vasorum density do not appear pathophysiologically important. Dermal connective tissue changes are not common in SCAD survivors. Translational Perspective SCAD, especially of distal coronary territories should be carefully assessed at post mortem in SCD cases, even where there are no signs of myocardial infarction. The immediate cause of SCAD is likely to be the development of a spontaneous intramural haematoma rather than an intimal disruption or ‘tear’. This does not seem to be directly related to increased vasa vasorum density, coronary fibromuscular dysplasia or local inflammation (except as a response to injury). Although SCAD is rarely associated with hereditary connective tissue disorders, there does not seem to be a more generalizable global connective tissue ultrastructural abnormality in most cases.

Prevalence and Disease Spectrum of Extracoronary Arterial Abnormalities in Spontaneous Coronary Artery Dissection

“…26 In addition, a histological correlate for the radiological FMD in SCAD remains to be demonstrated. 27 Further studies are needed to fully understand the interrelationship between SCAD and FMD.…”

Optical Coherence Tomography and Coronary Dissection: Precious Tool or Useless Surplus?

“…Intramural hematoma in patients with SCAD is frequently bounded at its proximal and distal extent by branch points (24). The differential diagnosis between SCAD and atheroma could be challenging due to a frequent overlap of angiographic findings (33).…”

Genome-wide association meta-analysis of spontaneous coronary artery dissection reveals common variants and genes related to artery integrity and tissue-mediated coagulation

“…2-6 However, in contrast with CAD, SCAD affects a younger, predominantly female population, 7 and arises from the development of a haematoma leading to dissection of the coronary tunica media with eventually formation of a false lumen, rather than atherosclerotic plaque erosion or rupture. 8 SCAD has been clinically associated with migraine 9 and extra-coronary arteriopathies including fibromuscular dysplasia (FMD). 10-13 However, co-existent coronary atherosclerosis is uncommon.…”

“…10-13 However, co-existent coronary atherosclerosis is uncommon. 8,14 Whilst the genetic basis of CAD is increasingly well established, 15 the pathophysiology of SCAD remains poorly understood. 4 The search for highly penetrant mutations in candidate pathways or by sequencing has had a low yield, often pointing to genes involved in other clinically undiagnosed inherited syndromes manifesting as SCAD.…”