Pathology of Genetic Variants in Spontaneous Coronary Artery Dissection

Spontaneous coronary artery dissection (SCAD) is characterized by a separation of the coronary artery wall, causing myocardial infarction and sudden death. This study is one of the first to clarify the impact of pathological genetic variants in candidate SCAD-related genes on the histopathological and morphological properties of human SCAD lesions.

A total of 28 SCAD cases were selected from the CVPath Autopsy Registry. Histological differences in collagen and smooth muscle cells were compared among 3 groups: culprit SCAD (C-SCAD), defined as the coronary segment containing a dissection in cases with SCAD; nonculprit SCAD, defined as unaffected coronary segments (ie, healthy arteries) in cases with SCAD; and non-SCAD controls. Whole-exome sequencing was performed, and the identified variants were filtered to isolate pathogenic or likely pathogenic variants. Protein expression corresponding to the identified variants was assessed by immunostaining.

Collagen content was significantly reduced in C-SCAD lesions compared with controls, and immunohistochemical staining for smoothelin was reduced in the media of C-SCAD lesions compared with controls, whereas there were no significant differences between C-SCAD and nonculprit SCAD. Further, the nuclear height/width ratio of smooth muscle cells was increased, suggesting smooth muscle cell phenotypic modulation. In whole-exome sequencing analysis, pathogenic or likely pathogenic variants were detected in 25% of cases, which showed a higher frequency of multivessel dissection. In SCAD cases with pathogenic or likely pathogenic variants in COL3A1 (collagen type III alpha 1), FBN1 (fibrillin-1), or FLNA (filamin A), the expression of the corresponding protein was reduced in the media.

Reduced medial collagen and smooth muscle cell phenotypic modulation may be possible predisposing conditions for SCAD, regardless of the presence of pathogenic or likely pathogenic variants. The presence of pathogenic variants in extracellular matrix-related genes may further compromise arterial wall medial integrity, contributing to more severe disease. These findings provide novel pathological and genetic insights into the pathogenesis of SCAD and may inform future diagnostic and therapeutic strategies.