FMD and SCAD: Sex-Biased Arterial Diseases With Clinical and Genetic Pleiotropy

Abstract

Multifocal fibromuscular dysplasia (FMD) and spontaneous coronary artery dissection are both sex-biased diseases disproportionately affecting women over men in a 9:1 ratio. Traditionally known in the context of renovascular hypertension, recent advances in knowledge about FMD have demonstrated that FMD is a systemic arteriopathy presenting as arterial stenosis, aneurysm, and dissection in virtually any arterial bed. FMD is also characterized by major cardiovascular presentations including hypertension, stroke, and myocardial infarction. Similar to FMD, spontaneous coronary artery dissection is associated with a high prevalence of extracoronary vascular abnormalities, including FMD, aneurysm, and extracoronary dissection, and recent studies have also found genetic associations between the two diseases. This review will summarize the relationship between FMD and spontaneous coronary artery dissection with a focus on common clinical associations, histopathologic mechanisms, genetic susceptibilities, and the biology of these diseases. The current status of disease models and critical future research directions will also be addressed.

Keywords: aneurysm; biology; fibromuscular dysplasia; genetics; prevalence.

Figure 1.

(Left panel) Volume rendered acquisition of computed tomography angiography of the abdomen and pelvis demonstrating multifocal FMD of the bilateral renal arteries (arrows) and right external iliac artery (bracket). (Right panel) Close up imaging of the right renal artery of the same patient demonstrates the classic “string of pearls” appearance of the right renal artery and a right renal artery aneurysm.

Figure 2.

Demographics and cardiovascular risk factors of patients included in studies of FMD^{, , , ,} and SCAD^{, , ,} . Reported ranges are shown for FMD (blue bars) and SCAD (red bars).

Figure 3.

Inverted maximal intensity projection image of computed tomography angiography of the head and neck demonstrating a bovine aortic arch configuration, multifocal FMD of the right internal carotid artery and bilateral vertebral arteries (dashed arrows), tortuosity of the proximal left vertebral artery (arrow head), and aneurysm of distal P2 segment of the left posterior cerebral artery (solid arrow)

Figure 4.

Coronary angiograms showing SCAD classification: (A) Type 1 SCAD of an obtuse marginal artery (arrow showing contrast staining of the arterial wall), (B) Type 2A SCAD of the mid left anterior descending artery (arrow), (C) Type 2B SCAD of the right posterior descending artery (arrow) that extends to the distal tip of the vessel, and (D) Type 3 SCAD of the mid left anterior descending artery (arrow).

Figure 5.

Genetic architecture of FMD and SCAD as defined by various genetic discovery approaches. Rare, high-impact variants typically underlie Mendelian or “monogenic” diseases, and examples have been identified for FMD and SCAD (Table, Category #1). Common variant associations are discovered through approaches such as GWAS and typically each identified variant has a relatively small effect estimate (Table, Category #3). In between these two categories may be low frequency variants with intermediate impact Associations or modifier effects (Table, Category #2).

Figure 6.

Overview of genes and loci associated with FMD and SCAD. Associated genes and loci are shown and related to known genes and loci associated with vascular connective tissue disease, and cervical artery dissection and/or migraine headache Adapted from Persu et al. Chr, Chromosome.