Fibromuscular dysplasia: Beginning to see the forest through the trees

Fibromuscular dysplasia (FMD) is a non-atherosclerotic, non-inflammatory arteriopathy that affects mostly women and may result in stenotic lesions, arterial tortuosity, aneurysm, or dissection. ¹ Data from healthy kidney donors suggest that FMD may affect approximately 4–5% of women, ¹ although rates may be even higher in patients with hypertension. Review of angiographic imaging by the core laboratory in the CORAL (Cardiovascular Outcomes in Renal Atherosclerotic Lesions) trial identified FMD in 5.8% of patients overall and in 8.8% of the women enrolled. ² FMD was an exclusion criterion for the trial, suggesting that the true prevalence is more common than appreciated.

Historically, renal artery FMD was considered a rare cause of renovascular hypertension in young-to-middle-aged women, and cervical artery FMD was thought to be generally benign. ³ Growing evidence over the past years, however, demonstrates that this perception was incorrect. The United States Registry for FMD and the European Assessment of Renal and Cervical Artery DysplasIA (ARCADIA) registry have commonly identified manifestations of FMD beyond the pathognomonic ‘string-of-beads’ of multifocal disease and single area of stenosis in focal FMD.^1,4,5 Dissection and/or aneurysm were observed in 41.7% of patients in the US Registry for FMD, which probably represents an underestimate of the true prevalence as not all patients were imaged from head to pelvis. ⁶ Data from the ARCADIA registry, which routinely imaged beyond the initial sites of FMD involvement, revealed that multisite disease is common (48% of patients), and even more so if the definition of FMD involvement was expanded to include aneurysm or dissection (66.3% of patients). ⁷ It is therefore recommended that all FMD patients undergo head-to-pelvis cross-sectional imaging with computed tomography angiography (CTA) or magnetic resonance angiography (MRA) at least once to screen for additional sites of FMD involvement, as well as occult aneurysm or dissection. ⁶

The most severe phenotypes of FMD include transient ischemic attack, ischemic or hemorrhagic stroke, and myocardial infarction, which are due to spontaneous arterial dissection and/or aneurysm rupture, supporting the notion that FMD is a systemic arteriopathy with heterogeneous presentation. Importantly, many conditions are associated with aneurysm, dissection, or tortuosity; therefore, these findings cannot universally be attributed to FMD unless typical multifocal or focal disease is visualized on CTA, MRA, or catheter-based angiography. Cohort studies evaluating patients with spontaneous coronary artery dissection (SCAD) for extra-coronary vasculopathy identified multifocal or focal FMD in 25–86% of cases. ⁸ As a result, expert consensus now recommends screening all patients with SCAD with head-to-pelvis cross-sectional imaging as well. ⁸ The best approach to evaluating patients with spontaneous cervical artery dissections (SCeAD) has been less clear. SCeAD was observed in 19% of patients from the US Registry for FMD and 37% of those patients experienced more than one cervical artery dissection. ⁶ Data from the Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) international consortium reported FMD in up to 15% of patients, with higher rates in those with multiple SCeAD. ⁹ However, this is probably also an underestimation of the true co-prevalence of FMD since most patients in CADISP are not screened in other vascular beds, nor are there other studies that have systematically evaluated patients with SCeAD for the presence of FMD below the neck.

In this issue of Vascular Medicine, Talarowska and colleagues present data from the ARCADIA-POL study, which was instituted in 2015 as a Polish collaboration with the French-Belgian ARCADIA registry. ¹⁰ The study prospectively enrolled 230 consecutive patients from six participating university centers over roughly 18 months with FMD, SCAD, and/or SCeAD, with the purpose of systematically evaluating FMD frequency, clinical characteristics, and vascular bed involvement in patients with SCeAD. All subjects were screened with whole-body CTA including the head, neck, chest, abdomen, arms, and legs. In addition, a detailed evaluation was performed including office and ambulatory blood pressure measurements, biochemical evaluation, biobanking, echocardiogram, and duplex ultrasound of the carotid and abdominal arteries. Of the 230 patients enrolled, 43 (18.7%) had SCeAD and 135 had typical multifocal or focal FMD findings without SCeAD (Figure 1). The remaining 52 were excluded from this analysis because they did not have FMD or SCeAD (e.g. SCAD but no multifocal/focal FMD or SCeAD). Among the 43 patients with SCeAD, multifocal or focal FMD was identified in 17 patients (39.5%).

These findings are novel as they relate to patients with SCeAD and FMD, although it is not clear if they are generalizable to all patients with SCeAD. It is important to note that this small study had more women (65.1%) than larger European (43–47%) or US series (50–52%) of patients with SCeAD published in the past, despite consecutive recruitment into ARCADIA-POL. The reasons for this are unclear, but the study may have selectively identified more patients with FMD as a result. On the other hand, these data may still under-represent the true co-prevalence of SCeAD and FMD because patients were recruited from academic neurology centers and thus likely only represent those with more clinically manifest disease. One patient in this study was found to have a silent (incidental) SCeAD on imaging after diagnosis of multifocal FMD in the renal arteries. Prior studies have not investigated the frequency of silent SCeAD in patients with FMD, which will be important going forward in order to clarify the true co-prevalence of these conditions.

For the majority (93%) of patients in the ARCADIA-POL study, the SCeAD event was the first dissection in the patient’s lifetime, and there were no dissections observed in arteries other than the cervical vessels. Multisite FMD, defined as the presence of multifocal and focal findings only, was observed in 29% of all patients with FMD in this analysis (Table 3 in Ref. 10). Though lower than previously published reports, the rate of multisite involvement rose to 44% when aneurysm was included as an additional manifestation of FMD.^7,11 These data confirm that FMD is a systemic disease with heterogeneous presentation.^6,7,11,12 The time has come to recognize an expanded definition of multivessel FMD involvement that includes aneurysm, dissection, and arterial tortuosity in the presence of multifocal or focal FMD findings.

The current study by Talarowska and colleagues is limited by the relatively small population included in ARCADIA-POL. Despite this, the results indicate that the co-prevalence of FMD among patients with SCeAD has been under-appreciated and has implications for patient care. It will be important for future investigations to include additional findings of systemic arteriopathy independent of FMD below the neck, such as aneurysm, which may further support routine screening of patients with SCeAD regardless of FMD co-prevalence. For now, it is reasonable, particularly in women presenting with SCeAD, to pursue CTA or MRA screening from head-to-pelvis to screen for the presence of FMD as well as occult aneurysm or dissection in other territories.