**1. Definition and Main Features of Fibromuscular Dysplasia (FMD)**

Fibromuscular Dysplasia (FMD) has been defined as "an idiopathic, segmental, non-atherosclerotic and non-inflammatory disease of the musculature of arterial walls, leading to stenosis of small and medium-sized arteries" [1]. In the last years, the perception of FMD has evolved from a rare cause of secondary hypertension involving renal arteries to a more diffuse vascular disease, affecting also cervico-cephalic, visceral, coronary and iliac arteries [1,2].

Renal and cervico-cephalic arteries are the most frequently affected vascular beds, and both lesions often coexist (65% in the US registry) [3]. In the Assessment of Renal and Cervical Artery Dysplasia (ARCADIA) Belgian-French registry [4], systematic, state of the art exploration of the main arterial beds in 469 patients with FMD revealed that 48% of patients have focal or multifocal FMD lesions of two vascular beds or more and 15% of three vascular beds or more (multivessel FMD). According to the affected arterial bed, FMD can lead to hypertension (renal artery FMD), as well as to severe complications including arterial aneurysms and dissections, subarachnoid haemorrhage, stroke or mesenteric ischemia [1,5]. While FMD was initially considered as a rare disease, silent FMD lesions have been detected in 3–6% of potential kidney donors [6,7].

Recently, multifocal FMD lesions of extracoronary vascular beds have been also identified in up to 75–80% of patients with spontaneous coronary artery dissection (SCAD). Patients who have had a SCAD share many similarities with FMD patients, including female predominance (>90%), age at diagnosis (≈50 years old) and few cardiovascular risk factors [8]. FMD affects predominantly women: 91% in the US registry [3], 84% in the ARCADIA study [4], and 83% in the European registry (A. Persu, personal communication). In contemporary cohorts, the age at diagnosis is in the range of 50–55 years, with a wide distribution from small infants [9] to octogenarians [4,5].

Based on angiographic patterns two subtypes have been defined for renal FMD [1,5,10], and subsequently for cervico-cephalic FMD [1,11], i.e., (i) multifocal FMD: "string-of-beads" appearance, alternation of stenosis and aneurysmal dilations (>80% of cases), corresponding to the medial form according to the former histological classification [12]; and (ii) focal FMD: isolated stenosis, whatever its length, in young patients (usually <40 year old) with few or no cardiovascular risk factors, in the absence of atherosclerotic or inflammatory lesions. While the pattern of multifocal FMD is almost pathognomonic, in order to establish the diagnosis of focal FMD, it is necessary to rule out early localized atherosclerosis, as well as a series of inflammatory and genetic arteriopathies (see Table 1).

**Table 1.** Differential diagnosis of focal Fibromuscular Dysplasia (FMD) in a nutshell (modified from [1]).


Until recently, the aetiology of FMD remains elusive. The classical aetiological hypothesis are summarized in the next section.

#### **2. Classical Aetiological Hypothesis**

#### *2.1. Female Hormones*

In view of the predominance of women among FMD patients, a role for female hormones has been assumed. In particular, it has been hypothesized that the estrogen-induced production of extracellular matrix proteins from vascular fibroblasts and vascular smooth muscle cells [13], may be responsible for some typical histopathological alterations of FMD [12,14]. Unfortunately, up to now, we lack consistent and powerful data to assess for associations between FMD and e.g., the number of pregnancies, age at menarche, history of hysterectomy, gynaecological problems, spontaneous abortion and/or oral contraceptive therapy [12,15]. In addition, all available studies are retrospective, small and underpowered. Therefore, large prospective registries are needed to test the female hormonal environment hypothesis.
