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Fibromuscular dysplasia: Advances in understanding and management

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ABSTRACTSeveral key findings in recent years have reshaped our understanding of fibromuscular dysplasia (FMD), an uncommon nonatherosclerotic disease of medium-sized arteries that affects mainly women. While the true prevalence of this disease remains unknown, studies suggest that more people may be affected than previously reported. Better understanding of the clinical manifestations and natural history of FMD and advances in diagnostic imaging have altered the clinical approach to managing patients with this uncommon vascular disease. Although there are a multitude of unanswered questions regarding FMD, this review highlights recent insights and how this information has modified clinical care for those affected.

KEY POINTS

  • There is no cure for FMD. Management focuses on thorough evaluation and surveillance, lifestyle modification, and treatment of symptoms. Vascular procedures, such as angioplasty or treatment of aneurysms, are required for some patients.
  • The overwhelming majority (> 90%) of patients with FMD are women. But men seem to have a more aggressive course, with a rate of aneurysm or dissection two times higher than that in women.
  • The disease can affect medium-sized vessels throughout the body. In addition to the typical “string-of-beads” appearance or focal lesions, manifestations include arterial tortuosity, aneurysm, and dissection.


 

References

Fibromuscular dysplasia (FMD) is an uncommon vascular disease that leads to narrowing (with either a beaded appearance or, less commonly, focal stenosis), dissection, or aneurysm of medium-sized arteries. Awareness of FMD within the medical community has rapidly expanded during the past decade owing to heightened interest among clinicians, multicenter coordinated research initiatives, and patient advocacy efforts.

In addition, a better understanding of the clinical manifestations and natural history of the disease along with advances in diagnostic imaging have altered the clinical approach to management. There are many unanswered questions regarding FMD, but this review highlights recent insights and how this information has modified clinical care for those affected.

DISTINCT FROM ATHEROSCLEROSIS

Reprinted with permission from Wolters Kluwer Health, Inc. (Poloskey SL, et al. Fibromuscular dysplasia. Circulation 2012; 125:e636–e639).
Figure 1. Multifocal fibromuscular dysplasia (FMD) involving the internal carotid artery (A) and a renal artery (B) with a “string-of-beads” appearance. The less common type, focal FMD, involving the internal carotid artery (C) and a renal artery (D).

FMD results from abnormal development of the arterial cell wall, most commonly the vessel media and less commonly the vessel intima (Figure 1).1,2 Distinct from atherosclerotic processes, FMD shares few typical cardiovascular risk factors aside from an association with tobacco smoking.3,4

The most common variant of FMD is the multi­focal type, with the affected arteries resembling a string of beads due to alternating regions of stenosis and dilation.1,5 FMD can also cause a singular stenosis (focal type FMD) and has more recently been associated with findings of arterial tortuosity, aneurysm, and dissection.6,7

Though the disease typically affects the renal and extracranial carotid arteries, it has been noted in most medium-sized arteries throughout the body, most commonly the mesenteric, external iliac, and brachial arteries.1 The location of diseased segments determines symptoms, which commonly include hypertension, headache, and pulsatile tinnitus.8 The overwhelming majority of people affected (> 90%) are women.8

The diagnosis of FMD should be suspected in the case of young or middle-aged women presenting with migraine headaches, pulsatile tinnitus, or hypertension and for women with cervical bruits without typical risk factors for atherosclerotic disease. The diagnosis should also be suspected among patients who have suffered an arterial dissection or who are found to have a cerebral, carotid, or renal aneurysm.

THE US REGISTRY FOR FMD

Key findings of publications from the US Registry for Fibromuscular Dysplasia

Since it began enrolling patients in 2009, the US Registry for Fibromuscular Dysplasia has grown to include 13 active centers. It collects longitudinal data on the clinical characteristics, presentation, vascular bed involvement, vascular procedures, and clinical outcomes of patients with FMD.8,9Table 1 highlights key findings and lessons learned from registry publications, many of which have altered previous concepts of this disease.3,7,8,10–12

EPIDEMIOLOGY AND PATHOPHYSIOLOGY

Prevalence

Although FMD is considered a rare disease (and recognized as such by the National Organization of Rare Diseases), the exact prevalence is unknown. A review of 8 studies conducted from 1963 to 2011 found the prevalence of FMD ranged from 2.0% (3 of 150) to 6.6% (47 of 716) among healthy renal transplant donors for a mean prevalence of 3.3% (268 of 8,029) among all donors.13–21 Findings from the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial, which studied the effectiveness of medical therapy alone vs medical therapy and stenting for treatment of significant renal artery stenosis and hypertension, found that 5.8% (58 of 997) of participants who underwent angiography had concomitant renal FMD.22 Importantly, patients with FMD were supposed to have been excluded from the trial, suggesting that FMD is often overlooked or underdiagnosed. A review published in 2010 reported the prevalence of cerebrovascular FMD to be 0.3% to 3.2% in patients undergoing cerebral angiography, but it noted significant heterogeneity in patient populations and definitions of FMD across published studies.23

Risk factors for FMD: Female sex and tobacco smoking

The mechanisms underlying the pathogenesis of FMD are still poorly understood, and its development is likely related to a combination of genetic and environmental factors. There seems to be a hormonal component to the pathogenesis of FMD, as most patients with this condition are women: approximately 91.5% of patients enrolled in the US Registry.10 Men with FMD, however, seem to have a more aggressive course with a rate of aneurysm or dissection two times higher than that in women with FMD.7

Studies have reported an increased risk of FMD in patients with a history of tobacco smoking.3,24 A US Registry report notes that FMD patients with a history of smoking had a statistically significant higher rate of aneurysm than those who had never smoked (24.8% vs 18.9%), and there was a trend toward increased prevalence of major vascular events in smokers, including subarachnoid hemorrhage, transient ischemic attack, stroke, mesenteric ischemia, renal infarction, and major coronary event.3 This study also found that patients with FMD who were smokers were more likely to have claudication symptoms (15.1% vs 7.4%) or to have undergone a vascular procedure (45.9% vs 36.7%).3 Further research is needed to fully understand the relationship between smoking and its interaction with other environmental, hormonal, and genetic factors.

FMD and connective tissue features

While studies have suggested a genetic component to the development of FMD, the specific genetic mechanisms are unknown.1 Studies have explored the potential relationship between FMD and genetic connective tissue disorders that can present with vascular manifestations, such as Loeys-Dietz, Marfan, and Ehlers-Danlos syndromes, and isolated case reports have noted concomitant FMD lesions in patients with these classical genetic disorders.25–31 In a series of patients with FMD from Cleveland Clinic who underwent genetic testing for selected connective tissue disorders, including Ehlers-Danlos syndrome and Loeys-Dietz syndrome, the overall yield of these tests was low.31 These studies suggest some overlap of FMD and other vascular connective tissue disorders, as well as the likelihood that the arterial manifestations of FMD may develop through multiple potential genetic pathways.

A series of 47 patients with FMD seen at the National Institutes of Health found a high incidence of connective tissue features on physical examination, with 95.7% of patients exhibiting at least four features of connective tissue disease, including marked hypermobility, scoliosis, craniofacial abnormalities, and pes planus (flat foot deformity).32 A study of a larger cohort of female patients seen at Cleveland Clinic did not find classical connective tissue features (such as pectus deformity, hypermobility, atrophic scaring, and club foot deformity) to a greater extent than what is reported in the general population, but it did find a significant prevalence of severe myopia (near sightedness), high-arched palate, dental crowding, and early-onset arthritis.33 Additional studies are needed to clarify the potential relationship between the spectrum of connective tissue disorders and FMD.

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