Introduction

For a disease that was first described nearly 80 years ago, there is still astonishingly little awareness about fibromuscular dysplasia (FMD) within the medical community. FMD is a non-atherosclerotic arterial disease that is due to abnormal cell growth (e.g., fibrosis) of the vessel wall. This disease can manifest as arterial dilatation, stenosis, tortuosity (loops or bends), and beaded-appearing lesions, or even more serious complications such as aneurysm formation or arterial dissections. The renal and extracranial carotid and vertebral arteries are most commonly affected, but FMD can be found in most medium-sized arteries of the body. While the large majority of patients are women (90%), the etiology and prevalence of FMD remain unknown.¹

FMD was first described in 1938 by Leadbetter and Burkland.² Aside from preliminary descriptions, classification systems, and case reports and small case series, little progress was made in research regard the disease until the last decade. The Fibromuscular Dysplasia Society of America (FMDSA) was founded in 2003. Through annual events and its website, FMDSA has been instrumental in increasing awareness of FMD and providing support to patients. Funded by FMDSA, the United States Registry for Fibromuscular Dysplasia began enrolling patients in 2009. It has since grown to include 13 actively enrolling centers across the U.S., with the Michigan Cardiovascular Outcomes Research and Reporting Program serving as the coordinating center. The registry recently celebrated the enrollment of its 1,100th patient in the summer of 2014 and continues to enroll an increasing number of patients each year. Information ascertained from the registry and other research studies has played a crucial role in understanding FMD, making the disease an emerging topic of interest. In addition to emerging data from the U.S. registry, recently published U.S. (American Heart Association [AHA] Scientific Statement) and French consensus documents have summarized state-of–the-art care for patients with this disorder.^3,4 Researchers have also begun to explore the pathophysiological mechanisms of FMD, its genetics, and its potential relationship to other connective tissue disorders.⁵

Overview of FMD

Classification
There are several distinct histological types of FMD, corresponding to the layer of the arterial wall involved.⁶ Medial fibroplasia is the most common form and presents as a string of beads, or alternating areas of stenosis and dilatation of the artery (Figure 1). Intimal fibroplasia and adventitial FMD are less commonly reported.^1,3 Simpler angiographic classifications have been proposed in an attempt to standardize the study of FMD.³ These definitions separate FMD into two cohorts – multifocal (string of beads) and focal (single, distinctive lesions).³

Figure 1 Computed tomographic angiogram demonstrating multifocal FMD of the right renal artery. Although the patient has a history of well controlled hypertension, FMD was incidentally diagnosed when she underwent imaging for abdominal pain and diarrhea. The mesenteric arteries were normal.

Vascular Bed Involvement
Historically, there was a misconception that FMD was principally a disease of the renal arteries. While the percentage of patients within the U.S. registry with renal FMD is high (79.7%), it can exist in a variety of vascular territories including the carotid (74.3%), vertebral (36.6%), celiac/mesenteric (26.3%) arteries, and less commonly in the intracranial vessels and lower (especially external iliac) and upper (especially brachial) extremity arteries.¹ FMD commonly affects multiple vascular beds, and in the U.S. registry approximately half of patients imaged in multiple areas will have multi-vessel involvement.⁷ Of patients in the registry who underwent both renal and cerebrovascular imaging, nearly 2/3 were found to have FMD in both domains.¹

Presentation
Early or acute onset hypertension has been previously described as a common symptom for renal FMD patients.² Recent findings from the registry show that FMD can present with a multitude of symptoms, depending on arterial involvement. These symptoms include hypertension (62.8%), headaches (52.4%), pulsatile tinnitus (27.5%), dizziness (26%), cervical bruit (22.2%), and neck pain (22.2%).^1,7 Sex differences also exist in presentation, men more commonly presenting with visceral manifestations, such as renal artery dissection and infarction.⁸ Some patients (5.6%) are asymptomatic with FMD diagnosis occurring due to incidental findings on angiographic studies.¹

Diagnosis
A major problem regarding the care of patients with FMD is the gap in time that exists between onset of symptoms and diagnosis. From the U.S. registry, the mean length of time from onset of symptoms to diagnosis was 3.6 ± 7.4 years; within a study from Paris, there was a nine-year delay in onset of hypertension and diagnosis in patients with multifocal renal artery FMD.^1,9,10 Recognition of the common presenting symptoms and thorough examination are essential to provide timely diagnoses to these patients. Pulsatile tinnitus is a relatively uncommon symptom in the general population but is present in more than 1/3 of FMD patients in the U.S. Registry.¹¹ Given the prevalence of audible bruits over the affected vascular bed, listening for a bruit is a preliminary diagnostic tool with high positive predictive value, but lack of one is not sufficient to rule out FMD.⁷ Noninvasive imaging is currently the primary method for diagnosing FMD, with catheter-based angiography serving as the gold standard.³ It is important to note that the severity of renal artery stenosis and hemodynamic significance of lesions cannot be determined based on angiography alone; translesional pressure gradients should be obtained before intervening and after angioplasty to confirm success.³

Treatment and Outcomes
Although FMD is not typically a life-threatening disease, the wide array of symptoms can be debilitating and serious. Approximately one in five patients in the registry experienced at least one dissection, of which 72.7% were located in the extracranial carotid arteries.¹² Aneurysms are frequent as well (21.6% of registry patients) and most commonly occur in the renal and extracranial carotid arteries.¹² Just under 40% of FMD patients have experienced a major vascular event (defined as death, dissection, myocardial infarction [MI], coronary revascularization, transient ischemic attack, stroke, subarachnoid hemorrhage [SAH], mesenteric ischemia, or renal infarction) upon enrollment in the registry.¹³ All FMD patients are managed medically with periodic follow-up and imaging surveillance as directed by a knowledgeable health care provider with referral for vascular procedures as indicated.^1,3 According to data from 2011, roughly half of patients in the U.S. registry have undergone a vascular procedure for FMD, most commonly balloon angioplasty of the renal arteries.^1,7

New Insights

The genetic mechanism underlying FMD is a focus of ongoing research studies in the U.S. and France. Assessment of plasma levels and dermal fibroblasts from 47 individuals with FMD revealed an association with elevated expression of transcription growth factors TGF-β1 and TGF-β2.⁵ These individuals also exhibited physical features consistent with an underlying connective tissue disorder, suggesting there may be some connection between these diseases and FMD.⁵

Recent findings have reported a correlation between FMD and spontaneous coronary artery dissection. These studies illustrated a high occurrence of spontaneous coronary artery dissection (SCAD) patients with FMD in multiple vascular beds, including the renal, carotid, and iliac arteries.^14-18 The causal relationship has yet to be identified, but some hypothesize that FMD may be a predisposing condition for SCAD.

While the prevalence of FMD within the general population remains unknown, research suggests it is commonly underdiagnosed. Evaluation of angiographic studies from participants in the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial with significant hypertension revealed that 5.8% of trial participants had FMD.¹⁹ This is particularly noteworthy given that an exclusion criterion for the CORAL trial was the presence of FMD.

The existence of tortuosity and redundancy, with S-curvature, of the internal carotid arteries (ICA) in FMD patients is a more recent discovery. In a study evaluating 116 FMD patients, Sethi and colleagues from Mt. Sinai Medical Center found 37 (32%) to have a carotid S-curve upon review of imaging studies (Figure 2).²⁰ The majority of these patients had both renal and carotid FMD, but an ICA S-curve was found in patients with FMD in either their renal or carotid arteries exclusively.²⁰ Although this anatomical feature is not unique to FMD patients, it is more prevalent in the FMD population, particularly in patients under the age of 70.²⁰

Figure 2 Color power angiogram ultrasound image demonstrating S-curve in the internal carotid artery in a woman with multifocal FMD involving the renal and carotid arteries. This marked carotid arterial tortuosity and redundancy has recently been recognized as a manifestation of FMD.20

Future Directions

Lessons learned from the U.S. registry for FMD and other research studies have informed the clinical care of FMD patients. However, despite the frequent occurrence of FMD in multiple vascular beds, imaging of multiple vascular beds was only conducted in 74.5% of patients in the registry in 2011.^1,7 Ensuring that FMD patients receive imaging of multiple vascular beds to rule out diffuse involvement and occult aortic, visceral, or brain aneurysms is recommended.³ There is also a need for increased awareness of FMD and its symptoms to reduce the delay to diagnosis that currently exists so that FMD patients can receive quality care from providers familiar with this uncommon disease.

The past decade has greatly increased the knowledge base of FMD, but there are still several unanswered questions. In May 2014, the first International FMD Research Network Symposium was held in Cleveland, Ohio. Key investigators from across the U.S., Canada, Poland, and France formed several working groups to discuss future directions for research of FMD. Topics of interest included FMD genetics, epidemiology, registry research, and imaging and clinical management. Development of this international collaborative research network aims to advance the knowledge of FMD and address remaining unanswered questions in the upcoming years.

References

1. Olin JW, Froehlich J, Gu X, et al. The United States Registry for Fibromuscular Dysplasia: results in the first 447 patients. Circulation 2012;125:3182-90.
2. Leadbetter W, Burkland L. Hypertension in unilateral renal disease. J Urol 1938;39:611-26
3. Olin JW, Gornik HL, Bacharach M, et al. Fibromuscular dysplasia: state of the science and critical unanswered questions: a scientific statement from the American Heart Association. Circulation 2014;129:1048-78.
4. Persu A, Giavarini A, Touzé E, et al. European consensus on the diagnosis and management of fibromuscular dysplasia. J Hypertens 2014;32:1367-78.
5. Ganesh SK, Morissette R, Xu Z, et al. Clinical and biochemical profiles suggest fibromuscular dysplasia is a systemic disease with altered TGF-β expression and connective tissue features. FASEB J 2014; 28:3313-24.
6. Harrison EG Jr, McCormack LJ. Pathologic classifications of renal arterial disease in renovascular hypertension. Mayo Clinic Proc 1971;46:161-67.
7. O'Connor S, Olin JW, Gornik HL. Top 8 lessons learned from the US Registry for FMD. Endovasc Today 2014;2:31-27.
8. Kim ESH, Olin JW, Froehlich JB, et al. Clinical manifestations of fibromuscular dysplasia vary by patient sex: a report of the United States registry for fibromuscular dysplasia. J Am Coll Cardiol 2013;61:2026-28.
9. Gavin J, Gu X, Gornik HL, et al. Factors associated with delay in diagnosis of patients with fibromuscular dysplasia. SVM Abstracts 2013.
10. Savard S, Steichen O, Azarine A, Azizi M, Jeunemaitre X, Plouin PF. Association between 2 angiographic subtypes of renal artery fibromuscular dysplasia and clinical characteristics. Circulation 2012;126:3062-69.
11. Mahmood RZ, Olin J, Gu X, et al. Unraveling pulsatile tinnitus in FMD: A report of the United States Registry for Fibromuscular Dysplasia. J Am Coll Cardiol 2014;63(12_S):A2060.
12. Kadian-Dodov D, Gornik HL, Gu X, et al. Aneurysm and dissection in fibromuscular dysplasia: Findings from the United States Registry for FMD. J Am Coll of Cardiol 2014;63(12_S):A2030.
13. O'Connor S, Olin JW, Gu X, et al. Fibromuscular dysplasia is a morbid disease with low associated mortality: A report of the United States Registry for Fibromuscular Dysplasia. SVM Abstracts 2014.
14. Saw J, Poulter R, Fung A, Wood D, Hamburger J, Buller CE. Spontaneous coronary artery dissection in patients with fibromuscular dysplasia: a case series. Circ Cardiovasc Interv 2012;5:134-7.
15. Saw J, Ricci D, Starovoytov A, Fox R, Buller CE. Spontaneous coronary artery dissection: prevalence of predisposing conditions including fibromuscular dysplasia in a tertiary center cohort. JACC Cardiovasc Interv 2013;6:44-52.
16. Tweet MS, Hayes SN, Pitta SR, et al. Clinical features, management, and prognosis of spontaneous coronary artery dissection. Circulation 2012;126:579-88.
17. Saw J. Spontaneous coronary artery dissection. Can J Cardiol 2013;29:1027-33.
18. Michelis KC, Olin JW, Kadian-Dodov D, d'Escamard V, Kovacic JC. Coronary artery manifestations of fibromuscular dysplasia. J Am Coll of Cardiol 2014;64:1033-46.
19. Hendricks NJ, Matsumoto AH, Angle JF, et al. Is fibromuscular dysplasia underdiagnosed? A comparison of the prevalence of FMD seen in CORAL trial participants versus a single institution population of renal donor candidates. Vasc Med 2014;19:363-7.
20. Sethi SS, Lau JF, Godbold J, Gustavson S, Olin JW. The S curve: A novel morphological finding in the internal carotid artery in patients with fibromuscular dysplasia. Vasc Med 2014;19:356-62.

Keywords: Abdominal Pain, Angiography, Angioplasty, Angioplasty, Balloon, Anthozoa, Arteries, Carotid Artery, Internal, Connective Tissue, Constriction, Pathologic, Coronary Vessel Anomalies, Diarrhea, Dilatation, Dizziness, Fibroblasts, Fibromuscular Dysplasia, Headache, Hemodynamics, Hypertension, Iliac Artery, Infarction, Intercellular Signaling Peptides and Proteins, Intracranial Aneurysm, Ischemic Attack, Transient, Mesenteric Arteries, Myocardial Infarction, Renal Artery, Renal Artery Obstruction, Stroke, Subarachnoid Hemorrhage, Vascular Diseases, Vascular Malformations, Vertebral Artery

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