Bringing Awareness to an Under-Recognized Medical Conundrum - Fibromuscular dysplasia: state of the science and critical unanswered questions

Fibromuscular dysplasia (FMD) is a non-inflammatory, arterial disease that most often affects women less than 65 years of age.¹ Initially described in 1938 by Leadbetter et al.,² FMD was further characterized and classified in 1971 based upon correlative pathological and angiographic findings.³ The prevalence of FMD may be as high as 4% to 6% in the general population.^4-6 Therefore, FMD could potentially affect millions of Americans. The natural history of and etiology for FMD are not well defined,^1,7 although there are numerous reports of FMD in first-degree relatives.⁸ However, discrete genes linked to FMD have yet to be delineated.⁹

The clinical manifestations of FMD are most often related to the arterial bed involved and the underlying vascular pathology present.^1,7,10 The vascular distributions most often affected by FMD include the renal and extracranial carotid arteries, but the vertebral, intracranial, brachial, subclavian, coronary, mesenteric, and common, internal, and external iliac arteries have been shown to be affected by FMD.⁷ FMD can be associated with symptomatic or asymptomatic arterial stenoses, occlusions, dissections, and/or aneurysms, with related hypertension, transient ischemic attacks, stroke, cardiac arrhythmias, myocardial ischemia, claudication, mesenteric ischemia, embolic phenomena, and/or intracranial, retroperitoneal, or intraperitoneal hemorrhages.⁷ In addition, the United States (U.S.) FMD Registry revealed a higher than expected presence of thoracic or abdominal aortic aneurysms in patients with FMD.⁷

A variety of classification schemes for FMD have been proposed over the past 50 years, but most recently, the 2011 French and Belgian expert consensus panel suggested movement away from a histology based classification (since surgical specimens are rarely available) to a simplified, imaging-based categorization of FMD into the subtypes of multifocal, unifocal (<1 cm lesion), and tubular (>1 cm lesion).¹¹ Recognizing the pragmatics of such a shift in classification, Olin et al. propose an American Heart Association (AHA) classification scheme based on imaging findings that is even more simplified than the European Consensus classification, dividing FMD into two categories: multifocal (classic “string of beads” appearance) or unifocal (independent of lesion length).¹² This classification allows for patients to have simultaneous multifocal and unifocal disease in different arterial territories. The rationale for this simplified classification system is twofold: to both standardize and simplify the classification of FMD and to try to determine if multifocal and unifocal FMD are the same disease with different manifestations and outcomes or different diseases that are related to each other or just different diseases.

Olin et al.¹² provide a very detailed review of the available literature on FMD, and a summary of the diagnostic, therapeutic, and surveillance strategies and differential diagnostic considerations, but, most importantly, the authors detail five common misconceptions and the clarifications regarding FMD, and challenge investigators interested in FMD to address 11 research priorities.

The five most common misconceptions about FMD as suggested by Olin et al.¹² are as follows:

1. All coronary, carotid, and renal artery diseases are due to atherosclerosis. Clarification - FMD can involve all of these vascular beds in the absence of atherosclerosis. In the U.S. FMD Registry, 63% of the patients had no history of tobacco use or other risk factors for atherosclerosis and their mean age at the time of diagnosis was ~52 years.
2. The severity of multifocal FMD (“string of beads”) can accurately be ascertained by visual inspection of the angiogram. Clarification - It is very difficult to determine the significance of these arterial lesions by visual estimation. Therefore, translesion pressure gradients or intravascular ultrasound should be performed to demonstrate the hemodynamic impact of the FMD.
3. Duplex ultrasound velocities predict the degree of carotid or renal FMD. Clarification - In contrast to Doppler assessment in atherosclerotic carotid or renal artery disease, diagnostic velocity criteria do not exist for carotid or renal artery FMD. Therefore, the authors recommend that the duplex ultrasound reports state “there are increased velocities, turbulence, and tortuosity consistent with FMD.”
4. Patients with renal or carotid artery FMD undergoing an endovascular intervention should receive a stent. Clarification - Percutaneous transluminal angioplasty (PTA) alone is often sufficient to treat a stenosis associated with FMD. For a stenosis related to FMD, a stent is reserved to treat a complication of the PTA procedure, such as an obstructing dissection flap or rupture.^12,13 On occasion, a bare metal, multilayer, or covered stent may be used primarily to treat an obstructing, spontaneous, and symptomatic dissection or aneurysm.^14-16
5. The most common presentation for carotid FMD is transient ischemic attack (TIA) or stroke. Clarification - Although TIAs or stroke can occur with multifocal carotid FMD, carotid FMD is most commonly asymptomatic or associated with nonspecific symptoms such as headaches, dizziness, neck pain, lightheadedness, and/or pulsatile tinnitus.

The top 11 research priorities for FMD as suggested by Olin et al.¹² include determining the following:

1. prevalence of FMD in the general population of women between the ages of 18-65 years;
2. unique biological and genetic factors affecting the vascular distribution of FMD and the development of a stenosis versus an aneurysm versus a dissection;
3. role of endogenous and exogenous hormones in the pathogenesis of FMD;
4. best evidence-based and most cost-effective approach for screening patients with FMD identified in a single arterial distribution for the presence of FMD in another vascular bed;
5. most valid Doppler criteria for the diagnosis of carotid and renal multifocal FMD;
6. natural history of FMD in symptomatic and asymptomatic patients, including understanding disease progression, risk stratification for the interval development of vascular events, and patient prognosis;
7. prevalence of cerebral aneurysms and rupture risk profile in patients with FMD;
8. risk of pregnancy in patients with FMD;
9. mechanism of headaches in patients with FMD and developing an effective algorithm for treatment and prevention of headaches;
10. feasibility of a randomized clinical trial to evaluate the optimal therapy for primary and secondary TIA and stroke prevention in patients with cerebrovascular FMD; and

feasibility of a randomized clinical trial comparing optimal medical therapy versus endovascular therapy for the treatment of hypertension in patients with renal artery FMD. In many ways, this state of the science manuscript by Olin et al.¹² is a call to arms for clinicians and research scientists to recognize that FMD is a conundrum that likely affects a large population of patients. Our understanding of this disease entity, for the most part, has been limited to a collection of observational and single institution studies. The U.S. FMD Registry represents a start towards garnering a broader and more collaborative understanding of FMD,⁷ but funding and federal support for more structured and meaningful prospective investigation of FMD remain extremely challenging. The creation of a more simplified classification of FMD into the two categories of multifocal and unifocal should allow for more consistent data collection in the future. In the meantime, by pointing out the most common misconceptions about FMD, the clinical management and understanding of patients with FMD should be improved, and by defining the research priorities for FMD, the advancement of knowledge for this disease entity can now be more focused.¹²