Introduction
Fibromuscular dysplasia (FMD) is a nonatherosclerotic disease of medium‐sized vessels
that can present with arterial stenosis, beading, dissection, and aneurysm. While
the most common sites of FMD are the renal and extracranial carotid and vertebral
arteries, FMD has been reported in most arterial segments.
1
FMD does not affect the venous system. During the past decade, there has been a resurgence
of research in understanding this uncommon and often misunderstood disease. Here,
we highlight new developments in FMD research and clinical care, including a recently
published multidisciplinary statement from the American Heart Association, a European
Consensus document on FMD, and new insights regarding this disease derived from findings
of the French and United States Registry for Fibromuscular Dysplasia (US Registry).
1–3
Pattern of Vascular Involvement and Clinical Presentation
Until recently, renal FMD, generally presenting as early‐onset or difficult to control
hypertension, was thought to account for the majority of cases, while cerebrovascular
FMD was thought to account for less than one‐third of cases.
4
Data from the US Registry for FMD has led to a paradigm shift. In the registry cohort,
nearly 80% of registrants had renal FMD and almost three‐quarters had carotid FMD.
2
Vertebral FMD was the third most common site affected (36.6%). Other reported sites
of involvement included the mesenteric arteries, iliac arteries, intracranial vessels,
and upper extremity (brachial) arteries. Multivessel involvement among patients with
FMD is common. In the registry, 65% of patients with renal artery FMD who underwent
cerebrovascular imaging had evidence of vertebral or carotid involvement, and 64%
of patients with cerebrovascular FMD with renal imaging demonstrated evidence of renal
artery FMD.
2
Though registry data may be subject to the bias of tertiary care referral centers,
cerebrovascular FMD is much more common than previously reported in the literature,
and a significant percentage of FMD patients have >1 vascular territory involved.
As discussed later, these data have led to an evolution in clinical practice, leading
to more comprehensive arterial imaging of at‐risk vascular beds for patients with
FMD.
The symptoms and signs of FMD depend on the arteries involved and the severity of
the arterial lesions. Table 1 illustrates the frequency of symptoms reported among
patients in the US Registry for FMD. Given the observational nature of the registry,
however, the FMD‐specific causality of these symptoms, some of which are common clinical
complaints, cannot be definitively determined.
2
Patients with renal FMD classically present with hypertension but may also present
with headache. Flank pain may indicate aneurysm or dissection and infarction of the
renal artery (especially if of acute onset) but can also be present among patients
with renal FMD without either of these complications. Renal insufficiency is a rare
clinical manifestation of FMD in adults (2% of patients in the US Registry).
2
Table 1.
Frequency of Presenting Signs and Symptoms of Patients in the US Registry for Fibromuscular
Dysplasia
Presenting Symptoms
n (%)
Hypertension
285 (63.8)
Headache
234 (52.4)
Pulsatile tinnitus
123 (27.5)
Dizziness
116 (26.0)
Cervical bruit
99 (22.2)
Neck pain
99 (22.2)
Tinnitus
84 (18.8)
Chest pain or shortness of breath
72 (16.1)
Flank/abdominal pain
70 (15.7)
Aneurysms
63 (14.1)
Cervical artery dissection
54 (12.1)
Epigastric bruit
42 (9.4)
Hemispheric TIA
39 (8.7)
Postprandial abdominal pain
35 (7.8)
Stroke
31 (6.9)
Claudication
23 (5.2)
Amaurosis fugax
23 (5.2)
Weight loss
23 (5.2)
Horner syndrome
21 (4.7)
Renal artery dissection
14 (3.1)
Azotemia
9 (2)
Myocardial infarction
8 (1.8)
Mesenteric ischemia
6 (1.3)
No symptoms or signs
25 (5.6)
Reprinted with permission from Olin et al.
2
TIA indicates transient ischemic attack.
Patients with carotid and/or vertebral FMD can present with diverse symptoms ranging
from headache, neck pain, and pulsatile tinnitus to arterial dissection, transient
ischemic attack or stroke, or, less commonly, subarachnoid hemorrhage.
2
A significant number of patients in the US Registry sustained a neurological event:
13.4% of patients experienced a hemispheric transient ischemic attack, 12.1% suffered
a cervical artery dissection, and 9.8% had a stroke. The combined frequency of carotid,
vertebral, cerebral, and basilar artery aneurysms was ≈7%; however, the frequency
of subarachnoid hemorrhage was very low (1.1%).
2
Pulsatile tinnitus (a pulsatile swooshing noise in the ear) has recently been recognized
as a highly prevalent manifestation of this disease, reported as a presenting symptom
of 32% of patients in the US Registry.
5
Pulsatile tinnitus is associated with cerebrovascular involvement, cervical artery
dissection, and multivessel FMD.
5
For many patients, this is a highly annoying symptom that can impair quality of life
and contribute to the morbidity of this disease.
There are no consistent diagnostic physical examination findings in FMD. In some patients,
cervical, abdominal, or femoral bruit may be the only sign present. However, presence
of a bruit over the affected artery is not a sensitive indicator of disease. In the
US Registry, 30.5% of registrants presented with a cervical bruit, 17.5% with an epigastric
bruit, and 6.1% with flank bruit.
2,6
The sensitivity of a cervical bruit for the diagnosis of extracranial carotid and/or
vertebral FMD was only 45%, and the sensitivity of an epigastric or flank bruit for
the diagnosis of renal and/or mesenteric FMD was only 24%.
6
Pulse deficits are uncommon in FMD, and a significant pulse deficit was noted in the
dorsalis pedis and/or posterior tibial arteries in only 5% of patients in the US FMD
Registry.
2
Pulse deficits in the brachial arteries were noted in <1% of patients.
2
To summarize, there is no physical examination finding that is adequately sensitive
for diagnosis of FMD in a specific vascular bed. Because of this, comprehensive vascular
imaging is required in the evaluation of FMD patients.
Evolving Nomenclature
Historically, FMD has been classified histopathologically into categories based on
the dominant arterial layer involved (media, intima, or adventitia) and the composition
of the arterial lesion (collagen deposition, known as fibroplasia, or, less commonly,
hyperplasia of smooth muscle cells).
7–9
Harrison, McCormack, and colleagues correlated pathological classification to angiographic
findings.
7–9
Medial fibroplasia presents as the classic “string of beads” on angiography. Intimal
and adventitial fibroplasia commonly present as tubular or focal stenosis. Classifying
FMD based on histopathologic findings has become increasingly difficult. In this era
of advanced imaging and endovascular procedures, few patients have pathological specimens
available for examination. The 2012 European Consensus proposed a simplified angiographic
classification system of multifocal, tubular, and unifocal FMD.
10
Savard and colleagues demonstrated that a binary (multifocal versus unifocal) classification
system for renal FMD lesions can practically distinguish between 2 distinct clinical
phenotypes.
11
Patients with focal renal lesions were younger (30 years versus 49 years at diagnosis
of FMD) with higher blood pressure at presentation, more frequently smokers (50% versus
26%), and more likely to be male (31% versus 17%), all P<0.02.
11
The recently published AHA Scientific Statement proposed a classification of FMD that
distinguishes patients with multifocal (beading) FMD from patients with focal lesions
(Table 2 and Figure 1).
1
It is hoped that this simplified classification will improve communication between
clinicians and researchers and provide a more clinically oriented distinction between
FMD subtypes.
Table 2.
2014 American Heart Association Classification of FMD
Multifocal FMD
Focal FMD
Angiographic appearance
Alternating dilatation and constriction of the vessel (string of beads)Areas of dilatation
are larger than the normal caliber of the arteryOccurs in the mid and distal portion
of the renal, internal carotid, and vertebral arteriesMay occur in any other artery
in the body*
Focal concentric or tubular stenosis*
Typical histology
Medial fibroplasia (most common)Perimedial fibroplasia (rare)*
Intimal fibroplasia (most common)Adventitial (periarterial) fibroplasia (rare)Medial
hyperplasia (rare)
Associated features
Aneurysm, dissection, and vessel tortuosity of medium‐sized arteries may be present;
multifocal and focal lesions may coexist in the same patient
Reprinted with permission from Olin et al.
1
FMD indicates fibromuscular dysplasia.
*
Lesions are not necessarily confined to the mid or distal portion of the artery (ie,
can occur in any arterial segment).
*
There are no cases of aortic FMD that are well documented pathologically.
*
This rare form of FMD typically occurs in young girls (eg, those 5 to 15 years of
age). Although there is a beaded appearance to the renal arteries, the beads are smaller
than the normal renal artery and less numerous. Histologically, collagen deposition
is localized to the outer portion of the medial layer.
Figure 1.
Angiographic images of multifocal (A) and focal (B) lesions in the renal artery.
Epidemiology
FMD has historically been considered a rare disease and has been recognized by the
National Organization for Rare Diseases as such, a designation that requires an estimated
prevalence of <200 000 US residents.
12
Recent data, however, suggest FMD is more common than previous estimates indicate.
A meta‐analysis based on kidney donor data found FMD in ≈4% of the potential kidney
donor population.
13–16
A recently published single‐center retrospective review of 1940 potential kidney donors
(58% female) found evidence of FMD in 3.9% in potential female kidney donors.
13
Most of these patients were asymptomatic, as only 2 (3.7%) of 54 patients were started
on new or additional antihypertensive agents following the screening.
13
Renal donor screening studies may not accurately reflect the prevalence of FMD in
the general population, because potential kidney donors tend to have few health issues,
such as hypertension or chronic kidney disease (underestimation of prevalence), but
may also enrich for familial FMD because most potential kidney donors have a family
member with severe chronic kidney disease (overestimation of prevalence).
13
As discussed earlier, the US Registry has demonstrated that cerebrovascular FMD is
nearly as common as renal FMD, although there are little data available regarding
the estimated prevalence of cerebrovascular FMD. A study examining consecutive cerebral
angiograms estimated the prevalence of cerebrovascular FMD to be 0.3% to 3.2%,
17
but this study was limited to patients undergoing invasive imaging, presumably for
symptomatic disease or major risk factors.
The US Registry has highlighted the potential for FMD patients to be entirely asymptomatic.
In the registry, 5.6% of patients were diagnosed with FMD based on imaging conducted
for another reason and were entirely asymptomatic at the time of diagnosis (including
absence of bruits on physical examination).
2
Thus, FMD may have a significant prevalence in the general population and likely represents
a spectrum of disease with a number of patients having “silent” or minimally symptomatic
lesions. Study of the prevalence of FMD has been identified as a top research priority
in a recently published AHA Scientific Statement.
1
(Table 3).
Table 3.
Top Research Priorities in FMD
Determination of the prevalence of FMD in the general population of women aged 18
to 65 years
Understanding of unique biological and genetic determinants of FMD, including identification
of determinants of arterial bed involvement and the development of arterial narrowing
versus aneurysm vs dissection
Understanding the role of sex hormones in the pathogenesis of FMD, including the female
preponderance of the disease and the potential contribution of exogenous hormones
(oral contraceptives and systemic hormone replacement) to its pathogenesis
Creation of a rational and cost‐effective approach to vascular screening for patients
with FMD identified in 1 vascular bed (ie, what additional imaging should be obtained
for a patient with isolated renal FMD)
Development and validation of Doppler criteria for diagnosis of carotid and renal
medial fibroplasia using duplex ultrasound
Characterization of the natural history of FMD in the symptomatic and asymptomatic
patient population, including disease progression and interval development of major
vascular events (eg, stroke, arterial dissection, mortality); development of tools
for risk stratification of FMD patients and prognosis based on these data
Determination of the prevalence of cerebral aneurysms in FMD patients and if FMD patients
with cerebral aneurysm are at higher risk of subsequent rupture
Characterization of the risk of pregnancy associated with FMD (eg, risk of uncontrolled
hypertension, arterial dissection)
Characterization and understanding of the mechanisms of headache among FMD patients
and development of effective treatment algorithms for symptom prevention and treatment
Determination of the feasibility of a randomized, clinical trial of optimal therapy
for primary/secondary prevention of stroke/TIA among patients with cerebrovascular
FMD
Determination of the feasibility of a randomized, clinical trial of medical therapy
vs endovascular therapy for treatment of hypertension among patients with renal FMD
Reprinted with permission from Olin et al.
1
FMD indicates fibromuscular dysplasia; TIA, transient ischemic attack.
FMD is primarily a disease of women. In the initial reports of the US Registry, 92%
of registrants were female.
2,18
Men with FMD have a distinctive clinical presentation as reported in a study by Kim
and colleagues based on data from the US Registry. In this analysis, men with FMD
were more likely to present with visceral involvement than were women, including flank/abdominal
pain, renal insufficiency, and renal infarction (43.8% versus 14.3%, 9.1% versus 2.2%,
and 42.9% versus 4.3%, respectively, all P<0.05).
18
Women were more likely to present with classic signs and symptoms of extracranial
cerebrovascular FMD: pulsatile tinnitus, neck pain, and cervical bruit (all P<0.05).
Male FMD patients had a 2‐fold increase in prevalence of arterial aneurysm (40.8%
versus 20.4%, P=0.002) and arterial dissection (39.6% versus 20.0%, P=0.0031) compared
with female FMD patients.
18
Men with FMD are also more likely to have focal disease.
11
It appears that FMD may have a more aggressive vascular course and has a predilection
for involvement of the renal and mesenteric arteries in men.
Genetics
The genetics of FMD is an active area of research. As of yet, no etiologic genes have
been identified. Early genetic data suggested an autosomal dominant inheritance pattern
with variable penetrance.
19–21
In a series of 20 cases, Rushton classified 60% as familial; however, positive family
members were identified based on cardiovascular events and early‐onset hypertension
rather than definitive confirmation of FMD on imaging.
20
Few studies provide radiographic proof of familial inheritance. Perdu and colleagues
studied 13 cases and 47 first‐degree relatives in 6 families screened for FMD using
high‐resolution carotid ultrasound.
22
High‐resolution echo tracking measurements of carotid arterial wall parameters were
used to develop an arterial scoring system. Elevated arterial scores served as a surrogate
marker for FMD. Segregation analysis showed 52% of descendants had an elevated arterial
score consistent with an autosomal dominant transmission.
22
However, no family member demonstrated classic vascular lesions clinically associated
with FMD, such as beading or stenosis, and the carotid ultrasound score is not widely
accepted as a marker for FMD. Thus, the prevalence of familial FMD is likely overestimated
in these studies. In a study with imaging confirmation of FMD diagnosis, 11% of FMD
cases were familial.
23
All familial cases were siblings, and no vertical transmission was reported.
23
In the US Registry, only 7.3% of patients report a confirmed diagnosis of FMD in ≥1
first‐ or second‐degree family members.
2
However, the high prevalence of aneurysms (23.5%), sudden death (19.8%), and stroke
(53.5%) among first‐ and second‐degree family members in the US Registry suggests
FMD may represent an inherited systemic arteriopathy with a diverse clinical phenotype.
Larger family studies with vascular imaging are needed to better identify the inheritance
pattern of FMD. Understanding the genetic (and biological) determinants of FMD has
been identified as another top research priority in the AHA Scientific Statement (Table
3).
1
It is hypothesized that FMD may have overlapping features with vascular connective
tissue diseases, such as Loeys‐Dietz syndrome or the vascular type of Ehlers‐Danlös
syndrome. However, the prevalence of genetic mutations associated with connective
tissue disease was negligible in a cohort of clinically confirmed FMD patients who
underwent genetic testing.
24
Two patients in this cohort were found to have distinct novel point mutations in TGFβ
receptor type 1 gene.
24
Both of these patients had a history of arterial dissection and had aortic ectasia
or aneurysm. Ganesh, Morrisette, and colleagues found elevated secretion of transforming
growth factor (TGF)‐β1 and TGF‐β2 by fibroblasts derived from FMD patients compared
with matched controls (P=0.0009 and P=0.0001, respectively). FMD patients also had
elevated plasma levels of circulating TGF‐β1 and TGF‐β2 relative to matched controls
(P=0.009 and P=0.004, respectively).
25
The potential involvement of TGF‐β pathways in the pathogenesis of FMD is an area
for future investigation, especially as this pathway could provide a potential target
for disease‐modifying medical therapies.
Evidence supports that gene–environment interactions influence FMD susceptibility.
Smoking and estrogen are 2 proposed interactions.
1,26
Savard and colleagues demonstrated that patients with renal FMD have a much higher
rate of smoking compared with matched hypertensive controls.
26
The striking predilection of female patients in the FMD population (>90%) suggests
estrogen and other hormonal factors as major contributors to the development of FMD.
Coronary FMD, Spontaneous Coronary Artery Dissection, and the Spontaneous Coronary
Artery Dissection–FMD Paradox
An emerging area of investigation involves coronary manifestations of FMD. Several
case reports previously described sudden death associated with the histopathologic
finding of FMD of the coronary arteries on autopsy.
27–29
Supporting these case reports, Hill and colleagues found histological findings of
FMD in 2% of patients with unexplained sudden cardiac death.
28
However, Zack and colleagues investigated the incidence of histopathologically confirmed
FMD of the nodal arteries in patients who sustained non–cardiac sudden death (eg,
accidents, suicides) and found microscopic alterations of the sinus node arteries
in 52 of 100 cases, atrioventricular nodal arteries in 63 of 100 cases, and 60 of
100 small vessels consistent with FMD.
30
Therefore, it seems likely that histopathologic findings of the nodal arteries mimicking
FMD seen in other vascular territories is a potential incidental autopsy finding and
is likely disease causing. It is our opinion and those of the authors of the AHA Scientific
Statement these pathological findings do not represent the clinical disease process
of FMD discussed in this manuscript.
1
The association of spontaneous coronary artery dissection (SCAD) with FMD has recently
been described (Figure 2). SCAD most commonly presents as biomarker‐positive acute
coronary syndrome (non–ST‐segment elevation or ST‐segment elevation myocardial infarction).
The most common coronary artery involved is the left anterior descending coronary
artery in its mid to distal segment.
31–32
In a case series published by Saw and colleagues, 86% (43 of 50) of patients with
SCAD had angiographic findings of FMD in the noncoronary vasculature: renal (58.1%),
iliac (48.8%), and cerebrovascular (46.5%) arteries. Of the 7 patients not found to
have FMD, 5 had not completed screening for all 3 major vascular territories (iliac,
renal, cerebrovascular), and 2 were found to be negative after complete screening.
31
Figure 2.
Angiogram of coronary arteries (top left) demonstrating spontaneous coronary artery
dissection of the posterior descending artery in a 58‐year‐old woman presenting with
non–ST‐segment elevation myocardial infarction. MRA demonstrated bilateral internal
carotid artery multifocal FMD (top right), and CTA demonstrated a left renal 6‐mm
aneurysm (bottom left) with mild FMD of the right renal artery (bottom left). MRA
indicates magnetic resonance angiography; FMD, fibromuscular dysplasia; CTA, computed
tomography angiography.
In contrast to the high prevalence of FMD in the Vancouver SCAD cohort, Toggweiler
and colleagues found evidence of renal artery abnormalities in only 3 of 12 patients
with SCAD who underwent head‐to‐pelvis imaging.
33
Two patients had multifocal FMD and 1 patient had a spontaneous renal artery dissection.
However, patients in this series underwent magnetic resonance angiography (MRA) imaging,
which has decreased sensitivity for diagnosis of mild FMD lesions compared with catheter‐based
angiography.
In the Mayo Clinic SCAD cohort of 87 patients, 9% of patients with SCAD had an incidental
finding of iliac (n=8) FMD seen on femoral angiograms taken before catheter removal.
34
Based on the growing association between SCAD and FMD, a specialized computed tomography
angiography (CTA) protocol of the neck, chest, abdomen, and pelvis was developed for
assessment for FMD and other vascular findings, including arterial aneurysm or dissection
at this institution.
35
In this study, 69% of patients with SCAD had extracoronary vascular abnormalities,
the majority of which were consistent with FMD.
35
Despite the significant prevalence of FMD among patients with SCAD, it is important
to note that SCAD and acute coronary syndrome seem to be an uncommon events among
all comers with a diagnosis of FMD. Indeed, there seems to be an SCAD–FMD paradox:
while 25% to 86% of SCAD patients in the largest published case series have imaging
evidence of FMD,
31,33,35–36
in the US Registry, any significant coronary artery disease (including atherosclerotic
disease) was reported in only 6.5% of patients, and only 3.1% of patients in the US
Registry had a history of myocardial infarction.
2
To summarize, SCAD seems to be the primary coronary artery manifestation of FMD, and
unlike other vascular beds, coronary FMD infrequently presents as a “string of beads.”
37
While underlying FMD is common among patients who have sustained an SCAD event, only
a small percentage of patients with FMD develop coronary events during follow‐up.
Future research efforts are needed to determine the predictors of SCAD among FMD patients
and to further understand this SCAD–FMD paradox.
Surveillance and Screening
Optimal diagnostic imaging and surveillance strategies for FMD are unknown. Catheter‐based
digital subtraction angiography remains the gold standard for diagnosis of FMD in
all vascular beds.
1
However, catheter‐based angiography is an invasive procedure, and other less‐invasive
imaging modalities are available for diagnosis and surveillance.
Renal Artery Imaging
In patients with hypertension and clinical suspicion of renal artery stenosis, duplex
ultrasound offers a noninvasive, first‐line screening test.
1,3
Duplex ultrasound is a readily available, low‐cost, and low‐risk imaging modality
that can give data on the flow characteristics within a vessel. However, there have
been no published validation studies of duplex ultrasound versus angiography for the
diagnosis of renal (or carotid) FMD. Although duplex ultrasound has limitations (i.e.,
technologist and interpreter expertise, patient body habitus, bowel gas), in experienced
vascular laboratories, vascular ultrasound plays a central role in the diagnosis and
surveillance of patients with renal FMD. Ultrasound features suggestive of renal FMD
include elevated velocities and color and spectral turbulence in the mid and distal
segments of the renal artery. In the case of severe lesions, there may be delayed
systolic upstroke in the spectral Doppler waveform of arterial segments distal to
the stenosis. Because of the limitations of ultrasound, confirmation by using another
imaging modality is often required.
Once the diagnosis of renal artery FMD is made, ultrasound is a useful tool for surveillance,
allows for periodic monitoring of renal artery velocities and kidney size, and can
be used to monitor for restenosis after angioplasty.
CTA and MRA demonstrate good sensitivity and specificity for the diagnosis of renal
artery FMD in small published case series performed in expert imaging centers (93%
to 100%), although accuracy for assessment of “severity” of FMD lesions is limited.
38–41
At the present time, the choice of technique between the 2 modalities for clinical
practice should be determined by local technology and expertise with FMD imaging.
Both CTA and MRA may miss mild FMD lesions and do not give information regarding the
hemodynamic significance of lesions. These modalities also have low sensitivity for
detecting FMD in the branch vessels. Thus, digital subtraction angiography remains
the gold standard but is rarely required for diagnostic confirmation. Digital subtraction
angiography is reserved for symptomatic patients for whom intervention is contemplated
or for cases with an uncertainty in diagnosis or disease severity despite noninvasive
imaging.
1,3
When a renal intervention is planned, translesional pressure gradients should be measured
to assess the severity of stenosis across multifocal or focal FMD lesions with angioplasty
reserved for those patients with a significant pressure gradient.
1
Carotid Artery Imaging
Little data exist regarding the use of noninvasive imaging to confirm the diagnosis
of carotid and vertebral artery FMD, and no published study has validated duplex ultrasound,
CTA, or MRA compared with digital subtraction angiography for the detection of cerebrovascular
FMD.
1,3
As in renal artery FMD, carotid duplex ultrasound provides a noninvasive and low‐cost
screening tool. Carotid FMD can be identified with velocity shifts, spectral broadening,
and turbulent color Doppler flow in the mid to distal cervical internal carotid artery
and vertebral arteries (although detection of vertebral FMD by ultrasound may be difficult).
Recently, tortuosity and redundancy of the internal carotid artery in an “S‐curve”
configuration were described by Sethi and colleagues.
42
Ultrasound findings of carotid FMD are in contrast to atherosclerotic lesions, which
are visualized as plaque with corresponding velocity shifts at the carotid bifurcation
or proximal segment of the internal carotid artery. Of note, carotid atherosclerosis
and FMD can coexist; therefore, to detect cervical FMD, it is necessary to investigate
the entire cervical internal carotid artery, especially the most distal segments.
Unlike atherosclerotic disease, it is not possible to show accurate percentage stenosis
for carotid FMD on a duplex ultrasound report, because of the complex nature of the
tandem lesions with areas of webbing and stenosis followed by dilatation in multifocal
FMD. In general, it is recommended that ultrasound reports not attribute a specific
percentage stenosis category (eg, 50% to 69%, >70%) to a case of internal carotid
artery FMD and instead report that findings are consistent with fibromuscular dysplasia.
As in renal FMD, ultrasound has limitations and, therefore, additional noninvasive
imaging is often necessary. For complete imaging of the carotid arteries above the
skull base, the vertebral arteries, and the intracranial vessels, MRA or CTA is required.
The European Consensus on FMD recommends MRA or CTA to establish the diagnosis of
cerebrovascular FMD.
3
Digital subtraction angiography remains the gold standard for diagnosing cerebrovascular
FMD; however, its use is reserved for patients in whom the diagnosis is highly suspected
despite inconclusive noninvasive imaging results.
1
Screening for Occult Aneurysms in Patients With FMD
Once the diagnosis of FMD has been established in a vascular territory (eg, the renal
and/or carotid arteries), it is our clinical practice to perform one‐time brain‐to‐pelvis
imaging study(ies) to screen for occult aneurysms with either CTA or MRA. This practice
is based on the significant prevalence of aneurysms among FMD patients reported in
the US Registry. Seventeen percent of registrants had an aneurysm of ≥1 vessel.
2,43
The most common sites were renal, carotid, and aortic arteries.
2,43
A surprisingly high number (3.4%) of registrants were found to have an aortic aneurysm
given the age and sex of the population. On the basis of these data, in our clinical
practice, we routinely screen patients once for aortic, visceral, and intracranial
aneurysms. However, it is important to note that there is need for more data regarding
the cost effectiveness and clinical benefit of this practice. A large meta‐analysis
and retrospective study by Cloft and colleagues found the prevalence of intracranial
aneurysms in patients with cervical FMD to be ≈7%, which is lower than previous estimates
but increased compared with that in the general population.
44
Given the risk for significant morbid events, screening for intracranial aneurysms
in all patients with FMD is recommended by the 2014 Scientific Statement Writing Group.
1
Based on the location and significance of FMD lesions, the presence or absence of
aneurysms or dissections that require imaging follow‐up, and the patient's clinical
symptoms, a program of surveillance imaging is customized for each FMD patient.
Managing the FMD Patient
Care of the FMD patient consists of medical management, imaging surveillance of affected
vascular beds, and referral for endovascular or surgical procedures when indicated.
Location and severity of arterial lesion(s), symptoms, comorbidities, and previous
vascular events due to FMD determine the type of therapy indicated.
There are little data regarding the optimal medical management of FMD patients, and
clinical practice is often based on the management of patients with atherosclerotic
disease. The 2011 multisocietal consensus guidelines for extracranial and vertebral
artery disease gave antiplatelet therapy for carotid and vertebral FMD a Class IIa
recommendation.
45
No specific agent or dosing was recommended.
45
Most experts prescribe 81 to 325 mg aspirin for patients with cerebrovascular FMD
as long as the patient has no contraindication to antiplatelet therapy. There are
no data on the use of clopidogrel or other antiplatelet agents for the management
of patients with cerebrovascular FMD, although single‐agent clopidogrel may be used
for select patients as an alternative to aspirin. For patients with carotid or vertebral
artery dissection, treatment often consists of heparin (or low‐molecular‐weight heparin)
followed by warfarin for 3 to 6 months, then, ultimately, antiplatelet therapy.
1
The optimal medical therapy for carotid and vertebral artery dissection is also a
matter of controversy. The ongoing trial Cervical Artery Dissection in Stroke Study
(CADISS) is investigating antiplatelet therapy versus anticoagulation in patients
with extracranial cervical artery dissection.
46
Results from the nonrandomized arm of this trial demonstrated no significant difference
between antiplatelet therapy and anticoagulation for the risk of recurrent stroke
at 3 months.
47
However, results from the entire randomized and nonrandomized cohort are pending.
Patients with renal, mesenteric, or external iliac FMD are generally prescribed aspirin
for thromboprophylaxis, although there are little data to support this practice. Expert
consensus and clinical experience suggest that the use of angiotensin‐converting enzyme
inhibitors and angiotensin II receptor blockers to be effective in treating hypertension
attributable to renal artery FMD.
1
Kidney function must be monitored when starting these medications due to the risk
(although low) of acute kidney failure in the setting of significant bilateral renal
artery stenosis. The recently reported data of elevated TGFβ1/TGFβ2 expression in
a cohort of patients with FMD opens the door to future investigations of the role
of TGF‐β signaling in this disease and potential pharmacological therapies that may
act on this molecular pathway (ie, angiotensin II receptor blockers).
25
Revascularization procedures can be beneficial in selected patients with renal FMD
and hypertension. In a meta‐analysis of 70 studies of revascularization in patients
with FMD involving >2600 patients, Trinquart and colleagues demonstrated that younger
age and shorter duration of hypertension are associated with increased likelihood
of cure with angioplasty or surgery.
48
Patients with long‐standing hypertension and older patients are less likely to benefit
from renal revascularization.
48
In addition, factors associated with decreased likelihood of clinical benefit from
renal percutaneous transluminal angioplasty (PTA) include abnormal renal function,
smaller ipsilateral kidney, or metabolic abnormalities such as abnormal fasting glucose
or hyperlipidemia.
49
Interestingly, the reported hypertension cure rates in surgical and endovascular case
series have declined by year of publication (Figure 3), perhaps reflecting less restrictive
criteria for patient selection as these procedures (ie, balloon angioplasty) have
become safer and more widely available. In 2014, the approach to renal FMD revascularization
is generally PTA as first‐line therapy with surgical procedures reserved for patients
with lesions not amenable to endovascular therapy, large aneurysms, or lesions that
have not responded to prior intervention. Appropriate indications for revascularization
in the setting of renal FMD, according to the 2014 Scientific Statement Writing Group,
are shown in Table 4. In most circumstances, revascularization for FMD is performed
for the management of hypertension, although in some cases, procedures may be undertaken
for the treatment of sizable aneurysm or preservation of renal function (rare).
Table 4.
Indications for Renal Artery Revascularization
Resistant hypertension (defined as failure to reach goal blood pressure on appropriate
3‐drug regimen including a diuretic)
Hypertension of short duration with the goal of hypertension cure.
Renal artery dissection: rarely is intervention needed, but if so, stenting is generally
the procedure of choice
Renal artery aneurysm(s): surgical resection, endovascular coiling, or placement of
a covered stent is usually used
Branch renal artery disease and hypertension: some lesions can be treated with PTA,
but if this is not possible, surgical revascularization may be required, often with
bench repair
Preservation of renal function in the patient with severe stenosis, especially in
the pediatric population with perimedial fibroplasia or intimal fibroplasia
Reprinted with permission from Olin et al.
1
PTA indicates percutaneous transluminal angioplasty.
Figure 3.
Meta‐regression analysis of published case series of renal FMD demonstrating the association
between hypertension cure post PTA and mean age (A) and year of study publication
(B). Size of the circle represents size of the case series. Adapted with permission
from Trinquart et al.
48
FMD indicates fibromuscular dysplasia; PTA, percutaneous transluminal angioplasty.
Hemodynamic assessment (measurement of pressure gradients across the area of FMD)
with or without procedure intravascular ultrasound is recommended before and after
PTA to ensure there is hemodynamic significance of lesions present and that these
lesions have been adequately treated with PTA. Admittedly, however, this recommendation
is an extrapolation from previous studies in patients with atherosclerotic renal artery
stenosis.
51
No study to date has evaluated the effectiveness of hemodynamic‐guided versus traditional
PTA in a cohort of FMD patients. Stenting of the renal artery is generally reserved
for lesions that fail PTA or for management of flow‐limiting dissection. Two cases
of FMD patients with renal artery stent fracture requiring bypass surgery have been
recently reported.
50
The European Consensus on FMD recommends against the use of cutting balloons in cases
of PTA failure due to the risk of renal artery rupture.
3
For patients with cerebrovascular FMD, surgical or endovascular therapy is reserved
only for symptomatic patients, with the exception of those with intracranial aneurysms.
The natural history of cerebrovascular FMD is different from that of atherosclerotic
disease, and revascularization procedures are not indicated to treat asymptomatic
lesions (eg, high velocities on an ultrasound examination), even for patients who
have low procedural risk. It is uncommon for patients with cerebrovascular FMD to
have neurological ischemic events while receiving antiplatelet therapy, although carotid
or vertebral artery dissection may occur with resultant neurological events. The 2014
AHA Scientific Statement on FMD provides a detailed discussion of revascularization
techniques for cerebrovascular FMD.
1
Multispecialty Care for the Patient With FMD
Some clinical pearls for FMD clinical management are presented in Table 5. The care
of the FMD patient requires a team‐based approach. Medical providers who may care
for FMD patients include vascular medicine physicians, vascular surgeons, cardiologists,
interventional radiologists, nephrologists, neurologists, and neurosurgeons, among
others. In addition to the need for medical therapy and imaging surveillance and the
potential need for revascularization or aneurysm repair, patients with FMD have many
symptoms that can impair their quality of life. As discussed earlier, severe and frequent
headaches, particularly migraines, are a common complaint among FMD patients. A specialized
headache clinic can provide great clinical benefit. Often, these clinics can offer
alternative treatments such as onabotulinumtoxinA (Botox) injections that can relieve
severe chronic migraine symptoms.
52
Investigation of migraine treatment in patients with FMD is an area ripe for research
with no prospective studies on this population to date. In general, the use of ergotamines
is avoided given the risk of sustained vasoconstriction in the FMD population at risk
for stroke and arterial dissection. Triptan medications are prescribed with caution
and generally avoided in FMD patients with history of myocardial infarction, stroke,
or arterial dissection. Pulsatile tinnitus is another symptom that can be troublesome
for FMD patients. Audiologists can assess for hearing loss and may help patients with
strategies for symptom management. For some patients who present for evaluation of
FMD but have physical features of a connective tissue disorder (eg, Loeys Dietz or
Ehlers‐Danlös) and/or an extensive family history or aneurysm and dissection, evaluation
by a clinical geneticist and genetic counselor may be of benefit.
Table 5.
Clinical Pearls in Managing the Patient With FMD
In addition to a complete vascular review of systems, query the FMD patient for common
and quality of life impairing symptoms such as migraine headaches, pulsatile tinnitus,
and neck pain
FMD patients should undergo screening for occult aortic or arterial aneurysms as clinically
indicated. All patients with FMD should be screened for intracranial aneurysm at least
once with MRA or CTA. The subsequent imaging surveillance program is customized to
the location and severity of arterial lesions identified
Obtain a complete family history from the FMD patient, not only for family members
with confirmed diagnosis of FMD, but also for stroke, MI, aneurysms, dissections,
vascular procedures, and sudden death
Reserve genetic testing for connective tissue disorders such as Ehlers‐Danlös and
Loeys‐Dietz for select patients with suggestive clinical features, family history,
or imaging findings that are atypical for FMD
In the absence of a contraindication, most FMD patients (eg, cerebrovascular FMD,
prior revascularization) should be treated with an anti‐platelet agent to prevent
thromboembolic events
Reserve renal PTA for FMD patients who have a significant likelihood of clinical success
and who have significant pressure gradients across the renal artery
Renal artery stenting for FMD is generally reserved for treatment of dissection or
when balloon angioplasty has failed
In general, do not intervene on patients with asymptomatic FMD, except in the case
of sizable arterial aneurysm for which the risk of rupture is significant
FMD indicates fibromuscular dysplasia; MRA, magnetic resonance angiography; CTA, computed
tomography angiography; PTA, percutaneous transluminal angioplasty.
In a study from our center investigating physical and mental quality of life scores
among patients at a tertiary center, female patients with FMD had decreased quality
of life compared with the general and healthy US population.
53
Headache, neck pain, and abdominal pain were significant contributing factors to reduced
quality of life scores. Thus, pain management is vitally important. Patients with
chronic disease often experience psychological distress, and FMD is no exception.
Compounding patient symptoms and potential need for invasive procedures is the anxiety
related to having an uncommon disease with which many health care providers are entirely
unfamiliar. Therefore, referral to psychology and/or psychiatry colleagues to develop
healthy coping practices is appropriate for those patients experiencing significant
distress. The FMD Society of America (www.fmdsa.org) provides an online source for
patient and health care provider information and support.
Conclusion
FMD is a disease that causes arterial stenosis, beading, dissection, and aneurysm
and can present with a broad spectrum of clinical manifestations. Many FMD patients
are minimally symptomatic or are diagnosed when an imaging study is performed for
another indication. Some FMD patients have mild or moderate nonspecific symptoms,
such as pulsatile tinnitus and migraine headaches or hypertension requiring medication
therapy. Other patients have experienced major morbid events such as cerebrovascular
and coronary dissections, stroke, and aneurysms. Fortunately, there appears to be
a relatively low mortality rate associated with FMD. To date, no patient enrolled
in the US Registry has died from vascular complications.
54
Medical management consisting of antiplatelet agents and antihypertensive therapy
is important for FMD patients, and a multidisciplinary plan should be in place for
management of symptoms such as headache. All FMD patients should be comprehensively
screened for occult aneurysms. Careful patient selection for revascularization procedures
can increase the likelihood of clinical benefit. While recent and ongoing efforts
have advanced our scientific and clinical understanding of this condition, recognizing
the symptoms of this disease and making the correct diagnosis in a timely fashion
constitute a vital first step in improving outcomes for FMD patients.