Author + information
- Esther S.H. Kim, MD, MPH†∗ (, )
- Jeffrey W. Olin, DO‡,
- James B. Froehlich, MD, MPH§,
- Xiaokui Gu, MA§,
- J. Michael Bacharach, MD‖,
- Bruce H. Gray, DO¶,
- Michael R. Jaff, DO#,
- Barry T. Katzen, MD∗∗,
- Eva Kline-Rogers, MS, RN, NP§,
- Pamela D. Mace, RN††,
- Alan H. Matsumoto, MD‡‡,
- Robert D. McBane, MD§§,
- Christopher J. White, MD‖‖ and
- Heather L. Gornik, MD, MHS†
- †Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio
- ‡Mount Sinai Medical Center, New York, New York
- §University of Michigan, Ann Arbor, Michigan
- ‖North Central Heart, Sioux Falls, South Dakota
- ¶Greenville Hospital System, Greenville, South Carolina
- #Massachusetts General Hospital, Boston, Massachusetts
- ∗∗Miami Baptist Cardiac/Vascular Institute, Miami, Florida
- ††Fibromuscular Dysplasia Society of America, Rocky River, Ohio
- ‡‡University of Virginia Health System, Charlottesville, Virginia
- §§Mayo Clinic, Rochester, Minnesota
- ‖‖Ochsner Medical Center, New Orleans, Louisiana
- ↵∗Department of Cardiovascular Medicine, Cleveland Clinic, Desk J3-5, 9500 Euclid Avenue, Cleveland, Ohio 44195
To the Editor:
Fibromuscular dysplasia (FMD) is an uncommon arteriopathy which can result in stenosis, aneurysm, dissection, and/or occlusion of arteries. It most commonly affects the renal, extracranial carotid, and vertebral arteries but can affect any artery. Although FMD occurs primarily in middle-aged women, it can also affect men and can occur across the life span. We recently reported findings of the first 447 patients enrolled in a multicenter registry of FMD involving 9 clinical centers in the United States (1). Although these findings included demographic information, presenting clinical symptoms, arterial bed involvement, and vascular events, there may be important sex-related differences in the clinical manifestation of FMD that have not been previously described. This present study aimed to determine if there are differences in the clinical characteristics and arterial involvement of FMD between men and women.
The multicenter U.S. Registry for FMD was formed in 2008 with the Michigan Cardiovascular Outcomes Research and Reporting Program serving as the coordinating center. Specifics of this registry are described in detail elsewhere (1). Since the publication of the first registry report (1), one additional clinical center has been added and an additional 168 patients have been enrolled as of September 11, 2012.
Differences in clinical characteristics by sex were determined using the Student t test and Fisher exact test with summary statistics presented as mean ± SD and percentages. All statistics were analyzed by the coordinating center statistician (X.G.) using SAS (SAS Institute, Inc., Cary, North Carolina).
There were 615 patients included in the analysis, including 52 men (8.5%). Mean age at diagnosis of FMD was 51.9 years (men 52.1 years vs. women 51.9 years; p = 0.94). Prevalence of hypertension and headaches was high in the overall registry cohort (73.1% and 63.2%, respectively), but there were no differences by sex. Although women were significantly more likely to have a family history of hypertension or stroke, there were no differences in family history of aneurysm, dissection, or sudden death (Table 1).
Hypertension and headache were the most common presenting symptoms leading to the diagnosis of FMD overall and for both sexes, but women were significantly more likely to present with other signs and symptoms of carotid and/or vertebral artery involvement than men, with higher rates of pulsatile tinnitus (35.7% vs. 9.1%; p = 0.0002), cervical bruit (26.8% vs. 4.5%; p = 0.0004), and neck pain (28.6% vs. 13.3%; p = 0.034). Men compared with women were significantly more likely to present with signs and symptoms of renal artery involvement including flank and/or abdominal pain (43.8% vs. 14.3%; p < 0.0001), azotemia/renal insufficiency (9.1% vs. 2.2%; p = 0.026), and renal infarction (42.9% vs. 4.3%; p = 0.0067) (Table 1).
Although not all patients had every vascular bed evaluated with imaging studies, differences in arterial bed distribution between men and women were seen (using conventional angiography, computed tomography angiography, magnetic resonance angiography, or duplex ultrasound) (Table 1). Renal and extracranial carotid arteries were the most commonly affected arterial beds in the overall cohort (75.3% and 72.7%, respectively), but there were significant differences in involvement by sex: men were more likely to have renal involvement (89.7% vs. 74.1% in women; p = 0.032), whereas women were more likely to have extracranial carotid involvement (74.9% vs. 44.1% in men; p = 0.00043). Men and women had similar average number of arterial beds involved (mean 1.8 beds; p = 0.84).
Arterial dissection and aneurysm were common among patients in the registry, with 21.7% of patients having at least one dissection and 22.2% of patients with one or more arterial aneurysms. Men had higher prevalence of both aneurysm (40.8% vs. 20.4% in women; p = 0.002) and dissection (39.6% vs. 20.0% in women; p = 0.0031) (Table 1). The most common sites of dissection for both sexes were the carotid (15.7%), vertebral (4.2%), and renal (4.1%) arteries. Renal artery dissections were significantly more common in men (18.5% vs. 2.7% in women; p < 0.0001).
We identified important sex-related differences in family history, clinical presentation, and location of arterial involvement in FMD. Men represent a minority of patients in the registry (8.5%), but men with FMD had higher rates of arterial aneurysm and dissection compared with women. Women with FMD were more likely to present with signs and symptoms related to cervical artery (carotid and/or vertebral) involvement, whereas men were more likely to present with signs and symptoms related to renal artery involvement.
There have been sex-related differences reported in the clinical manifestations and survival in other arteriopathies associated with arterial aneurysm and dissection, such as Loeys-Dietz syndrome, an autosomal dominant genetic disorder caused by mutations in the transforming growth factor beta receptor 1 or 2 genes (2). Unique genetic pathways for FMD have not yet been identified, however, and the prevalence of mutations associated with other arteriopathies, including those in Col3A1, TGFBR1/2, and ACTA2, is low in FMD (3,4).
As discussed in the first registry publication (1), there are several limitations to this study. A particularly pertinent limitation is the potential for surveillance bias because there was no standardized algorithm for vascular imaging in all patients. Significant corresponding differences in clinical presentation between sexes, however, make a compelling argument that the imaging findings are likely to be real. Practice guidelines for the care of patients with FMD, including recommendations for imaging to screen for disease in asymptomatic vascular territories, are eagerly anticipated.
In conclusion, there are important sex-related differences in the family history, presentation, and arterial involvement of FMD. Although FMD less commonly affects men, the frequency of arterial aneurysm and dissection is significantly higher among men with FMD. Although FMD can affect any arterial bed in both sexes, FMD should be particularly suspected in women who present with headache, neck pain, pulsatile tinnitus, or cervical bruit and in men who present with renal dissection or infarct or with arterial aneurysm.
Please note: This work was supported by the Fibromuscular Dysplasia Society of America, a nonprofit organization. Dr. Kim has served as a consultant for Philips Ultrasound and has received grant support from General Electric. Dr. Froehlich has been a consultant for Pfizer; Janssen Pharmaceuticals, Merck, and Boehringer Ingelheim. Drs. Olin and Gornik are unpaid members of the medical advisory board of the FMD Society of America, a nonprofit organization. Dr. Gray has a consultant agreement without financial benefit with Abbott Vascular and Trivascular and has received research support without financial benefit with SilkRoad, Medtronic, Abbott, and WL Gore. Dr. Jaff is a board member of the Fibromuscular Dysplasia Society of America and VIVA Physicians, a 501 c 3 not-for-profit education and research organization. Dr. Katzen has served on advisory boards for Boston Scientific, Medtronic, and WL Gore. Ms. Mace is an employee of the FMD Society of America, a nonprofit organization. Dr. Matsumoto has received consultant fees/honoraria from St. Jude and WL Gore; has received fees for participation in review activities for Bolton Medical; is a board member of Boston Scientific; has served as an unpaid consultant for Crux Medical; and has received grant support from Insightec. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2013 American College of Cardiology Foundation
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