Fibromuscular dysplasia (FMD) is an uncommon

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1 Top 8 Lessons Lerned From the US Registry for FMD Understnding the impct of registry dt on clinicl prctice. By Srh O Connor; Jeffrey W. Olin, DO; nd Hether L. Gornik, MD Fibromusculr dysplsi (FMD) is n uncommon nontherosclerotic disese of medium-sized rteries. The disese ws first described in 1938 by Ledbetter nd Burklnd nd lter clssified histologiclly by Hrrison nd McCormick in the erly 1970s. 1,2 Until recently, little progress hd been mde to elucidte the epidemiology, pthophysiology, nd nturl history of FMD. The estblishment of the United Sttes (US) Registry for FMD hs helped mke pprecible progress towrd understnding this disese. In Jnury 2009, the US Registry for FMD begn enrolling ptients t seven centers cross the United Sttes. Seven dditionl centers were dded since tht time (see the Currently Enrolling Centers in the US Registry for FMD sidebr). The registry is sponsored by the FMD Society of Americ ( nd is coordinted by the University of Michign Crdiovsculr Outcomes Reserch nd Reporting Progrm ( The registry protocol is pproved by the institutionl review bord of ech clinicl center. A stndrdized dt collection form is completed t the time of initil enrollment for ech prticipnt, which includes demogrphics, presenting symptoms/signs, comorbidities, fmily history, medictions, physicl exmintion, imging studies, vsculr procedures, renl function, lipid profile, nd history of vsculr nd clinicl outcome events. At ech follow-up visit, intervl vsculr nd clinicl outcome events re recorded, s well s vsculr imging studies, FMD-relted vsculr procedures, current medictions, select lbortory prmeters, nd blood pressure mesurement. Ech center follows stndrdized definition document for completing dt collection forms. Since the first ptients were enrolled in Jnury 2009, enrollment hs continued to climb (Figure 1). As of Jnury 9, 2014, there ws totl of 951 ptients enrolled in the registry. A welth of informtion hs come from the registry. Initil dt from the first 447 registrnts were published in 2012 in Circultion, nd n dditionl rticle highlighting differences between the sexes ws published in ,4 To dte, 10 bstrcts hve been presented t ntionl scientific meetings. Insights gined from the registry hve led to significnt chnges in our understnding of FMD nd our pproch to clinicl mngement of this disese. In this rticle, we summrize some of the key concepts lerned from the registry, nd highlight chnges we hve mde to clinicl prctice bsed on registry dt. Currently Enrolling Centers in the US Registry for FMD s of Jnury 2014 Clevelnd Clinic, Clevelnd, OH Mount Sini, New York, NY Greenville Helth System, Greenville, SC University of Michign, Ann Arbor, MI North Centrl Hert, Sioux Flls, SD Myo Clinic, Rochester, MN Ochsner Helth Center, Metirie, LA University of Virgini Helth System, Chrlottesville, VA Msschusetts Generl Hospitl, Boston, MA University of Cliforni Dvis, Scrmento, CA Mimi Bptist Crdic/Vsculr Institute, Mimi, FL University of Knss, Knss City, KS Vnderbilt Hert, Nshville, TN Children s Hospitl of Phildelphi, Phildelphi, PA (peditric only center) For complete list of registry center contct informtion nd locl principl investigtors visit 32 Endovsculr Tody Februry 2014

2 Tble 1. Distribution of Arteril Involvement in Men nd Women with FMD Figure 1. Registry enrollment by yer (s of Jnury 9, 2014). LESSON #1: (RE)DEFINING THE COMMON CLINICAL PRESENTATION OF FMD Although the ssocition between renl FMD nd hypertension is very well described, the common clinicl mnifesttions of FMD re ctully more diverse (see Figures 2 nd 3 for cse exmples). Among the first 447 ptients enrolled in the registry, hypertension ws the most common presenting mnifesttion, ffecting 63.8% of ptients; however, there ws number of other common signs nd symptoms of FMD, including hedche (52.4%), pulstile tinnitus or swooshing noise in the ers (27.5%), dizziness (26%), cervicl bruit (22.2%), nd neck pin (22.2%). 3 Most FMD ptients (80%) presented with multiple symptoms/clinicl signs t the time of dignosis. 3 Symptoms re determined lrgely by the vsculr beds involved, nd mny ptients hve FMD in multiple rteries. Interestingly, in the er of dvnced imging, number of ptients were identified when imged for other indictions. Incidentl FMD ws dignosed in 5.6% of registrnts who were symptomtic t the time of dignosis. 3 Becuse presenting symptoms extend beyond hypertension, FMD should be included in the differentil dignosis for ptients with other nonspecific complints, especilly hedches, pulstile tinnitus, neck pin, nd/or for ptients with cervicl bruit. LESSON #2: FMD INVOLVES MORE THAN THE RENAL ARTERIES Renl rtery FMD is the most common site of disese mong ptients in the registry (79.7% of ptients). 3 However, cerebrovsculr (extrcrnil crotid nd vertebrl) FMD is nerly s common, with 74.3% of registrnts presenting with crotid nd 36.6% with vertebrl involvement. 3 Nerly two-thirds of ptients with renl rtery FMD hve cerebrovsculr FMD nd vice vers if Artery Men Women P Vlue Renl 89.7% 74.1%.032 Mesenteric 34.4% 20%.071 Extrcrnil crotid 44.1% 74.9% Vertebrl 22.2% 34.4%.29 Intrcrnil 36.4% 15.4%.033 Reproduced with permission from Kim ESH et l. J Am Coll Crdiol. 2013;61: ssessed with imging exmintion. 3 Other commonly ffected vsculr beds include the celic/mesenteric rteries (26.3%), intrcrnil vessel (17%, primrily mnifesting s neurysms), nd lower (generlly externl ilic rtery) nd upper (generlly brchil rtery) extremities. 3 Becuse FMD presents so commonly in multiple vsculr beds, prticulrly the cerebrovsculr nd renl rteries, it is importnt to imge these territories t lest once to identify symptomtic FMD nd ssocited vsculr mnifesttions (eg, neurysms nd dissections). On the bsis of these dt, our current clinicl pproch to ptients with FMD is one-time brin-to-pelvis imging study with subsequent followup studies trgeted to res tht re found to hve evidence of disese. Unfortuntely, despite the frequent finding of FMD in multiple beds, imging multiple vsculr beds is not stndrd prctice mong ll physicins. 5 As of 2011, only 74.5% of registrnts with renl rtery FMD hd ever undergone crotid/vertebrl imging, nd only 63.7% of registrnts with crotid FMD hd undergone intrcrnil imging. 5 LESSON #3: MEN AND WOMEN WITH FMD PRESENT DIFFERENTLY Although FMD is primrily disese found in women, outnumbering men 9:1 in the registry, the course of the disese in men seems to be somewht different. Tble 1 demonstrtes the difference in rteril involvement by sex. 4 Women with FMD were more likely to present with clssic signs nd symptoms of crotid FMD, including pulstile tinnitus, neck pin, nd cervicl bruit (ll P <.05). Hedche ws lso more common in women thn in men (57.8% vs 46.8%; P =.17). 4 In contrst, men with FMD were more likely to present with signs nd symptoms of viscerl involve- Februry 2014 Endovsculr Tody 33

3 bruit for the dignosis of renl or mesenteric FMD ws only 24% sensitive. 6 However, usculttion ws highly specific for FMD involvement in prticulr re (cervicl bruit ws 93.7% specific for extrcrnil FMD with positive predictive vlue 95.4%; bdominl bruit 93.3% specific for renl/mesenteric FMD with positive predictive vlue 92.6%). 6 Therefore, usculttion of bruit in n FMD ptient indictes tht there is likely FMD in the ssocited vsculr bed, but lck of bruit does not rule out FMD. Physicl exmintion is n insensitive tool, nd imging is required. Figure 2. Mgnetic resonnce ngiogrphy demonstrtes left renl rtery mcroneurysm in 33-yer-old womn with renl FMD. She hd previously undergone ngioplsty of the right renl rtery for multifocl FMD nd ws ultimtely referred for open left renl rtery neurysm repir. She ws lso found to hve smll intrcrnil internl crotid rtery neurysm, which is being monitored. ment: flnk/bdominl pin, renl insufficiency, nd renl infrction (43.8% vs 14.3%, 9.1% vs 2.2%, nd 42.9% vs 4.3%, respectively; ll P <.05). 4 Renl rtery dissection with infrction represents clssic presenttion for FMD in mle ptient. In ddition, mle FMD ptients hd twofold increse in prevlence of rteril neurysm (40.8% vs 20.4%; P =.002) nd dissection (39.6% vs 20%; P =.0031) compred to femle ptients. 4 Bsed upon these dt, it seems tht FMD in men my hve more complicted vsculr course. LESSON #4: DIAGNOSIS OF FMD REQUIRES LISTENING, BUT MORE IMPORTANTLY, LOOKING Bseline physicl exmintions were recorded for ptients who were prospectively enrolled in the registry. As of 2012, some physicl exmintion dt were vilble for 92% of ptients. 6 Mny ptients presented with n udible bruit over the ffected vsculr bed. Crotid bruits were uscultted in 30.5% of ptients (bilterl in 18.1%); other bruits included epigstric/ bdominl (17.5% of ptients) nd flnk (6.1%). 6 Despite the frequency of bruits, usculttion is not n dequtely sensitive tool for FMD dignosis in given vsculr bed. Cervicl bruit for crotid or vertebrl FMD dignosis ws 45.4% sensitive, but bdominl LESSON #5: BEYOND THE STRING OF BEADS: FMD IS A SERIOUS VASCULAR CONDITION FMD (in its multifocl vrint) commonly presents with multiple res of stenosis nd dilttion (string of beds) with relted symptoms, but it lso my present with morbid vsculr events. 3,4,7,8 Arteril dissections nd neurysms were common finding mong ptients in the registry. Nerly one in five FMD ptients hs t lest one rteril dissection, nd of those, 20% hd more thn one dissection. 3,8 The extrcrnil crotid rteries, followed by the renl rteries, were the most common sites of dissection. 8 Aneurysms were lso frequent, with 22.2% of registrnts hving t lest one ortic or rteril neurysm. Among those, more thn one-third hd more thn one neurysm. 3,7 The renl nd extrcrnil crotid rteries were the most common sites for neurysm. Other common sites for dissections nd neurysms re listed in Tble 2. We do not yet understnd why some FMD ptients develop dissections or neurysms nd others do not, Figure 3. Complex, multifocl left renl rtery FMD with brnch vessel stenoses. 34 Endovsculr Tody Februry 2014

4 Tble 2. Prevlence nd Vsculr Distribution of Arteril Dissections nd Aneurysms in Fibromusculr Dysplsi (n = 447),b Prmeter n (%) Dissection 88 (19.7) Crotid rtery 68/88 (75) Renl rtery 19/88 (21.6) Vertebrl rtery 15/88 (17) Mesenteric rtery 4/88 (4.5) Coronry rtery 3/88 (3.4) Celic rtery 2/88 (2.3) Ilic rtery 2/88 (2.3) Aneurysm 76 (17) Renl rtery 25/76 (32.9) Crotid rtery c 16/76 (21.1) Aort 15/76 (19.7) Celic rtery 12/76 (15.8) Cerebrl rteries d 9/76 (11.8) Mesenteric 5/76 (6.6) Bsilr 5/76 (6.6) Vertebrl 2/76 (2.6) Subclvin 2/76 (2.6) Poplitel 2/76 (2.6) All vsculr beds were not imged in every ptient. b Reproduced with permission from Olin JW et l. Circultion. 2012;125: c Crotid rtery neurysm includes extr- nd intrcrnil internl crotid rtery nd ophthlmic rtery. d Cerebrl rteries include nterior, middle, nd posterior cerebrl rteries. nor do we hve relible methods for identifying those FMD ptients who re t the gretest risk. As mentioned, our stndrd clinicl prctice of brin-to-pelvis cross-sectionl imging (CT ngiogrphy or mgnetic resonnce ngiogrphy) t lest once for ll FMD ptients, regrdless of the initil site of disese dignosis, will identify occult neurysms in these ptients. LESSON #6: POTENTIAL GENETIC MECHANISMS OF FMD REMAIN UNKNOWN FMD is thought to hve genetic component. Erly reports suggested n utosoml dominnt disese with vrible penetrnce. 9,10 Yet, few FMD ptients (7.3%) in the registry report first- or second-degree reltive with dignosis of FMD. 3 This is lower thn previously published rtes for fmilil FMD of pproximtely 10%. 10 In contrst to low reported rtes of fmilil FMD in the registry, nerly one-qurter of ptients report first- or second-degree reltive with ortic or rteril neurysm, nd more thn hlf report fmily history of stroke. 3 These dt (nd others) suggest tht the rteril mnifesttions of FMD my represent broder inherited rteriopthy (or multiple genetic rteriopthies) with vrible clinicl vsculr phenotype (eg, presenting s string-of-beds lesions in some ptients, neurysms in others). Investigtions relted to the genetics of FMD re underwy t number of cdemic medicl centers in the United Sttes nd Europe. LESSON #7: HALF OF FMD PATIENTS HAVE UNDERGONE A VASCULAR PROCEDURE, THE MAJORITY OF WHICH ARE ENDOVASCULAR Hlf of ll ptients in the registry hve undergone t lest one therpeutic vsculr procedure for FMD. 11 Among those hving undergone t lest one procedure, the verge number of procedures per ptient is 1.9 ± 1.6, with rnge of one to 12 procedures. The most common clinicl indictions for intervention include hypertension (64.6%), dissection (8.2%), neurysm (7.3%), nd hedche (6.1%). 11 Endovsculr procedures (minly percutneous trnsluminl ngioplsty) on the renl rteries predominte. Although most ptients hd fvorble outcomes, procedurl complictions occurred in 9.8% of ptients who underwent vsculr procedure. Arteril dissection ws the most commonly reported compliction. Technicl filures occurred in 6.4% of procedures. 11 On the bsis of these dt nd our clinicl experience, it is cler tht mny FMD ptients benefit from therpeutic vsculr intervention, but like ll revsculriztion procedures, ptient selection is criticl. Opertor trining nd experience in the cre of FMD ptients is lso importnt, s there re mny procedurl fctors tht differ in the tretment of FMD compred to therosclerosis. For exmple, for symptomtic renl rtery FMD, blloon ngioplsty without stenting is the endovsculr strtegy of choice. Further, the mesurement of trnslesionl pressure grdients before nd 36 Endovsculr Tody Februry 2014

5 fter renl ngioplsty to ensure hemodynmic (s well s ngiogrphic) technicl success of the procedure hs become stndrd t mny experienced nd highvolume FMD clinicl centers. LESSON #8: THE MEDICAL COMMUNITY RARELY RECOGNIZES SYMPTOMS OF FMD, AND DIAGNOSIS IS OFTEN DELAYED There is significnt dely in dignosis from the time of symptom onset for ptients with FMD. 12 In the registry, the men length of time from first reported FMD symptom (by ptient recll) to confirmed dignosis ws 3.6 ± 7.4 yers. 3,12 In the series from Pris, there ws 9-yer dely from the onset of hypertension to the dignosis of FMD in ptients with multifocl FMD. 13 In the registry, fctors ssocited with longer time to dignosis were younger ge nd hypertension s the presenting symptom. 12 Ptients with stroke or rteril dissection hd shorter time to dignosis, reflecting the erlier trige to imging studies. 12 The dely in dignosis my be due to number of fctors. First, the signs nd symptoms of FMD re nonspecific, for exmple, hedche, tinnitus, hypertension, nd dizziness. Second, mong ptients with hypertension, the men ge of onset, 43.1 yers, overlps with the onset of essentil hypertension. This mkes it difficult to distinguish essentil hypertension from FMD-relted hypertension bsed on ge lone. We need to continue to educte the medicl community to consider FMD in the differentil dignosis, to sk for other symptoms of this disese in t-risk ptients, nd to incorporte thorough vsculr exmintion into the office visit. In middle-ged womn with hypertension, it is importnt to include FMD in the differentil dignosis nd identify ny other symptoms suggestive of FMD, which include bdominl, flnk, or neck bruits, hedches (especilly migrine type), pulstile tinnitus, nd resistnt hypertension. The ptient with pulstile tinnitus nd severe migrine hedches, especilly if bruit is present, wrrnts n investigtion to rule out cerebrovsculr FMD. Although we hve much to lern bout FMD, recognizing the signs nd symptoms of this disese nd referring ptients to qulified helth cre providers is vitl first step. n For those clinicins nd investigtors interested in lerning more bout FMD, the Interntionl FMD Reserch Network Symposium will be held in Clevelnd, Ohio, on My 15th nd 16th, The US FMD Registry, s well s other relted interntionl vsculr registries, will be discussed in detil. A stte-of-the-rt updte on FMD mngement is included in the progrm. Plese see www. clevelndclinic.org/fmdsymposium for dditionl detils. Acknowledgement: The uthors would like to thnk ll of the investigtors nd study coordintors prticipting in the US Registry for Fibromusculr Dysplsi, the Fibromusculr Dysplsi Society of Americ, the University of Michign Crdiovsculr Outcomes Reserch nd Reporting Progrm, nd ll of our FMD ptients who continue to inspire us to lern more bout this intriguing disese. Srh O Connor is fourth-yer medicl student t Clevelnd Clinic Lerner College of Medicine of Cse Western Reserve University in Clevelnd, Ohio. She stted tht she hs no finncil interests relted to this rticle. Jeffrey W. Olin, DO, is Professor of Medicine, Zen nd Michel A. Wiener Crdiovsculr Institute, nd Mrie- Josée nd Henry R. Krvis Center for Crdiovsculr Helth, Mount Sini School of Medicine in New York. He hs disclosed tht he serves in volunteer position s Chir of the Medicl Advisory Bord for the Fibromusculr Dysplsi Society of Americ. Hether Gornik, MD, is Stff Physicin in the Robert nd Suznne Tomsich Deprtment of Crdiovsculr Medicine, Section of Vsculr Medicine nd Medicl Director of the Non-Invsive Vsculr Lbortory of the Clevelnd Clinic Hert nd Vsculr Institute in Clevelnd, Ohio. She hs disclosed tht she serves in volunteer position on the Medicl Advisory Bord for the Fibromusculr Dysplsi Society of Americ. She my be reched t (216) or gornikh@ccf.org. 1. Ledbetter WF, Burklnd CE. Hypertension in unilterl renl disese. J Urol. 1938;39: Hrrison EG Jr, McCormck LJ. Pthologic clssifiction of renl rteril disese in renovsculr hypertension. Myo Clin Proc. 1971;46: Olin JW, Froehlich J, Gu X, et l. The United Sttes registry for fibromusculr dysplsi: results in the first 447 ptients. Circultion. 2012;125: Kim ESH, Olin JW, Froehlich JB, et l. Clinicl mnifesttions of fibromusculr dysplsi vry by ptient sex: report of the United Sttes registry for fibromusculr dysplsi. J Am Coll Crdiol. 2013;61: Rlko A, Gu X, Kline-Rogers E, et l. Dignostic nd follow-up imging for fibromusculr dysplsi: report from the United Sttes fibromusculr dysplsi ptient registry. J Am Coll Crdiol. 2012;59:E Poloskey SL, Olin J, Froehlich J, et l. Physicl exmintion findings in fibromusculr dysplsi: report of the United Sttes registry for fibromusculr dysplsi. J Am Coll Crdiol. 2012;59:E Gvin J, Gu X, Olin J, et l. Prevlence of rteril neurysms in ptients with fibromusculr dysplsi: report from the United Sttes Registry for fibromusculr dysplsi. J Am Coll Crdiol. 2013; Olin JW, Gu X, Froehlich J, et l. Peripherl rtery dissection in ptients with fibromusculr dysplsi: report from the United Sttes fibromusculr dysplsi ptient registry. J Am Coll Crdiol. 2012; 59:E Rushton A. The genetics of fibromusculr dysplsi. Arch Intern Med. 1980;140: Perdu J, Boutouyrie P, Bourgin C, et l. Inheritnce of rteril lesions in renl fibromusculr dysplsi. J Hum Hypertens. 2007;21: Gornik H, Froehlich JB, Gu X, et l. Morbidity, vsculr events nd interventionl therpy for fibromusculr dysplsi: report of the fibromusculr dysplsi ptient registry. J Am Coll Crdiol. 2011;57:E Gvin J, Gu X, Gornik H, et l. Fctors ssocited with dely in dignosis of ptients with fibromusculr dysplsi: report from the United Sttes registry for fibromusculr dysplsi. SVM Abstrcts Svrd S, Steichen O, Azrine A et l. Assocition between 2 ngiogrphic subtypes of renl rtery fibromusculr dysplsi nd clinicl chrcteristics. Circultion 2012;126: Februry 2014 Endovsculr Tody 37