Other FMD Research Findings
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Heather L Gornik (Co-Chair), Alexandre Persu (Co-Chair), David Adlam, Lucas S Aparicio, Michel Azizi, Marion Boulanger, Rosa Maria Bruno, Peter de Leeuw, Natalia Fendrikova-Mahlay, James Froehlich, Santhi K Ganesh, Bruce H Gray, Cathlin Jamison, Andrzej Januszewicz, Xavier Jeunemaitre, Daniella Kadian-Dodov, Esther SH Kim, Jason C Kovacic, Pamela Mace, Alberto Morganti, Aditya Sharma, Andrew M Southerland, Emmanuel Touzé, Patricia van der Niepen, Jiguang Wang, Ido Weinberg, Scott Wilson, Jeffrey W Olin and Pierre-Francois Plouin on behalf of the Working Group ‘Hypertension and the Kidney’ of the European Society of Hypertension (ESH) and the Society for Vascular Medicine (SVM)
Vascular Medicine. January 16, 2019.
This article is a comprehensive document on the diagnosis and management of fibromuscular dysplasia (FMD), which was commissioned by the working group ‘Hypertension and the Kidney’ of the European Society of Hypertension (ESH) and the Society for Vascular Medicine (SVM). This document updates previous consensus documents/scientific statements on FMD published in 2014 with full harmonization of the position of European and US experts. In addition to practical consensus-based clinical recommendations, including a consensus protocol for catheter-based angiography and percutaneous angioplasty for renal FMD, the document also includes the first analysis of the European/International FMD Registry and provides updated data from the US Registry for FMD. Finally, it provides insights on ongoing research programs and proposes future research directions for understanding this multifaceted arterial disease.
This study was conducted by Alexandre Persu and his team of FMD researchers out of UCL located in Brussels.
Abstract: Fibromuscular Dysplasia (FMD) is “an idiopathic, segmental, non-atherosclerotic and noninflammatory disease of the musculature of arterial walls, leading to stenosis of small and mediumsized arteries” (Persu, et al; 2014). FMD can lead to hypertension, arterial dissections, subarachnoid haemorrhage, stroke or mesenteric ischemia. The pathophysiology of the disease remains elusive. While familial cases are rare (<5%) in contemporary FMD registries, there is evidence in favour of the existence of multiple genetic factors involved in this vascular disease. Recent collaborative efforts allowed the identification of a first genetic locuzs associated with FMD. This intronic variant located in the phosphatase and actin regulator 1 gene (PHACTR1) may influence the transcription activity of the endothelin-1 gene (EDN1) located nearby on chromosome 6. Interestingly, the PHACTR1 locus has also been involved in vascular hypertrophy in normal subjects, carotid dissection, migraine and coronary artery disease. National and international registries of FMD patients, with deep and harmonised phenotypic and genetic characterisation, are expected to be instrumental to improve our understanding of the genetic basis and pathophysiology of this intriguing vascular disease. May 2018
Marianne H Khoury, Heather L Gornik
Vascular Medicine. Vol 22, Issue 3, 248 - 252. April 3, 2017
Fibromuscular dysplasia (FMD) is an uncommon vascular disease that affects the arteries of the body and is more commonly seen in women. Though FMD was first described in 1938, only in the past decade have there been major advances in the understanding of this condition. In 2017, FMD remains poorly understood by many medical professionals, and arriving at the right diagnosis can be difficult, even for patients who have symptoms of this disease.
Loss-of-Function Mutations in YY1Ap1 Lead to Grange Syndrome and a Fibrouscular Dysplasia-Like Vascular Disease
Dong-chuan Guo13, Xue-Yan Duan13, Ellen S. Regalado, Lauren Mellor-Crummey, Callie S. Kwartler, Dong Kim, Kenneth Lieberman, Bert B.A. de Vries, Rolph Pfundt, Albert Schinzel, Dieter Kotzot, Xuetong Shen, Min-Lee Yang, University of Washington Center for Mendelian Genomics, Michael J. Bamshad, Deborah A. Nickerson, Heather L. Gornik, Santhi K. Ganesh, Alan C. Braverman, Dorothy K. Grange, Dianna M. Milewicz
The American Journal of Human Genetics. Volume 100, Issue 1, 21 - 30. 2017
Fibromuscular dysplasia (FMD) is a heterogeneous group of non-atherosclerotic and non-inflammatory arterial diseases that primarily involves the renal and cerebrovascular arteries. Grange syndrome is an autosomal-recessive condition characterized by severe and early-onset vascular disease similar to FMD and variable penetrance of brachydactyly, syndactyly, bone fragility, and learning disabilities. Exome-sequencing analysis of DNA from three affected siblings with Grange syndrome identified compound heterozygous nonsense variants in YY1AP1, and homozygous nonsense or frameshift YY1AP1 variants were subsequently identified in additional unrelated probands with Grange syndrome. YY1AP1 encodes yin yang 1 (YY1)-associated protein 1 and is an activator of the YY1 transcription factor. We determined that YY1AP1 localizes to the nucleus and is a component of the INO80 chromatin remodeling complex, which is responsible for transcriptional regulation, DNA repair, and replication. Molecular studies revealed that loss of YY1AP1 in vascular smooth muscle cells leads to cell cycle arrest with decreased proliferation and increased levels of the cell cycle regulator p21/WAF/CDKN1A and disrupts TGF-β-driven differentiation of smooth muscle cells. Identification of YY1AP1 mutations as a cause of FMD indicates that this condition can result from underlying genetic variants that significantly alter the phenotype of vascular smooth muscle cells.
Bumpus SM, Krallman R, Heidt S, Kline-Rogers E.
JSM Atherosclerosis. 2017;2(1):1021.
Fibromuscular Dysplasia (FMD) is an arteriopathy that can affect any vascular territory, though most often affects the renal and carotid arterial beds. Symptoms are consistent with the vascular bed affected and are often attributed to other conditions, leading to delays in diagnosis. We present a case of a
middle-aged woman who presented to the emergency department (ED) with altered mental status and confusion, with an ED discharge diagnosis of altered mental state secondary to depression and alcohol abuse. During follow-up testing, she was diagnosed with hypertensive encephalopathy and, subsequently, FMD.
The true prevalence of FMD is unknown, although current estimates vary from 3-4%. Like other “uncommon” disorders, appropriate diagnoses are often delayed or missed altogether. This delay to diagnosis, in combination with non-specific symptoms and providers’ unfamiliarity with FMD, leads to frustration for many patients. A recent FMD qualitative publication revealed patients’ concerns about physical symptoms along with greater frequency of anxiety and depression. Importantly, these concerns decreased over time.
Through the work of many researchers, many health care institutions have created specialty centers for diagnosing and treating patients with FMD. There is now a strong community of patient support, partially due to the efforts of organizations like The Fibromuscular Society of America (fmdsa.org) and the U.S. Registry for FMD. This case illustrates that progress has been made in increasing the awareness of FMD and highlights that a lot of work still needs to be done.
Sherry M Bumpus, Christa Kuck, Steven T Heidt and Minnie Bluhm
"Fibromuscular dysplasia (FMD) is a vascular disorder about which little has been known until recently. Patients with FMD may suffer from hypertension, aneurysms, or strokes, as well as symptoms associated with local artery damage. As a result of advances in vascular medicine and growing outcomes registries, we now have a better understanding of the FMD disease process and epidemiology. Nevertheless, the consequences of FMD on patients’ day-to-day experiences and mental health status are not well understood. The purpose of this study was to begin to identify and characterize the experiences of living with FMD from the perspective of the patient using qualitative inquiry. Interviews with 19 FMD patients (18 female, 1 male) were conducted, audio-recorded, transcribed verbatim, and content analyzed. Individuals with FMD reported a complex array of psychological, physical, emotional, social, and health care concerns, which may be underdiagnosed. Findings suggest new opportunities for enhancing patient care"
Kim ESH, Serhal M.
Curr Treat Options Cardiovasc Med. 2016;18(6):37. DOI: 10.1007/s11936-016-0460-z.
Fibromuscular dysplasia (FMD) is a non-atherosclerotic, non-inflammatory polyvascular disease that may result in dissection, arterial stenosis, occlusion, and aneurysm [1••]. FMD can be asymptomatic but symptoms such as headache, pulsatile tinnitus, or uncontrolled hypertension may lead the cardiologist to the diagnosis [2••]. While FMD can affect any vascular bed, it has been reported to primarily involve the medium-sized vessels with the renal, extracranial carotid, and vertebral arteries most frequently affected [3••]. Most recently, FMD has garnered increased attention in cardiology because of its possible association with spontaneous coronary artery dissection (SCAD) [4••].
PHACTR1 Is a Genetic Susceptibility Locus for Fibromuscular Dysplasia Supporting Its Complex Genetic Pattern of Inheritance
Soto Romuald Kiando, Nathan R. Tucker, et al.
PLOS Genetics 2016;12(10): e1006367. https://doi.org/10.1371/journal.pgen.1006367
Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to stenosis, dissection and aneurysm affecting mainly the renal and cerebrovascular arteries. FMD is often an underdiagnosed cause of hypertension and stroke, has higher prevalence in females (~80%) but its pathophysiology is unclear. We analyzed ~26K common variants (MAF>0.05) generated by exome-chip arrays in 249 FMD patients and 689 controls. We replicated 13 loci (P<10−4) in 402 cases and 2,537 controls and confirmed an association between FMD and a variant in the phosphatase and actin regulator 1 gene (PHACTR1). Three additional case control cohorts including 512 cases and 669 replicated this result and overall reached the genomic level of significance (OR = 1.39, P = 7.4×10−10, 1,154 cases and 3,895 controls). The top variant, rs9349379, is intronic to PHACTR1, a risk locus for coronary artery disease, migraine, and cervical artery dissection. The analyses of geometrical parameters of carotids from ~2,500 healthy volunteers indicate higher intima media thickness (P = 1.97×10−4) and wall to lumen ratio (P = 0.002) in rs9349379-A carriers, suggesting indices of carotid hypertrophy previously described in carotids of FMD patients. Immunohistochemistry detected PHACTR1 in endothelium and smooth muscle cells of FMD and normal human carotids. The expression of PHACTR1 by genotypes in primary human fibroblasts showed higher expression in rs9349379-A carriers (N = 86, P = 0.003). Phactr1 knockdown in zebrafish resulted in dilated vessels indicating subtle impaired vascular development.
We report the first susceptibility locus for FMD and provide evidence for a complex genetic pattern of inheritance and indices of shared pathophysiology between FMD and other cardiovascular and neurovascular diseases.
Doctors Richard Hughes and Maria Nagel from the Department of Neurology,University of Colorado School of Medicine preseted an abstract titled "Herpes Simplax Virus (HSV) Infection in the Acute Presentation of Fibromuscular Dysplasia (FMD)" at the 2016 World Stroke Conference in Hyderabad India.
Poloskey SL, Olin JW, Mace P, Gornik HL.
Introduction - The circulatory system is made up of the heart and blood vessels. There are 3 major types of blood vessels: arteries, veins, and lymphatics. The heart is the pumping organ and helps to push oxygen- and nutrient-rich blood through the arteries to the organs and the limbs. The veins return blood from the organs and limbs to the heart so that it can be resupplied with oxygen from the lungs. The lymphatics connect with the veins and help to return fluid from tissues and skin. This article focuses on a disorder of the arteries known as fibromuscular dysplasia.
Bilateral internal mammary artery fibromuscular dysplasia discovered upon evaluation for reconstructive breast surgery.
Heidt ST, Ganesh SK, Liu P, Froehlich JB, Kline-Rogers E.
Vasc Med. 2015;20(5):487-488
Increased Prevalence of Preeclampsia among Women Undergoing Procedural Intervention for Renal Artery Fibromuscular Dysplasia.
C.J. Vance, R.N. Taylor, T.E. Craven, .S. Edwards, M.A. Corriere.
Annals of Vascular Surgery
Abstract - Background: Renal artery fibromuscular dysplasia (RA-FMD) has a higher prevalence among women and a presumed hormonal etiology. Although preeclampsia has a clinical presentation similar to symptomatic RA-FMD and occurs exclusively in women, associations between these 2 diseases have not been characterized. To explore epidemiologic associations between RA-FMD and preeclampsia, we administered a validated screening instrument for preeclampsia to a cohort of women with a history of pregnancy who had previously been treated with procedural intervention for symptomatic RA stenosis. Results: A total of 144 women were identified who met the study inclusion criteria, including 94 with atherosclerotic renal artery stenosis and 50 with renal artery FMD. Sixty nine patients were contacted, 59 consented to participate, and 52 had a history of pregnancy (and therefore were at risk for preeclampsia). Participants completed the survey instrument at a mean of 7.1 ± 3.1 versus 6.9 ± 3.6 years after renal artery procedural intervention, respectively. Survey responses indicated a history of preeclampsia in 19/52 (36.5%) of participants overall, including 14/27 (51.9%) with renal artery FMD versus 5/20 (20.0%) with renal artery atherosclerosis (P=0.02). Preeclampsia remained associated with FMD in a multivariable model adjusting for smoking status, age at time of surgery, and estimated glomerular filtration rate (OR 9.51; 95% CI [1.49-60.6]; P=0.017); age at time of surgery (OR 2.78; 95% CI [1.04-7.42]; P=0.041) and estimated glomerular filtration rate (OR 3.31; 95% CI [1.29-8.52]; P=0.013) were also associated with FMD in the multivariable model. Conclusions: Women with a history of procedural intervention for symptomatic renal artery stenosis have an overall prevalence of preeclampsia which greatly exceeds that expected in the general population, and our results suggest that preeclampsia is specifically associated with renal artery FMD. Further investigation is needed to characterize the mechanistic relationships between FMD and prseeclampsia and may have potential to decrease related cardiovascular morbidity and mortality.
A "pivot" Model to set up Large Scale Rare Diseases Information Systems: Application to Fibromuscular Dysplasia Registry.
L. Toubiana, A. Ugon, A. Giavarini, J. Riquier, J. Charlet, X. Jeunemaitre, P.F. Plouin, M.C. Jaulent.
Stud Health Technol Inform. 2015;210:887-91.
Abstract - The SIR-FMD project is a partnership between the Department of Genetics and Reference Centre for Rare Vascular Diseases at the Georges Pompidou European Hospital in Paris and the Medical Informatics and Knowledge Engineering Laboratory of Inserm. Its aim is to use an ontological approach to implement an information system for the French Fibromuscular Dysplasia Registry. The existing data was dispersed in numerous databases, which had been created independently. These databases have different structures and contain data of diverse quality. The project aims to provide generic solutions for the management of the communication of medical data. The secondary objective is to demonstrate the applicability of these generic solutions in the field of rare diseases (RD) in an operational context. The construction of the French FMD registry was a multistep process. A secure platform has been available since the beginning of November 2013. The medical records of 471 patients from the initial dataset provided by the HEGP-Paris, France have been included, and are accessible from a secure user account. Users are organized into a collaborative group, and can access patient groups. Each electronic patient record contains more than 2,200 items. The problem of semantic interoperability has become one of the major challenges for the development of applications requiring the sharing and reuse of data. The information system component of the SIR-FMD project has a direct impact on the standardisation of coding of rare diseases and thereby contributes to the development of e-Health.
Exome Sequencing in Seven Families and Gene-Based Association Studies Support Genetic Heterogeneity and Suggest Possible Candidates for Fibromuscular Dysplasia.
S. Kiando, P.F. Plouin, M.C. Barlassina, D. Cusi, P. Galan, M. Lathrop, X. Jeunemaître, N. Bouatia-Naji Journal of Hypertension. June 2015; 33 Suppl 1: e79. doi: 10. 1097/01.hjh.0000467566.26208.1a
Abstract- Objective: Fibromuscular dysplasia (FMD) is a group of nonatherosclerotic and noninflammatory vascular disease leading to stenosis, aneurysm and dissection of medium-sized arteries, mainly renal arteries and carotids. FMD occurs predominantly in females with a prevalence of ∼ 4/1000 for clinical forms that cause hypertension, renal ischemia or stroke. The pathogenesis of FMD is unknown and a genetic origin is suspected given its demonstrated familial aggregation. Our study objective is to identify genetic variants involved in FMD aetiology. Design and Method: We performed whole exome sequencing (WES) in 16 FMD cases from 7 families (5 sibpairs and 2 sibtrios). Coding variants in 3,971 genes confidently called (read depth>20X) were prioritized on their frequency (allele frequency<0.01) and in silico predicted functionality. Results: No gene harbored variants that were shared among all affected members of at least 3 out of 7 families. Rare coding variants from 16 known causative genes of vascular and connective tissue syndromes (e.g. FBN1, TGFB2 and COL3A1) were excluded as causative in these families. Genes with at least 4 rare coding variants identified in the 16 patients were followed-up using genotyping data by exome chip (Illumina HumanExome-12v1_A Beadchip) from 249 FMD unrelated cases and 689 controls. Gene-based association of rare variants using SKAT-O showed nominal significant (P<0.05) association with multifocal FMD (N=164) for OBSCN encoding a sarcomeric protein (P=0.003), DYNC2H1 encoding a cytoplasmic dynein (P=0.02) and RNF213 previously associated with Moyamoya disease (P=0.01). Conclusion: Our study reports data from the first WES investigation conducted for familial forms of FMD. It supports strong genetic heterogeneity for FMD and excludes the implication of several known vascular diseases causative genes in familial FMD etiology. We provide some evidence of association with multifocal FMD for OBSCN, DYNC2H1 and RNF213, though these findings need to be confirmed in independent cohorts. More powerful WES and association studies (e.g GWAS) will better decipher the genetic basis of FMD.
Flow-Mediated Dilatation (FMD) and Endothelium-Independent Dilitation (EID) in Patients with Multifocal Fibromuscular Dysplasia: A Cross-Sectional Study.
H. Khettab, A. Lorthior, R. Niarra, Y. Chambon, X. Jeunemaître, P.F. Plouin, S. Laurent, P. Boutouyrie, M. Azizi.
Journal of Hypertension. June 2015; 33 Suppl 1:e82-3. doi: 10.1097/01.hjh.0000467574.64325.90.
Abstract- Objective: Fibromuscular dysplasia (FD) is a rare idiopathic, segmental, non-atherosclerotic non-inflammatory vascular disease. We previously showed that FD is a general arterial disease with focal exacerbation of the trait. However, whether endothelial dysfunction may be involved in the pathophysiology of FD is unclear. Design and Method: In a cross sectional study, we compared the endothelial function between 50 patients with multifocal FD of renal/carotid arteries confirmed by CT-angiography, 50 essential hypertensive (EH) patients matched for age, sex, ethnicity and BP and 50 healthy subjects (HS) matched for age, sex and ethnicity. Exclusion criteria were: tobacco consumption, hypercholesterolemia, diabetes, aspirin or statin treatment. Brachial artery (BA) FMD after release of hand ischemia and glyceryl trinitrate (GTN)-induced EID was measured using a high-resolution radiofrequency-based echotracking system blind to the diagnosis. Results: FD, EH and HS were well matched (52yrs, 85% women, 80% caucasian). SBP was higher in FD (125±15mmHg) and EH (121±12mmHg) than EH (113±10mmHg) despite antihypertensive treatments. BA external diameter was significantly lower in FD than in both HS and EH before, during and after hand ischemia and after GTN. BA intima media thickness (IMT), internal diameter did not differ between the 3 groups. FMD (%) or EID (%) did not significantly differ between the 3 groups. BA flow velocity did not significantly differ in any experimental condition.(Figure is included in full-text article.) Conclusion: In conclusion, despite showing similar acute vasodilatory responses to flow and GTN, FD patients differed from EH and HS in terms of arterial morphology with smaller BA diameter associated with similar IMT. This paradoxical remodeling may suggest a chronic defect in the endothelium-dependent pathways involved in arterial remodeling in FD patients.
S.C. O'Connor, N. Poria, H.L. Gornik.
Headache: The Journal of Head and Face Pain. April 17, 2015. Published online before print.
Abstract - Background: Fibromuscular dysplasia (FMD) is an uncommon vascular disease that presents with stenosis, aneurysm, dissection, beading, and tortuosity of medium-sized arteries. It primarily manifests in the renal and extracranial carotid and vertebral arteries, and is associated with major vascular events such as carotid artery dissection, renal artery dissection, ruptured aneurysm, transient ischemic attack, stroke, and myocardial infarction (due to coronary artery dissection). Discussion: There is a wide spectrum of disease severity among FMD patients. Symptoms of FMD are related to the vascular beds involved and the severity of arterial stenoses. Headache is an extremely common and important symptom reported by patients with FMD, although the precise mechanism of headache in this population is not yet known. Conclusion: This review summarizes the most recent literature regarding FMD, including epidemiology, clinical manifestations, imaging practices, and treatment. Special attention will be paid to the association of headaches and FMD. Correct diagnosis, optimal medical management, and appropriate referral for vascular intervention are vital elements of the treatment of patients with FMD. There is a great need for more clinical research regarding the epidemiology, pathophysiology, and optimal treatment of headache in the FMD patient population.
E. Brinza, H.L. Gornik.
Journal of the American College of Cardiology. February 27, 2015. Published online before print.
Published last month in JACC, this piece by Ellen Brinza and Heather Gornik chronicles new findings in the world of FMD research and offers future directions for researchers in the field. For those recently diagnosed with FMD or anyone looking to learn about recent developments, this is a great article to get you up to speed. You can find the full article here.
J. Joux, N. Chausson, S. Jeannin, M. Saint-Vil, M. Mejdoubi, J.L. Hennequin, L. Deschamps, D. Smadja, S. Olindo.
Stroke. October 30, 2014. Published online before print.
Abstract: Background and Purpose—An atypical form of fibromuscular dysplasia located in the internal carotid-bulb (CaFMD) is thought to be uncommon and is poorly described as a cause of ischemic stroke in the young. This study aimed to obtain a better description of CaFMD in Afro-Caribbean population, who could be particularly affected by it.
Methods—This study included consecutive patients <55 years consulting at Fort-de-France University Hospital Stroke Center (Martinique, FWI) found to have CaFMD as the only cause after a comprehensive work-up. CaFMD was diagnosed when computed tomographic angiography showed a bulbar spur without calcification.
Results—Twenty-five patients with stroke and CaFMD were identified. Computed tomographic angiography showed 2 CaFMD patterns: a thin (n=15) or thick (n=10) spur. Three patients initial computed tomographic angiography images showed a mural thrombus overlying the CaFMD. CaFMD was surgically removed from 7 of 25 and 20 of 25 patients who received antiplatelet therapy; after mean follow-up of 25.3±19.5 months, their respective recurrence rates were 0% and 30%.
Conclusions—CaFMD could be a common condition in young Afro-Caribbeans with carotid-territory ischemic stroke. Recurrences were frequent under antiplatelet treatment, while surgical CaFMD removal seemed more effective.
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.
N.H. Hendricks, A.H. Matsumoto, J.F. Angle, A. Baheti, S.S. Sabri, A.W. Park, J.R. Stone, J.T. Patrie, L. Dworkin, C.J. Cooper, T.P. Murphy, D.E. Cutlip.
Vasc Med. October 2014, vol. 19. 5363-367
Abstract: Renal artery fibromuscular dysplasia (FMD) may be underdiagnosed. We evaluated the prevalence of FMD in CORAL (Cardiovascular Outcomes in Renal Atherosclerotic Lesions) renal artery stent trial participants, in which FMD was an exclusion criterion for inclusion. We also evaluated the prevalence of FMD in a relatively healthy population of patients undergoing computed tomographic angiographic (CTA) screening for renal donor evaluation. All renal donor CTAs performed at our institution from January 2003 through November 2011 were retrospectively reviewed for the presence of FMD along with patient sex and age. These results were compared to angiographic core lab (ACL) findings for the CORAL trial. The CORAL ACL database contained 997 patients (mean age 69.3 years; 50% female). Fifty-eight (5.8%) CORAL trial patients (mean age 71.8 years; 75.9% female) demonstrated incidental FMD. The renal donor cohort included 220 patients (mean age 40.5 years; 64.5% female). Five (2.3%) demonstrated FMD (mean age 48.6 years; all female). The odds of FMD in the CORAL cohort were 2.65 times that seen in the renal donor cohort (95% CI: 1.12, 7.57). In conclusion, the 5.8% prevalence of renal artery FMD in the CORAL trial population, the presence of which was biased against, suggests underdiagnosis.
The S curve: A novel morphological finding in the internal carotid artery in patients with fibromuscular dysplasia.
S.S. Sethi, J.F. Lau, J. Godbold, S. Gustavson, J.W. Olin.
Vasc Med. October 2014, vol. 19. 5356-362
Abstract: Fibromuscular dysplasia (FMD) is a non-atherosclerotic vascular disease commonly affecting the renal and internal carotid arteries (ICAs). A previously unrecognized finding is a redundancy of the mid-distal ICA in FMD patients causing an ‘S’-shaped curve. Carotid artery duplex ultrasounds were reviewed in 116 FMD patients to determine S-curve prevalence. FMD patients with an S curve were matched to four control patients divided equally into two groups: (1) age and sex-matched and (2) age ≥70 and sex-matched. S curves were present in 37 (32%) FMD patients. Of these, nine (24%) had angiographic evidence of FMD in their ICA only, 13 (35%) had renal artery FMD only, and 15 (41%) had both ICA and renal FMD. Two patients in the age and sex-matched group had S curves (odds ratio 16.86, 95% CI 3.92–72.48; p<0.0001) while 12 (16.2%) patients in the age ≥70 and sex-matched group had S curves (odds ratio 2.42, 95% CI 1.16–5.03; p=0.016). In conclusion, the S curve is a novel morphological pattern of the mid-distal ICA. While the S curve may not be specific, its presence in individuals <70 years old should alert the clinician to the possibility that FMD is present.
J. West, N. Hendricks, A. Matsumoto, A.M. Sharma.
Abstract: Background: Fibromuscular dysplasia (FMD) is a noninflammatory arteriopathy that has multiple different angiographic appearances. FMD can involve multiple vascular beds and typically involves renal arteries and cerebrovascular arteries. FMD of the brachial artery is a rare entity with only a handful of case reports in the literature. We present a case series of patients with brachial FMD. Methods: We queried our database at University of Virginia from March 2008 to December 2013 to identify patients with brachial FMD and a retrospective chart review was performed. Results: Of the 225 patients, 7 patients had brachial FMD: 6/7 were women. Brachial FMD was diagnosed with CT or invasive angiogram in six patients and one was diagnosed with duplex ultrasonography. Four were symptomatic: 3 presenting with embolic event and 1 with claudication. All symptomatic patients underwent angioplasty with some or complete relief of symptoms. Identification of 2/3 asymptomatic patients was by brachial bruit confirmed with imaging and 1 was incidentally diagnosed on imaging. Age ranged from 29 to 68 years, with delays between initial FMD diagnosis in other vessels and diagnosis of brachial FMD from 0 days to 9 years. Four of 7 patients had FMD in multiple arterial beds ranging from 2 to 6 different beds and all were multifocal in appearance. All of them had hypertension with 4 diagnosed with renal FMD. One patient had a cervical dissection and 1 had a radial pseudoaneurysm. Conclusion: Brachial FMD is a rare, easily overlooked finding, but can be clinically important. A thorough examination including assessing for brachial bruits and obtaining blood pressure in both arms is extremely vital in this group of patients.
This abstract was presented at the Society of Vascular Medicine's 25th Annual Meeting.
K.C. Michelis, J.W. Olin, D. Kadian-Dodov, V. d'Escamard, J.C. Kovacic.
J Am Coll Cardiol. 2014;64(10):1033-1046.
Abstract: Fibromuscular dysplasia (FMD) involving the coronary arteries is an uncommon but important condition that can present as acute coronary syndrome, left ventricular dysfunction, or potentially sudden cardiac death. Although the classic angiographic “string of beads” that may be observed in renal artery FMD does not occur in coronary arteries, potential manifestations include spontaneous coronary artery dissection, distal tapering or long, smooth narrowing that may represent dissection, intramural hematoma, spasm, or tortuosity. Importantly, FMD must be identified in at least one other noncoronary arterial territory to attribute any coronary findings to FMD. Although there is limited evidence to guide treatment, many lesions heal spontaneously; thus, a conservative approach is generally preferred. The etiology is poorly understood, but there are ongoing efforts to better characterize FMD and define its genetic and molecular basis. This report reviews the clinical course of FMD involving the coronary arteries and provides guidance for diagnosis and treatment strategies.
Olin JW, Kadian-Dodov D.
A 52-year-old woman presents with exertional right buttock and thigh pain that resolves within 2 minutes of rest. Exercise tolerance has worsened over the past year and is now limited to several blocks. Previously she was able to run 5 to 6 miles per day. Hypertension was diagnosed several months ago and is controlled with lisinopril (5 mg daily). She has no other cardiovascular risk factors. Her blood pressure is 124/76 mm Hg bilaterally. There is a high-pitched systolic bruit over the right subcostal region and the umbilicus. Peripheral pulses are normal. The ankle brachial index (ABI) at rest is borderline normal (0.91) on the right and normal (1.03) on the left. The remainder of the examination is normal.
After physical therapy and nonsteroidal anti-inflammatory agents failed to improve symptoms, a computed tomography angiogram (CTA) is performed, revealing a “beaded appearance” in the right renal artery and a long-segment stenosis of the right external iliac artery. There is no atherosclerosis. A catheter-based angiogram confirms the CTA findings.
Olin JW, Sealove BA.
Journal of Vascular Surgery. 2011;53(3):826-36.
Fibromuscular dysplasia (FMD) is a nonatherosclerotic noninflammatory vascular disease that primarily affects women from age 20 to 60, but may also occur in infants and children, men, and the elderly. It most commonly affects the renal and carotid arteries but has been observed in almost every artery in the body. FMD has been considered rare and thus is often underdiagnosed and poorly understood by many health care providers. There are, however, data to suggest that FMD is much more common than previously thought, perhaps affecting as many as 4% of adult women. When it affects the renal arteries, the most common presentation is hypertension. When it affects the carotid or vertebral arteries, the patient may present with transient ischemic attack or stroke, or dissection. An increasing number of patients are asymptomatic and are only discovered incidentally when imaging is performed for some other reason or by the detection of an asymptomatic bruit. FMD should be considered in the differential diagnosis of a young person with a cervical bruit; a “swishing” sound in the ear(s); transient ischemic attack, stroke, or dissection of an artery; or in individuals aged ≤35 years with onset hypertension. Treatment consists of antiplatelet therapy for asymptomatic individuals and percutaneous balloon angioplasty for patients with indications for intervention. Patients with aneurysms should be treated with a covered stent or open surgical repair. Little new information has been published about FMD in the last 40 years. The recently instituted International Registry for Fibromuscular Dysplasia will remedy that situation and provide observational data on a large numbers of patients with FMD.
Altered TGF-β Expression in FMD - FASEB - April 2014
Clinical and biochemical profiles suggest fibromuscular dysplasia is a systemic disease with altered TGF-β expression and connective tissue features.
S.K. Ganesh, R. Morisette, Z. Xu, F. Schoenhoff, B.F. Griswold, J. Yang, L. Tong, M. Yang, K. Hunker, L. Sloper, S. Kuo, R. Raza, D.M. Milewicz, C.A. Francomano, H.C. Dietz, J. Van Eyk, N.B. McDonnell.
Fibromuscular dysplasia (FMD) is a rare, nonatherosclerotic arterial disease for which the molecular basis is unknown. We comprehensively studied 47 subjects with FMD, including physical examination, spine magnetic resonance imaging, bone densitometry, and brain magnetic resonance angiography. Inflammatory biomarkers in plasma and transforming growth factor β (TGF-β) cytokines in patient-derived dermal fibroblasts were measured by ELISA. Arterial pathology other than medial fibrodysplasia with multifocal stenosis included cerebral aneurysm, found in 12.8% of subjects. Extra-arterial pathology included low bone density (P<0.001); early onset degenerative spine disease (95.7%); increased incidence of Chiari I malformation (6.4%) and dural ectasia (42.6%); and physical examination findings of a mild connective tissue dysplasia (95.7%). Screening for mutations causing known genetically mediated arteriopathies was unrevealing. We found elevated plasma TGF-β1 (P=0.009), TGF-β2 (P=0.004) and additional inflammatory markers, and increased TGF-β1 (P=0.0009) and TGF-β2 (P=0.0001) secretion in dermal fibroblast cell lines from subjects with FMD compared to age- and gender-matched controls. Detailed phenotyping of patients with FMD allowed us to demonstrate that FMD is a systemic disease with alterations in common with the spectrum of genetic syndromes that involve altered TGF-β signaling and offers TGF-β as a marker of FMD.
AHA Scientific Statement - Circulation - February 2014
Fibromuscular Dysplasia: State of the Science and Critical Unanswered Questions: A Scientific Statement From the American Heart Association.
J.W. Olin, H.L. Gornik, J.M. Bacharach, J. Biller, L.J. Fine, B.H. Gray, W.A. Gray, R. Gupta, N.M. Hamburg, B.T. Katzen, R.A. Lookstein, A.B. Lumsden, J.W. Newburger, T. Rundek, C.J. Sperati, J.C. Stanley.
Circulation 129.9 (2014): 1048-1078
This publication summarizes and encompasses all previous research on FMD, while also identifying important areas of future research, recommendations for imaging modalities and treatments, and suggests an updated classification system for the vascular disease. The article reviews the history of FMD, genetic considerations, epidemiology, clinical manifestations and much more. The authors suggest a reclassification of the disease into two distinct categories for ease of diagnosis and treatment: multifocal and focal FMD. With this important publication, physicians and patients should be able to more easily recognize, classify, and treat this disease. The paper is free and can be found on Circulation, Journal of the American Heart Association.
Olin JW, Gornik HL.
JACC Cardiovasc Interv. 2012;5(8):888-9.
We report 2 cases in which patients were misdiagnosed as having fibromuscular dysplasia (FMD) due to the finding of standing arterial waves on lower extremity angiography.
In the last 30 years there has been no new information regarding the cause and pathophysiology and little new information on the genetics and treatment of patients with FMD. The literature is inundated with single case reports and small case series, most adding little to the understanding of this uncommon disease. However, in the last 3 years there has been a resurgence of interest in FMD, leading to a better understanding of this condition. In 2012, the findings from the United States registry for Fibromuscular Dysplasia were reported on the first 447 patients entered into the registry. Additionally, a multidisciplinary State of the Science paper on FMD was commissioned by the American Heart Association, and those findings will be published in 2013.
It is therefore timely that in this issue of Circulation, an experienced group of investigators in Paris published a provocative study that provides a plethora of important new information related to the classification and phenotypic expression of FMD.11 Because pathological specimens are rarely available as a result of technical advances in endovascular therapy, Savard and his associates investigated whether using a binary angiographic classification would accurately discriminate between 2 distinct clinical phenotypes.
Olin JW, Pierce M.
Current Opinion in Cardiology. 2008;23(6):527-36.
Fibromuscular dysplasia is an underdiagnosed and misunderstood disease. The purpose of this review is to inform healthcare providers and the public about a condition that may be more common than previously thought.
Cleveland Clinic Journal of Medicine. 2007;74(4):273.
Fibromuscular dysplasia typically occurs in young women and most commonly presents with hypertension, transient ischemic attack, stroke, or an asymptomatic cervical bruit. The disease is nonatherosclerotic and noninflammatory and most often affects the renal and carotid arteries, although almost any artery can be involved. On angiography, affected blood vessels characteristically resemble a string of beads in the most common type of fibromuscular dysplasia, medial fibroplasia. Patients with renal artery stenosis and hypertension or renal impairment should be treated with percutaneous transluminal angioplasty without a stent. Patients with fibromuscular dysplasia of the internal carotid artery should also be treated with angioplasty if they develop focal neurologic symptoms such as a transient ischemic attack or stroke.
Slovut DP, Olin JW.
Curr Treat OptionsCardiovasc Med. 2005;7(2):159–69
The most common clinical manifestations of fibromuscular dysplasia (FMD) are hypertension due to renal artery involvement and transient ischemic attack or stroke due to carotid or vertebral artery involvement. Patients with renal artery FMD and hypertension should undergo primary angioplasty with the goal of curing the hypertension. If the blood pressure fails to normalize following angioplasty, the physician should institute antihypertensive medications according to the recommendations of the Joint National Committee on the Prevention, Detection, and Treatment of High Blood Pressure VII. In patients with cerebrovascular FMD, antiplatelet agents represent the cornerstone of therapy. Percutaneous angioplasty has emerged as the preferred treatment for symptomatic cerebrovascular FMD.
Slovut DP, Olin JW.
New England Journal of Medicine. 2004;350(18):1862-1871.
Fibromuscular dysplasia is a noninflammatory process that may be difficult to distinguish from vasculitis. It develops in the middle and distal arterial segments, and especially in younger patients, it may cause renovascular hypertension, stroke, and cranial-nerve palsies. Treatment increasingly involves the use of percutaneous angioplasty.
The utility of duplex ultrasound scanning of the renal arteries for diagnosing significant renal artery stenosis.
Olin JW, Piedmonte MR, Young JR, DeAnna S, Grubb M, Childs MB.
Annals of Internal Medicine. 1995;122(11):833-8.
Objective: To determine the utility of duplex ultrasound scanning of the renal arteries in identifying patients with renal artery stenosis of 60% or more and in excluding patients with either normal renal arteries or renal artery stenosis of less than 60%.
The abstracts below were presented at the American Society of Human Genetics Annual Meeting in October 2006.
A cohort of patients with generalized Fibromuscular Dysplasia and features of Ehlers-Danlos Syndrome: A new phenotype.
N.B. McDonnell, J. Yang, W. Chen1, B. Griswold, C.A. Francomano 1) National Institute on Aging, NIH, Baltimore, MD; 2) Harvey Inst Human Gen, Greater Baltimore Medical Center, Baltimore, MD.
The Ehlers-Danlos syndromes (EDS) are a heterogeneous group of hereditary disorders of connective tissue. Vascular dissections and aneurysms are a cardinal feature of the vascular form of EDS (VEDS) caused by mutations in COL3A1. Loeys-Dietz syndrome, a closely related phenotype, is caused by mutations in TGFBR1 or TGFBR2. We have identified a group of patients without mutations in COL3A1, TGFBR1 or TGFBR2 who presented with arterial dissections and aneurysms as well as stenotic lesions with a diagnosis of fibromuscular dysplasia (FMD) by pathology or radiology. Varying features of Ehlers-Danlos syndrome, such as atrophic scars, velvety or stretchy skin, joint hypermobility as evidenced by a high Beighton score, history of articular dislocations, uterine prolapse, joint pain, pectus deformities, pes planus and scoliosis were also present. Several of the patients had a family history of premature death from vascular events, as well as a family history of joint and skin abnormalities compatible with an autosomal dominant inheritance pattern. There were no reports of uterine or bowel rupture, or pregnancy related death in personal or family histories. The facial features were not characteristic of VEDS or Loeys-Dietz syndrome. The first patient identified was a 44 year old woman who had a history of carotid dissection, ruptured cerebral aneurysms, FMD of renal arteries and iliac vessels, multiple atrophic scars, frequent joint dislocations, and stretchy and doughy skin. A cohort of thirty patients with this syndrome has been identified and detailed phenotype and family history information has been assembled. The etiology of fibromuscular dysplasia is thought to be heterogeneous, with genetic and environmental factors proposed as possible contributors. Our findings suggest that there is a previously unrecognized variant of EDS, distinct from the VEDS and Loeys-Dietz syndrome, with FMD as a major clinical feature in addition to the skin and joint abnormalities.
Genome wide association study for Fibromuscular Dysplasia (FMD)
J. Yang1, M. Nalls2, B. Traynor2, D. Hernandez2, N. Washecka2, B. Griswold1, L. Sloper1, A. Singleton2, N. B. McDonnell1 1) LCI, NIA/NIH, Baltimore, MD; 2) LNG,NIA/NIH, Bethesda, MD.
Fibromuscular dysplasia is a heterogeneous disorder characterized by angiopathy of the arteries, which predominantly affects women in mid-life, resulting in stenosis, dissection or aneurysm. It may involve renal arteries, carotid, vertebral, coronary and abdominal vessels. Autosomal dominant inheritance has been suggested, however no genes have been identified to date. On detailed clinical examination of a cohort of 69 patients seen at the National Institute on Aging, features of connective tissue dysplasia as exemplified by joint hypermobility, scoliosis, pectus deformity, pes planus and high myopia were frequently noted, suggesting a defect in the extracellular matrix pathways. In order to elucidate the genetic factors underlying this disorder, we performed genome wide association study in 46 sporadic cases and 540 controls utilizing the Illumina HumanCNV370-Duo BeadChip and HumanHap550 Beadchip. By permutation analysis, we have identified a number of marker SNPs with significant differences between cases and controls. The candidate genes include CDH12, EXOC2, PACRG, HECW1, ZAN, CSMD1, SRA and DIP2B with p scores <10-6. Although the disorders has been suggested to be dominant, we did homozygosity analyses for our samples, our results show chromosome 4, 5, 12 could include some specific overlapping homozygous runs in FMD patients.
Morphometric Analysis of the Posterior Fossa and Spinal Cord in patients with Hereditary Disorders of Connective Tissue
J. C. Quo1,2, L. Sloper1, R. Raza2, N. B. McDonnell1 1) Clinical Research Branch, NIA, NIH, Baltimore, MD; 2) Harbor Hospital Center, Baltimore, MD.
Patients with hereditary disorders of connective tissue (HDCT) have increased incidence of Chiari I malformation, however, abnormalities of the posterior fossa or the spinal cord has not been systematically evaluated to date. We retrospectively evaluated midline sagittal brain, midline sagittal lumbar spine, and axial lumbar magnetic resonance imaging (MRI) of 94 subjects with HDCT (70 Female, 24 Male, aged 12-71) and 209 age matched controls (138 Female, 71 Males). HDCT subjects included those with diagnoses of Ehlers-Danlos syndrome (EDS), Marfan syndrome, and Fibromuscular Dysplasia with connective tissue features (FMD). The MRI images were obtained on a 1.5 Tesla MRI machine (Philips Interna, USA) with system 11.1 software. The measurement that showed significant differences between the subjects and the controls included the basiocciput measurement (p=0.0115), foramen magnum distance (p=0.0101), opisthion to internal occipital protuberance (IOP) (p=0.0188), dorsa sella to IOP (p=0.0176), tonsillar herniation (p<0.0001), fourth ventricle height (p=0.0020), brainstem length to the craniocervical junction (p<0.0001), brainstem length to the inferior portion of the gracile tubercle (p=0.0016), tentorium slope (p=0.0109), tentorium slope to the twining line (p=0.0044), height of cerebellum (p<0.0001), conus medullaris level (p=0.0383), and filum terminale thickness (p<0.0001). Measurements that were not statistically significant included the basisphenoid length, ponto-medullary height, medullary height, and odontoid angle. The significant p value observed in 13 of the 17 measurements suggests that there are consistent morphometric differences that are seen in HDCT patients that can contribute to increased incidence of clinical abnormalities such as Chiari I malformation, tethered cord syndrome and related complaints.
Sex Hormone Abnormalities in patients with Fibromuscular Dysplasia with Connective Tissue Features
B. F. Griswold, L. Sloper, S. Basaria, J. M. Egan, N. B. McDonnell National Institute on Aging Baltimore, Maryland.
We have identified a group of patients (n=28) who presented with arterial dissections and aneurysms as well as stenotic lesions with a diagnosis of fibromuscular dysplasia (FMD). Varying features of Ehlers-Danlos syndrome, such as atrophic scars, velvety or stretchy skin, joint hypermobility as evidenced by a high Beighton score, history of articular dislocations, uterine prolapse, joint pain, pectus deformities, pes planus and scoliosis were also present in this group of patients, and family history data suggested autosomal dominant inheritance with reduced penetrance. There was a female preponderance, 24 women and 4 men, consistent with prior observations that FMD affects women predominantly, leading to the hypothesis that sex hormones played a role in the penetrance of the disorder. As part of a longitudinal protocol studying the natural history of this disorder, laboratory analysis of sex hormone levels was completed. Of the 24 female patients aged 33-62, 15 were post-menopausal. Of the women subjects, 8/24 (0.33) had high levels of Sex Hormone Binding Globulin (SHBG) which included four post menopausal patients. Free testosterone was low in 36 percent; of women patients, and 4/24 (0.17) had low bioavailable levels of testosterone. Of the 8 patients found to have high levels of SHBG, five also had corresponding low free testosterone. None of the patients had liver function abnormalities or current birth control pill use which are known to increase SHBG. None of the premenopausal patients had low FSH or LH along with low estrogen which would suggest pituitary failure. By contrast, the four male patients had normal levels of testosterone and SHBG, however the sample size was too small to draw conclusions. Elevated SHBG and low testosterone in women with FMD may be a clue to pathways involved in the etiology of this disorder.