Fibromuscular Dysplasia Patients Research Articles

Natural History of Cervical Artery Fibromuscular Dysplasia and Associated Neurovascular Events

Background and Purpose: Fibromuscular dysplasia (FMD) is a non-atherosclerotic arteriopathy most often affecting the carotid and renal arteries. In the United States Registry for FMD, 41.7% of patients experienced an aneurysm and/or dissection by the time of entry into the Registry. We sought to determine the occurrence of neurovascular events after FMD diagnosis and any changes on cervical artery imaging that may be attributable to FMD. Methods: Patients followed at the Mount Sinai Medical Center (US Registry for FMD enrollment center) with confirmed FMD and > 1 cervical artery imaging study (at least ± 6 months from the baseline carotid duplex ultrasound [CDU]) between the years 2003 and 2015 were included. Medical records and cervical artery imaging ([CDU], magnetic resonance angiogram [MRA], and computed tomography angiogram [CTA]) were reviewed. New arterial dissection, aneurysm, transient ischemic attack, stroke, or new FMD findings were recorded. Results: Among 146 FMD patients with complete information, 52 (35.6%) had an aneurysm and 52 (35.6%) had a dissection. Mean clinical follow-up was 35.3 ± 25.3 months (range 5–153 months); patients underwent 4 ± 2.7 CDU (range 1–17); 86.3% had ≥1 neck MRA or CTA. After FMD diagnosis, 3 patients (2%) experienced a new carotid artery dissection; 1 patient experienced a stroke due to concomitant atherosclerosis. No new aneurysms occurred. In patients with cervical artery FMD, imaging findings remained stable throughout follow-up. No patient developed new cervical artery FMD findings on follow-up imaging. Conclusions: No new cervical artery FMD or aneurysm was observed on subsequent imaging. New carotid dissection was uncommon over a mean follow-up period of 35.3 ± 25.3 months and was the only non-atherosclerotic vascular event observed after FMD diagnosis.

ENDOTHELIAL FUNCTION IS ASSOCIATED WITH TRIPLE SIGNAL IN FIBROMUSCULAR DYSPLASIA

Objective: Triple signal (TS) is a subclinical lesion were found in the common carotid artery of individuals with renal fibromuscular dysplasia (FMD), However, the mechanisms underlying this alteration in FMD patients are still unknown and might involve endothelial and/or smooth muscle cell dysfunction. We aimed at investigated whether FMD or triple signal, is associated with systemic vascular dysfunction. Design and method: The MEDYA study is a case-control, cross-sectional study, enrolling 47 individuals with renal FMD,47 matched individuals with essential hypertension (HT) and 50 healthy controls (C). All individuals underwent an assessment of endothelium-dependent dilation (EDD) of the brachial artery by the flow-mediated dilation technique and endothelium-independent dilation (EID) by sublingual administration of glyceryl trinitrate 150 mcg. EDD and EID were allometrically corrected for baseline diameter. Triple signal score was also computed in the common carotid arteries bilaterally, based on B-mode and RF images. A cut-off of 8 was used to discriminate TS carriers. Results: FMD, but not HT, showed impaired EID in comparison to controls (p = 0.003). FMD (but not TS) was among the determinants of EID_corr in a multiple linear regression model (beta = −0.03, p = 0.005). TS prevalence (FMD 48.9%, HT 31.9%, C 16.0%) was higher in FMD than in C (p < 0.001), but tended to be increased in HT as well (p = 0.07). In a multiple logistic regression model adjusted for confounders, FMD (OR 4.54, CL95% 1.56–13.23) but not HT, was independently associated with TS. In the FMD subgroup, TS was associated with older age, higher peak shear stress and lower EDD. EDD was still reduced in FMD patients with TS after correction for confounders (1.14 ± 3.59 vs 3.55 ± 4.18, p = 0035). In the HT subgroup, TS was independently associated only with older age and hypercholesterolemia. Conclusions: FMD is characterized by impaired smooth muscle cell function and increased TS prevalence, subclinical alterations independent from each other. TS might have a different pathophysiological significance in FMD and HT. Indeed, among FMD patients TS is associated with impaired endothelial function. Conversely, in HT TS seems to be associated only with classical CV risk factors.

Echocardiographic assessment of left ventricular morphology and function in patients with fibromuscular dysplasia: the ARCADIA-POL study.

To provide a comprehensive assessment of left ventricle (LV) structure, and function and to detect alterations in cardiac properties in relationship to presence, subtypes and extent of fibromuscular dysplasia (FMD). We studied 144 patients with FMD. The control group consisted of 50 matched individuals. Office and ambulatory blood pressure levels were evaluated. Echocardiography was employed to assess: left ventricular mass index (LVMI), systolic function including speckle tracking echocardiography and diastolic function assessed by mitral flow and tissue Doppler imaging. There were no differences in LV morphology and function between patients with FMD and the control group. Among 128 patients with renal FMD, there were no differences in LVMI and LV systolic function between patients with unifocal and multifocal FMD. The patients with multifocal FMD were characterized by lower early diastolic velocity (e') as compared with unifocal FMD and control groups. However, in a multivariate regression model, e' was not independently correlated with FMD. There were no associations between echocardiographic indexes and vascular involvement of FMD. Also, there were no differences in LV morphology and function in patients with significant renal artery stenosis (RAS) compared with patients with history of significant RAS and patients with nonsignificant RAS. Our study in contrast to those with atherosclerotic RAS, did not show differences in LV morphology and function between FMD patients and matched controls. Although FMD can result in hypertension and serious vascular complications, there is no proof that it can alter LV regardless of FMD type and its extent.

FEASIBILITY OF ESTIMATING FIBROMUSCULAR DYSPLASIA PREVALENCE USING HEALTH ADMINISTRATIVE DATABASE

Objective: Fibro-muscular dysplasia (FMD) is a non-atherosclerotic and non-inflammatory vascular disease, occurring mainly in women aged 30–50 years. Its prevalence is not well-known and possibly underestimated due to asymptomatic forms. Our aim was to determine whether the French national summary discharge database could be used to estimate the prevalence of FMD. Design and method: Patients were selected by the first occurrence of the I773 ICD-10 code. This code was chosen after an exploratory analysis and advice from national hypertension specialists. In the French national summary discharge database system, all hospitalizations can be linked for a given patient. The zip code of residence was used for geographical analysis. We computed rates of prevalence by an indirect age- and sex-standardization. Results: Between 2008 and 2016, we identified 2798 patients (65.2% female; median age 55y IQR = [43.0–67.0]), for a total of 10835 stays (74.9% of patients had less than 2 stays) of which only 4061 contained the I773 code. No major change in annual incident cases was observed between 2008 to 2016: 317 (11.3%), 342 (12.2%), 292 (10.4%), 309 (11.0%), 299 (10.7%), 319 (11.4%), 294 (10.5%), 279 (9.97%) and 347 (12.4%), respectively. The most common associated codes were I10 (hypertension, 49.0%), I15.0 (vascular/renal hypertension, 19.7%) and E780 (essential hypercholesterolemia, 11.9%). Among all French hospitals, the largest number of patients was identified in the Paris University Hospitals, especially ESH excellence centers (15.7%) and 8 additional University Hospitals belong to the ’top 10’ recruiting centres. Using indirect standardization, we observed a geographical disparity with a low prevalence in the East/South-West part of France, which may indicate under-diagnosis of the disease and a very high unexplained prevalence in a single hospital.Conclusions: Both the stable estimate of yearly incident cases and demographic characteristics of the population study are consistent with the literature. Nevertheless, the observed geographical disparity suggests a diagnostic bias. We conclude that the use of the French national summary discharge database alone cannot provide a reliable estimation of the FMD prevalence. Both harmonization of diagnosis procedures and hospitalization coding could help identifying FMD patients in addition to existent multicentric registries.

Genomics of Fibromuscular Dysplasia.

Fibromuscular Dysplasia (FMD) is “an idiopathic, segmental, non-atherosclerotic and non-inflammatory disease of the musculature of arterial walls, leading to stenosis of small and medium-sized 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 locus 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.

Abstract 121: Anxiety and Depression in Patients With Fibromuscular Dysplasia: A Report From the US Registry for Fibromuscular Dysplasia

Introduction/Background: Fibromuscular dysplasia (FMD) is a non-inflammatory, non-atherosclerotic arterial disease that may result in arterial stenosis, dissection, aneurysm, and tortuosity. Anxiety (A) and depression (D) are prevalent in patients with rare and uncommon diseases compared to the general population; however, there are limited data on A and D in the FMD population. This study describes characteristics of FMD patients with and without A and/or D (A/D). Methods: Patients enrolled in the US Registry for FMD between 2009-2017 and had A/D information were analyzed (n=985). Diagnosis of A/D was ascertained from patient charts or self-reported via medical history questionnaires at time of registry enrollment. Demographics, family history, past medical history, presenting symptoms, and affected vascular beds were compared between patients with and without A/D. Results: A total of 351 (35.6%) had A/D. Of patients with A/D, 126 (35.9%) had both. Patients with A/D were more likely to have a family history of aneurysm (33.6% v. 23.7%, p=0.001) and stroke (53.6% v. 46.1%, p=0.03), and have a medical history of hemispheric TIA (15.5% v. 10.9%, p=0.04), subarachnoid hemorrhage (4.4% v. 1.8%, p=0.015) and smoking (43% v. 28%, p&lt;0.001). Patients with A/D were more likely to present at the time of diagnosis with headache (68.6% v. 53.8%, p&lt;0.001), pulsatile tinnitus (42.2% v. 34%, p=0.014), dizziness (45.3% v. 29.2%, p&lt;0.001), neck pain (40% v. 24.9%, p&lt;0.001) and carotid/vertebral arterial dissection (21.6% v. 14.7%, p=0.007). Patients with A/D were less likely to have renal artery FMD (58.4% v. 68.9%, p=0.002). No differences in the time between symptom onset and FMD diagnosis (2.7±6.2 v. 3.1±6.9 years, p=0.89) or number of vascular beds involved (1.9±1.1 v. 1.9±1.1, p=0.77) were seen between groups. Conclusions: More than 1/3 of patients in the FMD registry had A, D, or both, and these patients showed multiple differences compared to patients without A/D. More study is required to understand this relationship. Given the high prevalence of A/D in this population, FMD patients should be screened for the presence of A/D and offered appropriate treatment.

Abstract P509: Identification of Radial Vascular Wall Abnormalities by Very-high Frequency Ultrasound in Patients With Fibromuscular Dysplasia: The Fuchsia Study

Aim: This case-control study is aimed at identifying radial vascular wall abnormalities in patients with fibromuscular dysplasia (FMD). Methods: High-frequency ultrasound scans of the radial arteries and of FMD patients and healthy controls were obtained by Vevo MD (70 MHz probe, FUJIFILM, VisualSonics, Toronto, Canada). Radial wall showed in all individuals two echogenic interfaces: the 1 st ( lumen-media) and the 2 nd (media-adventitia). Intima-media (IMT), adventitia (AT), and global thickness (IMAT) were measured and wall cross-sectional area (WCSA) calculated. The disarray level of the two echogenic interfaces was assessed calculating the root mean square error (RMSE) between 20 gray-level profiles crossing the two interfaces and the profile obtained averaging them. For each echogenic interface, the RMSE was normalized for the maximum value of the corresponding mean profile (RMSE/mean). Results: 11 treated hypertensive female FMD patients and 8 healthy control women (C) were enrolled (age 52±5 vs 45±13 years, p=0.51; BMI 26±3 vs 23±3, p=0.12; mean BP 97±7 vs 85±10, p=0.01). Radial internal diameter was similar (1.938±0.432 vs 1.701±0.532 mm, p=0.21). IMT (0.166±0.037 vs 0.128±0.022 mm, p=0.03), AT (0.114±0.029 vs 0.083±0.019 mm, p=0.008) and IMAT (0.281±0.042 vs 0.211±0.027 mm, p=0.003) were higher in FMD. Wall/lumen ratio was similar and WCSA increased in FMD, calculated with either IMT or IMAT. The maximum values of 1 st (121±43 vs 157±22, p=0.09) and 2 nd interface 109 ±44 vs133±18, p=0.09) tended to be lower, whereas RMSE/mean was higher in FMD (1 st 1.31±0.24 vs 0.83±0.32, p=0.006; 2 nd 1.37±0.38 vs 0.94±0.32, p=0.03). The difference was attenuated for the 1 st but not for the 2 nd interface when considering age and mean BP as covariates (p=0.054 and p=0.016 respectively). Conclusions: Wall ultrastructure of radial arteries of hypertensive FMD patients showed eutrophic remodeling. Furthermore, a peculiar “blurred” pattern occurred, characterized of loss of echogenicity and inhomogeneity of the two echogenic layers, independent of age and mean BP.

Abstract P439: Fibromuscular Dysplasia Of The Iliac And Renal Arteries: A Rare Case Report And Literature Review

Background: Iliac arterial fibromuscular dysplasia (FMD) is an orphan type of FMD, a non-atherosclerotic non-inflammatory arteriopathy predominantly among women aging from 20 to 60. The demographic, clinical features and therapeutic algorithm of iliac arterial FMD have not been precisely described. Patient Concerns: A 31-year-old Chinese male was referred for 3-month-ago onset hypertension, low serum potassium, and small-sized right kidney with normal renal artery under ultrasound examination. Spirolactone was poorly effective in this patient. Diagnosis: Contrast-enhanced computed tomographic angiography (CTA) and three-dimensional reconstruction of the whole aorta discovered an aneurysm from right common iliac artery (CIA) to the internal iliac artery, consistent with left CIA dissection and a remarkable right renal artery aneurysm before a stenosis, which was then confirmed through digital subtraction angiography. Intervention: Percutaneous transluminal angioplasty (PTA) of right renal artery was operated and a stent was deployed in left CIA. Outcome: This patient was normotensive, asymptomatic and free from recurrence without any antihypertensive agents at an 8-month follow-up. Conclusions: A total of 111 iliac arterial FMD cases (female, 84.7%; median age, 52±12.8 years) have been reported. Asymptomatic condition (49.5%) and claudication (40.5%) consist the majority of clinical presentations. Bruit (64.9%) and pulse deficits (39.4%) are the most popular signs. External iliac artery involved is approximate threefold of common and internal iliac arteries, usually accompanied with renal artery (71.2%, presenting hypertension) or carotid artery involvement (50.5%). A system screening among iliac or renal arterial FMD patients is therefore suggested with CTA from neck to pelvis and MRA in head. Dissection accounts for 15.3% cases, usually presenting ischemia symptoms with an inclination to young males. Conservative medication is efficient among 61.3% patients and PTA was operated in 15 patients with satisfactory outcomes in 86.7%. Stenting is an optimal recommendation of iliac artery FMD with progressive dissection. PTA is the first choice of short-duration renovascular hypertension due to FMD especially in young patient.

Abstract 099: Prevalence of Headaches in Patients with Fibromuscular Dysplasia: A Report from the US Registry for FMD

Introduction: Fibromuscular dysplasia (FMD) is a polyvasculopathy that may result in aneurysm or dissection in affected arterial beds. A common symptom of FMD is headache (HA). The purpose of this study is to describe and compare characteristics of FMD patients with (w/HA) and without headaches (wo/HA) in the current US Registry for FMD. Method: Data regarding demographics, family history, medical history, and vascular beds affected in patients with FMD were collected from the US Registry for FMD between 2009 and 2016. Patients with complete HA data were included, and data were compared between patients w/HA and wo/HA as reported at time of registry enrollment. Results: Of the 1,433 patients in the registry, 1,251 (87.3%) had complete HA data. Most were female (94.1%), with a mean age of 56.0±12.4. A history of HA was reported in 844 (67.5%) patients and 54.2% reported a HA at least weekly. No difference in gender distribution was seen between HA groups. Patients w/HA were younger at the time of FMD diagnosis (50.6±11.8 years v 58.0±13.8 years, p&lt;0.001) and were less likely to have a history of HTN (66.8% v 74.8%, p=0.004), hyperlipidemia (36.9% v 47.2%, p=0.004), or renal failure (2.6% v 5.7%, p=0.009). Patients w/HA were more likely to have a history of aneurysm or dissection in the extracranial carotid, intracranial, or vertebral arteries (aneurysm: 13.0% v 7.2% p=0.003; dissection: 25.1% v 8.3%, p&lt;0.001). No differences in extracranial carotid, intracranial, or vertebral FMD involvement between patients w/ and w/o HA were seen when those with history of aneurysm or dissection of those arteries were excluded (71.2% v 66.8%, p=0.20). Headache patients more often reported a history of depression (25.1% v 16.5%, p=0.01) and anxiety (28.3% v 18.0%, p=0.003). Conclusion: More than half of FMD patients experience HAs, most on an at least weekly basis. FMD patients with HA tended to be younger, and more likely to have extracranial carotid, intracranial, or vertebral disease as well as aneurysm and dissection. Depression and anxiety was also more common in FMD patients with HA. Further research is needed to classify the types of headaches being experienced as well as effective management strategies.

FAMILY HISTORY OF ARTERIAL DISORDERS IN PATIENTS WITH SPONTANEOUS CORONARY ARTERY DISSECTION

Background: Spontaneous coronary dissection (SCAD) is an important cause of ACS in young women and is associated with fibromuscular dysplasia (FMD) in 45-72% of cases. ∼1/4 of FMD patients have a family history (FHx) of aneurysm, but FHx of arterial disorders among SCAD patients is not well

Fibromuscular dysplasia - results of a multicentre study in Flanders.

Fibromuscular dysplasia (FMD) is an idiopathic, non-inflammatory, non-atherosclerotic vascular disease, resulting in focal narrowing of small and medium-sized arteries. Systematic recording of clinical data in central databases as in the US and France provided new insights into FMD. The main objectives of this multicentre study were to explore the epidemiology, pattern of vascular involvement, clinical manifestations, and management of FMD patients in Flanders. Multicentre, retrospective registry of patients diagnosed with FMD based on medical imaging. Hundred-twenty-three FMD patients (83.7 % female) were included. Mean age at FMD diagnosis was 57.3 years (SD 15.8). More than half of patients (59.5 %) were hypertensive at the time of diagnosis. Neurological complaints such as headache (26.4 %) and dizziness (23.1 %) were also frequently reported. FMD was discovered incidentally in 10 patients (8.3 %). Nearly one quarter (22.8 %) of patients experienced a cerebrovascular event. Aneurysms were found in one-fifth (20.3 %) of patients and 11.4 % had an arterial dissection. FMD affected most frequently the renal (85.3 %), carotid (74.7 %), and vertebral (39.8 %) arteries. Renovascular FMD was more prevalent in men, whereas cerebrovascular FMD was more frequent in women. Multiple affected sites were documented in 25 of 61 (41.0 %) patients, having two or more vascular beds imaged. Digital subtraction angiography was most frequently used for detecting FMD. One third (32.9 %) of patients received an interventional treatment, mainly patients with renovascular FMD (32.8 % underwent percutaneous transluminal angioplasty) and patients with an intracranial carotid aneurysm (36.4 % were treated by means of coiling). Although differences existed, results of the Flemish registry were broadly in line with the US and French registries. Patient databases help to learn more about the natural history, progression, and management of FMD, based on real life clinical evidence.

PHACTR1 Is a Genetic Susceptibility Locus for Fibromuscular Dysplasia Supporting Its Complex Genetic Pattern of Inheritance.

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.

Diagnosed and living with fibromuscular dysplasia: A qualitative inquiry.

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.

Clinical Commentary on "My Life With Fibromuscular Dysplasia: A Sword of Damocles".

Reading the perspective written by Dr Young about her experiences with fibromuscular dysplasia (FMD) filled my mind with the faces of literally dozens of patients like her whom I have had the privilege to meet as they came to grips with their diagnosis of FMD and with what it would mean for them and their families. Dr Young’s experiences and observations, although clearly informed by her being an experienced physician, are nonetheless quite like most people who find themselves not only threatened by the seriousness of this diagnosis but isolated in a real way by the rarity of FMD, and the confusion the diagnosis can cause. There are 4 special challenges for us as we help our patients face rare, serious diseases. Dr Young describes them eloquently. One is the time that passed from the initial onset of her symptoms to a diagnosis. Second, she also shared the fright that comes from realizing that many of her physicians were …

OP.7C.04] GENETIC ASSOCIATION STUDY IDENTIFIES COMMON VARIATION IN PHACTR1 TO ASSOCIATE WITH FIBROMUSCULAR DYSPLASIA

Abstract Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to stenosis, dissection and aneurysm affecting mainly the renal and cerebrovascular arteries. FMD has higher prevalence in females (80-90%) and predisposes to hypertension and stroke but its pathophysiology is unclear. We performed a multistage genetic association study (1,154 patients and 3,895 controls) from five case-control cohorts. We investigated the association between rs9349379 in the phosphatase and actin regulator 1 gene (PHACTR1) and carotid traits by echo-tracking in healthy volunteers, the expression of PHACTR1 by genotypes in human fibroblasts, protein staining pattern in human carotids, and vasculature development after Phactr1 knockdown in zebrafish. We show significant and replicated association of rs9349379, a common variant (effect allele frequency 0.60) in PHACTR1 with FMD (OR = 1.39, P = 7.4 × 10-10). rs9349379 associates with greater intima media thickness (P = 3.9 × 10-5) and wall to lumen ratio (P = 0.001), previously reported to be increased in FMD patients. Immunohistochemistry detected PHACTR1 in endothelium and smooth muscle cells of FMD and normal carotid arteries. We also found higher expression of PHACTR1 in FMD risk allele carriers (N = 86, P = 0.003). Phactr1 knockdown in zebrafish resulted in dilated vessels indicating impaired vascular development. We report the first susceptibility locus for FMD in the largest genetic association study conducted so far. Our data reveal a common genetic variant in PHACTR1, previously reported to associate with coronary artery disease, migraine, and cervical artery dissection supporting a complex genetic pattern of inheritance and indices of shared pathophysiology between FMD and other cardiovascular and neuromuscular diseases.

My Life With Fibromuscular Dysplasia: A Sword of Damocles.

My story begins in December 2007 when I visited my general practitioner (GP) for one of the first times since the birth of my third son in 1992. At the time, I worked as a GP myself and had been at the same busy Scottish practice since qualifying in 1986. I also led an active life outside of work, ran a youth group at church and enjoyed regular gym workouts and several sports. Being a mother of 3 boys kept me constantly on the go! I had never suffered any major illness, was on no medication, and had no obvious risk factors for heart or vascular disease. Having suffered 3 months of morning headaches and some elevated blood pressure readings (around 170/100) taken at my office, I felt I should seek medical advice. I was also experiencing extra heart beats (ventricular ectopics) fairly frequently and some mild left-sided upper back discomfort. Some basic blood tests were done, along with another blood pressure reading, and I was referred to a cardiologist. The cardiologist performed an EKG, which showed normal patterns other than frequent ventricular ectopics. My blood pressure readings were mildly elevated at 158/100 and later 142/95. No heart murmurs were found, and an echocardiogram was normal. An appointment was arranged for me to have ambulatory blood pressure recordings to see how my blood pressure behaved over a 24-hour period, and an initial diagnosis of white coat hypertension was made. This is defined as blood pressure that is raised when measured by medical professionals but normal outside the doctor’s office. My ambulatory blood pressure recordings were within normal limits, and no further action was taken. My morning headaches and occasional palpitations continued, but I was able to manage the headaches with simple analgesics. In September 2009, at age 49, I suffered …

Incidence and risk factors for restenosis, and its impact on blood pressure control after percutaneous transluminal renal angioplasty in hypertensive patients with renal artery stenosis.

Percutaneous transluminal renal angioplasty (PTA) is one of the standard treatments for renal artery stenosis (RAS). We investigated the frequency and risk factors for restenosis, and its impact on blood pressure (BP) control. A total of 175 hypertensive patients with RAS [mean age 60 years; 34% women; 30.3% fibromuscular dysplasia (FMD)] with 207 treated renal arteries were included and followed for more than 1 year without reangioplasty. Diagnosis of restenosis was based on duplex ultrasonographic findings, and data including BP and antihypertensive medication were collected consecutively. During follow-up (mean, 5.1 years), 56 patients (32.0%) developed restenosis. In multivariate Cox regression analysis, FMD was an independent predictor of restenosis (hazard ratio 2.65, P < 0.05). When divided into two groups based on FMD or atherosclerotic RAS (ARAS), the presence of previous cardiovascular disease (hazard ratio 2.84) as well as severe RAS (≥90%) (hazard ratio 3.95) in ARAS were independent predictors of restenosis (P < 0.05, respectively). At 1 year after PTA, 35 patients (20.0%) had developed restenosis. When divided into four groups on the basis of FMD or ARAS, and the absence/presence of restenosis at 1 year, the number of antihypertensive drugs was significantly lower in both FMD and ARAS patients without restenosis (P < 0.01, respectively); however, a significant difference in decrease in SBP (-31 ± 19 vs. -12 ± 25 mmHg, P < 0.05) as well as cure of hypertension (36.4 vs. 5.0%, P < 0.01) between the absence/presence of restenosis was found only in FMD patients. The frequency of restenosis after renal PTA is significant, and the presence of restenosis diminishes the benefit of its treatment, especially for FMD.

Abstract 145: Differences in Presenting Symptoms of Fibromuscular Dysplasia Patients With Family History of Fibromuscular Dysplasia, Arterial Aneurysm, Dissection, or Sudden Death: A Report from the United States Registry for Fibromuscular Dysplasia

Introduction: Fibromuscular dysplasia (FMD) is a non-atherosclerotic, non-inflammatory vascular disorder which may lead to stenosis, tortuosity, dissection, or aneurysm in any arterial bed. Some affected patients have a family history of FMD, arterial aneurysm (AA), arterial dissection (AD) or sudden death (SD), supporting a genetic predisposition. The clinical characteristics of this patient population have not been described. We hypothesized that patients with a family history of FMD, AA, AD, or SD would present differently than those without. Methods: By July 2014, of 880 patients enrolled in the United States Registry for FMD, 295 had a family history of FMD, AA, AD, or SD. These patients were compared to those without family history, analyzing demographics, symptoms at time of diagnosis, and vascular bed involvement. Student’s t-tests and Fisher’s exact tests were used to analyze continuous and categorical variables, respectively. Results: Patients with a family history of FMD, AA, AD, or SD were younger at diagnosis and more likely to experience CNS symptoms (headache, tinnitus, neck pain), post-prandial abdominal pain, as well as stroke and TIA at time of diagnosis. They also exhibited a trend toward more frequent carotid dissection (Table 1). Conclusions: Patients with a family history of FMD, arterial aneurysm (AA), dissection (AD), or sudden death (SD) more commonly had extracranial arterial bed complications, and experienced symptoms related to this vascular territory at time of diagnosis. These results suggest that FMD may present differently in those with this family history.

Abstract 18: Defining Clinical Presentation, Imaging Findings, and Management of Intracranial Fibromuscular Dysplasia: a Single Center Experience

Introduction: Intracranial (IC) artery involvement in fibromuscular dysplasia (FMD) may manifest as stenosis, dissection, or cerebral aneurysm. We sought to identify clinical, imaging, and treatment characteristics of FMD patients with IC manifestations. Methods: Analysis of prospectively collected data from a single center of the US FMD patient registry with additional medical record and imaging review. Patients were consented for enrollment if FMD was confirmed by imaging in at least one vascular territory. Results: From 2/2/2009-7/10/2015, 474 FMD patients were enrolled in the registry. Of the 421 patients with IC arterial imaging, 52 (12.4%) had IC FMD, with catheter angiography available in 29 (55.8%) patients. Median age of initial FMD symptoms was 47 years (IQR 38 - 55) and 51 patients were female. Concomitant extracranial (EC) carotid FMD was present in 92.3%, vertebral FMD in 48.9%, and renal FMD in 50.0%. Among 52 patients with IC FMD, 41 (78.8%) had IC aneurysm (9.7% of entire cohort with IC imaging), 7 (13.5%) had IC dissection, 6 (11.5%) had focal IC stenosis, and 2 (3.8%) had multifocal IC FMD. Fifteen patients with IC FMD (28.8%) were symptomatic (9 TIA/ischemic stroke, 2 hemorrhagic stroke, 4 isolated cranial neuropathy). Among patients with IC FMD, 22 (42.3%) required intervention. Treatment included EC-IC carotid artery bypass in 2 patients, aneurysm coiling in 13, aneurysm clipping in 9, and IC stenosis stenting in 1 patient. At the time of last follow-up, 47 patients (90.4%) were treated with an anti- platelet agent. Conclusion: In a single center cohort, 12.4% patients with FMD had IC involvement. Arterial aneurysm was the most common manifestation followed by dissection and stenosis. Aneurysm was present in 9.7% of patients who underwent IC imaging, highlighting the importance of comprehensive vascular assessment of patients with FMD.

CO-43: Genetic study identifies common variation in phactr1 to associate with fibromuscular dysplasia

Background Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to arterial stenosis, aneurysm and dissection, mainly in renal and carotid artery. FMD has higher prevalence in females (80-90%) and is associated with hypertension and stroke. The pathophysiology of FMD is unclear and a genetic origin is suspected. Methods We performed a genetic association study in European ancestry individuals. The discovery included 249 cases and 689 controls, in which we analyzed 25,606 common variants (MAF>0.05) using an exome-chip array. Results We followed up 13 loci ( p −4 ) in 393 cases and 2537 controls and replicated a signal on Chr6. Three additional studies (combined n cases = 512, n controls = 669) confirmed this association, with an overall OR of 1.39, ( p = 7.4×10 −10 , n all cases = 1154, n all controls = 3895). The FMD risk variant is intronic to the phosphatase and actin regulator 1 gene (PHACTR1), involved in angiogenesis and cell migration. PHACTR1 is a risk locus for coronary artery disease, migraine, and cervical artery dissection, which may occur in FMD. We found a significant association between the risk allele and higher central pulse pressure ( p =0.0009), increased intima media thickness ( p =0.001) and wall cross-sectional area ( p =0.003) of carotids assessed by echotracking in 3800 population-based individuals. RNA expression of PHACTR1 in primary cultured human fibroblasts is 1.7 fold higher in FMD patients ( n =20, matched to 20 controls) and we showed that FMD risk allele is an eQTL for PHACTR1 in fibroblast of 57 FMD patients ( p =0.02). Finally, Phactr1 knockdown of zebrafish showed significantly dilated vessels ( p =0.003) indicating impaired development of vasculature. Conclusions Here we report the first risk locus for FMD with the largest genetic association study conducted so far. Our data reveal a common genetic variant at PHACTR1 providing indices of shared pathophysiology between FMD and other cardiovascular and neurovascular diseases.