Fibromuscular Dysplasia Patients Research Articles

CLINICAL CHARACTERISTICS OF PATIENTS WITH FIBROMUSCULAR DYSPLASIA WITH AND WITHOUT SPONTANEOUS CERVICAL ARTERY DISSECTION IN THE ARCADIA-POL STUDY

Objective: Fibromuscular dysplasia (FMD) is idiopathic, segmental, non-inflammatory, non-atherosclerotic disease affecting small and medium-sized arteries. FMD causes artery stenosis, although it may also lead to aneurysm, dissection, or arterial tortuosity. The aim of the study was to evaluate clinical characteristics of patients with spontaneous cervical artery dissection (SCeAD) and to assess prevalence of SCeAD among patients with FMD. Design and method: The ARCADIA-Pol is an ongoing study, initiated in 2015 at the Department of Hypertension, National Institute of Cardiology in Warsaw, Poland. Patients enrolled in the study met the inclusion criteria: presence or suspicion of FMD and/or radiologically documented episode of spontaneous dissection of any artery. Each patient underwent: clinical and 24h ambulatory blood pressure monitoring, biochemical tests, echocardiography, US Doppler of renal and carotid arteries and whole body angio-CT. We present data of 435 currently enrolled patients. Results: Among 435 patients included in the analysis SCeAD was confirmed in 77 subjects, most often in internal carotid arteries (68.8%). Mean age was 43,9 ± 9,6 years, majority of patients were women (64.9%). Hypertension (HT) was present in 59.7% patients, hypercholesterolemia in 44,2%. Among 77 subjects with SCeAD, the presence of typical FMD changes was confirmed in 35.1% cases. Patients with SCeAD and FMD were older and more often female as compared to those with SCeAD and without FMD. There were no differences in biochemical parameters or target organ damage parameters between SCeAD patients with and without FMD. Among 281 subjects with FMD, an episode of SCeAD was documented in 9.6% patients. Patients with FMD and SCeAD less often had HT. Women with FMD and SCeAD had more often a history of contraceptive pills use than those without SCeAD. No other differences were found between compared groups. Conclusions: FMD changes often coexist in patients with SCeAD (35.1%). In FMD patients complication of SCeAD occur relatively often (9.6%), which leads to conclusion that FMD is generalized arteriopathy. It is recommended to perform radiological screening in FMD patients to look for arterial complications in other vascular beds.

THE RISKS AND BENEFITS OF RENAL ARTERY STENTING IN FIBROMUSCULAR DYSPLASIA. LESSONS FROM ARCADIA-POL STUDY

Objective: Percutaneous transluminal angioplasty (PTA) is the recommended revascularization strategy in patients with renal artery stenosis (RAS) caused by fibromuscular dysplasia (FMD), limiting stenting to complications management. However this recommendation is based on cases reports and small series. The main aim of the study was to retrospectively analyze immediate and long-term results of renal stenting and PTA in FMD patients. The second aim was to evaluate the results of stenting as support of renal artery aneurysm (RAA) closure. Design and method: The study group consisted of 58 patients percutaneously treated due to significant RAS (70 arteries) and 9 patients (10 RAAs) with a history of stent implantation before aneurysm embolization, derived from 343 ARCADIA-POL registry patients. PTA was performed as initial treatment in 61 arteries (PTA-group), whereas primary stenting was done in 9 arteries (STENT-group). Stent-related complications(SRC) were defined as: in-stent restenosis (>50%) or occlusion (ISR/O); stent fracture; stent underexpansion (SU) or migration. Results: In PTA-group, the first restenosis rate was 50.8%. Subsequently, 22 arteries underwent a second procedure: re-PTA(12 arteries) or stent implantation(10 arteries) . The incidence of recurrent restenosis after re-PTA was 41.7%. In the 10 arteries initially treated with PTA that underwent stenting for restenosis, complications occurred in 7 of them (70%), including 2 SUs and 5 ISR/Os . In STENT-group, SU occurred in one case (11.1%) and in-stent restenosis in 33.3% (3 of 9 stents). In combined analysis, SRC occurred following 11/19 stenting procedures (57.9%) including 3 periprocedural (SUs) and 8 late complications (ISR/Os). Finally, despite several subsequent revascularization attempts, 4 of 19 (21%) stented arteries were totally occluded and one remained significantly stenosed at follow-up imaging (Figure). In contrast to FMD-RAS procedures, there was only one intraprocedural complication (partial stent migration) and no late SRC in RAA patients. Conclusions: Renal artery stenting in FMD provides modest benefit in terms of restenosis prevention but poses high risk of immediate and late complications, including stent occlusion. Our study supports recommendations limiting stenting to the management of complications. In contrast, renal artery stenting in FMD RAA closure is associated with favorable long-term outcomes.

A Retrospective Cohort Study of Cerebrovascular Fibromuscular Dysplasia

Fibromuscular dysplasia (FMD) is a rare vasculopathy for which limited data are available particularly from Europe. Our aim was to study the clinical characteristics of a regional cohort of carotid fibromuscular dysplasia patients to assess their clinical outcomes and the rate of vascular complications. A retrospective cohort study of all cases of carotid/cerebrovascular FMD presenting to our regional vascular service (catchment population approximately 2 million), between 1998 and 2020. Imaging reports and patient case notes were screened using the keywords "FMD", "Fibromuscular Dysplasia", and "carotid". From case-note and imaging review, all relevant clinical data were extracted and the anatomical extent of vascular disease recorded. Eighty six patients with a diagnosis of cerebrovascular fibromuscular dysplasia were identified on imaging (31 computed tomography angiography, 46 magnetic resonance angiography, and 9 digital subtraction angiography) by a neurovascular radiologist. The mean age was 64years, 78 (90%) patients were female, and 45/59 (75%) were Caucasian. Presenting clinical syndromes were Stroke/transient ischemic attack in 54 (63%) patients, symptomatic intracranial aneurysm in 6 (10%), and other neurological symptoms (headache/migraine, tinnitus) in 14 (16%), with 11 (13%) presenting incidentally. Six patients (7%) had a positive family history of FMD (2 patients) or other cerebrovascular event (4 patients: carotid dissection, intracerebral bleed, or stroke). Eight patients (9%) had a known or suspected hereditary connective tissue disorder (2 Ehlers-Danlos syndrome). Involved vessels were as follows: Carotid (mainly extracranial) in 79 (92%), vertebral 19 (22%), and a combination of these in 15 (17%) patients. Fifty eight (67%) patients had bilateral disease. Cerebrovascular complications were observed in 35 (41%) patients as follows: carotid dissection 11 (23%), carotid stenosis or occlusion 8 (9%), carotid aneurysm 8 (9%), cerebral aneurysm 9 (11%), vertebral aneurysm/dissection 2 (2%), and carotid-cavernous fistula 2 (2%). Of the 22 patients who had extracranial imaging, 14 (60%) had FMD affecting other beds-renal artery in 8 (36%) patients, other visceral arteries in 4 (18%), and aorta in 2 (9%). In addition, 4 (18%) patients had aneurysm or dissection affecting renal, splenic, and lower limb arteries. Overall, 67 (80%) patients had FMD affecting more than 1 vessel and 50 (58%) had multisite FMD (>/=2 vascular beds involved). Fifty nine (68%) patients were managed conservatively on close surveillance. Nineteen (21%) patients required carotid/cerebrovascular intervention and 9 (10%) required vascular intervention at other sites. Recurrent cerebrovascular events (stroke/transient ischemic attack, symptomatic Berry aneurysm) were seen in 20 (23%) patients. Overall mortality was 7% over a median follow-up period of 47months. Carotid FMD patients have a high rate of multisite involvement, extracerebral vascular complications, and evidence of hereditary vasculopathy, requiring careful screening and surveillance.

S-22-4: GENOME WIDE ASSOCIATION STUDY OF FIBROMUSCULAR DYSPLASIA REVEALS MECHANISTIC LINKS WITH BLOOD PRESSURE REGULATION AND OTHER VASCULAR DISEASES

Introduction: Fibromuscular dysplasia (FMD) is a non-atherosclerotic arteriopathy of unknown etiology, afflicting mostly middle-aged women. It is characterized by stenotic lesions of the vascular wall in middle-size arteries, sometimes associated with dissection, aneurysm or tortuosity. Renovascular hypertension is a major presentation of FMD and 50–85% of FMD patients are hypertensive. Methods & Results: We report results from the first genome-wide association meta-analysis of six studies including 1556 FMD cases and 7100 controls. We identified four robustly associated loci (PHACTR1, LRP1, ATP2B1, and LIMA1). Using colocalization and transcriptome-wide association analysis with arterial expression datasets, we found PHACTR1, LRP1 and ATP2B1 as target genes at FMD loci and identified one additional locus (SLC24A3). We analysed chromatin accessibility in artery-derived primary cells and found that FMD associated variants were located in arterial specific regulatory elements active in smooth muscle cells. Target genes were broadly involved in mechanisms related to actin cytoskeleton and intracellular calcium homeostasis, central to vascular contraction. All FMD loci were also associated to at least one blood pressure trait. Colocalization analysis supported the same genetic variants to cause association to FMD and systolic blood pressure at PHACTR1, ATP2B1 and LIMA1 loci, and for FMD and pulse pressure at PHACTR1, LRP1 and ATP2B1 loci. Using genome-wide genetic correlation, we found a significant association between FMD and blood pressure. Mendelian Randomization analysis supported genetically determined systolic blood pressure to significantly increase the risk of FMD. However, we confirmed using adjusted and stratified analyses that hypertension status alone was not driving the association with FMD at top loci. We also report an important genetic overlap of FMD with migraine, intracranial aneurysm, coronary artery disease and myocardial infarction. Conclusion: Our study confirms FMD as a polygenic disease following a complex genetic mode of inheritance. We find that FMD shares an important part of its genetic basis with blood pressure regulation, involving in particular several genes related to intracellular calcium homeostasis and vascular smooth muscle contraction. These results are consistent with previous studies showing systemic alterations in vascular contraction in FMD patients, even outside of affected arterial beds. While the mechanisms through which FMD may cause renovascular hypertension are well known, further studies will be required to determine how alterations in vascular contraction may lead to the arterial remodeling observed in FMD.

CLINICAL CHARACTERISTICS OF PATIENTS WITH FIBROMUSCULAR DYSPLASIA ASSOCIATED WITH ANEURYSMS (ARCADIA-POL STUDY)

Objective: To assess the prevalence and distribution of aneurysms among patients with fibromuscular dysplasia (FMD) and to compare clinical characteristics of FMD patients with and without aneurysms. Design and method: Out of 435 patients enrolled into ongoing ARCADIA-POL study FMD was confirmed in 281 cases. A standardized FMD data form was used for data collection. All patients underwent detailed clinical evaluation including ABPM, biochemical evaluation, biobanking and imaging, duplex Doppler of carotid and abdominal arteries and whole body angio-CT. Results: Among 281 patients with FMD enrolled into study the presence of at least one aneurysm was documented in 92 patients. Mean age was 52,3 ± 12,0 years. Most of patients were women (91.3%). Hypertension was found in 81.4% and hyperlipidemia in 51.2% patients. Almost one third (27.3%) of subjects were active smokers during time of admission. History of use of contraceptive pills was reported by 20.7% women. Among patients with aneurysms FMD lesions were classified as multifocal in 89.1% patients. Single-site FMD was observed in 66.3% patients. The most frequent localization of FMD lesions were renal, cervical and intracranial arteries. In almost half of patients (45.7%) with FMD and aneurysm the presence of two or more aneurysms was confirmed, giving the total number of 124 aneurysms. Aneurysms were most frequently documented in renal arteries (14.6%), intracranial arteries (11.7%), splenic artery (10.7%) and cervical arteries (3.9%). Among 70 patients with newly diagnosed aneurysms 72.9% subjects were qualified for interventional treatment. Two out of 92 patients with FMD and aneurysm presented severe complications caused by ruptured aneurysm. FMD patients with aneurysms as compared to those without aneurysms were more often female, were older, had more often history of contraceptive use and hyperlipidemia. There were no significant differences in other clinical parameters between analysed groups. Conclusions: Among FMD patients we confirmed high prevalence of aneurysms (32.7%). This supports the concept that FMD is generalized arteriopathy and all patients should be systematically evaluated and if needed qualified for interventional treatment.

A STUDY OF SOME GENETIC FACTORS FOR FIBROMUSCULAR DYSPLASIA

Objective: Fibromuscular dysplasia (FMD) is relatively rare idiopathic nonatherosclerotic noninfectious disease of the layers of the elastic arteries. Up to the current knowledge, there are not genes/mutations, which can be unequivocally associated with the disease. Eastern Europeans are under-studied and under-represented in the studies in the field. We started to study this group from the database of the Molecular Medicine center Sofia, BG and tested it to rs9349379 in gene PHACTR1, which showed some association in other studies, but is also associated with coronary artery disease (CAD) and arterial hypertension (AH). Design and method: Eleven patients with angiographically proven FMD, 108 patients with AH, 89 patients with angiographically proven CAD and 112 healthy population controls were included. We used TaqManTM technology (Applied Biosystems) for the real time PCR sequencing of the rs9349379 in gene PHACTR1. SPSS 19, p = 0.05, CI 95% was used for the statistics. Results: The allelic and genotypic frequencies of rs9349379 in Bulgarians (Eastern European) do not differ from the European. The frequency of the A allele was higher (without reaching statistical significance) in FMD patients. This is in accordance with the results from literature. There was also a tendency (without reaching statistical significance) for association of G allele with CAD. Conclusions: We were not able to prove a significant association between rs9349379 in gene PHACTR1 and FMD. However, the group of FMD patients is very small. Maybe FMD is not the perfect “candidate’’ disease for genetic studies for the very few familial cases, multiple genes overlapping in common diseases, varieties in the clinical presentation. Nonetheless, this can be the basis for further research and attempts to study the disease should continue. The study is conducted with Contract D-132/24.06.2020 from the proposal Grant 2020 of Medical University - Sofia

RENAL EXTRACTION EFFICIENCY FOR PAH IS COMPARABLE IN ESSENTIAL HYPERTENSION AND RENAL FIBROMUSCULAR DYSPLASIA

Objective: Previously, we demonstrated that intrarenal blood flow in most patients with renal fibromuscular dysplasia (FMD) does not differ from that of patients with essential hypertension and patent renal arteries. In the present study, we assessed whether the renal extraction of para-aminohippurate (PAH) as a marker of tubular function was affected by the presence of FMD. Design and method: We studied 136 hypertensive patients who were scheduled for diagnostic renal angiography with arterial and renal venous blood sampling. In all of them, a continuous infusion of PAH was started two hours before the procedure to obtain steady state plasma levels at the time of sampling. Blood was collected simultaneously from the arterial and venous catheter prior to the administration of contrast material. Mean renal blood flow (MRBF) was measured simultaneously using the 133Xenon washout technique. Results: Altogether, 21 patients were diagnosed with renal FMD, 45 with atherosclerotic renal artery stenosis (ARAS) and 70 with essential hypertension (EH). Extraction ratio of PAH (ER-PAH) in the patients with renal FMD averaged 72 + 4% which did not differ significantly from that in patients with EH (74 + 3%). MBRF did not differ between these two groups either. Per contra, in patients with ARAS both MRBF and ER-PAH were significantly lower as compared to the other groups. ER-PAH in FMD patients was not modified by age, sex, height of blood pressure or MBRF. Conclusions: The ER of PAH in patients with renal FMD does not differ from that in EH. Thus, both flow and tubular function are well preserved in FMD when is EH is taken as control. This suggests that the pathophysiological mechanism which contribute to hypertension in FMD are different from those which are active in ARAS.

VERTEBRAL ARTERY DISSECTION AND INCIDENTAL FINDING OF FIBROMUSCULAR DYSPLASIA: A CASE REPORT

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Fibromuscular Dysplasia (FMD) is a nonatherosclerotic, noninflammatory vascular disease. It is a rare condition that occurs more frequently in middle-aged Caucasian women. Its prevalence is not well known. We present a case of FMD in a man with stroke secondary to dissection of the vertebral artery. Increased reporting of FMD cases in recent studies raises concern about under-diagnosis of the condition. CASE PRESENTATION: A 61-year-old Caucasian male with a past medical history of hypertension presented with dysarthria, extreme disequilibrium, and left-sided headache. The patient had normal strength and sensation in all four extremities and negative cerebellar testing on physical exam. He also had a productive cough upon presentation. Computed tomography (CT) head revealed a 3 cm acute non-hemorrhagic left cerebellar infarction. Computed tomography angiography (CTA) Head and Neck showed evidence of vertebral artery dissection on the left side, including the origin of the left posterior inferior cerebellar artery (PICA). The patient had a trial of cerebral angiogram for the vertebral artery dissection, which showed incidental evidence of FMD in the femoral arteries bilaterally. The patient also had vasospasm with the angiography that resolved post-injection of five milligrams of Verapamil intraarterial, and the procedure was discontinued. He was discharged on aspirin and statin, and anticoagulation starting in two weeks. DISCUSSION: There is no clear consensus on the prevalence of FMD in the general population [1]. However, many studies have assessed the prevalence in different patient populations to be around 3%-4% [2]. The United States Registry of FMD revealed the incidence of dissection of the carotid artery in the FMD patient population to be about 75% [1]. The incidence of dissection of the vertebral artery in patients diagnosed with FMD is much lower, about 17% [1]. The most common manifestations of cervical artery dissection (CeAD) are cerebral infarction and transient ischemic attack (TIA). In FMD patients with ischemic stroke or TIA secondary to CeAD, general guidelines for thrombolysis and thrombectomy should be followed. Most recent guidelines recommend treatment with either an anticoagulant or an antiplatelet agent for at least 3–6 months [3]. Endovascular or surgical repairs are mainly reserved for patients with recurrent ischemia despite initial antithrombotic therapy. CONCLUSIONS: FMD is an intriguing vascular disorder with unclear underlying etiology, challenging manifestations, and complex clinical diagnosis. Increased reporting of FMD cases in recent literature raises concern for underdiagnosis. Furthermore, in our case, FMD was incidentally discovered during a diagnostic procedure to evaluate the vertebral artery dissection. Therefore, we recommend further screening of any patient who presents with cephalo-cervical dissection or aneurysm for underlying FMD. REFERENCE #1: Olin, J.W., Froehlich, J., Gu, X., et al. 2012, "The United States Registry for Fibromuscular Dysplasia: results in the first 447 patients", Circulation, vol. 125, no. 25, pp. 3182-3190. REFERENCE #2: Hendricks, N.J., Matsumoto, A.H., Angle, J.F., et al. 2014, "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", Vascular medicine (London, England), vol. 19, no. 5, pp. 363-367. REFERENCE #3: Powers, W.J., Rabinstein, A.A., Ackerson, et al. "2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association", Stroke, vol. 49, no. 3, pp. e46-e110. DISCLOSURES: No relevant relationships by Elizabeth Mause, source=Web Response No relevant relationships by Mohammad Selim, source=Web Response

Abstract 127: Aspirin Resistant Biomechanical Platelet Activation In Fibromuscular Dysplasia: Novel Mechanisms Of Platelet Activation & Stroke

Background: Fibromuscular dysplasia (FMD) is a non-atherosclerotic, non-inflammatory disorder characterized by abnormal arterial morphology and turbulent blood flow. In regions of disturbed blood flow, circulating platelets may become activated. Cerebrovascular FMD is common and increases the risk of stroke in affected patients. Most FMD patients are treated with antiplatelet agents, however these medications target biochemical and not biomechanical pathways of platelet activation. Methods: Thrombotic outcomes were determined by multivariate regression analysis of 105,887 patients with FMD. Platelets were isolated from humans and activation was assessed by FACS and aggregometry following exposure to ex vivo steady laminar and disturbed flow (SF and DF, respectively) conditions using a cone and flow system. Single-cell phenotyping of control and FMD platelets with transcriptomics (RNAseq) and proteomics were performed. Cellular bioenergetics were evaluated by real-time metabolic analyses. Results: In patients with FMD, long-term aspirin therapy is paradoxically an independent risk factor for acute ischemic stroke (OR 1.64, 95% CI 1.29-1.94) but seems to protect against acute hemorrhagic stroke (OR 0.47, 95% CI 0.24-0.89). FMD platelet activation and aggregation were hyporeactive to biochemical agonists, but hyperreactive to ex vivo mechanical, disturbed blood flow conditions compared to age/gender-matched controls. FMD platelet activation in DF was attenuated by the mechanosensitive channel inhibitor, GsMTx4. Principle component analyses of RNAseq and proteomics identified markedly different platelet phenotypes with key differences in mitochondrial function/fission. Platelet imaging and metabolic analyses revealed abnormal mitochondrial architecture and respiration in FMD. Conclusions: FMD platelets display a divergent, dysregulated platelet phenotype with attenuated biochemical but augmented biomechanical activation. DF exposure of platelets in irregularly shaped arteries in FMD may alter the platelet phenotype and metabolic function. Therapeutics targeting biomechanical pathways of platelet activation may provide a superior mechanism for stroke prevention without unintended bleeding consequences.

Fibromuscular dysplasia: its various phenotypes in everyday practice in 2021.

Fibromuscular dysplasia (FMD) is a non-atherosclerotic vascular disease that may involve medium-sized muscular arteries throughout the body. The pathogenesis of FMD remains poorly understood, but a combination of genetic and environmental factors may be involved. The majority of FMD patients are women, but men may have a more progressive disease, especially when smoking. Besides the classical phenotype of string of beads or focal stenosis, arterial aneurysms, dissections, and tortuosity are frequent manifestations of the disease. However, the differential diagnosis of FMD is extensive and includes imaging artefacts as well as other arterial diseases. Diagnosis is based on CT-, MR-, or conventional catheter-based angiography during work-up of clinical manifestations, but clinically silent lesions may be found incidentally. Arterial hypertension and neurological symptoms are the most frequent clinical presentations, as renal and cerebrovascular arteries are the most commonly involved. However, involvement of most arteries throughout the body has been reported, resulting in a variety of clinical symptoms. The management of FMD depends on the vascular phenotype as well on the clinical picture. Ongoing FMD-related research will elaborate in depth the current progress in improved understandings of the disease's clinical manifestations, epidemiology, natural history and pathogenesis. This review is focused on the clinical management of adult FMD in daily practice.

High prevalence of extrarenal artery involvement in children with fibromuscular dysplasia - a single-center experience.

Although the clinical presentation of fibromuscular dysplasia (FMD) and its generalized character has been previously described in adults, data on FMD in children are limited. In this study, we aimed to assess visceral artery involvement in pediatric FMD patients with documented renal artery stenosis (RAS) and renovascular hypertension (RVH) in comparison with healthy individuals. We retrospectively analyzed the results of angiographic studies of 16 patients with a median age of 13.9 years (10 girls) in comparison with 16 age- and sex-matched healthy controls. Out of the 16 FMD patients, 10 (63%) had stenotic lesions identifiable only in renal arteries, whereas six (37%) had additional stenoses in other vascular beds - in the celiac trunk (four patients), superior mesenteric artery (four patients), inferior mesenteric artery (one patient), splenic artery (one patient), common hepatic artery (three patients), and abdominal aorta (one patient). The comparison of ostial diameters of vessels, in which no periostial narrowing, stents, or occlusions were found, revealed that patients with FMD had a significantly smaller diameter of the celiac trunk (P = 0.017), splenic arteries (P = 0.007), and common hepatic artery (P = 0.026) than their age- and sex-matched healthy peers. We found that 69% of children with RVH caused by FMD had clinically silent stenoses or tortuosity of visceral arteries. The results of our study suggest that pediatric FMD is a generalized arterial condition, and the patients may need screening for both renal as well as nonrenal manifestations of the disease.

Clinical Characteristics and Long-Term Outcomes of Endovascular Treatment of Renal Artery Fibromuscular Dysplasia With Branch Lesions

Renal artery fibromuscular dysplasia (FMD) can cause arterial stenosis, dissection, and aneurysm of renal arteries. This study aimed to analyze the clinical characteristics and evaluate the long-term outcomes of renal branch artery FMD in children and adults. Sixty-one patients with renal artery FMD underwent endovascular treatment, including 23 children and 38 adults. They were divided into two groups, the main artery FMD group (n = 40, with severe stenosis located in the main renal artery) and the branch artery FMD group (n = 21, with only the branch lesions in unilateral or bilateral branch artery). The clinical characteristics and long-term outcomes of these pediatric and adult patients were evaluated. The incidence of branch FMD was higher in children than in adults (P = 0.005). Thirteen children showed one or more branch artery involvements. Hypertension and headache were the most common symptoms. The branch aneurysm with coexisting stenosis was more common in patients with branch artery FMD. During the follow-up, blood pressure was normal in 8 patients and lowered in 11 patients in the branch FMD group. The patient’s glomerular filtration was increased in 61 patients (P < 0.001). Four-year freedom from reintervention in 21 branch artery FMD patients was lower than that in 40 main artery FMD patients (P < 0.05). A higher incidence of renal branch artery FMD was observed in children than in adults. Endovascular treatment with balloon angioplasty can be used for treating renal branch artery FMD.

Clinical characteristics and long-term outcomes of endovascular treatment of renal artery fibromuscular dysplasia with branch lesions.

Renal artery fibromuscular dysplasia (FMD) can cause arterial stenosis, dissection, and aneurysm of renal arteries. This study aimed to analyze the clinical characteristics and evaluate the long-term outcomes of renal branch artery FMD in children and adults. Sixty-one patients with renal artery FMD underwent endovascular treatment, including 23 children and 38 adults. They were divided into two groups, the main artery FMD group (n = 40, with severe stenosis located in the main renal artery) and the branch artery FMD group (n = 21, with only the branch lesions in unilateral or bilateral branch artery). The clinical characteristics and long-term outcomes of these pediatric and adult patients were evaluated. The incidence of branch FMD was higher in children than in adults (P = 0.005). Thirteen children showed one or more branch artery involvements. Hypertension and headache were the most common symptoms. The branch aneurysm with coexisting stenosis was more common in patients with branch artery FMD. During the follow-up, blood pressure was normal in 8 patients and lowered in 11 patients in the branch FMD group. The patient's glomerular filtration was increased in 61 patients (P < 0.001). Four-year freedom from reintervention in 21 branch artery FMD patients was lower than that in 40 main artery FMD patients (P < 0.05). A higher incidence of renal branch artery FMD was observed in children than in adults. Endovascular treatment with balloon angioplasty can be used for treating renal branch artery FMD.

GENETIC ASSOCIATION STUDIES OF FIBROMUSCULAR DYSPLASIA IDENTIFY NEW RISK LOCI AND SHARED GENETIC BASIS WITH MORE COMMON VASCULAR DISEASES

Abstract Objective: Fibromuscular dysplasia (FMD) is an arteriopathy that presents mainly by hypertension, stroke or dissection. Diagnosis is often made in middle-aged women with few cardiovascular risk factors. We aim at identifying common genetic variants associated to FMD. Design and method: We tested ∼6.5 million common genetic variants (MAF &gt; 0.01) in 1962 cases and 7100 controls from 6 studies using variants and gene-based association analyses. Participants were of European ancestry, with similar characteristics (91% multifocal, 88% women), diagnosis methods and inclusion/exclusion criteria. Transcriptome-wide association (TWAS), eQTL, gene expression by sex and colocalization analyses used expression data in arteries from GTEx and/or FMD patients and matched controls. Open chromatin regions were defined using ATAC-Seq on primary human fibroblasts, smooth muscle and endothelial cells. Genetic correlations were assessed using summary statistics from UKBiobank and/or published studies by linkage disequilibrium score regression and multi-trait-based conditional and joint analyses (mtCOJO). Results: We confirmed the previously identified PHACTR1 locus and identified three new loci (LRP1, ATP2B1, and LIMA1) associated with FMD. TWAS in arteries identified one additional locus (SLC24A3). Through integration of annotation datasets, we provided prioritization of variants and genes. These are consistently and specifically expressed in fibroblasts, smooth muscle cells, and arterial tissues. PHACTR1 and SLC24A3 showed sex differences in gene expressions consistent with the direction of effects of FMD risk alleles. FMD genes are involved in regulatory mechanisms related to actin cytoskeleton and intracellular calcium homeostasis, two mechanisms central to vascular contraction. We found significant genetic overlaps between FMD and blood pressure traits, for the associated loci and globally at the genome level, but demonstrated that hypertension is not driving the genetic association with FMD. We also found positive genetic correlations with migraine and intracranial aneurysm, and an inverse correlation with coronary artery disease, independently from the genetics of blood pressure. Conclusions: We describe robustly associated loci and genes with FMD and provide several new leads toward understanding biological mechanisms of stenosis and dissection in young women in the absence of atherosclerosis, which shares part of its genetic basis with more common cardiovascular and neurovascular diseases.

RARE LOSS-OF-FUNCTION MUTATIONS OF PTGIR IDENTIFIED IN FIBROMUSCULAR DYSPLASIA AND SPONTANEOUS CORONARY ARTERY DISSECTION

Objective: Fibromuscular Dysplasia (FMD) and Spontaneous Coronary Artery Dissection (SCAD) are related, non-atherosclerotic arterial diseases mainly affecting middle-aged women. Little is known about their physiopathological mechanisms. We aimed to identify rare genetic causes to elucidate molecular mechanisms implicated in FMD and SCAD. Design and method: We analyzed 29 exomes that included familial and sporadic FMD. Follow-up was conducted by targeted or Sanger sequencing (1,071 FMD and 365 SCAD patients) or lookups in exome (264 FMD) or genome sequences (488 SCAD), all independent and unrelated. We used TRAPD burden test to test for enrichment in patients compared to gnomAD controls. The biological effects of variants on receptor signaling and protein expression were characterized using transient overexpression in human cells. Results: We identified one rare loss-of-function variant (LoF) (MAFgnomAD = 0.000075) shared by two FMD sisters in the prostaglandin I2 receptor (hIP) gene (PTGIR), a key player in vascular remodeling. Follow-up in &gt;1,300 FMD patients revealed four additional LoF allele carriers and a putative enrichment in FMD (PTRAPD = 8 × 10-4), in addition to several rare missense variants. We confirmed the LoFs (Q163X and P17RfsX6) and one missense (L67P) to severely impair hIP function in vitro. Genetic analyses of PTGIR in SCAD revealed one patient who carries Q163X, one with L67P and one carrying a rare splicing mutation (c.768+1C&gt;G), but not a significant enrichment (PTRAPD = 0.12) in SCAD. Conclusions: Our study shows that rare genetic mutations in PTGIR are enriched among FMD patients and found in SCAD patients, suggesting a role for prostacyclin signaling in non-atherosclerotic stenosis and dissection.

Rare loss-of-function mutations of PTGIR identified in fibromuscular dysplasia and spontaneous coronary artery dissection

Fibromuscular Dysplasia (FMD) and Spontaneous Coronary Artery Dissection (SCAD) are related, non-atherosclerotic arterial diseases mainly affecting middle-aged women. Little is known about their physiopathological mechanisms. We aimed to identify rare genetic causes to elucidate molecular mechanisms implicated in FMD and SCAD. We analyzed 29 exomes that included familial and sporadic FMD. Follow-up was conducted by targeted or Sanger sequencing (1,071 FMD and 365 SCAD patients) or lookups in exome (264 FMD) or genome sequences (488 SCAD), all independent and unrelated. We used TRAPD burden test to test for enrichment in patients compared to gnomAD controls. The biological effects of variants on receptor signaling and protein expression were characterized using transient overexpression in human cells. We identified one rare loss-of-function variant (LoF) (MAFgnomAD = 0.000075) shared by two FMD sisters in the prostaglandin I2 receptor (hIP) gene (PTGIR), a key player in vascular remodeling. Follow-up in > 1,300 FMD patients revealed four additional LoF allele carriers and a putative enrichment in FMD (PTRAPD = 8 × 10-4), in addition to several rare missense variants. We confirmed the LoFs (Q163X and P17RfsX6) and one missense (L67P) to severely impair hIP function in vitro. Genetic analyses of PTGIR in SCAD revealed one patient who carries Q163X, one with L67P and one carrying a rare splicing mutation (c.768 + 1C > G), but not a significant enrichment (PTRAPD = 0.12) in SCAD. Our study shows that rare genetic mutations in PTGIR are enriched among FMD patients and found in SCAD patients, suggesting a role for prostacyclin signaling in non-atherosclerotic stenosis and dissection.

Spontaneous visceral artery dissections in otherwise normal arteries: Clinical features, management, and outcomes compared with fibromuscular dysplasia

ObjectiveVisceral artery dissection with otherwise normal-appearing arteries (VADNA), diagnosed on imaging and suggestive of segmental arterial mediolysis, is a poorly understood disease entity. Study objectives were to define the clinical features, management, and outcomes of patients with VADNA compared with patients with fibromuscular dysplasia (FMD). MethodsIn this single-center retrospective cohort study, consecutive patients with a diagnosis of VADNA or FMD evaluated in the Mayo Clinic Gonda Vascular Center (January 1, 2000-April 1, 2017) were identified. Patient demographics, symptom presentation, management, composite adverse arterial events (recurrent arterial dissection, stroke or transient ischemic attack, myocardial infarction, mesenteric or renal infarction, or need for revascularization), and overall survival were compared between VADNA and FMD patients. ResultsThere were 103 VADNA patients (age [mean ± standard deviation], 51.7 ± 11.0 years; 27.9% female) and 248 FMD controls (49.8 ± 8.9 years; 81.8% female) identified. The most common symptom for VADNA patients was abdominal or flank pain (80.6%). For FMD, chest pain, headache, and dizziness were more frequent presenting complaints. The median follow-up was longer for VADNA patients (42 months; interquartile range, 9-76 months) compared with FMD patients (19 months; interquartile range, 0.6-52 months; P < .001). During this time interval, there were twofold more composite arterial events in the VADNA group compared with the FMD group (17% vs 8.1%; P = .01). This difference was primarily driven by recurrent dissections. All-cause mortality was low and similar for both groups (3.8% vs 0.4%; P = .10). ConclusionsVADNA patients carry a higher risk of recurrent arterial events compared with those with FMD. This difference was primarily driven by recurrent dissections.

Systematic and Multidisciplinary Evaluation of Fibromuscular Dysplasia Patients Reveals High Prevalence of Previously Undetected Fibromuscular Dysplasia Lesions and Affects Clinical Decisions: The ARCADIA-POL Study.

Fibromuscular dysplasia (FMD), regarded as a generalized vascular disease, may affect all vascular beds and may result in arterial stenosis, occlusion, aneurysm, or dissection. It has been proposed to systematically evaluate all vascular beds in patients with FMD, regardless of initial FMD involvement. However, the impact of this approach on clinical decisions and on management is unknown. Within the prospective ARCADIA-POL study (Assessment of Renal and Cervical Artery Dysplasia-Poland), we evaluated 232 patients with FMD lesions confirmed in at least one vascular bed, out of 343 patients included in the registry. All patients underwent a detailed clinical evaluation including computed tomography angiography of intracranial and cervical arteries, as well as computed tomography angiography of the abdominal aorta, its branches, and upper and lower extremity arteries. In the study group, FMD lesions were most frequently found in renal arteries (87.5%). FMD was also found in cerebrovascular (24.6%), mesenteric (13.8%), and upper (3.0%) and lower extremity (9.9 %) arteries. Newly diagnosed FMD lesions were found in 34.1% of the patients, and previously undetected vascular complications were found in 25% of the patients. Among all FMD patients included in the study, one out of every 4 evaluated patients qualified for interventional treatment due to newly diagnosed FMD lesions or vascular complications. The ARCADIA-POL study shows for the first time that the systematic and multidisciplinary evaluation of patients with FMD based on a whole-body computed tomography angiography scan has an impact on their clinical management. This proved the necessity of the systematic evaluation of all vascular beds in patients with FMD, regardless of initial FMD involvement.

IMPACT OF SYSTEMATIC AND MULTIDISCIPLINARY EVALUATION OF FMD PATIENTS ON NUMBER OF NEWLY REVEALED FMD LESIONS AND COMPLICATIONS -POLISH ARCADIA-POL STUDY

Objective: Analysis of large cohorts of FMD patients allowed to reevaluate fibromuscular dysplasia (FMD) as a systemic arteriopathy. The aim of this analysis is to evaluate to what extent systematic and multidisciplinary evaluation of FMD patients results in novel FMD findings and reveals newly diagnosed vascular complications Design and method: Out of 272 patients enrolled into ARCADIA-POL study since January 2015 (instituted on the basis of Polish-French collaboration) we present 192 patients with confirmed FMD in at least one vascular bed.. All patients underwent detailed clinical evaluation including ABPM, biochemical evaluation, biobanking, duplex Doppler of carotid and abdominal arteries and whole body angio-CT. All patients included in the study were evaluated by the multidisciplinary team including specialists in cardiology and hypertension, interventional cardiology, radiology, interventional radiology, neuroradiology and vascular surgery. Results: Systematic evaluation of all 192 FMD patients included into the study revealed new FMD lesions in 61 (31.9 %) patients. Newly diagnosed vascular complications were found in 46 (24.0%) patients and in 2 patients more than one new vascular complications were revealed. Newly diagnosed aneurysms were found in 45 (32.4%) of patients and in 13 (6.8%) patients more than one aneurysms were found (Table). In 35 (18.2 %) FMD patients significant RAS was diagnosed.(Table).Conclusions: Systematic and multidisciplinary evaluation of FMD patients reveals a high incidence of previously unknown FMD lesions and newly diagnosed vascular complications.

Prevalence, Presentation, and Associated Conditions of Patients With Fibromuscular Dysplasia

Fibromuscular dysplasia (FMD) is defined by focal narrowing of small and medium-sized arteries due to an idiopathic, noninflammatory, nonatherosclerotic vascular disease. The population-based prevalence of FMD remains unknown. Using the National Inpatient Sample database, we evaluated the prevalence, clinical presentation, mortality, and associated conditions of FMD from January 1, 2004, to September 30, 2015. Among 2,420 patients who presented with FMD, 2,086 (86.20%) of patients were female. The mean age was 55.18 ± 18.99 years in men and 63.37 ± 17.10 years in women. FMD patients most commonly presented with hypertension (67.3%), transient ischemic attack (3.7%), headache (2.1%), dizziness (1.1%), abdominal pain (0.6%), or hematuria (0.3%). In-hospital mortality of FMD patients was 0.74%. In conclusion, FMD is a rare condition with low in-hospital mortality that may be considered among female patients presenting with hypertension.