Nonatherosclerotic Vascular Disease Research Articles

A case report with literature review: long-term follow-up of kidney autotransplantation in fibromuscular dysplasia.

Fibromuscular dysplasia is a rare, idiopathic, systemic, non-inflammatory, and non-atherosclerotic vascular disease that primarily affects young women. It often presents as renal artery stenosis. Fibromuscular dysplasia can induce tissue damage in the post-stenotic kidney. Treatment options include antihypertensive therapy, surgical revascularization, and transluminal angioplasty with stent implantation. However, kidney autotransplantation is an alternative when these treatments are not feasible. This study presents a case report of a 22-year-old woman with fibromuscular dysplasia, highlighting the long-term success of kidney autotransplantation and reviewing the related literature. A multidisciplinary approach was employed in the treatment of this patient presenting with intermittent headaches, hypertension, and acute kidney disease, andwho was diagnosed with fibromuscular dysplasia. She underwent left aorta-renal bypass and right autotransplantation. Following the procedure, her serum creatinine level decreased from 2.74 to 1.1mg/dL, with an eight-year follow-up confirming the favorableoutcome. Renal artery stenosis is a significant contributor to secondary hypertension, with fibromuscular dysplasia being a rarecause. While medical and interventional treatments are usually effective, complex cases may necessitate alternative approaches. Kidney autotransplantation, albeit uncommon, is an effective option for patients who are unresponsive to conventional therapies. This case demonstrates the successful management of fibromuscular dysplasia-associated renovascular hypertension via kidney autotransplantation, resulting in controlled blood pressure and preserved kidney function. In conclusion, kidney autotransplantation represents a valuable therapeutic option for severe renal artery stenosis caused by fibromuscular dysplasia, particularly when percutaneous procedures are impractical.

Tortuosity in non-atherosclerotic vascular diseases is associated with age, arterial aneurysms, and hypertension

BackgroundIncreased arterial tortuosity has been associated with various cardiovascular complications. However, the extent and role of arterial tortuosity in non-atherosclerotic vascular diseases remain to be fully elucidated. This study aimed to assess arterial tortuosity index (ATI) in patients with non-atherosclerotic vascular diseases and the associated factors.MethodsThis is a retrospective analysis of patients with non-atherosclerotic vascular diseases referred to the Malformation and Rare Vascular Disease Center at the University Hospital in Lausanne (Switzerland). Computed tomography angiography (CTA) images performed between October 2010 and April 2022 were retrieved and the aortic tortuosity index (ATI) was calculated. Patients were classified based on diagnosis into the following groups: arterial dissection & aneurysm, arteritis & autoimmune disease, hereditary connective tissue diseases, and fibromuscular dysplasia (FMD). Univariate and multivariate logistic regression analysis was used to determine potentially relevant predictors of aortic tortuosity.ResultsThe mean age upon computed tomography angiography (CTA) was 46.8 (standard deviation [SD] 14.6) years and 59.1% of the patients were female. Mean ATI was higher in patients over 60 years old (1.27), in those with arterial aneurysms (mean: 1.11), and in those diagnosed with hypertension (mean: 1.13). When only patients over 60 years old were considered, those diagnosed with connective tissue diseases had the highest ATI. At multivariate regression analysis, increasing age (p < 0.05), presence of arterial aneurysms (p < 0.05), and hypertension (p < 0.05) were independently associated with ATI.ConclusionsThe ATI may be a promising tool in diagnostic evaluation, cardiovascular risk stratification, medical or surgical management, and prognostic assessment in several non-atherosclerotic vascular conditions. Further studies with longitudinal design and larger cohorts are needed to validate the role of ATI in the full spectrum of vascular diseases.

Medical Management of Vascular Disease

Although surgeons may be able to bypass or open blocked arteries and replace aneurysms with minimally invasive surgery, patients continue to die from the other cardiovascular consequences of vascular disease. Surgeons must become more involved in the nonsurgical treatments of peripheral artery disease (PAD). A good understanding of the role of lipids in atherosclerosis is critical but surgeons must also recognize the threats of diabetes; smoking; hypertension; and hyperlipidemia on PAD. Treatments, including lifestyle modification, diet, exercise, and the influence of lipid-lowering agents is described. Medications that can alter PAD are described in detail and include statins; fibrates; niacin; bile acid sequestrants; ezetimibe; and antiplatelet agents. Side effects and monitoring is also described. Although much of the review covers the general principles of medical management of patients with PAD, components of this overall disease process are also provided and include pharmacological intervention for claudication; stroke; aortic aneurysms; and nonatherosclerotic vascular disease. This review contains 2 figures, 2 tables, and 181 references.

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.

Nonatherosclerotic Vascular Abnormalities Associated with Chronic Kidney Disease.

Nonatherosclerotic vascular diseases are manifested by endothelial dysfunction, hypertension, vascular calcification, coronary microvascular dysfunction, and calciphylaxis. Unfortunately, there are no definitive treatments for many of these disorders other than hypertension. In addition, although hypertension is more difficult to treat in the chronic kidney disease population, it is necessary to try and target a blood pressure of less than 130/80mm Hg through the use of aggressive angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, diuretics, and other antihypertensive medications. New therapies are being actively investigated in an attempt to treat nonatherosclerotic vascular diseases in the chronic kidney disease population.

Fibromuscular dysplasia of mesenteric arteries: a rare cause of multiple bowel resections\u2014a case report and literature review

BackgroundFibromuscular dysplasia (FMD) is a type of unexplained nonatherosclerotic vascular disease that usually involves the renal and internal carotid arteries and rarely involves the mesenteric artery. Mesenteric artery FMD is difficult to distinguish from Crohn’s disease (CD) and Behcet’s disease (BD) solely based on symptoms. Patients with mesenteric artery FMD can present with an acute abdomen, but case reports of patients who have a long medical history and undergo multiple bowel resections are extremely rare.Case presentationThe patient was a 45-year-old woman with an 11-year history of intermittent lower abdominal pain and fever. At the age of 34 years, she underwent right hemicolectomy and appendectomy due to an acute abdomen. She suffered from oral ulcers between 34 and 36 years old. A clinical diagnosis of presumed CD was made by the age of 41, and she was treated with mesalazine; however, the effect was poor. At the age of 42, she came to our centre, and based on her atypical symptoms and examination results, we thought she had CD. Hence, she was treated with glucocorticoids for 3 years. However, when she was 45, due to steroid dependence, thalidomide tablets were added. Unfortunately, she suffered from another episode of intestinal obstruction. Therefore, she underwent enterectomy. The postoperative histopathological diagnosis was mesenteric artery FMD. She no longer underwent pharmacotherapy after the surgery. Although she did not have any of her previous symptoms and postoperative colonoscopy showed no signs of recurrence, splenomegaly and abnormal routine blood results were still present.ConclusionsPatients with mesenteric artery FMD can present with an acute abdomen. In addition, the symptoms and endoscopic manifestations of mesenteric artery FMD may appear similar to CD and BD. Hence, it is difficult to make a clear clinical diagnosis and proceed with treatment. Mesenteric artery FMD often requires surgical pathology to confirm its diagnosis. For patients who suffer from this disorder, surgery may be the best choice to improve the patient’s quality of life.

Current progress in clinical, molecular, and genetic aspects of adult fibromuscular dysplasia.

Fibromuscular dysplasia (FMD) is a non-atherosclerotic vascular disease that may involve medium-sized muscular arteries throughout the body. The majority of FMD patients are women. Although a variety of genetic, mechanical, and hormonal factors play a role in the pathogenesis of FMD, overall, its cause remains poorly understood. It is probable that the pathogenesis of FMD is linked to a combination of genetic and environmental factors. Extensive studies have correlated the arterial lesions of FMD to histopathological findings of arterial fibrosis, cellular hyperplasia, and distortion of the abnormal architecture of the arterial wall. More recently, the vascular phenotype of lesions associated with FMD has been expanded to include arterial aneurysms, dissections, and tortuosity. However, in the absence of a string-of-beads or focal stenosis, these lesions do not suffice to establish the diagnosis. While FMD most commonly involves renal and cerebrovascular arteries, involvement of most arteries throughout the body has been reported. Increasing evidence highlights that FMD is a systemic arterial disease and that subclinical alterations can be found in non-affected arterial segments. Recent significant progress in FMD-related research has led to improve our understanding of the disease's clinical manifestations, natural history, epidemiology, and genetics. Ongoing work continues to focus on FMD genetics and proteomics, physiological effects of FMD on cardiovascular structure and function, and novel imaging modalities and blood-based biomarkers that can be used to identify subclinical FMD. It is also hoped that the next decade will bring the development of multi-centred and potentially international clinical trials to provide comparative effectiveness data to inform the optimal management of patients with FMD.

Stem Cell Therapy for Thromboangiitis Obliterans (Buerger’s Disease)

Buerger’s disease or Thromboangiitis Obliterans (TAO) is a nonatherosclerotic segmental vascular disease which affects small and medium arteries and veins in the upper and lower extremities. Based on pathological findings, TAO can be considered as a distinct form of vasculitis that is most prevalent in young male smokers. There is no definitive cure for this disease as therapeutic modalities are limited in number and efficacy. Surgical bypass has limited utility and 24% of patients will ultimately require amputation. Recently, studies have shown that therapeutic angiogenesis and immunomodulatory approaches through the delivery of stem cells to target tissues are potential options for ischemic lesion treatment. In this review, we summarize the current knowledge of TAO treatment and provide an overview of stem cell-based treatment modalities.

ROLE OF PERIVASCULAR ADIPOSE TISSUE IN THE DEVELOPMENT OF ATHEROSCLEROTIC AND NONATHEROSCLEROTIC DISEASES

Perivascular adipose tissue surrounds most large blood vessels and plays an important role in vascular homeostasis. Recent studies have shown that perivascular adipose tissue effects vasodilation and vasoconstriction, which indicates that the perivascular adipose tissue regulates tone and diameter of the vessels. Adipocytokines and chemokines, secreted from the perivascular adipose tissue, apparently have direct access to the adjacent arterial wall by diffusion, or through vasa vasorum . The present data indicate that perivascular adipose tissue plays an important role in atherosclerosis, hypertension. Recently, some studies were performed that examined the role of perivascular adipose tissue in non-atherosclerotic vascular diseases, such as neointimal formation, aortic aneurysm, arterial stiffness and vasculitis. The present review will discuss a role of perivascular adipose tissue in pathogenesis of atherosclerosis, hypertension and non-atherosclerotic vascular diseases.

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.

The Role of Perivascular Adipose Tissue in Non-atherosclerotic Vascular Disease.

Perivascular adipose tissue (PVAT) surrounds most large blood vessels and plays an important role in vascular homeostasis. PVAT releases various chemokines and adipocytokines, functioning in an endocrine and paracrine manner to regulate vascular signaling and inflammation. Mounting evidence suggests that PVAT plays an important role in atherosclerosis and hypertension; however, the role of PVAT in non-atherosclerotic vascular diseases, including neointimal formation, aortic aneurysm, arterial stiffness and vasculitis, has received far less attention. Increasing evidence suggests that PVAT responds to mechanical endovascular injury and regulates the subsequent formation of neointima via factors that promote smooth muscle cell growth, adventitial inflammation and neovascularization. Circumstantial evidence also links PVAT to the pathogenesis of aortic aneurysms and vasculitic syndromes, such as Takayasu's arteritis, where infiltration and migration of inflammatory cells from PVAT into the vascular wall may play a contributory role. Moreover, in obesity, PVAT has been implicated to promote stiffness of elastic arteries via the production of reactive oxygen species. This review will discuss the growing body of data and mechanisms linking PVAT to the pathogenesis of non-atherosclerotic vascular diseases in experimental animal models and in humans.

Non-Atherosclerotic Vascular Disease in Women.

Takayasu arteritis, fibromuscular dysplasia (FMD), spontaneous arterial dissection, Raynaud's phenomenon, and chilblains are vascular conditions that are associated with an increased predisposition in women and are often underdiagnosed. Takayasu arteritis has an incidence rate of 2.6 cases per million individuals per year in the USA and predominantly affects women of childbearing age. HLA-B5 genetic locus is linked with Takayasu arteritis susceptibility. Methods to determine active disease are limiting; currently utilized clinical and imaging findings and laboratory tests are of limited value for this purpose. Pregnancy poses risks for maternal and fetal complications, and these patients need additional monitoring and care before and after conception. Controlling hypertension and immunosuppression using steroids, biological and non-biological immunosuppressants, are key components of managing patients with this arteritis. FMD commonly affects middle-aged, white females. Its true prevalence is unknown. Renal and cerebrovascular beds are the most frequently involved vascular beds. Its clinical presentation varies from no symptoms to catastrophic events. Controlling vascular risk factors, periodic surveillance, and revascularization when indicated are important factors in FMD management. Spontaneous arterial dissections are less common, but are an important cause of morbidity and mortality in specific populations. Cervicocephalic dissection causes 10-20% of the strokes in young adults, and coronary artery dissection is the culprit in almost one fourth of young women presenting with acute myocardial infarction. Early diagnosis is key to improving prognosis in these patients, as the majority of patients have spontaneous resolution of the dissection with conservative management alone. Increased clinician awareness of the presentation features and angiographic findings are imperative for early diagnosis. Raynaud's phenomenon and chilblains are cold- or stress-induced cutaneous lesions, commonly involving distal extremities. Secondary causes such as connective tissue diseases and malignancies must be thoroughly excluded during evaluation of these conditions. Cold avoidance, systemic and local warming, and oral vasodilator therapy are the mainstays of therapy.

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.

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.

Fibromuscular dysplasia of the coronary arteries: a case report and review of the literature

Fibromuscular dysplasia is a nonatherosclerotic and non-inflammatory vascular disease with primary lesion of renal and internal carotid arteries. We present a neonatal case of fibromuscular dysplasia who died on the second day of life. The newborn suffered from fibromuscular dysplasia of the coronary arteries and a congenital heart defect. The interesting feature of this case was the formation of aneurysms of the coronary arteries with pulmonary atresia. This case demonstrates a casuistically rare form of association between fibromuscular dysplasia of the coronary arteries and pulmonary artery atresia.

CO-29: Carotid artery phenotyping using high-resolution radiofrequency – based echotracking system in patients with multifocal fibromuscular dysplasia: across-sectional study

Background Fibromuscular dysplasia (FD) is a rare idiopathic, segmental, non-atherosclerotic non-inflammatory vascular disease, which occurs mostly in middle-aged patients and affects medium-sized arteries (renal and carotid arteries). We previously showed that renal FD is associated with supernumerary echo interfaces (triple signal pattern) detectable on echotracking tracings of the carotid artery (CA) compared to healthy subjects (HS), but we did not study patients with essential hypertension (EH). Abstract CO-29 – Table FD EH HS Age, yrs 52 ± 9 52 ± 9 52 ± 9 Women, n (%) 43 (86%) 43 (86%) 42 (84%) Caucasian, n (%) 38 (76%) 38 (76%) 42 (84%) Office SBP, mmHg 125 ± 15 *** 121 ± 12 *** 113 ± 10 Antihypertensive drugs, n (range) 2 (1-4) 2 (1-4) 0 FD score, right CA 3.50 ± 1.43 ** 3.14 ± 1.16 2.84 ± 0.96 FD score, left CA 3.98 ± 1.57 ** 3.56 ± 1.43 ** 2.92 ± 1.07 Right CA triple signal, n (%) 11 (22%) ** 8 (16%) * 1 (2%) Left CA triple signal, n (%) 19 (38%) *** 15 (30%) ** 3 (6%) Right CA external diameter, mm 6.92 ± 0.57 7.10 ± 0.72 6.93 ± 0.66 Left CA external diameter, mm 6.89 ± 0.59 6.99 ± 0.63 6.81 ± 0.59 Right CA distensibility, μm 372 ± 105 381 ± 113 379 ± 116 Left CA distensibility, μm 347 ± 110 360 ± 117 360 ± 105 Right CA IMT, μm 610 ± 107 649 ± 134 601 ± 129 Left CA IMT, μm 655 ± 137 691 ± 171 637 ± 126 PWV, m/s 10.93 ± 2.07 ** 11.13 ± 2.02 *** 9.92 ± 1.70 * P ** P *** P Methods In a cross sectional study, we compared the geometry and the mechanical properties of CA between 50 patients with multifocal FD of renal/carotid arteries, 50 patients with EH matched for age, sex, ethnicity and BP and 50 HS matched for age, sex and ethnicity. We used 1) a high-resolution radiofrequency – based echotracking system to perform a semi-quantitative arterial phenotypic scoring and to detect additional interface at the level of the CA wall, and 2) Sphygmocor® to measure carotid-to-femoral pulse wave velocity (PWV). All measurements were performed blind to the diagnosis. Results FD, EH and HS were well matched. FD and EH had significantly higher SBP than HS despite antihypertensive treatments. The FD score was significantly higher and the triple signal pattern was observed more frequently in both FD and EH (especially for the left CA) than in HS, with no difference between FD and EH. This was also the case for PWV. All other parameters (CA diameter, distensibility and intima-media thickness [IMT]) did not significantly differ between the 3 groups. Conclusions In conclusion, even though the FD score is much higher and the prevalence of the triple signal is largely more frequent at the level of CA and PWV is higher in FD than in age, sex-, ethnicity-matched HS, this arterial phenotype is not specific for FD when compared to age-, sex- and BP-matched EH.

CO-28: Flow-mediated dilatation (FMD) and endothelium-independent dilation (EID) in patients with multifocal fibromuscular dysplasia: a cross-sectional study

Background Fibromuscular dysplasia (FD) is a rare idiopathic, segmental, non-atherosclerotic non-inflammatory vascular disease, which occurs mostly in middle-aged patients and affects medium-sized arteries (renal and carotid arteries). 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. Abstract CO-28 – Table FD EH HS Age, yrs 52 ± 9 52 ± 9 52 ± 9 Women, n (%) 43 (86%) 43 (86%) 42 (84%) Caucasian, n (%) 38 (76%) 38 (76%) 42 (84%) Office SBP, mmHg 125 ± 15*** 121 ± 12*** 113 ± 10 Antihypertensive drugs, n (range) 2 (1-4) 2 (1-4) 0 BA structure External diameter, mm 3.91 ± 0.72° 4.19 ± 0.69 4.00 ± 0.64 Distensibility, μm 114 ± 64 115 ± 57 135 ± 73 IMT, μm 319 ± 79 330 ± 85 303 ± 97 Internal diameter, mm 3.34 ± 0.64 3.56 ± 0.66 3.47 ± 0.57 FMD Basal BA diameter; mm 3.86 ± 0.70*° 4.17 ± 0.63 4.02 ± 0.65 BA diameter (hand ischemia), mm 3.91 + 0.71°° 4.22 + 0.64 4.04 + 0.61 BA diameter (hand hyperhemia), mm 3.98 ± 0.73*° 4.29 ± 0.63 4.16 ± 0.62 Change in BA diameter, % 2.39 [0.31; 5.41] 2.85 [–0.23; 6.15] 2.67 [0.20; 5.73] Basal BA flow velocity, cm/s 7.70 ± 5.99 7.39 ± 5.98 7.66 ± 8.53 BA flow velocity (ischemia), cm/s 3.71 ± 5.25 2.68 ± 5.01 0.98 ± 2.54 BA flow velocity (hyperhemia) cm/s 73 ± 29 69 ± 27 78 ± 38 EID Basal BA diameter, mm 3.92 ± 0.69°° 4.22 ± 0.67 4.07 ± 0.67 Post-GTN BA diameter, mm 4.43±0.69**°° 4.82 ± 0.61 4.74 ± 0.71 Change in BA diameter, % 13.8 [7.9;19.0] 15.3 [10.2; 18.9] 18.4 [12.9;21.1] Post-GTN BA flow velocity, cm/s 7.27 ± 8.12 5.56 ± 6.84 4.76 ± 10.29 * P < 0.05, ** P < 0.01, *** P < 0.001 vs. HS Full-size table Table options View in workspace Download as CSV Methods 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 were measured using a high-resolution radiofrequency – based echotracking system blind to the diagnosis. Results FD, EH and HS were well matched. FD and EH had significantly higher SBP than HS 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 and distensibility did not differ between the 3 groups. The percent changes in BA diameter after release of hand ischemia (FMD) or GTN administration (EID) did not significantly differ between the 3 groups. BA flow velocity did not significantly differ in any experimental condition. Conclusions In conclusion, despite showing similar acute vasodilatory responses to flow and GTN, FD patients differed from EH and HS in terms arterial morphology with smaller BA diameter associated with similar IMT. The similarity of the IMT between the groups, combined with the reduction of the BA diameter in FD patients suggests that the BA underwent inward eutro-phic remodeling despite normal blood flow velocity. This paradoxical remodeling may suggest a chronic defect in the endothelium-dependent pathways involved in arterial remodeling in FD patients.

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.

Abstract 15370: Genetic Study Identifies Common Variation in PHACTR1 to Associate With Fibromuscular Dysplasia (Best of Basic Science Abstract)

Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to arterial stenosis, aneurysm and dissection, mainly in renal and carotid arteries. 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. We performed a genetic association study in European ancestry individuals. The discovery included 249 cases and 689 controls, in which we analyzed ∼26K common variants (MAF&gt;0.05) using an exome-chip array. We followed up 13 loci (P&lt;10-4) in 393 cases and 2537 controls and replicated a signal on Chr6. Three additional studies (combined Ncases=512, Ncontrols=669) confirmed this association, with an overall OR of 1.39, (P=7.4х10e-10 , All Ncases=1154, All Ncontrols=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. The correlation of genotypes with the expression of PHACTR1 in primary cultured human fibroblasts showed higher expression in FMD risk allele carriers, compared to non carriers (N=57, P=0.02). Finally, Phactr1 knockdown of zebrafish showed significantly dilated vessels (P=0.003) indicating impaired vascular development. In conclusion, 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.