Daniella Kadian-Dodov

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.

Prevalence of Intracranial Aneurysm in Women With Fibromuscular Dysplasia: A Report From the US Registry for Fibromuscular Dysplasia

Importance The prevalence of intracranial aneurysm in patients with fibromuscular dysplasia (FMD) is uncertain. Objective To examine the prevalence of intracranial aneurysm in women diagnosed with FMD. Design, Setting, and Participants This cross-sectional study included 669 women with intracranial imaging registered in the US Registry for Fibromuscular Dysplasia, an observational disease-based registry of patients with FMD confirmed by vascular imaging and currently enrolling at 14 participating US academic centers. Registry enrollment began in 2008, and data were abstracted in September 2015. Patients younger than 18 years at the time of FMD diagnosis were excluded. Imaging reports of all patients with reported internal carotid, vertebral, or suspected intracranial artery aneurysms were reviewed. Only saccular or broad-based aneurysms 2 mm or larger in greatest dimension were included. Extradural aneurysms in the internal carotid artery were included; fusiform aneurysms, infundibulae, and vascular segments with uncertainty were excluded. Main Outcomes and Measures Percentage of women with FMD with intracranial imaging who had an intracranial aneurysm. Results Of 1112 female patients in the registry, 669 (60.2%) had undergone intracranial imaging at the time of enrollment (mean [SD] age at enrollment, 55.6 [10.9] years). Of the 669 patients included in the analysis, 86 (12.9%; 95% CI, 10.3%-15.9%) had at least 1 intracranial aneurysm. Of these 86 patients, 25 (53.8%) had more than 1 intracranial aneurysm. Intracranial aneurysms 5 mm or larger occurred in 32 of 74 patients (43.2%), and 24 of 128 intracranial aneurysms (18.8%) were in the posterior communicating or posterior arteries. The presence of intracranial aneurysm did not vary with location of extracranial FMD involvement. A history of smoking was significantly associated with intracranial aneurysm: 42 of 78 patients with intracranial aneurysm (53.8%) had a smoking history vs 163 of 564 patients without intracranial aneurysm (28.9%; P < .001). Conclusions and Relevance The prevalence of intracranial aneurysm in women diagnosed with FMD is significantly higher than reported in the general population. Although the clinical benefit of screening for intracranial aneurysm in patients with FMD has yet to be proven, these data lend support to the recommendation that all patients with FMD undergo intracranial imaging if not already performed.

Diagnostic utility of carotid artery duplex ultrasonography in the evaluation of syncope: a good test ordered for the wrong reason.

AIMS Syncope refers to a transient loss of consciousness and postural tone secondary to cerebral hypoperfusion. Guidelines recommend against neurovascular testing in cases of syncope without neurologic symptoms; however, many pursue carotid artery duplex ultrasonography (CUS) due to the prognostic implications of identified cerebrovascular disease. Our objective was to determine the diagnostic utility of CUS in the evaluation of syncope and the identification of new or severe atherosclerosis with the potential to change patient management. METHODS AND RESULTS We reviewed records of 569 patients with CUS ordered for the primary indication of syncope through an accredited vascular laboratory at an academic, urban medical centre. Findings on CUS, patient demographic, clinical and laboratory information, and medications within 6 months of the CUS exam were reviewed. Bivariate relationships between key medical history characteristics and atherosclerosis status (known vs. new disease) were examined. Among 495 patients with complete information, cerebrovascular findings could potentially explain syncope in 2% (10 patients). Optimization of cardiovascular risk factors would benefit patients with known (56.6%) and new atherosclerosis (33.5%) with suboptimal lipid control, (LDL > 70 in 42.2 and 34.9% respectively; LDL > 100 in 15.7 and 20.4%), and those not on high-intensity statin therapy (80 and 87.5%) or antiplatelet medications (13.2 and 50.6%). CONCLUSION CUS is a low-yield diagnostic test in the evaluation of syncope, but it is useful in the diagnosis of atherosclerosis and identification of subjects who would benefit from optimal medical therapy.

Multimodality imaging of fibromuscular dysplasia

ObjectiveFibromuscular dysplasia (FMD) is an uncommon non-inflammatory and non-atherosclerotic cause of arterial disease that may result in stenosis, tortuosity, aneurysm, or dissection. The clinical presentation depends on the vascular bed involved and ranges from asymptomatic to multisystem disease and end organ ischemia. The purpose of this article is to review the role of imaging in patients with FMD with an emphasis on renal FMD. The relevant epidemiology, histopathology, imaging techniques, and interpretation of images will be discussed.ConclusionRenal artery FMD requires a high index of suspicion for accurate and prompt diagnosis and implementation of appropriate therapy. The treatment will vary based on clinical presentation and distribution of involvement. Noninvasive imaging with duplex ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI) are reasonable alternatives for the depiction of FMD in comparison to catheter-directed angiography (CA). Patients with FMD are often treated by multispecialty practice including the interventional radiologist.

ANEURYSM AND DISSECTION IN FIBROMUSCULAR DYSPLASIA: FINDINGS FROM THE UNITED STATES REGISTRY FOR FMD

The clinical phenotype and prognosis in Fibromuscular Dysplasia (FMD) patients (pts) with Dissection (D) and Aneurysm (A) are poorly defined. Clinical features, locations and therapeutic procedures were reviewed in 732 pts enrolled in the United States Registry for FMD. Aneurysm (A) was present in

Exercise-Induced Leg Pain and High Blood Pressure

A 52-year-old woman presents with exertional right buttock and thigh pain that resolves within 2 minutes of rest. Exercise tolerance has worsened over the past year and is now limited to several blocks. Previously she was able to run 5 to 6 miles per day. Hypertension was diagnosed several months ago and is controlled with lisinopril (5 mg daily). She has no other cardiovascular risk factors. Her blood pressure is 124/76 mm Hg bilaterally. There is a high-pitched systolic bruit over the right subcostal region and the umbilicus. Peripheral pulses are normal. The ankle brachial index (ABI) at rest is borderline normal (0.91) on the right and normal (1.03) on the left. The remainder of the examination is normal. After physical therapy and nonsteroidal anti-inflammatory agents failed to improve symptoms, a computed tomography angiogram (CTA) is performed, revealing a “beaded appearance” in the right renal artery and a long-segment stenosis of the right external iliac artery. There is no atherosclerosis. A catheter-based angiogram confirms the CTA findings (Figure). Quiz at jama.com A Selective renal arteriogram of the right renal artery B Catheter-based angiogram of the right external iliac artery

Fibromuscular Dysplasia: Contemporary Concepts and Future Directions

Fibromuscular dyplasia (FMD) is an under-recognized non-atherosclerotic, non-inflammatory arteriopathy that occurs most commonly in middle-aged women, but may affect individuals of all age groups. FMD may result in stenosis, aneurysm, dissection, occlusion, or arterial tortuosity. Recently published data demonstrated a genetic association of FMD with a variant in the phosphatase and actin regulator 1 gene (PHACTR1), substantiating that the pathogenesis of this condition has genetic contribution. The renal and extracranial carotid and vertebral arteries are most often involved, although any arterial bed may be affected. Clinical manifestations often reflect the vascular territory affected, and can include hypertension, headaches, pulsatile tinnitus, myocardial infarction, transient ischemic attack and stroke. While the gold standard for diagnostic evaluation of FMD remains catheter-based angiography, noninvasive imaging, including duplex ultrasound, computed tomographic angiography, and magnetic resonance angiography, may be used for diagnosis. Treatment of FMD depends upon symptoms as well as the nature and location of arterial lesions, but may include both medical (blood pressure control, antiplatelet agents) and interventional (angioplasty, stents, coils, surgery) therapies. This contemporary analysis of the literature, combined with our own clinical experience in treating patients with FMD, will highlight pathophysiology, evaluation, management, and common misconceptions in the care of individuals with FMD.

NATURAL HISTORY OF CERVICAL ARTERY FIBROMUSCULAR DYSPLASIA AND ASSOCIATED NEUROVASCULAR EVENTS

Fibromuscular dysplasia (FMD) is a non-atherosclerotic, non-inflammatory arteriopathy that most often affects the carotid and renal arteries. In the US Registry for FMD an aneurysm was identified in 21.7% and dissection in 25.7% of patients before or at FMD diagnosis. Occurrence of vascular events

DIAGNOSTIC UTILITY OF CAROTID ARTERY ULTRASOUND FOR THE PRIMARY INDICATION OF SYNCOPE

Syncope refers to a transient loss of consciousness and postural tone. The etiology is often elusive, resulting in extensive diagnostic testing. The medical records and results of 495 carotid artery ultrasounds performed in an accredited vascular laboratory for the primary indication of syncope

Warfarin pharmacogenetics: A controlled dose–response study in healthy subjects

The aim of this study was to determine how genetic variants contribute to warfarin dosing variability when non-genetic factors are controlled. Thirty healthy subjects were subjected to a warfarin dosing algorithm with daily international normalized ratio (INR) measurements to INR ≥ 2.0, then off warfarin to INR ≤ 1.2. The primary outcome was the cumulative dose required to achieve INR ≥ 2.0 for 2 consecutive days. CYP2C9 (p=0.004) and VKORC1 (p=0.02) variant carriers required lower cumulative doses, and CYP4F2 carriers required higher doses (p=0.04). Subjects with variants in both CYP2C9 and VKORC1 required fewer days to reach INR ≥ 2.0 than wild-type subjects or those with variants in CYP2C9 or VKORC1 (p=0.01). Genetic contribution to dose variability (~62%) was greater than previously reported, suggesting that uncontrolled clinical variables influence the effect of these variants. In conclusion, genotype-guided warfarin-dosing algorithms may rely more on genetic variables in healthier individuals than in patients with clinical confounders. ClinicalTrials.gov Identifier: NCT01520402