Nonatherosclerotic Vascular Disease Research Articles

Exome sequencing in seven families and gene-based association studies indicate genetic heterogeneity and suggest possible candidates for fibromuscular dysplasia.

Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to stenosis, aneurysm and dissection, mainly of renal arteries and carotids. FMD occurs predominantly in women with nearly four out of 1000 prevalence and cause hypertension, renal ischemia or stroke. The pathogenesis of FMD is unknown and a genetic origin is suspected given its demonstrated familial aggregation. We performed whole exome sequencing (WES) in 16 cases (seven families). Coding variants in 3971 genes were prioritized on frequency (minor allele frequency < 0.01) and in silico predicted functionality. No gene harbours variants that are shared among all affected members of at least three families. Variants from 16 genes of vascular and connective tissue diseases are excluded as causative in these families. Genes with at least four variants in the 16 patients and vascular genes were followed-up using genotypes from 249 unrelated cases and 689 controls. Gene-based association analyses using SKAT-O shows nominal significant association with multifocal FMD (N = 164) for myosin light chain kinase (MYLK, P = 0.01) previously involved in thoracic aortic aneurysm, obscurin (OBSCN), a sarcomeric protein (P = 0.003), dynein cytoplasmic heavy chain 1 (DYNC2H1, P = 0.02) and RNF213 previously associated with Moyamoya disease (P = 0.01). Our study indicates genetic heterogeneity and the unlikely existence of a major gene for FMD and excludes the role of several vascular genes in familial FMD. We also suggest four possible candidate genes for multifocal FMD, though these findings need further genetic and functional confirmation. More powerful WES and association studies [e.g. genome-wide association study (GWAS)] will better decipher the genetic basis of FMD.

0382 : Exome sequencing in seven families and gene-based association studies indicate genetic heterogeneity and suggest possible candidates for fibromuscular dysplasia

Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to stenosis, aneurysm and dissection, mainly of renal arteries and carotids. FMD occurs predominantly in females with ~4/1000 prevalence and cause hypertension, renal ischemia or stroke. The pathogenesis of FMD is unknown and a genetic origin is suspected given its demonstrated familial aggregation. We performed whole exome sequencing (WES) in 16 cases (seven families). Coding variants in 3,971 genes were prioritized on frequency (minor allele frequency <0.01) and in silico predicted functionality. No gene harbors variants that are shared among all affected members of at least three families. Variants from 16 genes of vascular and connective tissue diseases are excluded as causative in these families. Genes with at least four variants in the 16 patients and vascular genes were followed-up using genotypes from 249 unrelated cases and 689 controls. Gene-based association analyses using SKAT-O shows nominal significant association with multifocal FMD (N=164) for myosin light chain kinase (MYLK, P=0.01) previously involved in thoracic aortic aneurysm, obscurin (OBSCN), a sarcomeric protein (P=0.003), dynein cytoplasmic heavy chain 1 (DYNC2H1, P=0.02) and RNF213 previously associated with Moyamoya disease (P=0.01). Our study indicates genetic heterogeneity and the unlikely existence of a major gene for FMD and excludes the role of several vascular genes in familial FMD. We also suggest four possible candidate genes for multifocal FMD, though these findings need further genetic and functional confirmation. More powerful WES and association studies (e.g. GWAS) will better decipher the genetic basis of FMD.

Patología arterial en la migraña: disfunción endotelial y cambios estructurales en la vasculatura cerebral y sistémica

The pathophysiology underlying the association between migraine and other non-atherosclerotic vascular diseases is largely unknown. Endothelial dysfunction has been proposed as a common link. Besides, endothelial dysfunction is considered as a predictor of structural changes in the arterial walls. To review the current knowledge about the functional (endothelial dysfunction) and structural (arterial stiffness and atherosclerotic diseases) arterial properties associated with migraine. Studies of biological markers of endothelial dysfunction in peripheral blood, systemic and cerebral vasoreactivity, arterial stiffness indexes and direct visualization of macroscopic changes in the arterial wall have shown differences between patients with and without migraine, as well as between the different migraine subtypes. Endothelial dysfunction, as a predictor of structural changes in arteries, has been proposed as an early marker for vascular pathology associated with migraine. In migraine patients there is an increase of biomarkers of endothelial dysfunction, but the correlation with vasoreactivity studies does not allow definite conclusions. Available data do not allow to conclude that migraine is associated with macroscopic alterations outside the cerebral arterial bed.

The S curve: a novel morphological finding in the internal carotid artery in patients with fibromuscular dysplasia.

Fibromuscular dysplasia (FMD) is a non-atherosclerotic vascular disease commonly affecting the renal and internal carotid arteries (ICAs). A previously unrecognized finding is a redundancy of the mid-distal ICA in FMD patients causing an 'S'-shaped curve. Carotid artery duplex ultrasounds were reviewed in 116 FMD patients to determine S-curve prevalence. FMD patients with an S curve were matched to four control patients divided equally into two groups: (1) age and sex-matched and (2) age ≥70 and sex-matched. S curves were present in 37 (32%) FMD patients. Of these, nine (24%) had angiographic evidence of FMD in their ICA only, 13 (35%) had renal artery FMD only, and 15 (41%) had both ICA and renal FMD. Two patients in the age and sex-matched group had S curves (odds ratio 16.86, 95% CI 3.92-72.48; p<0.0001) while 12 (16.2%) patients in the age ≥70 and sex-matched group had S curves (odds ratio 2.42, 95% CI 1.16-5.03; p=0.016). In conclusion, the S curve is a novel morphological pattern of the mid-distal ICA. While the S curve may not be specific, its presence in individuals <70 years old should alert the clinician to the possibility that FMD is present.

Nonatherosclerotic obstructive vascular diseases of the mesenteric and renal arteries.

Nonatherosclerotic vascular diseases of the mesenteric and renal arteries are considered to occur less frequently than those caused by occlusive atherosclerotic disease. However, when present, they pose a significant diagnostic and therapeutic challenge. Such disorders include fibromuscular dysplasia, median arcuate ligament syndrome, the renal nutcracker syndrome, and some forms of acute and chronic mesenteric ischemia (embolic and thrombotic). This is a heterogeneous group of disorders with substantial differences in the pathogenesis and diagnostic approaches to these diseases. We provide an overview of the pathogenesis, clinical presentation, diagnosis, and current management of fibromuscular dysplasia, median arcuate ligament syndrome, and the renal nutcracker syndrome.

Renal Artery Stent Fracture in Patients With Fibromuscular Dysplasia

Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease that most commonly affects the renal, carotid, and vertebral arteries.1 Renal FMD is associated with renovascular hypertension, and patients may be referred for revascularization, generally with balloon angioplasty. We report a series of 2 patients with renal artery FMD who developed stent fracture. A 16-year-old girl was seen for a second opinion on renal FMD. Hypertension was diagnosed at the age of 13 years and initially treated medically; however, bilateral renal artery angioplasty was subsequently performed for poorly controlled blood pressure. She subsequently underwent placement of a drug eluting stent in the right renal artery for restenosis. Although she initially improved, there was gradual worsening of her blood pressure control. Noninvasive testing was consistent with severe restenosis of the right renal artery stent. Renal arteriography revealed a severe stenosis estimated at 80% in the right renal artery (Figure 1). There was severe narrowing noted at the ostium, resulting in a 70 mm Hg gradient across the lesion. …

Fibromuscular dysplasia presenting with asymptomatic bilateral renal infarctions

Fibromuscular dysplasia (FMD) is a noninflammatory nonatherosclerotic vascular disease. It is the second cause of renovascular hypertension after atherosclerosis. Although FMD usually has a good prognosis, renal infarctions and artery dissections have been described. We present the case of a 38-year-old woman with hypertension and asymptomatic bilateral renal infarctions. Bilateral FMD of segmental branches of the renal arteries was diagnosed by digital subtraction angiography after an exhaustive study. Previous intake of nonsteroidal anti-inflammatory drugs may also have played a significant role in the development of renal infarctions. To our knowledge, bilateral renal infarctions complicating FMD have been reported in only four previous cases; only in one of those cases, renal infarctions were asymptomatic.

Spontaneous Dissection of the External Iliac Artery Secondary to Golf Club Manufacturing

Spontaneous dissection of the external iliac artery in the absence of aortic disease is extremely uncommon. We report the conservative treatment of a 46-year-old male patient who presented with acute left lower limb ischemia due to an isolated dissection of the external iliac artery secondary to repetitive swinging movements during golf club manufacturing. Although syndromes of nonatherosclerotic vascular disease secondary to repetitive movements in high-level athletic activity have been previously described in cyclists, long distance runners, and rugby players, we believe this to be the first occupational case associated with golf.

C6 Radiculopathy: The Initial Presentation of Fibromuscular Dysplasia

Fibromuscular dysplasia is a noninflammatory, nonatherosclerotic vascular disease that causes aneurysmal dilatation and stenosis of smalland medium-sized arteries. Although most commonly affecting the renal and carotid arteries, it may occur in any arterial bed. The clinical presentation is dependent upon the affected vascular supply. Common clinical presentations of fibromuscular dysplasia include hypertension, transient ischemic attack, stroke, syncope, and vertigo [1-3]. We report an unusual case of cervical radiculopathy as the initial presentation of fibromuscular dysplasia that affected the vertebral arteries.

Leveraging informatics for genetic studies: use of the electronic medical record to enable a genome-wide association study of peripheral arterial disease

There is significant interest in leveraging the electronic medical record (EMR) to conduct genome-wide association studies (GWAS). A biorepository of DNA and plasma was created by recruiting patients referred for non-invasive lower extremity arterial evaluation or stress ECG. Peripheral arterial disease (PAD) was defined as a resting/post-exercise ankle-brachial index (ABI) less than or equal to 0.9, a history of lower extremity revascularization, or having poorly compressible leg arteries. Controls were patients without evidence of PAD. Demographic data and laboratory values were extracted from the EMR. Medication use and smoking status were established by natural language processing of clinical notes. Other risk factors and comorbidities were ascertained based on ICD-9-CM codes, medication use and laboratory data. Of 1802 patients with an abnormal ABI, 115 had non-atherosclerotic vascular disease such as vasculitis, Buerger's disease, trauma and embolism (phenocopies) based on ICD-9-CM diagnosis codes and were excluded. The PAD cases (66+/-11 years, 64% men) were older than controls (61+/-8 years, 60% men) but had similar geographical distribution and ethnic composition. Among PAD cases, 1444 (85.6%) had an abnormal ABI, 233 (13.8%) had poorly compressible arteries and 10 (0.6%) had a history of lower extremity revascularization. In a random sample of 95 cases and 100 controls, risk factors and comorbidities ascertained from EMR-based algorithms had good concordance compared with manual record review; the precision ranged from 67% to 100% and recall from 84% to 100%. This study demonstrates use of the EMR to ascertain phenocopies, phenotype heterogeneity and relevant covariates to enable a GWAS of PAD. Biorepositories linked to EMR may provide a relatively efficient means of conducting GWAS.

Fibromuscular dysplasia: a rare disease that can mimic vasculitis

Fibromuscular dysplasia (FMD) is an uncommon angiopathy that occurs mainly in young to middle-aged female individuals. It is an idiopathic, segmental, non-inflammatory and non-atherosclerotic vascular disease leading to stenosis of small- and medium-sized arteries. Clinical manifestations are determined by the artery involved, most commonly hypertension (renal artery) and stroke (carotid artery). When FMD affects multiple vascular beds, it may mimic a systemic vasculitis. Here, we present the case of a young female patient with FMD. The patient had a clinical history of bilateral internal carotid artery dissection that required surgical repair. Since a systemic vascular disease was suspected, abdominal angiography was done, showing evidence of a "string of beads" appearance involving the distal two-thirds of the right renal artery. This lesion is considered to be pathognomonic of the medial FMD that accounts for 70-95% of all cases of FMD. Two years later, a new magnetic resonance angiography confirmed the "string of beads" appearance of the middle to distal part of the right renal artery, with significant hemodynamic stenosis that was successfully dilated with percutaneous transluminal angioplasty.

Buerger's disease and anticardiolipin antibodies

Thromboangiitis obliterans or Buerger's disease is an occlusive, inflammatory, nonatherosclerotic vascular disease of unknown etiology, which affects mainly the small and medium arteries, veins and nerves. Anticardiolipin antibodies are associated with arterial and venous thrombosis, repetitive miscarriages and thrombocytopenia. The aim of this study is to bring to attention the diagnosis of Buerger's disease when found in conjunction with anticardiolipin antibodies. Three clinical cases that satisfy Shionoya's criteria for Buerger's disease (except the lack of smoking in one of the cases) are documented in this work. The following examinations were performed: hemogram, creatinine, glycemia, cholesterol, anticardiolipin antibodies, echocardiogram and angiogram. Shionoya's criteria for Buerger's disease were compatible with the two diseases: anticardiolipin antibody syndrome and Buerger's disease, both of which can occur in isolation or associated, thereby complicating the diagnosis. It is concluded that anticardiolipin can be associated with Buerger's disease and may worsen the thrombotic event of the disease but the two entities are separate. The diagnosis is not complicated.

Increased Prevalence of Hyperhomocysteinemia in Cervical Artery Dissection Causing Stroke

Background: Spontaneous cervical artery dissection (sCAD) is a nonatherosclerotic vascular disease of unknown etiology. Mild elevation of total plasma homocysteine (tHcy) levels may be a risk factor for sCAD, but the precise mechanism remains unknown. On the other hand, mild hyperhomocysteinemia is also associated with ischemic stroke related to atherothrombotic or small artery disease. We undertook a case-control study to compare the prevalence of mild hyperhomocysteinemia and tHcy levels between patients with a first ischemic stroke due to sCAD and healthy volunteers, as well as patients with a first ischemic stroke due to atherothrombotic or small artery disease. Methods: Fasting tHcy levels were determined in 346 consecutive patients with a first ischemic stroke due to sCAD (n = 86) and atherothrombotic or small artery disease (n = 260) within 24 h after the onset of symptoms, and in 100 healthy volunteers. Results: Mild hyperhomocysteinemia was more prevalent in patients with sCAD causing ischemic stroke (n = 33, 38%) than in healthy volunteers (n = 23, 23%; p = 0.034), and less prevalent than in patients with ischemic stroke due to atherothrombotic or small artery disease (n = 149, 57%; p = 0.001). Mean fasting tHcy levels of patients with ischemic stroke caused by sCAD showed a trend to be higher (11.4 ± 3.8 μmol/l) than those of healthy volunteers (10.2 ± 3.0 μmol/l, p = 0.61), but were lower than those of patients with stroke due to atherothrombotic or small artery disease (13.6 ± 6.6 μmol/l, p = 0.002). Conclusion: Our results suggest that mild hyperhomocysteinemia may be a risk factor for sCAD causing ischemic stroke, but further studies are needed to identify a possible mechanism. This study confirms the association of hyperhomocysteinemia with ischemic stroke due to atherothrombotic or small artery disease.

Hypoplasia and fibromuscular dysplasia of infrarenal abdominal aorta with downstream aneurysm: Case report and review of the literature

Fibromuscular dysplasia represents one of the more common types of arterial fibrodysplasia, a heterogeneous group of nonatherosclerotic vascular occlusive and aneurysmal diseases. This disorder mainly affects renal and cerebral arteries, and less frequently, arm, leg, and visceral arteries. Exceptionally, it has been described in the abdominal aorta. Aortic hypoplasia is a tubular narrowing of a long segment of the aorta and is a rare congenital defect, different from coarctation, which is a focal stricture. We present the first case, to our knowledge, of an elderly man with infrarenal aortic fibromuscular dysplasia associated with aortic hypoplasia, without involvement of renal arteries, and contiguous aortoiliac aneurysm.

Ruptured Cerebral Aneurysm and Acute Coronary Artery Dissection in the Setting of Multivascular Fibromuscular Dysplasia

Fibromuscular dysplasia (FMD) is a segmental noninflammatory nonatherosclerotic vascular disease that has been described in almost every arterial bed, including the cerebral and coronary arteries. FMD of cerebral vessels has been associated with development of saccular aneurysms in the involved vessels. Acute dissection of coronary arteries is also a rare complication of FMD. Herein, we report the first case of both complications of FMD occurring in a single patient-a ruptured anterior communicating artery aneurysm and a right coronary artery dissection occurring in a 38-year-old woman. At autopsy, FMD was found in multiple vascular beds. Our findings reveal the potential for involvement of several vascular beds in patients with FMD, resulting in multiple vascular complications.

Middle aortic syndrome: Surgical treatment in a child with neurofibromatosis

A 9-year-old boy was referred to our institution for management of severe renovascular hypertension (controlled with 6 antihypertensive medications), postprandial abdominal pain, and bilateral lower-limb claudication. He was diagnosed with neurofibromatosis at age 6, manifested by multiple cafe-au-lait macules ( 5cm), axillary and inguinal freckling, and brain lesions on magnetic resonance imaging consistent with neurofibromas. Physical findings included a midepigastric bruit and attenuated lower limb arterial pulses (ankle-brachial index (ABI), 0.67[Rt]/0.7[Lt]). Digital subtraction angiography revealed segmental narrowing of the abdominal aorta frombelowtheceliac to the inferiormesenteric artery (meanpressuregradient 30mmHg)andorificial stenoses ( 75%)of the right renal (A)andsuperiormesenteric arteries (A, insert). Investigation excluded a pheochromocytoma. Surgery, through a midline incision, entailed an aortoaortic bypass (14-mm gelatin-coated polyester) from the supraceliac to distal infrarenal aorta, tunneled posterior to the left kidney, and a retrograde bypass to the superior mesenteric (end-to-side) and right renal (end-to-end) arteries, using 6-mm collagen-coated polyester grafts from the infrarenal aorta (B [Cover]). The patient was discharged on the fifth post-operative day on a single antihypertensive medication, with normal pulses and pressure indexes (ABI, 1.07[Rt]/1.09[Lt]), and a serum creatinine of 0.86. Four months postoperatively the child was normotensive on no drug treatment, free of abdominal pain and claudication, with all of his grafts patent and stenosis-free, as depicted in 3-dimensional contrast computed tomography imaging of the reconstructed aortovisceral circulation (C). Segmental narrowing of the abdominal aorta, designated middle aortic syndrome (MAS), represents an uncommon variety (0.5%-2%) of aortic coarctations attributable to acquired or congenital etiologies. Acquired etiologies include non-specific (Takayasu’s) and giant cell arteritis and neurofibromatosis, whereas congenital aortic hypoplasia is ascribed to a developmental anomaly in the fusion and maturation of the paired embryonic dorsal aortas. 1-4

Intestinal Ischemia as a Single Manifestation of Thromboangiitis Obliterans

Thromboangiitis obliterans (TAO) is an inflammatory, nonocclusive, and nonatherosclerotic vascular disease. It commonly affects arteries, veins, and surrounding neural elements and is directly related to smoking. Although distal vessels of lower and upper extremities are the most commonly involved, other vessels such as intestinal arteries can be rarely affected. The authors describe a 41-year-old white male smoker who presented with abdominal pain for 3 months and developed an acute bowel ischemia. He underwent urgent surgery, and segmental enterectomy was performed. Histopathologic findings were suggestive of TAO, showing typical involvement of small-sized veins and arteries with intact internal elastic lamina, preserved media, a local nonspecific inflammatory reaction, with new and older arterial and venous thromboses associated. Although mesenteric arteries are seldom injured by TAO, this diagnosis must be considered when the usual causes of intestinal ischemia are ruled out. In this case, even without any other clinical symptoms of TAO, this rare diagnosis could be made.

Non-Atherosclerotic Vascular Disease in the Young

There are a large variety of non-atherosclerotic causes of ischemic stroke in the young. Arterial dissection, most commonly associated with non-traumatic causes, is among the most common. Both the carotid and vertebrobasilar circulations can be affected. The vasculitidies represent a rare, but potentially treatable series of conditions that can lead to stroke through diverse mechanisms. Moyamoya is a nonatherosclerotic, noninflammatory, nonamyloid vasculopathy characterized by chronic progressive stenosis or occlusion of the distal internal carotid arteries and/or proximal portions of the middle and/or anterior cerebral arteries. Moyamoya can be idiopathic (moyamoya disease) or the result of other conditions. An appreciation of the unusual causes of stroke in the young is important when considering secondary prevention measures.

Inpatient Treatment of Severe Nicotine Dependence in a Patient With Thromboangiitis Obliterans (Buerger's Disease)

Thromboangiitis obliterans (TAO), or Buerger's disease, is an inflammatory, occlusive, and nonatherosclerotic vascular disease that most commonly affects small and medium-sized arteries and veins. The association between tobacco use and the development of TAO is incontestable; however, a substantial number of patients with TAO continue to use tobacco despite progression of disease and amputation. Herein we describe a patient with advanced TAO whose severe, refractory nicotine dependence was successfully treated in a specialized nicotine-dependence inpatient program. After cessation of smoking, the patient's disease stabilized. Inpatient nicotine-dependence treatment may represent an alternative for recidivist smokers with severe tobacco-related disease.

Isolated Iliac Artery Dissection Secondary to Fibromuscular Dysplasia

Among the nonatherosclerotic vascular diseases leading to ischemic complications in young adults, fibromuscular dysplasia (FMD) is relatively common. Manifestations of this abnormality most frequently occur secondary to stenosis, aneurysm formation, or embolization of the renal or internal carotid arterial beds. Although 3 cases of external iliac artery dissection (2 with confirmed FMD) have been reported, no reports exist of isolated dissection of the common iliac artery in the absence of a more proximal aortic entry point. Three otherwise healthy men were diagnosed with acutely symptomatic isolated iliac artery dissection (2 common iliac, 1 external iliac). Two patients required arterial bypass grafting for the relief of ischemia; histologic examination demonstrated FMD. The third patient had early findings on arteriography of associated renal arterial FMD. Although a dissection of the common iliac artery was confirmed in this patient on imaging studies as well as arteriography, he manifested no ischemic symptoms or aneurysmal dilation and is being managed nonoperatively. The diagnosis of arterial dissection secondary to FMD should be strongly considered in the differential diagnosis of young patients with signs and symptoms of lower extremity ischemia. Noninvasive diagnostic modalities (computerized tomography [CT], magnetic resonance imaging [MRI], and duplex scans) will establish the diagnosis, but arteriography remains essential to delineate the extent of involvement. The associated finding of FMD in other vascular beds may help to confirm the diagnosis as well as contribute to the future management of these patients.