Moyamoya Vasculopathy and Moyamoya-Related Systemic Vasculopathy: A Review With Histopathological and Genetic Viewpoints.

Systemic vasculopathy has occasionally been reported in cases of moyamoya disease (MMD). Since the pathological relationship between moyamoya vasculopathy (MMV) and moyamoya-related systemic vasculopathy (MMRSV) remains unclear, it was examined herein by a review of histopathologic studies in consideration of clinicopathological and genetic viewpoints. Although luminal stenosis was a common finding in MMV and MMRSV, histopathologic findings of vascular remodeling markedly differed. MMV showed intimal hyperplasia, marked medial atrophy, and redundant tortuosity of the internal elastic lamina, with outer diameter narrowing called negative remodeling. MMRSV showed hyperplasia, mainly in the intima and sometimes in the media, with disrupted stratification of the internal elastic lamina. Systemic vasculopathy has also been observed in patients with non-MMD carrying the RNF213 (ring finger protein 213) mutation, leading to the concept of RNF213 vasculopathy. RNF213 vasculopathy in patients with non-MMD was histopathologically similar to MMRSV. Cases of MMRSV have sometimes been diagnosed with fibromuscular dysplasia. Fibromuscular dysplasia is similar to MMD not only in the histopathologic findings of MMRSV but also from clinicopathological and genetic viewpoints. The significant histopathologic difference between MMV and MMRSV may be attributed to a difference in the original vascular wall structure and its resistance to pathological stress between the intracranial and systemic arteries. To understand the pathogeneses of MMD and MMRSV, a broader perspective that includes RNF213 vasculopathy and fibromuscular dysplasia as well as an examination of the 2- or multiple-hit theory consisting of genetic factors, vascular structural conditions, and vascular environmental factors, such as blood immune cells and hemodynamics, are needed.

Lesions of the Cardiac Conduction System and Sudden Death.

ABSTRACT: When a young previously healthy person dies suddenly, occasionally, the scene is noncontributory and the autopsy and drug screen are negative. In such cases, additional studies, including genetic assessment and cardiac conduction system examination, should be performed. We performed a literature search and reviewed our own material to identify possible or definite conduction system anomalies that may cause death. We identified intrinsic conduction system disease including cystic tumor of the atrioventricular node, atrioventricular node (cystic tumor of the AV node), and fibromuscular dysplasia of the atrioventricular node artery to be likely causes of death. Extrinsic causes, in which a generalized disease affects the conduction system, include tumors, autoimmune disease, infiltrative disorders, and others, are a second category of diseases that can affect the conduction system and cause atrioventricular block and sudden death.

FMD and SCAD: Sex-Biased Arterial Diseases With Clinical and Genetic Pleiotropy.

Multifocal fibromuscular dysplasia (FMD) and spontaneous coronary artery dissection are both sex-biased diseases disproportionately affecting women over men in a 9:1 ratio. Traditionally known in the context of renovascular hypertension, recent advances in knowledge about FMD have demonstrated that FMD is a systemic arteriopathy presenting as arterial stenosis, aneurysm, and dissection in virtually any arterial bed. FMD is also characterized by major cardiovascular presentations including hypertension, stroke, and myocardial infarction. Similar to FMD, spontaneous coronary artery dissection is associated with a high prevalence of extracoronary vascular abnormalities, including FMD, aneurysm, and extracoronary dissection, and recent studies have also found genetic associations between the two diseases. This review will summarize the relationship between FMD and spontaneous coronary artery dissection with a focus on common clinical associations, histopathologic mechanisms, genetic susceptibilities, and the biology of these diseases. The current status of disease models and critical future research directions will also be addressed.

Endovascular interventions in main renal artery pathologies: an overview and update.

Renal arteries are involved in a wide spectrum of pathologies including atherosclerosis, fibromuscular dysplasia, Takayasu arteritis, aneurysms, and aortic type B dissections extending into main renal arteries. They manifest as renovascular hypertension, renal ischemia, and cardiovascular dysfunction. The location of the renal arteries in relation to the abdominal aortic aneurysm is a critical determinant of interventional options and long-term prognosis. This article provides a comprehensive review of the role of interventional radiologists in transcatheter interventions in various pathologies involving the main renal arteries with analysis of epidemiology, pathophysiology, newer interventional techniques, and management options.

Coronary fibromuscular dysplasia with three-vessel involvement: a rare cause of ischaemic dilated cardiomyopathy in a very young male.

Coronary artery disease of non-atherosclerotic aetiology, while rare in incidence, can have a wide aetiology, such as fibromuscular dysplasia, which is a non-inflammatory arteriopathy of numerous histopathological types of fibromuscular tissue accumulation. This brief report describes the case of a 22-year-old male with a recently developed dilated cardiomyopathy and a history of aborted cardiac arrest at the age of 14 years. Coronary angiogram revealed severe three vessels disease, while optical coherence tomography established fibromuscular dysplasia as aetiology. Balloon and stent angioplasty was performed guided by fractional flow reserve with acceptable angiographic result.

[Arterial fibromuscular dysplasia as a factor in sudden cardiac death in young adults]. / Fibromuskulyarnaya displaziya arterii ­ odin iz faktorov vnezapnoi serdechnoi smerti lits molodogo vozrasta.

The objective of the study is to consider the problem of diagnostics of a rare vasculopathy, fibromuscular dysplasia of coronary arteries, by the case study of a 19-year-old serviceman, an athlete with sudden death occurred during slight physical exertion. After repeated histological examination as part of the forensic medical examination, the diagnosis was made: «multifocal fibromuscular dysplasia of the coronary arteries and ascending aortic arch, complicated by acute left ventricular failure.¼ This disease often manifests with the acute coronary syndrome in people of young age. Therefore, special attention was given to the macroscopic and histological features of fibromuscular dysplasia of arteries.

A Novel Recurrent COL5A1 Genetic Variant Is Associated With a Dysplasia-Associated Arterial Disease Exhibiting Dissections and Fibromuscular Dysplasia.

OBJECTIVE: While rare variants in the COL5A1 gene have been associated with classical Ehlers-Danlos syndrome and rarely with arterial dissections, recurrent variants in COL5A1 underlying a systemic arteriopathy have not been described. Monogenic forms of multifocal fibromuscular dysplasia (mFMD) have not been previously defined. Approach and Results: We studied 4 independent probands with the COL5A1 pathogenic variant c.1540G>A, p.(Gly514Ser) who presented with arterial aneurysms, dissections, tortuosity, and mFMD affecting multiple arteries. Arterial medial fibroplasia and smooth muscle cell disorganization were confirmed histologically. The COL5A1 c.1540G>A variant is predicted to be pathogenic in silico and absent in gnomAD. The c.1540G>A variant is on a shared 160.1 kb haplotype with 0.4% frequency in Europeans. Furthermore, exome sequencing data from a cohort of 264 individuals with mFMD were examined for COL5A1 variants. In this mFMD cohort, COL5A1 c.1540G>A and 6 additional relatively rare COL5A1 variants predicted to be deleterious in silico were identified and were associated with arterial dissections (P=0.005). CONCLUSIONS: COL5A1 c.1540G>A is the first recurring variant recognized to be associated with arterial dissections and mFMD. This variant presents with a phenotype reminiscent of vascular Ehlers-Danlos syndrome. A shared haplotype among probands supports the existence of a common founder. Relatively rare COL5A1 genetic variants predicted to be deleterious by in silico analysis were identified in ≈2.7% of mFMD cases, and as they were enriched in patients with arterial dissections, may act as disease modifiers. Molecular testing for COL5A1 should be considered in patients with a phenotype overlapping with vascular Ehlers-Danlos syndrome and mFMD.

Standing Waves on Computed Tomography Angiography in Multiple Vessels in a Young Trauma Patient.

ABSTRACT: Standing waves are a phenomenon of uncertain etiology seen on imaging. We present the first case demonstrating standing waves on computed tomography angiography in multiple vessels in a single patient with imaging evidence of resolution in some of the vessels. Our case further supports the literature that standing waves are a physiologic phenomenon, likely because of flow mechanics, rather than modality.

Carotid web: an occult mechanism of embolic stroke.

The carotid web is a proposed stroke mechanism that may underlie cryptogenic stroke, particularly in younger patients without vascular risk factors. The web appears as a shelf-like projection into the lumen of the proximal cervical internal carotid artery without evidence of calcification. It is pathologically defined as intimal fibromuscular dysplasia. Altered haemodynamics distal to the web cause flow stagnation and remote embolisation of fibrin-based clots. It is best demonstrated and diagnosed on CT angiography (CTA) of the neck because of its ability to resolve calcium and create multiplanar reconstructions. Although they can be readily visualised on CTA, carotid webs may be missed or misinterpreted because they do not typically cause haemodynamically significant stenosis and can mimic arterial dissection, non-calcified atherosclerotic plaque and intraluminal thrombus. Options for management include antiplatelet therapy, carotid endarterectomy and carotid artery stenting. Modern management strategies for cryptogenic stroke include long-term cardiac monitoring, further investigation for structural cardiac disease and a diagnostic workup for arterial hypercoagulability, however, these strategies are not likely to capture the possibility of a carotid web. Carotid webs should be suspected in a young patient presenting with recurrent unihemispheric strokes particularly when conventional vascular risk factors are not present.

Case reports of coronary fibromuscular dysplasia and spontaneous coronary artery dissections.

Spontaneous coronary artery dissection (SCAD) is an important cause of acute coronary syndrome especially in women. The most common underlying predisposing cause of SCAD is fibromuscular dysplasia (FMD), a non-inflammatory arteriopathy that results in weakening of the affected arteries, and can cause dissection or aneurysm. Coronary FMD (CFMD) was described as rare, and was shown to cause SCAD in histopathological case reports. Unfortunately, CFMD is challenging to diagnose on coronary angiography, as the findings can be similar to other causes of coronary artery disease. Therefore, we illustrate two case examples of CFMD on coronary angiography, and highlight findings on optical coherence tomography to aid diagnosis.

Ruptured Superior Mesenteric Artery Aneurysm due to Fibromuscular Dysplasia: A Rare Vascular Presentation in a Patient with Schizophrenia.

Visceral aneurysms are rare entities, with a reported incidence of 0.01-2%. Fibromuscular dysplasia is a nonatherosclerotic, noninflammatory artery disease, which may predispose to aneurysmal degeneration. Schizophrenia has been linked to an increased cardiovascular risk because of the influence of traditional and disease-specific risk factors. We report the case of a 44-year-old male schizophrenic patient presenting with a ruptured giant aneurysm of superior mesenteric artery, managed by mesenteric ligation. The histologic diagnosis was fibromuscular dysplasia. Another case of visceral aneurysm in schizophrenic patient with similar histologic features has been previously reported in literature.

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.

"Basilar Web" Causing Basilar Branch Infarction.

We present a young patient with no vascular risk factors with a basilar branch infarction secondary to a shelf-like filling defect of the basilar artery. This defect was present and unchanged on repeat imaging and determined to be most consistent with a basilar web. Similar to carotid webs, a basilar web is believed to be an area of focal intimal fibroplasia that increases the risk of brainstem infarction. Focal fibroplasia of the posterior circulation should be considered when evaluating young adults with posterior circulation strokes of otherwise undetermined cause.

Imaging studies in pediatric fibromuscular dysplasia (FMD): a single-center experience.

BACKGROUND: Fibromuscular dysplasia (FMD) is a non-inflammatory vascular disease that in children unlike in adults shows no sex predilection. FMD is often underdiagnosed, and its pathophysiology is unclear. Delayed diagnosis may lead to refractory hypertension and decreases the chance of successful treatment. Doppler ultrasound (US), magnetic resonance angiography (MRA), computed tomography angiography (CTA), and catheter-based angiography (angiography) are currently used to help make a clinicoradiological diagnosis of FMD. The main aim of the study was to compare the efficacy of imaging modalities which can allow for earlier and improved detection. Furthermore, an anatomical mapping of the location of lesions can help determine the best treatment modalities. METHODS: All patients with non-syndromic non-inflammatory renovascular hypertension were recruited from the Nephrology Department at the Children's Hospital of Philadelphia (CHOP) and enrolled in the U.S. FMD Registry maintained at the University of Michigan. Clinical presentation and imaging findings on US, CT, and MRI of children diagnosed with FMD were evaluated. RESULTS: Mean age at diagnosis was 7 ± 4.9 years (4 months-17 years). Family history of hypertension (HTN) (52%), FMD (8.7%), Caucasian (60%), headache (48%), and HTN (80%) were the most prevalent symptom and sign at presentation. Bruits were 100% specific for renal artery stenosis (RAS) diagnosis but were heard in the minority of patients (3 patients, 12%). FMD was mainly unifocal within a single site (68%) or multiple sites (28%) and involved the main or first order renal branch in about 68% of children. Isolated distal lesions beyond the second order branches were found in about 25% of children. US imaging was significantly less sensitive than angiography (28%, p = 0.003). MRA had a better sensitivity (62.5%, p = 0.3) than US. Overall, CTA had the best sensitivity (84.2%, p = 0.4) compared to angiography; however, only angiography showed distal vessel disease. CONCLUSIONS: Limitations of the study include the sample size and biases-only patients diagnosed with FMD were included in this study and most patients were referred to a pediatric nephrologist for unexplained hypertension. Angiography should be performed as part of the initial work-up of any child suspected of having renovascular FMD, regardless of the findings seen on US, MRA, or CTA.

Right Subclavian Artery Aneurysms with Fibromuscular Dysplasia.

Subclavian artery aneurysms (SAAs) are rare and even more uncommon in patients with fibromuscular dysplasia (FMD). A 20-year-old man with a past medical history of moyamoya disease presented with an abnormal mass shadow in the apex of the right lung on chest X-ray. Based on computed tomography imaging, a diagnosis of right SAA was established, and an excision of the aneurysm was performed. Because the left vertebral artery is dominant, the proximal and distal right subclavian artery and right vertebral artery were clamped. Then, the aneurysm was excised, and resection anastomosis was performed. Histological findings revealed FMD. The postsurgical course has been uneventful after 2 years. Among treatment modalities, open surgery would be the first choice for SAAs with FMD, despite the current era of endovascular surgeries.

Sudden Death Due to Cystic Tumor of the Atrioventricular Node and Fibromuscular Dysplasia Involving Branches of the Coronary Arteries.

In this paper, we report the autopsy findings of a 42-year-old White male who was found deceased at his home by his brother in the early morning hours with a history of excessive alcohol consumption 1 day before his death. A medical record review revealed chronic alcohol use with alcohol dependence syndrome, hypertension, and cardiac arrhythmias by electrocardiogram 2 years prior. External examination revealed only a single bruise on the forehead. Internal examination revealed changes associated with chronic alcohol abuse and mild atherosclerosis. The lack of a cause of death at autopsy resulted in a dissection of the cardiac conduction system and the detection of a small cystic lesion at the atrioventricular node region. Microscopic examination revealed a cystic tumor of the atrioventricular node and fibromuscular dysplasia of the coronary artery branches near the sinoatrial and atrioventricular nodes. Based on the case history and autopsy findings, death was attributed to a fatal cardiac arrhythmia due to cystic tumor of the atrioventricular node with fibromuscular dysplasia of the coronary artery branches near the sinoatrial and atrioventricular nodes a possible contributing factor.

Genomics of Fibromuscular Dysplasia.

Fibromuscular Dysplasia (FMD) is “an idiopathic, segmental, non-atherosclerotic and non-inflammatory disease of the musculature of arterial walls, leading to stenosis of small and medium-sized arteries” (Persu, et al; 2014). FMD can lead to hypertension, arterial dissections, subarachnoid haemorrhage, stroke or mesenteric ischemia. The pathophysiology of the disease remains elusive. While familial cases are rare (<5%) in contemporary FMD registries, there is evidence in favour of the existence of multiple genetic factors involved in this vascular disease. Recent collaborative efforts allowed the identification of a first genetic locus associated with FMD. This intronic variant located in the phosphatase and actin regulator 1 gene (PHACTR1) may influence the transcription activity of the endothelin-1 gene (EDN1) located nearby on chromosome 6. Interestingly, the PHACTR1 locus has also been involved in vascular hypertrophy in normal subjects, carotid dissection, migraine and coronary artery disease. National and international registries of FMD patients, with deep and harmonised phenotypic and genetic characterisation, are expected to be instrumental to improve our understanding of the genetic basis and pathophysiology of this intriguing vascular disease.

Internal Carotid Artery Web as the Cause of Recurrent Cryptogenic Ischemic Stroke.

Carotid artery web is considered an exceptional cause of recurrent ischemic strokes in the affected arterial territory. The underlying pathology proposed for this entity is an atypical fibromuscular dysplasia. We present the case of a 43-year-old woman with no cardiovascular risk factors who had experienced 2 cryptogenic ischemic strokes in the same arterial territory within an 11-month period. Although all diagnostic tests initially yielded normal results, detailed analysis of the computed tomography angiography images revealed a carotid web; catheter angiography subsequently confirmed the diagnosis. Carotid surgery was performed, since which time the patient has remained completely asymptomatic. The histological finding of intimal hyperplasia is consistent with previously reported cases of carotid artery web. Carotid artery web is an infrequent cause of stroke, and this diagnosis requires a high level of suspicion plus a detailed analysis of vascular imaging studies.

Symptomatic Carotid-Bulb Atypical Fibromuscular Dysplasia.

Fibromuscular dysplasia (FMD) is known as rare cause ischemic stroke and usually involves the internal carotid or vertebral arteries in middle age women. A poorly known type of FMD located at the carotid bulb is called atypical fibromuscular dysplasia. We present the case of 3 young black patients suffering from recurrent ischemic strokes in the same middle cerebral artery territory. Computed tomographic angiography and arteriography showed a moderate diaphragmatic stenosis of the carotid bulb. After surgical removal of the dysplasia, postoperative course was uneventful without any recurrence. Pathologic examination confirmed atypical FMD. Carotid-bulb atypical FMD is a rare cause of stroke and concerns mostly young black patients. Surgical approach should be recommended to avoid recurrent stroke.

Carotid diaphragm: Atypical fibromuscular dysplasia or atheromatous lesions?

Atypical fibromuscular dysplasia (FMD) is an underdiagnosed cause of ischemic stroke. The typical angiographic pattern of a septum on the posterolateral side of a carotid megabulb is highly suggestive of atypical FMD. We report here on two patients with this highly suggestive pattern of carotid atypical FMD, but which histological examination revealed to be atheromatous lesions. Interestingly, contrast-enhanced ultrasound of the carotid artery showed enhancement of the spur, which should never be the case with an FMD lesion, which has no vasa vasorum. Our findings suggest that the results of studies reporting stenting of atypical FMD in cervical arteries should be interpreted with caution.