Fibromuscular dysplasia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohsen Basiri M.D.

The definition of Fibromuscular Dysplasia(FMD) on the Medical Subject Headings is “an idiopathic, segmental, nonatheromatous disease of the musculature of arterial walls, leading to stenosis of small and medium-sized arteries. There is a true proliferation of smooth muscle cells and fibrous tissue formation. however, this systemic arteriopathy is a noninflammatory process and is therefore not associated with inflammatory biomarkers.

According to the definition, FMD is a condition which can involve every vascular bed in the body, therefore it can cause very heterogeneous and extensive spectrum of clinical manifestations from asymptomatic involvement to devastating consequences and morbidity and mortality.

Unlike routine conception that FMD is a rare disease of middle-aged female, current data from the French and US registries showed that the awareness about FMD must be raised, and every health provider at any level should be familiar with suggestive symptoms and signs of FMD which is more frequent and more often systematic than previously thought.^[1]

Fibromuscular dysplasia was first discovered by Leadbetter and Burkland, in 1938 following evaluation of severe hypertension in a 5-year-old boy. The first histopathological description of fibromuscular dysplasia and pathologic classification for this condition was proposed in 1958 and 1971 by McCormack and coworkers, respectively.^{[2] [3]}

Fibromuscular dysplasia with involvement of extrarenal arteries has been considering in recent years. However numerous aspects of molecular biology and genetic etiology of this condition remain unanswered, and there are various top research priorities in the field of FMD to improve our understanding of this condition.

The classification system for fibromuscular dysplasia (FMD) was first according to the arterial layer involved. (tunica intima, tunica media , or adventitia) . However, with use of transluminal percutaneous angioplasty (TPA) for treatment of FMD lesions and its preference rather than surgery, the obtaining of pathological specimens are restricted. Thus, today, FMD is a disease diagnosed radiographically and histopathological classification has been replaced by the arteriographic findings.^[4]

In Fibromuscular dysplasia, the proliferation of vascular smooth muscle of one or more small or medium-sized arteriesundergo dysplasia and cause stenosis. this abnormal cellular development is characterized by fibrous thickening of the intima, media, or adventitia of the involved arteries; which ultimately lead to arterial narrowing.

The cause of fibromuscular dysplasia has not been identified. To review risk factors for the development of FMD, click here.

Fibromuscular dysplasia must be differentiated from other diseases that present clinical features of multisystem involvement, hypertension, aneurysm, and dissection, such as atherosclerotic vascular disease, vasculitis, and Ehlers-Danlos Type IV.

There is a significant delay in diagnosis from the first onset of clinical symptoms/signs of 4.4 years in men and 4.1 years in women. There are several possible reasons for such a delay, including the possibility that FMD is not considered in the differential diagnosis of a patient’s symptoms because of under-recognition of this disorder, the mistaken belief that FMD is predominately a rare disease of young patients, and the fact that many of the signs and symptoms of FMD are nonspecific, such as dizziness, tinnitus, and headaches.^[5]

The prevalence of FMD in the general population is not known. In some studies, the prevalence of renal artery FMD has been calculated to be approximately 4 per 100 adults.^[6][7][8]

There are no established risk factors for fibromuscular dysplasia; nevertheless, there are some evidences that cigarette smoking, hypertension and other classic risk factors for atherosclerosis may be risk factors in the development of FMD. FMD has a greater prevalence among women but no definite association has been found between this condition and use of oral contraceptives or disturbances of endogenous sex hormones. Since the disease is more common among the first-degree relatives of patients with FMD, Genetic factors may play a role in the development of FMD. ^[9]

According to the American Heart Association (AHA)/American College of Cardiology guidelines, and European consensus on the diagnosis and management of fibromuscular dysplasia, there are some recommendations and indications for the screening of FMD-related RAS, cervicocephalic FMD, and in first-degree relatives of patients with FMD.^[10][4][7]

Current knowledge about natural history, the efficacy of medical therapies, complications, and prognosis of FMD, are really restricted; however the natural history of FMD is benign, and the long-term prognosis of patients with FMD is good, and its existence alone is not an indication for preventive intervention or surgery.

Renal or cervival artery dissection and Intracranial aneurysms rupture and SAH are the most common complications of FMD.^[1]

Catheter-based angiography is the gold standard test for the diagnosis of renovascular fibromuscular dysplasia. Imaging modalities are the methods for diagnosing FMD. Duplex ultrasonography, accompanied by computed tomographic angiography(CTA), and magnetic resonance angiography (MRA), are imaging techniques for detecting FMD lesions but the gold standard remains catheter-based angiography.^[1]

Since Fibromuscular dysplasia can involve virtually every artery of the body, thus the clinical presentations of FMD vary widely and are determined by the vessels territories that are involved.The clinical presentations of FMD may result from the stenosis, occlusion, ischemia, dissection, rupture of aneurysms and embolization of intravascular thrombi from dissection or aneurysms.^[5]

Patients with FMD usually appear normal. In physical examination of patients with FMD mild to moderate hypertension may be detected. In the auscultation of neck among patients with involvement of carotid artery or auscultation of epigastric or flank of renovascular FMD bruits may be heard. Eventullay due to nonspecific sypmtoms and sings of FMD, the diagnosis of this disease needs highly clinical suspicion of healthcare provider.

There are no diagnostic laboratory findings associated with fibromuscular dysplasia.

There are no ECG findings associated with FMD.

However, duplex (doppler with B-mode) ultrasound is less sensitive than CT-angiography and MRA for detecting atherosclerotic RAS and FMD-related RAS, but convenient availability, modest expenditure, non-irradiating and easily providing information about kidney size, the hemodynamic impact of the stenosis, and associated renal disease, makes DUS as a reasonable first-line screening imaging modality.

Computed tomography angiography (CTA) has really excellent diagnostic exactness for FMD of the renal arteries. CTA may use in the diagnosis of FMD of the cervicocephalic arteries and to find associated intracranial lesions.

Magnetic resonance angiography (MRA) in comparison with DUS and CTA is less preferred. In MRA images there is an inadequate spatial resolution in the branch vessels, as well as pseudo-beading features from artifact impact. However, MRA can be useful for detecting aneurysms and dissections.

Arteriography remains the gold standard in diagnosis of FMD. Angiography with contrast will show a characteristic “string of beads” morphology in a vessel affected by FMD.

Pharmacologic medical therapies for treatment of renovascular hypertension in FMD patients include ACE inhibitors and angiotensin receptor blockers (ARBs).If a second medication is needed, the addition of a thiazide diuretic is an acceptable choice. Among patients with an ischemic event, antiplatelet therapy is generally used

Revascularization by surgical intervention or percutaneous transluminal angioplasty (PTA) , are not the first-line treatment options for patients with FMD, however in cases of FMD-related RAS with signs of downstream reduction of renal function or in case of drug-resistant HTN vascular reconstruction should be considered.

There are no established measures for the primary prevention of fibromuscular dysplasia.

There are no established measures for the secondary prevention of FMD.

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohsen Basiri M.D.

Fibromuscular dysplasia was first discovered by Leadbetter and Burkland, in 1938 following evaluation of severe hypertension in a 5-year-old boy. The first histopathological description of fibromuscular dysplasia and pathologic classification for this condition was proposed in 1958 and 1971 by McCormack and coworkers.

Fibromuscular dysplasia with involvement of extrarenal arteries has been considering in recent years. However numerous aspects of molecular biology ang genetic etiology of this condition remains unanswered, and there are various top research priorities in the field of FMD to improve our understanding of this condition.

• Fibromuscular dysplasia was first introduced by Leadbetter and Burkland in 1938 in a 5-year-old boy with severe hypertension in a unilateral intra-arteria mass. this American-African boy underwent a unilateral nephrectomy and his hypertension was remedied.^[1]
• Although the first histopathological description of this condition performed by McCormack and coworkers by the report of four cases of “fibromuscular hyperplasia” in 1958.^[2]
• The first conception of these occlusive masses was described as hyperplasia and it lasted about 13 years until the exact pathologic classification of fibromuscular dysplasia was proposed in 1971 by Harrison and McCormack.^[3]

• FMD with involvement of extrarenal arteries was first recognized angiographically in 1964 by Palubinskas and Ripley as a non-atherosclerotic stenosis of internal carotid artery. Also, extrarenal FMD has been noted in external carotid arteries and its branches and in vertebral arteries.^[4]

• In 1965, Hill and Antonius were the first to report FMD in coronary arteries.^[5]

• In 2012, after several months of the release of the French Registry for FMD and European Consensus on the diagnosis and management of FMD, the United States Registry for Fibromuscular Dysplasia (US Registry) reported data from the first 447 patients were enrolled.^[6][7][8]

• During past decades and especially in recent years, these efforts and publications have dispelled some aspects of FMD enigma.these are significant efforts to improve our clarification of non-atherosclerotic causes vascular accidents. Nevertheless, FMD remains a medical myth specifically at the genetic and molecular levels. It is hoped that the new researches and studies provide more effective and evidence-based information for diagnosis and treatment of FMD.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohsen Basiri M.D.

In Fibromuscular dysplasia, the proliferation of vascular smooth muscle of one or more small or medium-sized arteries undergo dysplasia and cause stenosis. this abnormal cellular development is characterized by fibrous thickening of the intima, media, or adventitia of the involved arteries; which ultimately lead to arterial narrowing. Despite numerous genetic, hormonal and mechanical factors have been proposed, the etiology of fibromuscular dysplasia remains unknown.

In Fibromuscular dysplasia, the proliferation of vascular smooth muscle of one or more small or medium-sized arteries undergo dysplasia and cause stenosis. this abnormal cellular development is characterized by fibrous thickening of the intima, media, or adventitia of the involved arteries; which ultimately lead to arterial narrowing.

Despite numerous genetic, hormonal and mechanical factors have been proposed, the etiology of fibromuscular dysplasia remains unknown. A variety of factors have been implicated. These include:

• Cigarette smoking and a history of hypertension^[1]
• Genetic factors, with a reported autosomal mode of inheritance in some families.^[2]

• Some studies suggest fibromuscular dysplasia is a systemic disease with altered TGF-β expression and connective tissue features.

• Hormonal influence, The increased incidence of FMD in women as compared with men suggests a possible hormonal given the predominance in women of childbearing age but no association has been found between fibromuscular dysplasia and previous use of oral contraceptives or abnormalities of endogenous sex hormones.^[3]

• Some authors have proposed the sex difference to be related to immune system functioning, but overt inflammation, as is observed in most classic autoimmune diseases, is histologically lacking.
• Mechanical factors due to stretching of smooth muscle cells and microtrauma to the vessel wall.
• Ischemia due to fibrotic occlusion of the vasa vasorum.

• Genetic predisposition may play a role in the development of fibromuscular dysplasia. Owing to, FMD is more common among the first-degree relatives of patients with this condition.

• Some studies showed an autosomal dominant transmission pattern for fibromuscular dysplasia; however, as of yet, no etiologic genes have been identified for this disease. Applying molecular genetics investigations will reveal information about FMD pathogenesis, and family-based studies, evaluating genome of candidates, and wide genome studies can help to recognize pathophysiology of FMD.

• In the US Registry, about eight percent of patients report a confirmed diagnosis of FMD in one or more in first- or second-degree family members. However, the high prevalence of aneurysms, sudden death, and stroke among first- and second-degree family members in the US Registry shows that FMD may be associated with systemic arteriopathy with a great diversity of clinical phenotype traits. It is hypothesized that FMD may have common features with vascular connective tissue diseases, such as Loeys-Dietz syndrome or the vascular type of Ehlers-Danlos syndrome.

• Increased level of TGF-β1 and 2 secreted by fibroblasts in patients with FMD in comparison to matched

FMD patients also had elevated plasma levels of circulating TGF-β1 and TGF-β2 relative to matched controls. The potential involvement of TGF-b pathways in the pathogenesis of FMD is an area for future investigation, especially as this pathway could provide a potential target for disease-modifying medical therapies.^[4]

• Polymorphisms of angiotensin-converting–enzyme allele ACE-I among patients with multifocal renal arterial fibromuscular

dysplasia has been investigated.^[5]

• In some case reports, the association of FMD with neurofibromatosis, Alport syndrome, and pheochromocytoma have been considered; And mutations in collagen, and with alpha1-antitrypsin deficiency have also been suggested.^[6][7][8]

• The underlying connective tissue problem among arteries with FMD, causes weakening of arterial wall and leads to vessel dilatation.The combined prevalence of aneurysms and FMD is estimated to be about 8%.

• FMD is a predisposing factor for spontaneous cervical carotid, or renal artery dissections. Dissection through the weakening of the arterial wall, in FMD are more commonly multiple than in patients without an identified underlying arteriopathy.

• On gross pathology, focal, irregular, thickening in medium and large muscular arteries are characteristic findings of FMD.

• On microscopic histopathological analysis, circumferential or eccentric deposition of collagen in intima but no lipid or inflammatory component are characteristic findings of FMD.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohsen Basiri M.D.

The cause of fibromuscular dysplasia has not been identified.

The cause of fibromuscular dysplasia has not been identified. A variety of factors have been implicated. These include:

• Genetic predisposition with a reported autosomal mode of inheritance in some families^[1][2]
• Hormonal influence, given the predominance in women of childbearing age
• Mechanical factors such as stretching of smooth muscle cells and trauma to the blood vessel wall
• Ischemia of the blood vessel wall due to fibrotic occlusion of the vasavasorum

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohsen Basiri M.D.

Fibromuscular dysplasia must be differentiated from other diseases that present clinical features of multisystem involvement, hypertension, aneurysm, and dissection, such as atherosclerotic vascular disease, vasculitis, and Ehlers-Danlos Type IV.

There is a significant delay in diagnosis from the first onset of clinical symptoms/signs of 4.4 years in men and 4.1 years in women. There are several possible reasons for such a delay, including the possibility that FMD is not considered in the differential diagnosis of a patient’s symptoms because of under-recognition of this disorder, as well as the mistaken belief that FMD is predominately a rare disease of young patients, and the fact that many of the signs and symptoms of FMD are nonspecific, such as dizziness, tinnitus, and headaches.

Fibromuscular dysplasia must be differentiated from atherosclerotic vascular disease. Patients with atherosclerosis often have multiple atherosclerotic risk factors, whereas most individuals with FMD are younger and have fewer risk factors.^[1]

In general, Atherosclerosis occurs proximally and usually involves the proximal segment of the arteries, whereas FMD involves the mid or distal portion of the blood vessel. The “string of beads” appearance is remarkable for FMD; and atherosclerotic disease and FMD can be differentiated radiographically.

• Ehlers-Danlos Type IV may be associated with medial fibroplasia. This differential diagnosis should be considered in patients who have multiple aneurysms in addition to the routine angiographic characteristics of FMD.^[2]

• Multisystem involvement is observed in both vasculitis and FMD. Those with FMD generally will not have associated anemia, thrombocytopenia, or abnormalities of acute phase reactants.

Large vessel vasculitis may occur in the absence of changes in acute phase reactants in up to 40% of cases. If histologic proof of FMD or inflammation is not available, distinguishing these entities may at times be difficult because the angiographic appearance can be similar, especially if the intimal fibroplasia is of the multivessel type.

• Segmental arterial mediolysis is a poorly understood condition characterized by spontaneous dissections, occlusion, or aneurysm formation, which may be difficult to differentiate from FMD. Similar to FMD, segmental arterial mediolysis is a noninflammatory, nonatherosclerotic arterial disease. A definitive diagnosis of segmental arterial mediolysis requires tissue examination. This lesion of segmental arterial mediolysis is characterized by the vacuolar degeneration of smooth muscle cells. ^[3]

• Differential diagnosis of FMD Involving the coronary arteries, are cocaine vasculitis, coronary vasospasm, and atherosclerotic plaque.^[4]

• Moyamoya disease (MMD) is a unique disease by bilateral stenosis of the arteries of the circle of Willis and arterial collateral vessels and formation of an abnormal vascular network in the vicinity of the arterial occlusion. The most presentations of this disease are ischemic cerebrovascular events, and hemorrhagic stroke.^[5]

Diseases	Clinical manifestations								Para-clinical findings						Gold standard	Additional findings
	Symptoms				Physical examination
									Lab Findings			Imaging
	Headache	Chest pain	Cerebrovascular accident	Systemic symptoms	Hypertension	Heart attack	motor or/and sensory deficit	Arterial occlusion or/and rupture	Metabolic disturbances (Hyperlipidemia/Hyperglycemia)	Inflammatory biomarkers	Specific Lab Data	Angiography	CTA/MRA	Duplex ultrasound
Fibromuscular dysplasia	+	+/-	+/-	–	+/-	+/-	+/-	+/-	–	–		+	+	+	Angiography
Atherosclerotic Vascular Disease	+/-	+	+	–	+/-	+	+/-	+/-	+	–		+/-	+/-	+/-	Angiography	Generally older than 60 yrs of age
Takayasu Arteritis	+	+/-	+/-	+	+/-	+/-	+/-	+/-	–	+		+	+	+		Female, younger than 40 yrs of age, hypertension, absent or decreased pulses, bruits, murmur of aortic regurgitation
Moyamoya disease	+	–	+		–		+	+	–			+	+	+	Angiography	Children with MMD often exhibit abnormalities on EEG. The most characteristic is the “rebuild-up” phenomenon following hyperventilation.
Ehlers-Danlos Type IV	+/-	+/-	+/-	–	–	+/-	+/-	+/-	–	–		–	–	–	Sequence and deletion/duplication testing of the COL3A1 gene/Analysis of type III procollagen from fibroblasts culture	Younger than 40 yrs of age, small body habitus, characteristic facial appearance, translucent skin, easy bruising, hypermobile joints
Segmental arterial mediolysis	+	–	+		+/-	–	–	+/-	–	–		+	+	+	Histology	A rare conditions in the elderly
Cocaine vasculitis	+/-	+/-	+/-	+	+	+/-	–	–	–	+		–	–	–	Urine toxicology/MPO-ANCA/PR3-ANCA	Men with fewer cardiovascular risk factors

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohsen Basiri M.D.

The prevalence of FMD in the general population is not known. In some studies, the prevalence of renal artery FMD has been calculated to be approximately 4 per 100 adults. Patients of all age groups may develop FMD, but women are more commonly affected by FMD than men. The women to men ratio is approximately 9:1.5.

• The prevalence of FMD in the general population is not known; however, the prevalence of renal artery FMD has been estimated to be as high as 4 per 100 adults.^[1][2]
• In one of the largest series of >1000 patients with FMD, 58% had involvement the renal artery, 32% involved the extracranial cerebrovascular arteries and 10% involved other arterial territories such as the visceral arteries or external iliac arteries. Approximately 70% of patients have multiple arteries involvement.^[3]

• Among patients with renovascular hypertension, FMD accounts for 35 to 50 percent of cases in children and 5 to 10 percent of cases in adults under the age of 60 years.

• Extracranial cerebrovascular (eg, carotid and vertebral arteries) involvement is common in patients with established renal FMD. Data from the first 447 patients entered into the United States FMD Registry reveal that approximately 65 percent have extracranial cerebrovascular disease When cerebrovascular disease is present, there is often bilateral carotid involvement, coexisting vertebral artery disease, and, less commonly, disease in the external carotid, middle cerebral, anterior cerebral, basilar, and anterior communicating arteries. FMD may also be associated with intracranial aneurysms.^[3]

• Patients of all age groups may develop FMD.
• The mean age at diagnosis of the first 447 patients enrolled in the U.S. Registry for FMD was 51.9 ± 13.1 years (range of 5 to 86 years),^[4]

• Women are more commonly affected by FMD than men. The women to men ratio is approximately 9:1.5.
• In the US Registry, 91%of registrants were female.^[4]

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohsen Basiri M.D.

There are no established risk factors for fibromuscular dysplasia; neverteless there are evidences that cigarette smoking, hypertension and other classic risk factors for atherosclerosis may be risk factors in the development of FMD .

However FMD has a greater prevalence among women but no definite association has been found between this condition and use of oral contraceptives or disturbances of endogenous sex hormones.

Since the disease is more common among the first-degree relatives of patients with FMD, genetic factors may play a role in the development of FMD.

There are no established risk factors for FMD, however cigarette smoking, hypertension and other classic risk factors for atherosclerosis, such as hyperlipidemia may be risk factors in the development of FMD. ^[1]

• Common risk factors in the development of FMD include:
  • Hypertension
  • Cigarette smoking
  • Genetic

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohsen Basiri M.D.

Current knowledge about natural history, the efficacy of medical therapies, complications and prognosis of FMD, are really restricted; however the natural history of FMD is benign, and the long-term prognosis of patients with FMD is good, and its existence alone is not an indication for preventive intervention or surgery.

Renal or cervival artery dissection and Intracranial aneurysms rupture and SAH are the most common complications of FMD.

Current knowledge about natural history, the efficacy of medical therapies, complications and prognosis of FMD, are really restricted; however the natural history of FMD is benign.

There are numerous top research priorities in determination of the natural history of FMD in the asymptomatic and symptomatic patient, progression, vascular events, complications, and many unanswered aspects of FMD.

• Common complications of FMD include:
  • Renal or cervival artery dissection
  • Intracranial aneurysms rupture and SAH
  • Carotid-cavernous fistula
  • Vertebral arteriovenous fistula

Cervical artery dissection is a classical complication of cervicocranial FMD In the US FMD registry, about 20% of patients suffered from carotid arteries dissection.^[1]

• The long-term prognosis of patients with the cervico-cranial FMD is good, and its existence alone is not an indication for preventive surgery.

Template:WH Template:WS