Fibromuscular dysplasia pathophysiology
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Management of Patients With Fibromuscular Dysplasia of the Extracranial Carotid Arteries |
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohsen Basiri M.D.
Overview
Pathophysiology
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.
Pathogenesis
- Despite numerous genetic, hormonal and mechanical factors have been proposed, the etiology fibromuscular dysplasia remains unknown. A variety Of factors have been implicated. These include:
1)Cigarette smoking and a history of hypertension
. Sang CN, Whelton PK, Hamper UM, et al. Etiologic factors in renovascular fibromuscular dysplasia: a case-control study. Hypertension 1989;14:472-9.
2)Genetic factors with a reported autosomal mode of inheritance in some families . Perdu J, Boutouyrie P, Bourgain C, et al. Inheritance of arterial lesions in renal fibromuscular dysplasia. J Hum Hypertens 2007; 21:393. . Ganesh SK, Morissette R, Xu Z, et al. Clinical and biochemical profiles suggest fibromuscular dysplasia is a systemic disease with altered TGF-β expression and connective tissue features. FASEB J 2014; 28:3313.
3) Hormonal influence, given the predominance in women of childbearing age No association has been found between fibromuscular dysplasia and previous
use of oral contraceptives or abnormalities of endogenous sex hormones.21 21. Sang CN, Whelton PK, Hamper UM, et al. Etiologic factors in renovascular fibromuscular dysplasia: a case-control study. Hypertension 1989;14:472-9. The increased incidence of FMD in women as compared with men suggests a possible hormonal or genetic influence. 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.
4) Mechanical factors such as stretching of smooth muscle cells and trauma to
the blood vessel wall
5) Ischemia of the blood vessel wall due to fibrotic occlusion of the vasa
Vasorum
Genetics
- [Disease name] is transmitted in [mode of genetic transmission] pattern.
- Genes involved in the pathogenesis of [disease name] include [gene1], [gene2], and [gene3].
- The development of [disease name] is the result of multiple genetic mutations.
Genetic factors may play a part in the development of fibromuscular dysplasia, since the disease is more common among the first-degree relatives of patients with fibromuscular dysplasia of the renal arteries 22,23 22. Pannier-Moreau I, Grimbert P, Fiquet- Kempf B, et al. Possible familial origin of multifocal renal artery fibromuscular dysplasia. J Hypertens 1997;15:1797-801. 23. Grimbert P, Fiquet-Kempf B, Coudol P,et al. Étude génétique de la dysplasie fibromusculaire des artères rénales. Arch Mal Coeur Vaiss 1998;91:1069-71.
and among persons with the angiotensin-converting–enzyme allele ACE-I. 24
24. Bofinger A, Hawley C, Fisher P, Daunt N, Stowasser M, Gordon R. Polymorphisms
of the renin-angiotensin system in patients with multifocal renal arterial fibromuscular
dysplasia. J Hum Hypertens 2001;15:185-90.
Although the multiple manifestations of a structural arteriopathy in FMD hint of a genetic cause, such as collagen or elastin mutation, epidemiologic data suggesting familial transmission are generally weak.
Many reports exist of familial occurrences of FMD, mostly in siblings. Some studies have even suggested that familial occurrence is relatively common. For example, Rushton in 1980 suggested familial occurrences in relatives of 12 out of 20 identified probands. [18] However, histologic proof was established in only the index cases, and vascular events such as early strokes and hypertension were used to identify the other affected family members. Most large series have reported that the great preponderance of FMD cases are sporadic. Bilateral renal FMD has been noted in a pair of identical twins. [19] In case reports, FMD has been associated with mutations in collagen [20] , with cutis laxa [21] , and with alpha1-antitrypsin deficiency [22] . Associative links to neurofibromatosis, Alport syndrome, and pheochromocytoma have also been suggested. [2]
Evidence supports a genetic basis for susceptibility to FMD. (there are genetic evidences supporting genetic basis of FMD) Multiple barriers have impeded the identification and characterization of genes that may contribute to FMD. (Several restrictions are hindering the characterization process of genes leading to FMD)
Disease rarity hinders the establishment of large cohorts required for robust genetic studies. (FMD is a rare disease and so there is a problem with establishing large cohort studies to reinforce genetic evidences) The disease phenotype in FMD is variable, and it remains possible that genetic abnormalities are confined to specific subsets of FMD patients.(FMD has variable traits and it is probable that genetic deviants are restricted to smaller groups) Gene-environment interactions may influence the predisposition for FMD and are difficult to detect in small study samples. (there are interactions between genotype and environment that have impacts on potentiality of FMD which is hard to be distinguished in small study groups) We anticipate that the application of molecular genetics in future studies will yield novel information on the pathogenesis of FMD. (Applying molecular genetics will reveal informations about FMD pathogenesis.) Ideally, complementary genetic approaches, including family-based studies, candidate gene evaluation, and genome-wide association studies, would be pursued to identify potential causative pathways for this disease. (family based studies, evaluating genome of candidates, and wide genome studies can help recognizing pathophysiology of FMD) Genetics from AHA The genetics of FMD is an active area of research. As of yet, no etiologic genes have been identified. (till now there is no specific gene found to cause FMD). Early genetic data suggested an autosomal dominant inheritance pattern with variable penetrance.( there are resent data suggesting an autosomal dominant pattern with variable penetrance.) 19–21 In a series of 20 cases, Rushton classified (arranged) 60% as familial; however, positive family members were identified based on cardiovascular events and early onset hypertension rather than definitive confirmation of FMD on imaging.20 Few studies provide radiographic proof of familial inheritance. (there are radiographic proofs of familial transmission provided by some studies.) Perdu and colleagues (used high resolution carotid ultrasound to study13 cases and 47 first-degree relatives in 6 families screened for FMD) studied 13 cases and 47 first-degree relatives in 6 families screened for FMD using high-resolution carotid ultrasound.22(23) High-resolution echo tracking measurements of carotid arterial wall parameters were used to develop an arterial scoring system. (To develop an arterial scoring system high resolution echo tracking measurements of carotid arterial wall parameters were used). Elevated arterial scores served as a surrogate marker (replacing marker) for FMD. Segregation analysis showed 52% of descendants (next generation) had an elevated arterial score (which is in correlation with autosomal dominant inheritance). consistent with an autosomal Dominant transmission.22 However, no family member demonstrated classic vascular lesions clinically associated with FMD, such as beading or stenosis, and the carotid ultrasound score is not widely accepted as a marker for FMD. (But still no family member showed classic vascular problems related to FMD and carotid ultrasound score is not an accepted marker for FMD generally.) Thus, the prevalence of familial FMD is likely overestimated in these studies. (so the prevalence of familial FMD is probably overestimated in such studies.) In a study with imaging confirmation of FMD diagnosis (In a study which FMD diagnosed by imaging) , 11% of FMD cases were familial. All familial cases were siblings, and no vertical transmission was reported.23 In the US Registry, only 7.3% of patients report a confirmed diagnosis of FMD in ≥1 first- or second-degree family members. 2 However, the high prevalence of aneurysms (23.5%), sudden death (19.8%), and stroke (53.5%) 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 traits.) suggests FMD may represent an inherited systemic arteriopathy with a diverse clinical phenotype. Larger family studies with vascular imaging are needed to better identify the inheritance pattern of FMD. It is hypothesized that FMD may have overlapping (common) features with vascular connective tissue diseases, such as Loeys-Dietz syndrome or the vascular type of Ehlers-Danlos syndrome. However, the prevalence of genetic mutations associated with connective tissue disease was negligible in a cohort of clinically confirmed FMD patients who underwent genetic testing.24 Two patients in this cohort were found to have distinct novel point mutations in TGFb receptor type 1 gene.24 Both of these patients (both patients) had a history of arterial dissection and had (had ro hazf kon) aortic ectasia or aneurysm. Ganesh, Morrisette, and colleagues found (increased level of TGF-b1 and 2 secreted by fibroblasts in patients with FMD in comparison to matched controls) elevated secretion of transforming growth factor (TGF)-b1 and TGF-b2 by fibroblasts derived from FMD patients compared with matched controls. FMD patients also had elevated plasma levels of circulating TGF-b1 and TGF-b2 relative to matched controls. 25(25) 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. Evidence supports that gene–environment interactions influence FMD susceptibility. Smoking and estrogen are 2 proposed interactions. (smoking and estrogen are two environmental factors that have impact on FMD susceptibility.)1,26
Savard and colleagues demonstrated (showed) patients with renal FMD have a much higher rate of smoking compared with matched hypertensive controls.26 (Savard and colleagues showed that there is a higher rate of smoking in people with renal FMD in comparison with matched hypertensive controls.)
The striking predilection of female patients in the FMD population (>90%) suggests estrogen and other hormonal factors as major contributors to the development of FMD. (Female are more predisposed to FMD (>90%) and this fact recommends that there is a great contribution between FMD and estrogen and other hormonal factors.
Associated Conditions
Associated vascular pathologies In 1982, Mettinger and Ericson [14] scrutinized 4000 consecutively performed cerebral angiographies and found 37 that were consistent with FMD. Of these, 19 patients had aneurysms. In 1988, Cloft et al performed a meta-analysis including 498 FMD patients as well as examined 117 of their own patients and found a combined prevalence of aneurysms to be 7.3%. [15] In 1975, Stanley et al found that 8 of their 17 cerebrovascular FMD cases had intracranial aneurysms, and they proposed a classification system that includes a "medial fibroplasias with aneurysms" subtype. [11] The beadlike dilatations observed within FMD lesions share gross and histologic characteristics of aneurysms. The casual link between FMD and aneurysms is less clear but is possibly related to an underlying connective tissue problem that results in loss of arterial wall strength. This wall weakness may allow for vessel dilation (aneurysm formation and beading in FMD) as well as injury, which then causes compensatory fibroplasia. Besides aneurysms, many case series and reports have identified FMD in patients presenting with arterial dissection. [16, 17]
FMD lesions likely predispose the artery to dissection through weakening of the arterial wall. FMD is a predisposing factor in 15% of spontaneous cervical carotid dissections. Dissections in FMD are more commonly multiple than in patients without an identified underlying arteriopathy.
Gross Pathology
- On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
Microscopic Pathology
- On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].