Current progress in clinical, molecular, and genetic aspects of adult fibromuscular dysplasia.

Fibromuscular dysplasia (FMD) is a non-atherosclerotic vascular disease that may involve medium-sized muscular arteries throughout the body. The majority of FMD patients are women. Although a variety of genetic, mechanical, and hormonal factors play a role in the pathogenesis of FMD, overall, its cause remains poorly understood. It is probable that the pathogenesis of FMD is linked to a combination of genetic and environmental factors. Extensive studies have correlated the arterial lesions of FMD to histopathological findings of arterial fibrosis, cellular hyperplasia, and distortion of the abnormal architecture of the arterial wall. More recently, the vascular phenotype of lesions associated with FMD has been expanded to include arterial aneurysms, dissections, and tortuosity. However, in the absence of a string-of-beads or focal stenosis, these lesions do not suffice to establish the diagnosis. While FMD most commonly involves renal and cerebrovascular arteries, involvement of most arteries throughout the body has been reported. Increasing evidence highlights that FMD is a systemic arterial disease and that subclinical alterations can be found in non-affected arterial segments. Recent significant progress in FMD-related research has led to improve our understanding of the disease's clinical manifestations, natural history, epidemiology, and genetics. Ongoing work continues to focus on FMD genetics and proteomics, physiological effects of FMD on cardiovascular structure and function, and novel imaging modalities and blood-based biomarkers that can be used to identify subclinical FMD. It is also hoped that the next decade will bring the development of multi-centred and potentially international clinical trials to provide comparative effectiveness data to inform the optimal management of patients with FMD.

Rare loss-of-function mutations of PTGIR are enriched in fibromuscular dysplasia.

AIMS: Fibromuscular dysplasia (FMD) and spontaneous coronary artery dissection (SCAD) are related, non-atherosclerotic arterial diseases mainly affecting middle-aged women. Little is known about their physiopathological mechanisms. We aimed to identify rare genetic causes to elucidate molecular mechanisms implicated in FMD and SCAD. METHODS AND RESULTS: We analysed 29 exomes that included familial and sporadic FMD. We identified one rare loss-of-function variant (LoF) (frequencygnomAD = 0.000075) shared by two FMD sisters in the prostaglandin I2 receptor gene (PTGIR), a key player in vascular remodelling. Follow-up was conducted by targeted or Sanger sequencing (1071 FMD and 363 SCAD patients) or lookups in exome (264 FMD) or genome sequences (480 SCAD), all independent and unrelated. It revealed four additional LoF allele carriers, in addition to several rare missense variants, among FMD patients, and two LoF allele carriers among SCAD patients, including one carrying a rare splicing mutation (c.768 + 1C>G). We used burden test to test for enrichment in patients compared to gnomAD controls, which detected a putative enrichment in FMD (PTRAPD = 8 × 10-4), but not a significant enrichment (PTRAPD = 0.12) in SCAD. The biological effects of variants on human prostaclycin receptor (hIP) signalling and protein expression were characterized using transient overexpression in human cells. We confirmed the LoFs (Q163X and P17RfsX6) and one missense (L67P), identified in one FMD and one SCAD patient, to severely impair hIP function in vitro. CONCLUSIONS: Our study shows that rare genetic mutations in PTGIR are enriched among FMD patients and found in SCAD patients, suggesting a role for prostacyclin signalling in non-atherosclerotic stenosis and dissection.

[Surgical treatment of internal carotid artery kinking following fibromuscular dysplasia]. / Rezul'taty khirurgicheskogo lecheniya patologicheskoi izvitosti vnutrennei sonnoi arterii na fone fibrozno-myshechnoi displazii.

OBJECTIVE: To evaluate the results of surgical treatment of internal carotid artery kinking following fibromuscular dysplasia. MATERIAL AND METHODS: There were 32 patients who underwent surgical treatment of internal carotid artery kinking following fibromuscular dysplasia. Structural changes of carotid artery wall were analyzed using immunohistochemical survey. Considering destructive changes revealed, we divided all patients into 2 groups in order to assess long-term postoperative outcomes: 1 - ICA resection followed by anastomosis in end-to-end fashion; 2 - ICA replacement. Postoperative analysis included incidence of stroke, thrombosis and deformities of anastomosis zone, regression of cerebrovascular insufficiency. RESULTS: The main «phenotype¼ of arterial wall in patients with ICA kinking following fibromuscular dysplasia is a large number of smooth muscle cells releasing matrix matelloproteinases-2 and -9 and low level of their tissue inhibitor type 1. Postoperative deformities are more common within a year after surgery. Maximum incidence is observed after 12 months. Both ICA resection and replacement are followed by similar incidence of deformity later. No severe deformities were diagnosed. Resection of ICA kinking on the background of fibromuscular dysplasia is followed by comparable results with ICA replacement regarding the incidence stroke, thrombosis and regression of cerebrovascular insufficiency. CONCLUSION: Despite degradation of extracellular matrix, destruction of elastic fibers and their fragmentation, no significant deformities are observed in long-term postoperative period in patients with ICA kinking and fibromuscular dysplasia.

Intranuclear expression of progesterone receptors in smooth muscle cells of renovascular fibromuscular dysplasia: a pilot study.

BACKGROUND: The pathogenesis of fibromuscular dysplasia (FMD) remains poorly understood. Yet, understanding this mechanism has taken on new urgency after recent evidence indicating that FMD is not as rare as previously thought. We speculated that hormonal receptors in the walls of dysplastic renal arteries were implicated in the pathogenesis of FMD. METHODS: We undertook a pilot prospective case-control study comparing histologic findings from renal arteries that were surgically removed in 2 patient groups. The case group included 6 samples from FMD patients who underwent surgery for stenosis or aneurysm caused by FMD. The control group included 3 FMD-free patients who underwent nephrectomy for nonvascular causes. Surgical specimens were sent to the histology laboratory. FMD was defined preoperatively using conventional radiologic criteria and was confirmed by histologic examination. RESULTS: Immunohistochemical staining detected intense progesterone receptor expression in the nuclei of smooth muscle cells in FMD patients. No progesterone receptor expression was found in the FMD-free patients. Estrogen receptor expression was not noted in the 2 groups. CONCLUSIONS: This preliminary finding may suggest that progesterone plays a key role in the pathogenesis of FMD and opens the fields of genetic and therapeutic approaches.

Clinical and biochemical profiles suggest fibromuscular dysplasia is a systemic disease with altered TGF-ß expression and connective tissue features.

Fibromuscular dysplasia (FMD) is a rare, nonatherosclerotic arterial disease for which the molecular basis is unknown. We comprehensively studied 47 subjects with FMD, including physical examination, spine magnetic resonance imaging, bone densitometry, and brain magnetic resonance angiography. Inflammatory biomarkers in plasma and transforming growth factor ß (TGF-ß) cytokines in patient-derived dermal fibroblasts were measured by ELISA. Arterial pathology other than medial fibrodysplasia with multifocal stenosis included cerebral aneurysm, found in 12.8% of subjects. Extra-arterial pathology included low bone density (P<0.001); early onset degenerative spine disease (95.7%); increased incidence of Chiari I malformation (6.4%) and dural ectasia (42.6%); and physical examination findings of a mild connective tissue dysplasia (95.7%). Screening for mutations causing known genetically mediated arteriopathies was unrevealing. We found elevated plasma TGF-ß1 (P=0.009), TGF-ß2 (P=0.004) and additional inflammatory markers, and increased TGF-ß1 (P=0.0009) and TGF-ß2 (P=0.0001) secretion in dermal fibroblast cell lines from subjects with FMD compared to age- and gender-matched controls. Detailed phenotyping of patients with FMD allowed us to demonstrate that FMD is a systemic disease with alterations in common with the spectrum of genetic syndromes that involve altered TGF-ß signaling and offers TGF-ß as a marker of FMD.

Accidente cerebrovascular isquémico en mujer de 15 años como consecuencia de una displasia fibromuscular / Ischemic cerebrovascular accident in 15-year old women due to fibromuscular dysplasia

La displasia fibromuscular es una enfermedad vascular poco frecuente, de etiología desconocida, que afecta a arterias de pequeño y mediano calibre. Frecuentemente afecta a las arterias renales y cervicocraneales, en especial a la arteria carótida interna. Consiste en cambios histológicos heterogéneos en la pared vascular que originan un estrechamiento arterial. Las manifestaciones clínicas son variables y dependen del vaso afectado, siendo las más comunes la hipertensión arterial (si se afectan las arterias renales) y el accidente cerebrovascular (arterias carótidas). Presentamos el caso de una adolescente de 15 años que acudió a nuestra consulta por presentar cefalea, mareo e inestabilidad como manifestación inicial. Ante la persistencia de la sintomatología y la detección de una hemihipoestesia izquierda en la exploración neurológica, se le realizó una angiorresonancia, diagnosticándose de displasia fibromuscular (AU)

Fibromuscular dysplasia is an uncommon vascular disease of unknown etiology that affects the small and medium sized arteries. It frequently affects the renal and cervicocranial arteries, especially the internal carotid. It consists in heterogeneous histological changes in the vascular wall that cause arterial narrowing. Its clinical manifestations vary, depending on the vessel involved. The most common ones are high blood pressure (renal artery involvement) and stroke (carotid artery involvement). We present the case of a 15-year old woman who consulted due to headache, dizziness and instability as initial manifestation. As the symptoms persisted and left hemihypoesthesia was detected in the neurological examination, an angioresonance was performing and she was diagnosed with dysplasia fibromuscular (AU)

Non-dysplastic and dysplastic Barrett's mucosa and adenocarcinoma lack a subepithelial myofibroblastic cell layer.

A subepitheal myofibroblastic (SMF) cell layer has been described in the colon, and referred to as pericryptal myofibroblastic cell layer. SMF cells have been shown to produce basement membrane proteins, including type IV collagen and laminin. The aim of this work was to determine the status of the SMF cell layer in Barrett's metaplasia (BM), with and without dysplasia, and compare that to the previously reported distribution of SMF in normal colon and colonic adenomas and carcinoma. Sections of formalin-fixed, paraffin-embedded biopsies from 6 colonic adenomas and 5 colonic adenocarcinomas, as well as 4 cases of BM without dysplasia, 4 with low grade dysplasia, 4 high grade dysplasia and 4 with invasive adenocarcinoma were immunohistochemically stained for alpha smooth muscle actin using the immunoperoxidase method. A continuous layer of SMF cells was present in all normal colonic tissue and adenomas but was absent in all colorectal adenocarcinomas. Surprisingly, none of the cases of BM with or without dysplasia or carcinoma showed an organized SMF cell layer. Unlike the colon, the SMF cell layer is absent in BM even without dysplasia. We hypothesize that lack of the SMF cell layer in BM may contribute to the quick progression to esophageal adenocarcinoma, which, unlike that in the colon, occurs before an exophytic lesion becomes evident.

Alpha-1-antitrypsin phenotypes in patients with renal arterial fibromuscular dysplasia.

Fibromuscular dysplasia (FMD) is a significant cause of renal artery stenosis, especially in young females. A rare association between FMD and alpha 1-antitrypsin (alpha 1-AT) deficiency has been reported. We compared the alpha 1-AT phenotype distribution in 83 patients with renal arterial FMD with those published for Australian populations. alpha 1-AT phenotyping was performed by isoelectric focusing between pH 4.2 and pH 4.9 on polyacrylamide gels with PiM1M2, PiFM (non-deficiency alleles), PiMS and PiMZ (deficiency alleles) markers. Following phenotyping, alpha 1-AT genotyping was performed in 10 patients to confirm the presence of S and/or Z alleles. The phenotype distribution and allele frequencies were similar to those reported for normal subjects from two Australian populations (72 (86.7%) PiMM phenotype, one (1.2%) PiFM, seven (8.4%) PiMS, two (2.4%) PiMZ and one (1.2%) PiSZ), suggesting that alpha 1-AT deficiency is not a common aetiological factor in renal arterial FMD. However, despite FMD being three times less common in males than females, and carotid artery dissection being a rare occurrence, a male with PiMS deficiency phenotype presented with internal carotid artery dissection and had bilateral renal artery FMD. Further, a patient with PiSZ deficiency phenotype was one of two sisters with FMD and was more severely affected than her PiMM normal phenotype sibling. These two patients from the present series together with nine culled from the literature with alpha 1-AT deficiency phenotype and FMD suggest that the chance combination of alpha 1-AT deficiency and FMD may predispose to severe manifestations of FMD.

Pathology of restenosis in saphenous bypass grafts after long-term stent implantation.

The implantation of saphenous vein grafts on the coronary arterial tree eventually leads to graft narrowing, which can be treated by the implantation of intravascular stents. However, long-term restenosis after stent implantation occurs in at least 30% of cases. Ten saphenous bypass grafts, in which a total of 12 stents had been implanted for an average of 32 months, were retrieved at least 10 months after implantation for angiographic diagnosis of reocclusion or severe restenosis. The metal struts were removed after macroscopic inspection of the vein, and the grafts were examined by light microscopy. Angiography revealed total occlusion in 9 stents and severe narrowing in 3. Pathologic examination revealed graft occlusion due to cellular hyperplasia in 4 cases and to recent thrombus formation in 5. Progression of atherosclerotic plaque was the cause of restenosis in the 3 severely narrowed grafts. In 2 of 5 grafts implanted with Palmaz-Schatz stents, the metallic struts had induced a local inflammatory reaction. Therefore, the long-term reocclusion of saphenous bypass grafts after stent implantation may be due to atherosclerotic plaque or fibromuscular hyperplasia. However, thrombus formation may still occur several years after implantation. In specific cases, stent implantation also induces inflammation around the stent struts.

[Two cases of fibromuscular dysplasia of the aorta (intimal hyperplasia)]. / Dva nabliudeniia fibrozno-myshechnoi displazii aorty (intimal'noi giperplazii).

Two cases of this rare disease are described: in a 8-year-old girl and in a 6-year-old boy. In the former case there was a combination of a widespread damage to the aorta and coronary arteries while in the latter case intimal proliferation of the renal region of the aorta with stenosis of the renal arteries orifice were observed. Immunohistochemistry in this case showed intimal thickening in FMD to have a similar structure as in other processes. The cells of the smooth muscle type containing vimentin and some of them desmin showing a synthetic fibroplastic phenotype were found in the intimal polyps. The lack of apoprotein B in the deep layers allows to reject atherosclerotic nature of the processes. This observation confirms the opinion according to which intimal dysplasia should be recognized as a form of FMD.

Arterial fibromuscular dysplasia associated with severe alpha 1-antitrypsin deficiency.

OBJECTIVE: To elucidate the putative arteriopathy associated with alpha 1-antitrypsin (alpha 1-AT) deficiency. DESIGN: We retrospectively studied the frequency of occurrence of fibromuscular dysplasia (FMD) in patients with alpha 1-AT deficiency in whom a postmortem examination had been done during a 10-year period at the Mayo Clinic. MATERIAL AND METHODS: The medical records of all patients in whom an autopsy was done at the Mayo Clinic between 1983 and 1992 were reviewed to identify all those with a diagnosis of alpha 1-AT deficiency or FMD. RESULTS: Arterial FMD was found in 2 of 6 patients with alpha 1-AT deficiency (33.3%; 95% confidence interval, 4.3 to 77.7%) in comparison with 23 of 6,690 patients without alpha 1-AT deficiency (0.3%; 95% confidence interval, 0.2 to 0.5%). In both patients with alpha 1-AT deficiency and FMD, the arterial media was thickened and composed of irregular arrays of muscular and connective tissue fibers in a background of mucoid ground substance. CONCLUSION: These findings provide further evidence for an underlying arteriopathy in patients with alpha 1-AT deficiency and suggest that FMD may be a non-specific disorder.

Effect of the calcium entry blocker, flunarizine, on ruthenium red uptake by endothelial cells following acute electrical stimulation of rabbit carotid arteries.

Local transmural electrical stimulation with DC of a carotid artery by means of implanted electrodes causes subendothelial fibromuscular proliferates or atheroma (if the animal receives a cholesterol-containing diet) beneath the anode. The endothelial lining is maintained when weak current is used for stimulation. The model permits studies of permeability of the endothelium in all stages of the plaque development. Ruthenium red as a marker for the glycocalyx is transiently taken up into the cytoplasm of the endothelial cells beneath the anode immediately after a 30 or 60 min lasting stimulation period. When staining the endothelium later than two hours after the end of an acute stimulation period, the ruthenium red staining is again normal. This indicates that the increased permeability to large molecules is reversible. Injection of the calcium entry blocker Flunarizine inhibited the cytoplasmic uptake of ruthenium red, showing that an increased entry of calcium into the endothelial cells may contribute to the disturbance in the permeability of large molecules into the endothelium.

Enhanced oxygen uptake and lactate production of smooth muscle cell proliferates of rabbit carotid arteries.

In rabbit carotid arteries intimal smooth muscle cell proliferations were induced by repeated local electrical stimulation of the artery wall. Oxygen uptake and lactate production of the proliferating tissue were determined in vitro and compared with the results obtained from nonstimulated arterial wall segments. Under the incubation conditions employed, oxygen consumption and lactate production of the proliferating tissue were 91.3 and 62.5 nmol x min-1 x mg-1 DNA, compared with the control values of 70.8 and 41.6 nmol x min-1 x mg-1 DNA. The DNA content of the proliferates and normal arterial wall tissue amounted to 9.6 and 12.0 microgram DNA x mg-1 dry weight. The results show that in proliferates obtained with the described procedure there is an increased capacity for ATP regenerating systems, respiration and glycolysis, indicating a modified function of the proliferating smooth muscle cells.