Acute aortic dissection and stroke in multivessel fibromuscular dysplasia.
ABSTRACT: Fibromuscular dysplasia is a rare, nonatherosclerotic, noninflammatory vascular disease that typically affects women between the ages of 20 and 60 years. Although any artery can be affected, fibromuscular dysplasia most commonly affects the renal and carotid arteries. Fibromuscular dysplasia of the renal arteries usually presents with hypertension, while carotid or vertebral artery disease causes transient ischemic attacks, strokes, or dissection. Fibromuscular dysplasia of the brachial arteries is extremely uncommon. It can induce extremity ischemia, nerve compression, or both-causing coldness, discoloration, pain, ulceration or gangrene of the fingers, paresthesias, or paralysis. We report a rare case of multivessel fibromuscular dysplasia manifested by acute stroke in association with type I aortic dissection, which progressed rapidly to ascending aortic false aneurysmal development that necessitated arch replacement. Outcomes of aortic arch replacement in this setting are currently unknown. Therefore, our case might well offer some insight.
Project description:Fibromuscular dysplasia (FMD), formerly called fibromuscular fibroplasia, is a group of nonatherosclerotic, noninflammatory arterial diseases that most commonly involve the renal and carotid arteries. The prevalence of symptomatic renal artery FMD is about 4/1000 and the prevalence of cervicocranial FMD is probably half that. Histological classification discriminates three main subtypes, intimal, medial and perimedial, which may be associated in a single patient. Angiographic classification includes the multifocal type, with multiple stenoses and the 'string-of-beads' appearance that is related to medial FMD, and tubular and focal types, which are not clearly related to specific histological lesions. Renovascular hypertension is the most common manifestation of renal artery FMD. Multifocal stenoses with the 'string-of-beads' appearance are observed at angiography in more than 80% of cases, mostly in women aged between 30 and 50 years; they generally involve the middle and distal two-thirds of the main renal artery and in some case also renal artery branches. Cervicocranial FMD can be complicated by dissection with headache, Horner's syndrome or stroke, or can be associated with intracerebral aneurysms with a risk of subarachnoid or intracerebral hemorrhage. The etiology of FMD is unknown, although various hormonal and mechanical factors have been suggested. Subclinical lesions are found at arterial sites distant from the stenotic arteries, and this suggests that FMD is a systemic arterial disease. It appears to be familial in 10% of cases. Noninvasive diagnostic tests include, in increasing order of accuracy, ultrasonography, magnetic resonance angiography and computed tomography angiography. The gold standard for diagnosing FMD is catheter angiography, but this invasive procedure is only used for patients in whom it is clinically pertinent to proceed with revascularization during the same procedure. Differential diagnosis include atherosclerotic stenoses and stenoses associated with vascular Ehlers-Danlos and Williams' syndromes, and type 1 neurofibromatosis. Management of cases with renovascular hypertension includes antihypertensive therapy, percutaneous angioplasty of severe stenoses, and reconstructive surgery in cases with complex FMD that extends to segmental arteries. The therapeutic options for securing ruptured intracerebral aneurysms are microvascular neurosurgical clipping and endovascular coiling. Stenosis progression in renal artery FMD is slow and rarely leads to ischemic renal failure.
Project description:BACKGROUND:Fibromuscular dysplasia (FMD) is a rare noninflammatory, nonatherosclerotic arteriopathy of medium-sized arteries affecting up to 7% of the population. The disease can affect any artery but commonly affects renal, extracranial carotid, and vertebral arteries. The epidemiology and natural course of cerebrovascular FMD is unknown and requires further investigation. METHODS:We present demographic and outcomes data on a case series of 81 patients with cerebrovascular FMD from Massachusetts General Hospital presenting between 2011 and 2015 followed by a review of the peer-reviewed literature. RESULTS:Patients were a median age of 53 years (±12 SD) and the majority were women. Approximately 50% had a history of tobacco use and more than two-thirds had hypertension. Most patients were on monoplatelet therapy with aspirin; during follow-up, 7 of 67 had progressive disease or additional symptoms. One of 67 patients had a cerebrovascular event: TIA. There were 5 of 67 who had noncerebrovascular events or disease progression and 1 death of unclear cause. CONCLUSIONS:Cerebrovascular FMD may present with myriad symptoms. Our data support that patients with FMD with symptomatic disease have a low rate of recurrent symptoms or disease progression and can be managed conservatively with stroke risk modification, antiplatelet agents, surveillance imaging, and counseling.
Project description: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.
Project description: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.
Project description:Fibromuscular dysplasia (FMD) involving the coronary arteries is an uncommon but important condition that can present as acute coronary syndrome, left ventricular dysfunction, or potentially sudden cardiac death. Although the classic angiographic "string of beads" that may be observed in renal artery FMD does not occur in coronary arteries, potential manifestations include spontaneous coronary artery dissection, distal tapering or long, smooth narrowing that may represent dissection, intramural hematoma, spasm, or tortuosity. Importantly, FMD must be identified in at least one other noncoronary arterial territory to attribute any coronary findings to FMD. Although there is limited evidence to guide treatment, many lesions heal spontaneously; thus, a conservative approach is generally preferred. The etiology is poorly understood, but there are ongoing efforts to better characterize FMD and define its genetic and molecular basis. This report reviews the clinical course of FMD involving the coronary arteries and provides guidance for diagnosis and treatment strategies.
Project description:Spontaneous coronary artery dissection is a very rare cause of acute coronary syndromes and can be life threatening given the rarity of the condition. It should be part of differentials in young females presenting with acute coronary syndromes without routine risk factors for coronary artery disease, especially before, during, and after pregnancy. It is closely associated with fibromuscular dysplasia and management can be very challenging at times. We present a case of spontaneous coronary artery dissection presenting with recurrent ST segment elevation myocardial infarction in association with fibromuscular dysplasia.
Project description:Reconstruction of the aortic major branches during thoracic endovascular aortic repair is complicated because of the complex anatomic configuration and variation of the aortic arch. In situ laser fenestration has shown great potential for the revascularization of aortic branches. This study aims to evaluate the feasibility, effectiveness, and safety of in situ laser fenestration on the three branches of the aortic arch during thoracic endovascular aortic repair.Before clinical application, the polytetrafluoroethylene and Dacron grafts were fenestrated by an 810-nm laser system ex vivo, which did not damage the bare metal portion of the endografts and created a clean fenestration while maintaining the integrity of the endografts. In vivo, 6 anesthetized female swine survived after this operation, including stent-graft implantation in the aortic arches, laser fenestration, and conduit implantation through the innominate arteries and the left carotid arteries. Based on the animal experiments, in situ laser fenestration during thoracic endovascular aortic repair was successively performed on 24 patients (aged 33-86 years) with aortic artery diseases (dissection type A: n=4, type B: n=7, aneurysm: n=2, mural thrombus: n=7). Fenestration of 3 aortic branches was performed in 2 (8.3%) patients. Both the left carotid artery and the left subclavian artery were fenestrated in 6 (25%) patients. Only left subclavian artery fenestration surgery was done in 16 (66.7%) patients. Among these patients, 1 fenestration was abandoned secondary to an acute takeoff of the innominate artery in a type III aortic arch. The average operative time was 137±15 minutes. The technical success rate was 95.8% (n=23). No fenestration-related complications or neurological morbidity occurred after this operation. During a mean postoperative 10-month follow-up (range: 2-17 months), 1 patient died of severe pneumonia, and all the left subclavian artery and carotid artery stents were patent with no fenestration-related endoleaks upon computed tomography angiography images.In situ laser fenestration is a feasible, effective, rapid, repeatable, and safe option for the reconstruction of aortic arch during thoracic endovascular aortic repair, which might be available to revascularize the 3 branches. However, follow-up periods should be extended to evaluate the robustness of this technique.
Project description: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 ? (TGF-?) 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-?1 (P=0.009), TGF-?2 (P=0.004) and additional inflammatory markers, and increased TGF-?1 (P=0.0009) and TGF-?2 (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-? signaling and offers TGF-? as a marker of FMD.
Project description:While common in the general population, the developmental origins of "normal" anatomic variants of the aortic arch remain unknown. Aortic arch development begins with the establishment of the second heart field (SHF) that contributes to the pharyngeal arch arteries (PAAs). The PAAs remodel during subsequent development to form the mature aortic arch and arch vessels. Retinoic acid signaling involving the biologically active metabolite of vitamin A, plays a key role in multiple steps of this process. Recent work from our laboratory indicates that the E3 ubiquitin ligase Hectd1 is required for full activation of retinoic acid signaling during cardiac development. Furthermore, our study suggested that mild alterations in retinoic acid signaling combined with reduced gene dosage of Hectd1, results in a benign aortic arch variant where the transverse aortic arch is shortened between the brachiocephalic and left common carotid arteries. These abnormalities are preceded by hypoplasia of the fourth PAA. To further explore this interaction, we investigate whether reduced maternal dietary vitamin A intake can similarly influence aortic arch development. Our findings indicate that the incidence of hypoplastic fourth PAAs, as well as the incidence of shortened transverse arch are increased with reduced maternal vitamin A intake during pregnancy. These studies provide new insights as to the developmental origins of these benign aortic arch variants.
Project description:Chemokine CXCL12 (stromal derived factor 1: SDF1) has been shown to play important roles in various processes of cardiovascular development. In recent avian studies, CXCL12 signalling has been implicated in guidance of cardiac neural crest cells for their participation in the development of outflow tract and cardiac septum. The goal of this study is to investigate the extent to which CXCL12 signalling contribute to the development of aortic arch and pulmonary arteries in mammals.Novel Cxcl12-LacZ reporter and conditional alleles were generated. Using whole mount X-gal staining with the reporter allele and vascular casting techniques, we show that the domain branching pattern of pulmonary arteries in Cxcl12-null mice is completely disrupted and discordant with that of pulmonary veins and airways. Cxcl12-null mice also displayed abnormal and superfluous arterial branches from the aortic arch. The early steps of pharyngeal arch remodelling in Cxcl12-null mice appeared to be unaffected, but vertebral arteries were often missing and prominent aberrant arteries were present parallel to carotid arteries or trachea, similar to aberrant vertebral artery or thyroid ima artery, respectively. Analysis with computed tomography not only confirmed the results from vascular casting studies but also identified abnormal systemic arterial supply to lungs in the Cxcl12-null mice. Tie2-Cre mediated Cxcr4 deletion phenocopied the Cxcl12-null phenotypes, indicating that CXCR4 is the primary receptor for arterial patterning, whereas Cxcl12 or Cxcr4 deletion by Wnt1-Cre did not affect aortic arch patterning.CXCL12-CXCR4 signalling is essential for the correct patterning of aortic arches and pulmonary arteries during development. Superfluous arteries in Cxcl12-null lungs and the aortic arch infer a role of CXCL12 in protecting arteries from uncontrolled sprouting during development of the arterial system.