Cystic Medial Necrosis Research Articles

Positive Correlation Between the Dysregulation of Transforming Growth Factor-β<sub>1</sub> and Aneurysmal Pathological Changes in Patients With Marfan Syndrome

Our goal was to investigate the correlation between the dysregulation of transforming growth factor-β1 (TGF-β1) and cystic medial degeneration in the aortic aneurysmal tissues of in Marfan syndrome (MFS) patients. Although aortic aneurysm in animal models of MFS is related to the dysregulation of TGF-β, it has yet to be determined whether TGF-β dysregulation correlates with pathogenic aneurysmal characteristics in MFS patients. Compared with aortic tissue from normal individuals, the medial layers of aortic tissue from MFS patients exhibited profound cystic medial degeneration and cellular apoptosis. These histopathologic changes positively correlated with the extent of TGF-β1 signaling activation (Smad2 phosphorylation) in aneurysmal aortic tissue. In addition, the level of TGF-β1 expression in peripheral blood and aneurysmal aortic tissues was significantly elevated in MFS patients. A significant positive correlation was observed between the plasma level of active TGF-β1 in MFS patients and the severity of cystic medial degeneration and Smad2 phosphorylation in aneurysmal aortic medial layers. We found a strong association between the dysregulation of TGF-β1 and aortic pathogenesis in human MFS patients. This suggests that the plasma concentration of TGF-β1 in MFS patients might be a useful biomarker of the progression of aortic aneurysms.

Analysis of SOD3 and Akt in ascending aortic aneurysm

Ascending aortic aneurysm (AsAA) is divided into three different forms: syndromic, familial non-syndromic, and degenerative. Bicuspid aortic valve (BAV), occuring in 2% of the population, is the most frequent cardiac congenital abnormality, associated to AsAA. All the different forms of AsAAs are a consequence of cystic medial necrosis (CMN), characterized by apoptotic loss of smooth muscle cells (SMCs), fragmentation of elastic and collagen fibers and increased accumulation of mucoid material. The extracellular superoxide dismutase (SOD3) is a Cu/Zn enzyme, affecting redox state and homeostasis of extracellular matrix (ECM) (1). Moreover, the outsidein signalling from ECM modulates intracellular pathways regulating many cellular functions. The multifunctional Akt pathway affects survival and cellular proliferation and has important effects on the cardiovascular function. In this study we examined the relevance of SOD3 and Akt in AsAA pathogenesis. To this aim, the SOD3 and Akt protein levels were evaluated in normal ascending aortic tissues (n=6) and in tissues from AsAAs associated both to tricuspid aortic valve (TAV) (n=6) and BAV (n=6); moreover, we measured SOD3 activity in sera from healthy donors and patients with AsAA. Our data showed a reduction of SOD3 and phospho-Akt (pAkt) protein levels in AsAAs from BAV patients compared to normal donors; on the other hand, no differences emerged in SOD3 activity. Furthermore, immunohistochemical analysis performed on normal and pathological ascending aortic tissues showed a SOD3 immunostaining in both extracellular space and tunica media cells from normal ascending aortic tissues; conversely, no SOD3 immunostaining was detected in AsAAs tissues from both TAV and BAV patients. Our data show that SOD3 and pAkt could be associated to AsAA pathogenesis and suggest a link between ECM homeostasis and Akt survival pathway.

A true aneurysm of the superficial temporal artery: Is there an underlying pre-disposition to such rarities?

INTRODUCTIONA 32 year old man presented to our vascular clinic with a lump over the left eyebrow. It had become larger in size and was cosmetically unacceptable. PRESENTATION OF CASEClinical examination of the lump demonstrated a pulsatile swelling consistent with an aneurysm of the superficial temporal artery (STA). Doppler ultrasound demonstrated arterial flow within the lump that could be controlled with pressure over the proximal branch of the vessel.The STA aneurysm was excised under local anaesthesia by ligation of the feeding and draining branches. It measured 3.4cm×3.7cm. Histological examination confirmed a rare finding of a true aneurysm of the STA. DISCUSSIONAneurysms are classified into false or true types, with false aneurysms of the STA accounting for 95% of cases reported. It has therefore been suggested that true aneurysms of the STA may develop from a yet unknown pre-existing vessel condition.The histological findings in our case demonstrated myxoid/mucoid deposits replacing elastin fibres of the media layer, in addition to cystic lesions seen in the adventitia. These features were thought to be nonspecific but have been reported in rare conditions known as cystic adventitial disease and cystic medial necrosis. Such is their obscurity that we speculate that both of these may represent variations of the same underlying pathology. As myxoid/mucoid changes are also noted in more well-known connective tissue disorders including Marfan's syndrome, imaging was arranged to screen our patient for thoracic and abdominal aneurysms. These proved negative and there were no Marfanoid features noted prior. CONCLUSIONAneurysms of the STA are easily treated by surgical excision. This should be considered when they become large, painful or are cosmetically undesirable. Unusual histological findings in the specimen may indicate a connective tissue disorder that should be investigated if indicated.

Histological characteristics and classifications of coarctation of the aorta

Coarctation of the thoracic aorta is defined as a congenital narrowing of the upper part of the descending aorta, adjacent to the place of joining of ductus arteriosum or ligament, which produces a difference in the pressure above the narrowing and below it. One of the most widely accepted classifications of the coarctation is its division on the basis of the age of patients. According to this classification, coarctation is divided into the neonatal and adult type. The neonatal type of coarctation is characterized by the presence of the ductal sling and coarctational shelf placed proximally in relation to the ductal orifice. In newborn babies and younger nurslings, the shelf and neighboring parts of coarctational segment contain ductal tissue. The ductal tissue forms a 'sling' which completely surrounds the juxtaductal aorta. Clinical characteristics of the neonatal type are heart insuficiency at infancy, diffused narrowing of the aortic arch, called tubular hypoplasia, together with the wide open ductus and other congenital heart diseases. In the adult type of coarctation, the histological findings shows cystic medial necrosis. It is characterized by necrosis of smooth muscle cells, presence of cysts in the elastic lamellae filled with basophile mucopolysaccharides, followed by fibrosis with irregular fibroelastic tissue in the media. The adult type is characterized by clearly limited external narrowing of a short aorta segment in the shape of a sandglass, usually in place of the connection of ductus or ligament, or just distal. Concomitant heart diseases are rarely found in this type of coarctation.

Segmental arterial mediolysis: A clinical-pathologic review, its role in fibromuscular dysplasia and description and differential diagnosis of the masquerader-muscular artery cystic necrosis

Segmental arterial mediolysis (SAM) is an uncommon non-inflammatory iatrogenic arteriopathy caused by alpha-1 adrenergic agonists or Beta-2 agonists able to release norepinephrine from the peripheral nervous system. Causative agents include adrenergic agonists used to control blood pressure, B-2 tocolytic agonists, and ractopamine used as a repartitioning agent in animal husbandry. The liberated norepinephrine both injures and stimulates a robust reparative response in the muscular arteries in the abdomen, brain base, and coronary arteries. This response may be augmented by endothelin-1 formed in the arterial adventitia. Three types of arterial lesions develop in the injurious stage: 1) apoptotic induced mediolysis, 2) separation of the outer media from the adventitia and 3) the formation of arterial gaps. The latter enlarge, particularly in elderly patients, to form gap-aneurysms complicated by dissections and dissecting an- eurysms that when ruptured cause the calamitous hemorrhages that clinically announce SAM. The other types of injury remain clinically silent but with repair develop sequelae and can metamorphose into fibromuscular dysplasia. The sequelae are mainly asymptomatic but may cause arterial stenosis and ischemic lesions. The definitive diagnosis of SAM re- quires histological conformation but misinterpreta- tion of smooth muscle vacuolar change has caused di- agnostic errors. Muscular artery cystic necrosis a newly named non-inflammatory muscular artery ar- teriopathy may be confused with SAM both clinically and pathologically. This arteriopathy represents the muscular artery equivalent of cystic media necrosis of the elastic arteries since it exhibits similar morphol- ogic features and can occur concomitantly with this entity. Adrenergic agents to counter hemorrhagic shock in SAM are contraindicated since they may intensify injury and create new lesions. The use of norepinehrine antagonists introduces a new, but as yet untested, treatment option for SAM.

Focus on the unique mechanisms involved in thoracic aortic aneurysm formation in bicuspid aortic valve versus tricuspid aortic valve patients: clinical implications of a pilot study

The involvement of different factors in the onset of thoracic aortic aneurysm (TAA) in patients with a bicuspid aortic valve (BAV) vs those with a tricuspid aortic valve (TAV) is well recognized. However, the molecular, genetic and cellular mechanisms driving TAA remain unclear. The aim of this study was to identify the different mechanisms involved in TAA development in patients with BAV vs TAV. Aorta specimens and DNA samples were collected from 24 BAV (18 men and 6 women; mean age: 54.2 ± 14.39 years) and 110 TAV (79 men and 31 women, mean age: 66 ± 9.8 years) patients. A control group of 128 subjects (61 men and 67 woman, mean age: 61.1 ± 5.8 years) was also enrolled. Histopathological and immunohistochemical analyses were performed, as well as genotyping of 10 polymorphisms. In BAV-associated ascending aortas, significant severe plurifocal apoptosis of smooth muscle cells and matrix metalloproteinase-9 (MMP-9) amounts were detected. In contrast, TAV-associated ascending aortas were characterized by a significant severity of elastic fragmentation, cystic medial necrosis, medial fibrosis and inflammation. In addition, in BAV cases, the -1562TMMP-9 and -735TMMP-2 alleles represent independent risk factors for TAA. The effects of these genotypes combined with hypertension and smoking in BAV cases result in an increase in both the apoptosis (P = 0.0001) and levels of MMP-9 (P = 0.001). In TAV cases, the D angiotensin-converting enzyme and +896A Toll-like receptor-4 alleles seem to be the predictive factors for TAA risk. They, combined with hypertension and age, significantly increase both the microscopic lesions and inflammation. Our data seem to suggest that TAA in BAV and TAV patients arises from different molecular, cellular and genetic mechanisms. They might help to identify the potential molecular and genetic biomarkers that are useful to detect BAV subjects at high TAA risk, to monitor and treat them differently from those with TAV, with approaches such as the complete removal of the ascending aorta, including the aortic root with or without dilatation.

A particular phenotype of ascending aorta aneurysms as precursor of type A aortic dissection

We aimed to identify a phenotype of ascending thoracic aortic aneurysm (TAA), which, more than others, evolves into type A dissection (TAD). Aortic specimens were obtained from patients undergoing surgical repair of TAA and TAD (108 and 26, respectively). Histopathological and immunohistochemical analyses were performed by using adequate tissue specimens, appropriate techniques and criteria. We identified the three following TAA phenotypes: phenotype I (cystic medial degeneration balanced by a substitutive fibrosis, in absence of medial apoptosis and with a faint collagenase concentration), phenotype II (cystic medial degeneration of higher grade, respectively, than substitutive fibrosis, with focal medial apoptosis and moderate collagenase concentration), and phenotype III (elevated cystic medial degeneration without substitutive fibrosis, with plurifocal medial apoptosis and severe collagenase concentration). The same medial degenerative lesions of TAA phenotype III were observed in TAD tissue samples. The morphological identity of medial lesions observed in both the TAA phenotype III and in TAD aortas might be assumed to be the precursor-and consequently the optimal biomarker- of dissection, independently of aneurysm diameter or valvular disorder. Identification of genetic risk factors, useful both in diagnostics and in developing more targeted treatment for individual patients, might also be needed.

Spontaneous Coronary Artery Dissection

Spontaneous coronary artery dissection (SCAD) is a rare clinical entity of unknown cause that typically affects young women without coronary risk factors.1–5 Initial reports were scarce and based on autopsy findings after episodes of sudden cardiac death, suggesting that the condition had a dismal prognosis.1,2 An intimal tear was seldom found in autopsy series and, therefore, primary disruption with bleeding of vasa vasorum and intramedial hemorrhage was proposed as the underlying mechanism.1,2 Alternatively, an intimal tear may lead to separation of coronary wall layers and, eventually, to a double lumen. Pressure-driven expansion of the false lumen induces axial propagation of the disease and true lumen compression, resulting in myocardial ischemia.2–4 In some patients, weakening of the arterial wall (hormonal changes, cystic medial necrosis, proteolytic enzymes from periadventitial eosinophils)2 may provide an underlying vulnerable coronary wall. Coronary angiography is widely used in the diagnosis of SCAD and the classical intimal flap represents the hallmark of this disease. Most patients present with an acute coronary syndrome but have a favorable prognosis.2–5 However, available evidence on this condition is limited to multiple case reports and small retrospective case series with short follow-up.1–5 Therefore, 8 decades after its first pathological description,1 the diagnosis and management of SCAD remains elusive. Tweet et al6 present the characteristics, management, and outcome of a uniquely large cohort of patients with SCAD seen at the Mayo Clinic during the last 3 decades. Eighty-seven consecutive patients with SCAD were included. In all cases a dissection plane was visible on angiography, but associated atherosclerosis was absent. Mean age was 43 years, and 82% were female. Predisposing conditions included extreme exertion (44% of males) and postpartum status (18% of females). Half …

Spontaneous bilateral carotid artery dissection following cervical manipulation

We report an autopsy case of a bilateral carotid artery dissection, following cervical manipulation by a chiropractor. To establish the etiology of a cervical artery dissection is important in view of possible legal implications and to exclude hereditary disorders, since cervical artery dissection has been linked to several arteriopathies. The underlying arteriopathy in the presented case was an idiopathic cystic medial degeneration. This report emphasizes the role of the pathologist in defining the underlying arteriopathy in carotid artery dissection.

Aneurysm of the Internal Mammary Artery with Cystic Medial Degeneration

We herein report the histopathology of a rare case of an idiopathic internal mammary artery aneurysm in a 61-year-old asymptomatic woman. Chest radiography during an annual medical check-up incidentally revealed the aneurysm, which was initially mistaken for a mediastinal tumor. Given that a rupture of the aneurysm could have been life-threatening, it was removed surgically, and found to possess a paper-thin arterial wall with cystic medial degeneration.

Acute Aortic Dissection Associated with Cystic Medial Necrosis of Unknown Etiology

A 61-year-old man without a Marfan-like phenotype was admitted to the hospital because of acute Stanford type A aortic dissection. The patient underwent surgical repair with total arch replacement. Histological examination of the excised aorta showed a connective tissue abnormality, which could have contributed to the development of aortic dissection. The cause of the connective tissue abnormality could not be determined through physical examination. Recently, however, many novel gene mutations have been found to be related to aortic diseases that do not always produce physical signs and symptoms. In this case, unknown causes of connective tissue abnormalities might be existed.

Iatrogenic type A aortic dissection during cardiac procedures: early and late outcome in 48 patients

Iatrogenic aortic dissection (IAD) is a rare complication of cardiac procedures. We herein describe our management and results of this complication. A total of 55 279 patients underwent open heart surgery at our centre from 1995 to 2010, and 135 262 patients underwent cardiac catheterization over the same time period. We identified 48 patients from this cohort who underwent emergency surgery for IAD that occurred either during or shortly after cardiac surgery, or following cardiac catheterization. The incidence of IAD was 0.06% (n = 36) for cardiac surgical procedures and 0.01% (n = 12) for cardiac catheterization procedures. The mean patient age was 66 ± 14 years and 50% were female. Intraoperative IAD occurred during aortic cannulation in 12 patients, insertion of the cardioplegia cannula in 7 patients, manipulation of the aortic crossclamp in 4 patients or during other events in 8 patients. IAD occurred early postcardiac surgery in 5 patients, and during cardiac catheterization in the remaining 12 patients. IAD was treated by emergent replacement of the ascending aorta and the aortic arch (when involved), as well as aortic root replacement or repair as indicated. Early mortality was 41.7: 35.5% for intraoperative IAD, 60.0% for postoperative IAD and 50.0% for cardiac catheterization-associated IAD (P = 0.5). Histological investigation revealed atherosclerosis in 61.2% of patients, cystic medial necrosis in 22.2%, aortitis in 2.8% and other pathologies in 13.8%. Follow-up was 100% complete with a 5-year survival of 40 ± 0.4%. IAD is a rare but dangerous complication of cardiac surgery and cardiac catheterization, and is frequently associated with pre-existing aortic pathology.

Endovascular stent-graft placement for ruptured dissecting aortic aneurysm in an adolescent patient with systemic lupus erythematosus: case report

Systemic lupus erythematosus (SLE) is a chronic autoimmune connective tissue disease with multi-organ involvement that is associated with the presence of autoantibodies, and it is influenced by genetic, endocrine, or environmental backgrounds such as exposure to ultraviolet rays and viral infections for the etiopathogenesis [1]. In the cardiovascular system, it frequently causes pericarditis, nonbacterial verrucous endocarditis, coronary artery disease, and cardiomyopathy [2]. Cardiovascular complications in SLE are generally presumed to be associated with inflammatory activity as well as premature development of atherosclerosis [1]. The overall morbidity and death from these complications have been increasing in recent years, and they are now the major cause of death in SLE [3]. Dissecting aortic aneurysm in SLE has been recognized as a rare life-threatening complication, but its pathogenesis is still obscure. The pathogenesis of aortic aneurysms and dissection in SLE has been attributed to aortic circulatory disturbances resulting from vasculitis and cystic medial degeneration as well as to atherosclerosis. The occurrence of atherosclerosis is considered to be due to long-term steroid treatment, hyperlipidemia, hypertension, and nephrotic syndrome [4]. The importance of the high prevalence of premature atherosclerosis and cardiovascular disease in SLE should be addressed, even in young adolescents, and especially those with early childhood-onset disease. Nevertheless, aortic dissection is a life-threatening disorder that requires immediate diagnosis and treatment to prevent mortality. To our knowledge, this is the second adolescent patient with childhood-onset SLE complicated with aortic dissection, but the first case treated with endovascular stent-grafting.

Aortic dissecting aneurysms—Histopathological findings

Acute aortic dissection is a life-threatening disease with a high rate of mortality. At the Institute of Legal Medicine of the Hanover Medical School, 30 cases with aortic dissections were found during autopsy and examined histologically between 2006 and 2009. The grade of medial alterations in the form of cystic medial necrosis, elastin fragmentation, fibrosis and medionecrosis were estimated semi-quantitatively. In order to assess the normal aging process, samples of the aortic wall of 25 decedents without dissecting aneurysms were analyzed histologically. This study demonstrates that there are partly quantitative differences, particularly with a statistically significant increase in cystic medial necrosis (p<0.001) and elastin fragmentation (p<0.001), between aortas from dissecting aneurysms and the normal aging aorta, which may help to identify genetically predisposed relatives of patients with a dissection of the aorta.

Congenital-idiopathic superficial femoral artery aneurysm in a 7-year-old child

Superficial femoral artery aneurysm in children is distinctly uncommon, and usually results from infection, vasculitis, connective tissue disorder, or trauma. We report a 7-year-old girl who had multiple fusiform aneurysms of the right superficial femoral artery, with no evidence of related disorders. The patient successfully underwent aneurysm resection and femoral artery reconstruction with autogenous saphenous vein. Histologic examination revealed intimal thickening with fibroplasia without severe inflammatory infiltrates or cystic medial necrosis, suggesting a congenital-idiopathic arterial aneurysm. Three years after the procedure, the saphenous vein graft is fully patent and the patient is in good condition.

Cystic medial necrosis: pathological findings and clinical implications

Cystic medial necrosis (CMN) is a disorder of large arteries, in particular the aorta, characterized by an accumulation of basophilic ground substance in the media with cyst-like lesions. CMN is known to occur in certain connective tissue diseases such as Marfan syndrome, Ehlers-Danlos syndrome, and annuloaortic ectasia, which usually result from degenerative changes in the aortic wall. The relationships between CMN and congenital heart defects as well as other disorders have been evidenced. The mechanisms are still controversial, even though many molecular studies have been conducted. The aim of the present article is to provide a comprehensive overview of the CMN lesion in terms of pathologic features, clinical implications and etiologies based on molecular research results.

Rapidly growing aortic arch aneurysm in Behçet's disease

We present a patient with a nine-year history of Behçet's disease (BD), who developed a rapidly expanding aneurysm of the aortic arch. Three-dimensional computed tomography demonstrated a saccular aortic arch aneurysm with a maximal diameter of 5cm. No bacteria were detected by serial blood cultures. The aneurysm, however, showed a multi-lobular cavity, mimicking an infectious aneurysm. Therefore, we prescribed antibacterial agents for one week. The patient still had a high-fever and an elevated C-reactive protein level thereafter. Aortic arch replacement was performed emergently. Because we were unable to determine whether the aneurysm was caused by infection or BD, the implanted prosthetic graft and the anastomotic sites were covered with a pedicle graft of the greater omentum, and we continued to administer antibacterial agents for four weeks postoperatively. The pathological examination showed neither bacteria nor cystic medial necrosis in the resected aortic wall. Inflammatory changes with eosinophilic infiltration were recognized mainly around the adventitia near the aneurysm. The patient had a favorable postoperative course without any complications.

Cystic medial necrosis Erdheim Gsell as a rare reason for spontaneous rupture of the ascending aorta

Spontaneous rupture of the ascending aorta is a life-threatening condition requiring immediate intervention. The rupture usually leads to sudden death as a result of hemopericardium or hemothorax. The underlying histopathological condition in the cases described so far was mostly an atheromatous plaque. Some other rare underlying conditions were also described. We report a case of cystic medial necrosis Erdheim Gsell as a reason for fatal spontaneous rupture of the ascending aorta.

Surgical repair of an idiopathic pulmonary artery aneurysm

We report a rare case of idiopathic pulmonary artery aneurysm (PAA) in a 56-year-old woman without any causative conditions, such as congenital heart disease, inflammation, pulmonary artery hypertension, or systemic vasculitis. She presented with sudden back pain, and examination revealed the PAA. She electively underwent resection of the aneurysm and graft replacement. Pathology examination revealed cystic medial necrosis, which was considered the underlying pathology of the aneurysm.

A young man with intimomedial mucoid degeneration of the brachial artery

Intimomedial mucoid degeneration is a rare disorder and has been described as a distinctly different entity from Erdheim's cystic medial necrosis. Most studies show a strong predominance in African American females with hypertension. In our case report, we describe the presence of a large brachial aneurysm in a young white male with intimomedial mucoid degeneration.