Pathogenesis Of Aortic Dissection Research Articles

093 Endovascular intervention for hypertension caused by “functional renal artery stenosis” after acute aortic dissection

Hypertension is widely recognized as a principal factor in the pathogenesis of aortic dissection. Optimal control of resting and exercise blood pressure is of paramount importance in preventing further aneurysmal dilation and rupture of the acutely dissected aorta. In cases of refractory hypertension, it is possible that the dissection itself exacerbates the elevation in blood pressure. By acutely altering systemic vascular flow properties, the dissection flap may produce renal malperfusion and a phenomenon of “functional renal artery stenosis”.

Identification of Genomic Aberrations by Array Comparative Genomic Hybridization in Patients with Aortic Dissections

BackgroundThe aim of the present study was to identify chromosomal loci that contribute to the pathogenesis of aortic dissection (AD) in a Korean population using array comparative genomic hybridization (CGH) and to confirm the results using real-time polymerase chain reaction (PCR).Materials and MethodsEighteen patients with ADs were enrolled in this study. Genomic DNA was extracted from individual blood samples, and array CGH analyses were performed. Four corresponding genes with obvious genomic changes were analyzed using real-time PCR in order to assess the level of genomic imbalance identified by array CGH.ResultsGenomic gains were most frequently detected at 8q24.3 (56%), followed by regions 7q35, 11q12.2, and 15q25.2 (50%). Genomic losses were most frequently observed at 4q35.2 (56%). Real-time PCR confirmed the results of the array CGH studies of the COL6A2, DGCR14, PCSK6, and SDHA genes.ConclusionThis is the first study to identify candidate regions by array CGH in patients with ADs. The identification of genes that may predispose an individual to AD may lead to a better understanding of the mechanism of AD formation. Further multicenter studies comparing cohorts of patients of different ethnicities are warranted.

A microRNA profile comparison between thoracic aortic dissection and normal thoracic aorta indicates the potential role of microRNAs in contributing to thoracic aortic dissection pathogenesis

Our aim was to identify important microRNAs (miRNAs) that might play an important role in contributing to aortic dissection by conducting a miRNA profile comparison between thoracic aortic dissection (TAD) and normal thoracic aorta. The differentially expressed miRNA profiles of the aortic tissue between TAD patients (n = 6) and age-matched donors without aortic diseases (NA; n = 6) were analyzed by miRNA microarray. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was further performed to verify the expression of 12 selected miRNAs with an increased number of samples (TAD n = 12; NA n = 8). The potential targets of the differentially expressed miRNAs were predicted using computational searches. Bioinformatic analyses of the predicted target genes (gene ontology, pathway and network analysis) were done for further research. Additionally, Western blotting was performed to confirm the bioinformatics findings. The miRNA microarray revealed differentially expressed miRNAs between the TAD and NA groups. In the TAD group, 18 miRNAs were upregulated and 56 were downregulated (fold change >2, P < .01). qRT-PCR verified statistically consistent expression of seven selected miRNAs with microarray analysis. Combined with our previous proteomics study, target gene prediction revealed that some miRNAs reciprocally expressed with their targeted proteins. Target gene-related pathway analysis showed a significant change in five pathways in the TAD group compared with the NA group, especially the focal adhesion and the mitogen-activated protein kinase (MAPK) signaling pathways. By further conducting miRNA gene network analysis, we found that the mir-29 and mir-30 families are likely to play a role in the regulation of these two pathways, respectively. Our results indicate that miRNAs expression profiles in aortic media from TAD were significantly changed. These results may provide important insights into TAD disease mechanisms. This study also suggests that the focal adhesion and MAPK signaling pathways might play important roles in the pathogenesis of TAD.

Pathogenesis of Acute Aortic Dissection: A Finite Element Stress Analysis

Type A and type B aortic dissections typically result from intimal tears above the sinotubular junction and distal to the left subclavian artery (LSA) ostium, respectively. We hypothesized that this pathology results from elevated pressure-induced regional wall stress. We identified 47 individuals with normal thoracic aortas by electrocardiogram-gated computed tomography angiography. The thoracic aorta was segmented, reconstructed, and triangulated to create a geometric mesh. Finite element analysis using a systolic pressure load of 120 mm Hg was performed to predict regional thoracic aortic wall stress. There were local maxima of wall stress above the sinotubular junction in the ascending aorta and distal to the ostia of the supraaortic vessels, including the LSA, in the aortic arch. No local maximum of wall stress was found in the descending thoracic aorta. Comparison of the mean peak wall stress above the sinotubular junction (0.43 ± 0.07 MPa), distal to the LSA (0.21 ± 0.07 MPa), and in the descending thoracic aorta (0.06 ± 0.01 MPa) showed a significant effect for wall stress by aortic region (p < 0.001). In the normal thoracic aorta, there are peaks in wall stress above the sinotubular junction and distal to the LSA ostium. This stress distribution may contribute to the pathogenesis of aortic dissections, given their colocalization. Future investigations to determine the utility of image-derived biomechanical calculations in predicting aortic dissection are warranted, and therapies designed to reduce the pressure load-induced wall stress in the thoracic aorta are rational.

Aortic Dissection Complicated with Hemothorax in an Adolescent Patient with Systemic Lupus Erythematosus: Case Report and Review of Literature

To report a young patient with systemic lupus erythematosus (SLE) complicated by aortic dissection. The relevant literature on the association of SLE and aortic dissection is reviewed. We describe an adolescent patient with childhood-onset SLE diagnosed aortic dissection with presentation of hemothorax. The literature review was performed by a PubMed search using the keywords systemic lupus erythematosus (SLE), aortic dissection, hemothorax, and carotid intima-media thickness (CIMT). A 17-year-old male was admitted to the hospital for severe abdominal pain. His past medical history included childhood-onset SLE complicated with lupus nephritis. Acute aortic dissection complicated with hemothorax was diagnosed and he died despite medical therapy. The accelerated CIMT progression of our patient, 0.14 mm in 20 months, might suggest ongoing premature atherosclerotic changes in the aortic wall. On reviewing the English literature, 21 cases of aortic dissection in SLE have been analyzed and discussed. Patients younger than 40 years of age, hypertension, and long-term steroid use are common features of aortic dissection in SLE patients. The possible pathogenesis of aortic dissection in SLE includes atherosclerosis, degeneration, and vasculitis. The widely accepted CIMT measured by ultrasound could be a potential diagnostic tool to access the risk of cardiovascular events. Aortic dissection is a rare complication of SLE, but could take place in an adolescent patient with childhood-onset disease. It is important to include aortic dissection as a differential diagnosis in SLE patients with unexplained sharp abdominal, chest, or back pain.

Pathogenesis of aortic dissection: elastic fiber abnormalities and aortic medial weakness.

Although aortic dissection was previously a disease with an extremely poor prognosis, recent advances in diagnostic imaging and therapeutic modalities may improve its prognosis.1, 2) However, much of its etiology and pathogenesis remains unknown. In addition, new pathological variants of aortic dissection, such as intramural hematoma (IMH) and penetrating atherosclerotic ulcer, and related diseases have been identified, raising a new problem. Against this background, this paper revisits the basic pathology of aortic dissection, and discusses the structural abnormalities of the aortic media and mechanism of aortic dissection, as extrapolated from them.

Pathogenesis of Aortic Dissection: Elastic Fiber Abnormalities and Aortic Medial Weakness

Pathogenesis of Aortic Dissection: Elastic Fiber Abnormalities and Aortic Medial Weakness

Pathology of the thoracic aorta: a morphologic review of 338 surgical specimens over a 7-year period

A total of 338 surgical specimens of the thoracic aorta were studied morphologically. These were obtained from patients (238 males, 100 females) operated on for aortic aneurysm or dissection at the Careggi Hospital, Florence, Italy, between January 1999 and June 2005. Medial degeneration was diagnosed in 299 cases (138 aneurysms, 161 dissections), atherosclerosis with extensive medial destruction was seen in 32 cases (26 aneurysms, 6 dissections), and giant cell arteritis (GCA) was found in 7 cases (all aneurysms). These data show that medial degeneration was a common nonspecific histologic diagnosis in aortic resection after the occurrence of aneurysm or dissection. Considering that this diagnosis was made in as many as 118 patients over 70 years of age and in 175 patients over 65, normal advancing age would appear as the most frequent correlation with these aortic events. Ageing is also associated with the increasing number of cases of GCA with aortic involvement. Angiogenesis, always observed next to areas of medial damage whatever the underlying pathology, may contribute to the pathogenesis of aortic dissection and aneurysm.

Biglycan Deficiency Causes Spontaneous Aortic Dissection and Rupture in Mice

For the majority of cases, the cause of spontaneous aortic dissection and rupture is unknown. An inherited risk is associated with Marfan syndrome, Ehlers-Danlos syndrome type IV, and loci mapped to diverse autosomal chromosomes. Analysis of pedigrees however has indicated that it may be also inherited as an X-linked trait. The biglycan gene, found on chromosome X in humans and mice, encodes a small leucine-rich proteoglycan involved in the integrity of the extracellular matrix. A vascular phenotype has never been described in mice deficient in the gene for small leucine-rich proteoglycans. In the breeding of BALB/cA mice homozygous for a null mutation of the biglycan gene, we observed that 50% of biglycan-deficient male mice died suddenly within the first 3 months of life. Necropsies revealed a major hemorrhage in the thoracic or abdominal cavity, and histology showed aortic rupture that involved an intimal and medial tear as well as dissection between the media and adventitia. By transmission electron microscopy and biomechanical testing, the aortas of biglycan-deficient mice showed structural abnormalities of collagen fibrils and reduced tensile strength. Similar collagen fibril changes were observed in male as well as in female biglycan-deficient mice, which implies a role of additional determinants such as gender-related response to stress in the development of this vascular catastrophe only in male mice. The spontaneous death of biglycan-deficient male mice from aortic rupture implicates biglycan as essential for the structural and functional integrity of the aortic wall and suggests a potential role of biglycan gene defects in the pathogenesis of aortic dissection and rupture in humans.

2310 大動脈解離の成因に関する力学的検討(OS23.生命体統合シミュレーション(2),ポスターセッションP-2)

2310 大動脈解離の成因に関する力学的検討(OS23.生命体統合シミュレーション(2),ポスターセッションP-2)

Increased Carotid Artery Stiffness Without Atherosclerotic Change in Patients With Aortic Dissection

The arterial properties and pathogenesis of aortic dissection remain obscure. To examine the arterial properties of patients with aortic dissection, the authors studied the ultrasonographic characteristics of the carotid artery in patients with an aortic dissection (AD, n = 86), and compared these findings with data of patients suffering from arteriosclerosis obliterans (ASO, n = 151), coronary artery disease (CAD, n = 163), and with healthy controls (HC, n = 77). Atherosclerotic intimal changes, such as intima-media thickness (IMT) and plaque formation, were milder in AD than in ASO or CAD (IMT: 0.83 +/- 0.16 vs 0.93 +/- 0.20/0.86 +/- 0.17 mm, p < 0.05; plaque number: 0.6 +/- 1.1 vs 2.7 +/- 2.4/2.5 +/- 2.1, p <0.05). Luminal diameter in AD, ASO, and CAD was significantly higher than in HC. The luminal distensibility in AD was decreased compared with HC but was the same as in ASO and CAD. Intra-AD group analysis showed that in patients with an intramural hematoma (IMH) or a dissection with a thrombosed false lumen (TLF) the IMT was higher than in patients with a classic dissection. In addition, plaque formation was more severe in AD patients with a coexisting abdominal aortic aneurysm (AAA). Reduced distensibility without severe intimal disease was found in AD. These findings suggest that patients with AD may have several arterial alterations, including structural abnormalities. Patients with IMH, TFL, or coexisting AAA may differ from patients who have a classic type of dissection or who do not have AAA, in terms of arterial characteristics including intimal disease and wall elastic property, and the initiating cause of the dissection.

Decreased expression of fibulin-5 correlates with reduced elastin in thoracic aortic dissection

Thoracic aortic aneurysmal diseases are characterized by degeneration of elastin within the aortic wall. Although proteinases, such as matrix metalloproteinase, appear to contribute to elastin degradation, little is known about the role of elastic fiber assembly in such diseases. Fibulin-5 is an extracellular protein that is expressed in the vascular basement membrane and regulates elastic fiber assembly by microfibril machinery. In this study, we examined whether thoracic aortic dissection (TAD) is associated with abnormal fibulin-5 expression. Intraoperative aortic samples were obtained from 21 patients with proximal aortic dissection. Control aortic tissue was obtained from 11 organ donors, heart transplant recipients, and patients undergoing coronary artery bypass. An in vitro culture of vascular smooth muscle cells was obtained from 2 TAD patients and 1 control subject. To evaluate elastin expression, we stained tissue sections with Verhoeff-Van Gieson stain. Fibulin-5 messenger RNA (mRNA) expression was determined by quantitative real-time reverse-transcriptase-polymerase chain reaction. Aortic fibulin-5 mRNA and elastin content were decreased in TAD patients, compared with controls (P=.001 and P=.02, respectively). Decreased fibulin-5 expression strongly correlated with decreased amounts and fragmentation of elastin in aortic samples from patients with TAD (r=0.83, P < .0001 and F=20.7, P < .0001 respectively). The fibulin-5 mRNA in aortic vascular smooth muscle cells collected from TAD demonstrated a 38% decrease in expression, compared with the control. Patients with proximal aortic dissection exhibited significantly decreased expression of aortic fibulin-5. Decreased fibulin-5 may contribute to the pathogenesis of aortic dissection by impairing elastic fiber assembly.

Histopathological Studies of Aortic Dissection in Streptozotocin-Induced Diabetic APA Hamsters

Syrian hamsters of the APA strain (APA hamsters) are known to show continuous diabetes accompanied by its complications, such as glomerulosclerosis and atherosclerosis, following a single injection of streptozotocin (SZ). Recently, we observed Stanford type B aortic dissection in three diabetic APA hamsters and histopathological analysis was performed. The histopathologic observations in the false lumen, such as proliferation of granulation tissues, neointima and pseudoneointima, corresponded to the non-thrombosed type of human aortic dissection, and blood clots of the thrombosed type were similar to the remodeling structures of aortic dissection found in human cases. Thus, this model may be useful for investigating the etiology and pathogenesis of aortic dissection accompanying diabetes mellitus in humans.

Role of aortic root motion in the pathogenesis of aortic dissection.

The downward movement of the aortic root during the cardiac cycle may be responsible for producing the circumferential tear observed in aortic dissections. Contrast injections were investigated in 40 cardiac patients, and a finite element model of the aortic root, arch, and branches of the arch was built to assess the influence of aortic root displacement and pressure on the aortic wall stress. The axial displacement of the aortic root ranged from 0 to 14 mm. It was increased in patients with aortic insufficiency (22+/-13% of the sino-tubular junction diameter versus 12+/-9%) and reduced in patients with hypokinesis of the left ventricle (10+/-9% of sino-tubular junction versus 17+/-12%). The largest stress increase due to aortic root displacement was found approximately 2 cm above the sino-tubular junction, where the longitudinal stress increased by 50% to 0.32 Nmm(-2) when 8.9-mm axial displacement was applied in addition to 120-mm Hg luminal pressure. A similar result was observed when the pressure load was increased to 180 mm Hg without axial displacement. Both aortic root displacement and hypertension significantly increase the longitudinal stress in the ascending aorta. For patients with hypertension who are at risk of dissection, aortic root movement may be monitored as an important risk factor.

Interventional management of aortic dissection.

Modern high-resolution imaging techniques have provided new insights into the pathogenesis of aortic dissection during recent years. Distinct pathologic entities or potential precursors of classic false-lumen aortic dissection such as intramural hematoma or penetrating atherosclerotic ulcer have been identified. As a result, a novel classification according to Svensson used in addition to the standard differentiation according to DeBakey or Stanford has been introduced. Due to improved diagnostic imaging, preoperative mortality has decreased but mortality remains substantial (up to 1.4% per hour within the first 2 days) related to complications of aortic dissection such as aortic rupture, bleeding, pericardial tamponade, critical branch vessel ischemia, multiorgan failure, and myocardial infarction. Transesophageal echocardiography, angiography, magnetic resonance imaging or computed tomography as well as intravascular ultrasound are used for a complete vascular "staging" of patients with aortic dissection after initial stabilization (with or without surgery). New catheter-based interventional techniques have been developed to improve the poor prognosis of aortic dissection: 1 Percutaneous balloon fenestration (PTF) of the intimal flap improves perfusion in case of bowel, limb, or renal ischemia. 2. Aortic stent-graft placement allows for occlusion of the intimal entry tear by implantation of a membrane-covered, self-expanding stent-graft to initiate progressive thrombus formation within the false lumen. Compared to the traditional surgical approaches, both techniques have a low complication rate. The development of these techniques may help to further improve to decrease patients' morbidity and mortality.

Acute Aortic Dissection and Its Variants

Acute dissection of the aorta is an uncommon yet potentially catastrophic clinical event that mandates prompt recognition and expeditious treatment. Diagnosis begins with a high clinical index of suspicion in a patient presenting with chest pain and one or more predisposing risk factors, most notably, hypertension or an inherited disorder of connective tissue. Verification can be rapidly achieved with a high degree of accuracy using one of several noninvasive imaging techniques and, when necessary, contrast angiography. Involvement of the ascending aorta (type A) requires surgical intervention, whereas clinically stable dissection limited to the descending thoracic aorta (type B) can in general be treated medically. Negative inotropic andantihypertensive medical therapy is provided to all patients. Hospital and long-term survival has improved substantially over the past 40 years, yet there remains ample room for continued progress. For centers with an active interest in the evaluation and management of acute dissection, hospital mortality rates have been lowered to 15% to 25%.1 2 3 Five-year actuarial survival rates range between 50% and 70%,2 4 5 with a 7% to 20% incidence of late reoperation, usually for aneurysmal enlargement or redissection.2 6 7 There has long been some debate over the pathogenesis of aortic dissection. In the majority of cases, the initiating event is a tear in the intima of the aorta through which blood surges into the middle to outer third of the media.8 9 10 Intimal disease, such as that associated with atherosclerosis, is not a prerequisite, although underlying medial disease due to both elastic fiber and smooth muscle cell degeneration is the rule.11 12 13 Intimal tears are most commonly located a few centimeters above the aortic valve, along the right anterolateral aspect of the aorta, where hydrodynamic and torsional forces are greatest.9 The second most …

Managemetn of ascending aortic dissections

Recent advances in the diagnosis and surgical management of acute type A aortic dissection have been discussed. Trans-esophageal echocardiography is becoming the initial diagnostic procedures of choice. Intramural hematoma may be an important early element in the pathogenesis of aortic dissection, but clinical knowledge of this dynamic entity is limited. As best we know today, the optimal therapeutic approach for patients with IMH appears to be similar to that for those individuals with conventional aortic dissection. Treating patients with aortic dissection involving the arch presents a continuing surgical challenge: concomitant “hemi-arch” repair is a prudent option in most patients. The technique of profound hypothermia and circulatory arrest has become recognized to be a valuable adjunct in the treatment of patients with acute type A aortic dissections.

Abnormal mechanical properties of the aorta in Marfan's syndrome

Aortic dilatation, dissection and rupture are among the major causes of death in subjects with Marfan's syndrome. The aim of the study was to investigate the mechanical properties or compliance of the aorta in these subjects and compare them with a healthy age- and sex-matched reference population. An ultrasound phase-locked echo-tracking system was used to determine diameter and pulsatile diameter change of the infrarenal aorta in nine subjects with Marfan's syndrome which were then compared with the values for 165 healthy individuals. Compliance, defined as the inverse of Ep (pressure strain elastic modulus) or stiffness (beta), was calculated from pulsatile diameter change and blood pressure obtained by the auscultatory method with a sphygmomanometer. For statistical analysis confidence intervals (95%) obtained from the healthy controls were used for comparison. Analysis of covariance (ANCOVA) was performed for the female patients. The sample size for males (n = 2) was too small for the latter analysis. Compared with normal subjects and their confidence intervals, subjects with Marfan's syndrome had an increased Ep and stiffness (beta) and decreased strain (fractional diameter change) in the infrarenal aorta. Furthermore, ANCOVA in the female patients showed increased beta (p < 0.01) and Ep (p < 0.01) and a decreased strain (p < 0.001). Aortic diameters, MAP, as well as the pulse pressure, were similar in the two groups. This investigation demonstrates alterations in the mechanical properties of the aorta in Marfan's syndrome in the form of increased stiffness of the aortic wall. This may be of importance in the pathogenesis of aortic dissection and rupture.