Thoracic aortic diseases that involve progressive enlargement, acute dissection, or rupture are influenced by the hemodynamic loads and mechanical properties of the wall. We have only limited ...understanding, however, of the mechanobiological processes that lead to these potentially lethal conditions. Homeostasis requires that intramural cells sense their local chemomechanical environment and establish, maintain, remodel, or repair the extracellular matrix to provide suitable compliance and yet sufficient strength. Proper sensing, in turn, necessitates both receptors that connect the extracellular matrix to intracellular actomyosin filaments and signaling molecules that transmit the related information to the nucleus. Thoracic aortic aneurysms and dissections are associated with poorly controlled hypertension and mutations in genes for extracellular matrix constituents, membrane receptors, contractile proteins, and associated signaling molecules. This grouping of factors suggests that these thoracic diseases result, in part, from dysfunctional mechanosensing and mechanoregulation of the extracellular matrix by the intramural cells, which leads to a compromised structural integrity of the wall. Thus, improved understanding of the mechanobiology of aortic cells could lead to new therapeutic strategies for thoracic aortic aneurysms and dissections.
Aortic aneurysm, focal dilation of the aorta, results from impaired integrity of aortic extracellular matrix (ECM). Matrix metalloproteinases (MMPs) are traditionally known as ECM-degrading enzymes. ...MMP2 has been associated with aneurysm in patients and in animal models. We investigated the role of MMP2 in thoracic aortic aneurysm using 2 models of aortic remodeling and aneurysm.
Male 10-week-old MMP2-deficient (MMP2(-/-)) and wild-type mice received angiotensin II (Ang II, 1.5 mg/kg/day) or saline (Alzet pump) for 4 weeks. Although both genotypes exhibited dilation of the ascending aorta after Ang II infusion, MMP2(-/-) mice showed more severe dilation of the thoracic aorta and thoracic aortic aneurysm. The Ang II-induced increase in elastin and collagen (mRNA and protein) was markedly suppressed in MMP2(-/-) thoracic aorta and smooth muscle cells, whereas only mRNA levels were reduced in MMP2(-/-)-Ang II abdominal aorta. Consistent with the absence of MMP2, proteolytic activities were lower in MMP2(-/-)-Ang II compared with wild-type-Ang II thoracic and abdominal aorta. MMP2-deficiency suppressed the activation of latent transforming growth factor-β and the Smad2/3 pathway in vivo and in vitro. Intriguingly, MMP2(-/-) mice were protected against CaCl2-induced thoracic aortic aneurysm, which triggered ECM degradation but not synthesis.
This study reveals the dual role of MMP2 in ECM degradation, as well as ECM synthesis. Moreover, the greater susceptibility of the thoracic aorta to impaired ECM synthesis, compared with vulnerability of the abdominal aorta to aberrant ECM degradation, provides an insight into the regional susceptibility of the aorta to aneurysm development.
Natural history of thoracic aortic aneurysms Kuzmik, Gregory A., BA; Sang, Adam X., BA; Elefteriades, John A., MD
Journal of vascular surgery,
08/2012, Letnik:
56, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Understanding the natural history of thoracic aortic aneurysms (TAAs) is essential to patient care and surgical decision making. In this evidence summary we discuss some of the most clinically ...relevant features of the disease. The true incidence of TAAs is likely to be higher than currently reported because of the inherently silent nature of TAAs. However, TAAs can become rapidly lethal once dissection or rupture occurs, highlighting the need for more robust screening. The impressive discovery of familial patterns and novel genetic loci for TAAs challenges the idea that most TAAs are simply sporadic. Although the aorta grows in an indolent manner, its rate of growth and its current diameter both have important clinical implications. Biomechanical studies have supported clinical findings of 6.0 cm as a dangerous threshold. Surgical extirpation of TAAs is currently the mainstay of effective treatment. Although endovascular TAA repair is becoming increasingly common, long-term safety remains unproven. We still need more data to support the concept that any medical therapy is effective.
Objective Thoracoabdominal aortic aneurysm (TAAA) repair remains a challenging clinical pathology. Endovascular technology, in particular the evolution of fenestrated and branched (F/B) endografts ...used in endovascular aneurysm repair (EVAR) has provided a less invasive method of treating these complex aneurysms. This study evaluated the technical and clinical outcomes of F/B-EVAR for extensive type II and III TAAA. Methods Data from 354 high-risk patients enrolled in a physician-sponsored investigational device exemption trial (2004-2013) undergoing F/B-EVAR for type II and III TAAA were evaluated. Technical success, perioperative clinical outcomes, and midterm outcomes (36 months) for branch patency, reintervention, aneurysm-related death, and all-cause mortality were analyzed. Data are presented as mean ± standard deviation and were assessed using Kaplan-Meier, univariate, and multivariate analysis. Results F/B-EVARs incorporating 1305 fenestration/branches were implanted with 96% of target vessels successfully stented. Completion aortography showed 2.8% patients had a type I or III endoleak. Procedure duration (6.0 ± 1.7 vs 5.5 ± 1.6 hours; P < .01) and hospital stay (13.1 ± 10.1 vs 10.2 ± 7.4 days; P < .01) were longer for type II TAAA. Perioperative mortality was greater in type II repairs (7.0% vs 3.5%; P < .001). Permanent spinal cord ischemia occurred in 4% and renal failure requiring hemodialysis occurred in 2.8% of patients. Twenty-seven branches (7.6%) required reintervention for stenosis or occlusion; and celiac artery, superior mesenteric artery, and renal artery secondary patency at 36 months was 96% (95% confidence interval CI, 0.93-0.99), 98% (95% CI, 0.97-1.0), and 98% (95% CI, 0.96-1.0), respectively. Eighty endoleak repairs were performed in 67 patients, including 55 branch-related endoleaks, 4 type Ia, 5 type Ib, and 15 type II endoleaks. At 36 months, freedom from aneurysm-related death was 91% (95% CI, 0.88-0.95), and freedom from all-cause mortality was 57% (95% CI, 0.50-0.63). The treatment of type II TAAA ( P < .01), age ( P < .01), and chronic obstructive pulmonary disease ( P < .05) negatively affected survival. Conclusions F/B-EVAR is a robust treatment option for patients at increased risk for conventional repair of extensive TAAAs. Technical success and branch patency are excellent, but some patients will require reintervention for branch-related endoleak. Aneurysm extent portends a higher risk of perioperative and long-term morbidity and mortality. Additional efforts are needed to improve outcomes and understand the utility of this treatment option in the general TAAA population.
Abstract Purpose To investigate outcomes of manufactured fenestrated and branched endovascular aortic repair (F-BEVAR) endografts based on supraceliac sealing zones to treat pararenal aortic ...aneurysms and thoracoabdominal aortic aneurysms (TAAAs). Methods A total of 127 patients (91 male, mean age 75 ± 10 years old) were enrolled in a prospective, nonrandomized single-center study using manufactured F-BEVAR (November 2013-March 2015). Stent design was based on supraceliac sealing zone in all patients with ≥ four vessels in 111 (89%). Follow-up included clinical examination, laboratory studies, duplex ultrasound, and computed tomography imaging at discharge, 1 month, 6 months, and yearly. End points adjudicated by independent clinical event committee included mortality, major adverse events (any mortality, myocardial infarction, stroke, paraplegia, acute kidney injury, respiratory failure, bowel ischemia, blood loss >1 L), freedom from reintervention, and branch-related instability (occlusion, stenosis, endoleak or disconnection requiring reintervention), target vessel patency, sac aneurysm enlargement, and aneurysm rupture. Results There were 47 pararenal, 42 type IV, and 38 type I-III TAAAs with mean diameter of 59 ± 17 mm. A total of 496 renal-mesenteric arteries were incorporated by 352 fenestrations, 125 directional branches, and 19 celiac scallops, with a mean of 3.9 ± 0.5 vessels per patient. Technical success of target vessel incorporation was 99.6% (n = 493/496). There were no 30-day or in-hospital deaths, dialysis, ruptures or conversions to open surgical repair. Major adverse events occurred in 27 patients (21%). Paraplegia occurred in two patients (one type IV, one type II TAAAs). Follow-up was >30 days in all patients, >6 months in 79, and >12 months in 34. No patients were lost to follow-up. After a mean follow-up of 9.2 ± 7 months, 23 patients (18%) had reinterventions (15 aortic, 8 nonaortic), 4 renal artery stents were occluded, five patients had type Ia or III endoleaks, and none had aneurysm sac enlargement. Primary and secondary target vessel patency was 96% ± 1% and 98% ± 0.7% at 1 year. Freedom from any branch instability and any reintervention was 93% ± 2% and 93% ± 2% at 1 year, respectively. Patient survival was 96% ± 2% at 1 year for the entire cohort. Conclusions Endovascular repair of pararenal aortic aneurysms and TAAAs, using manufactured F-BEVAR with supraceliac sealing zones, is safe and efficacious. Long-term follow-up is needed to assess the impact of four-vessel designs on device-related complications and progression of aortic disease.
Abstract
Aortic aneurysm is a life-threatening disease due to the risk of aortic rupture. The only curative treatment available relies on surgical approaches; drug-based therapies are lacking, ...highlighting an unmet need for clinical practice. Abdominal aortic aneurysm (AAA) is frequently associated with atherosclerosis and cardiovascular risk factors including male sex, age, smoking, hypertension, and dyslipidaemia. Thoracic aortic aneurysm (TAA) is more often linked to genetic disorders of the extracellular matrix and the contractile apparatus but also share similar cardiovascular risk factors. Intriguingly, a large body of evidence points to an inverse association between diabetes and both AAA and TAA. A better understanding of the mechanisms underlying the negative association between diabetes and aortic aneurysm could help the development of innovative diagnostic and therapeutic approaches to tackle the disease. Here, we summarize current knowledge on the relationship between glycaemic parameters, diabetes, and the development of aortic aneurysm. Cellular and molecular pathways that underlie the protective effect of diabetes itself and its treatment are reviewed and discussed, along with their potential implications for clinical translation.
Abstract
Vascular smooth muscle cells (vSMCs) play a crucial role in both the pathogenesis of Aneurysms and Dissections of the ascending thoracic aorta (TAAD) in humans and in the associated adaptive ...compensatory responses, since thrombosis and inflammatory processes are absent in the majority of cases. Aneurysms and dissections share numerous characteristics, including aetiologies and histopathological alterations: vSMC disappearance, medial areas of mucoid degeneration, and extracellular matrix (ECM) breakdown. Three aetiologies predominate in TAAD in humans: (i) genetic causes in heritable familial forms, (ii) an association with bicuspid aortic valves, and (iii) a sporadic degenerative form linked to the aortic aging process. Genetic forms include mutations in vSMC genes encoding for molecules of the ECM or the TGF-β pathways, or participating in vSMC tone. On the other hand, aneurysms and dissections, whatever their aetiologies, are characterized by an increase in wall permeability leading to transmural advection of plasma proteins which could interact with vSMCs and ECM components. In this context, blood-borne plasminogen appears to play an important role, because its outward convection through the wall is increased in TAAD, and it could be converted to active plasmin at the vSMC membrane. Active plasmin can induce vSMC disappearance, proteolysis of adhesive proteins, activation of MMPs and release of TGF-β from its ECM storage sites. Conversely, vSMCs could respond to aneurysmal biomechanical and proteolytic injury by an epigenetic phenotypic switch, including constitutional overexpression and nuclear translocation of Smad2 and an increase in antiprotease and ECM protein synthesis. In contrast, such an epigenetic phenomenon is not observed in dissections. In this context, dysfunction of proteins involved in vSMC tone are interesting to study, particularly in interaction with plasma protein transport through the wall and TGF-β activation, to establish the relationship between these dysfunctions and ECM proteolysis.
Although hypertension is the most common risk factor for thoracic aortic diseases, it is not understood how increased pressures on the ascending aorta lead to aortic aneurysms. We investigated the ...role of angiotensin II type 1 receptor activation in ascending aortic remodeling in response to increased biomechanical forces using a transverse aortic constriction (TAC) mouse model.
Two weeks after TAC, the increased biomechanical pressures led to ascending aortic dilatation and thickening of the medial and adventitial layers of the aorta. There was significant adventitial hyperplasia and inflammatory responses in TAC ascending aortas were accompanied by increased adventitial collagen, elevated inflammatory and proliferative markers, and increased cell density attributable to accumulation of myofibroblasts and macrophages. Treatment with losartan significantly blocked TAC-induced vascular inflammation and macrophage accumulation. However, losartan only partially prevented TAC-induced adventitial hyperplasia, collagen accumulation, and ascending aortic dilatation. Increased Tgfb2 expression and phosphorylated-Smad2 staining in the medial layer of TAC ascending aortas were effectively blocked with losartan. In contrast, the increased Tgfb1 expression and adventitial phospho-Smad2 staining were only partially attenuated by losartan. In addition, losartan significantly blocked extracellular signal-regulated kinase activation and reactive oxygen species production in the TAC ascending aorta.
Inhibition of the angiotensin II type 1 receptor using losartan significantly attenuated the vascular remodeling associated with TAC but did not completely block the increased transforming growth factor-β1 expression, adventitial Smad2 signaling, and collagen accumulation. These results help to delineate the aortic transforming growth factor-β signaling that is dependent and independent of the angiotensin II type 1 receptor after TAC.
The importance of maintaining contractile function in aortic smooth muscle cells (SMCs) is evident by the fact that heterozygous mutations in the major structural proteins or kinases controlling ...contraction lead to the formation of aneurysms of the ascending thoracic aorta that predispose to life-threatening aortic dissections. Force generation by SMC requires ATP-dependent cyclic interactions between filaments composed of SMC-specific isoforms of α-actin (encoded by ACTA2) and myosin heavy chain (MYH11). ACTA2 and MYH11 mutations are predicted or have been shown to disrupt this cyclic interaction predispose to thoracic aortic disease. Movement of the myosin motor domain is controlled by phosphorylation of the regulatory light chain on the myosin filament, and loss-of-function mutations in the dedicated kinase for this phosphorylation, myosin light chain kinase (MYLK) also predispose to thoracic aortic disease. Finally, a mutation in the cGMP-activated protein kinase (PRKG1) results in constitutive activation of the kinase in the absence of cGMP, thus driving SMC relaxation in part through increased dephosphorylation of the regulatory light chain and predisposes to thoracic aortic disease. Furthermore, SMCs cannot generate force without connections to the extracellular matrix through focal adhesions, and mutations in the major protein in the extracellular matrix, fibrillin-1, linking SMCs to the matrix also cause thoracic aortic disease in individuals with Marfan syndrome. Thus, disruption of the ability of the aortic SMC to generate force through the elastin-contractile units in response to pulsatile blood flow may be a primary driver for thoracic aortic aneurysms and dissections.
Elucidating critical aortic diameters at which natural complications (rupture, dissection, and death) occur is of paramount importance to guide timely surgical intervention. Natural history knowledge ...for descending thoracic and thoracoabdominal aortic aneurysms is sparse. Our small early studies recommended repairing descending thoracic and thoracoabdominal aortic aneurysms before a critical diameter of 7.0 cm. We focus exclusively on a large number of descending thoracic and thoracoabdominal aortic aneurysms followed over time, enabling a more detailed analysis with greater granularity across aortic sizes.
Aortic diameters and long-term complications of 907 patients with descending thoracic and thoracoabdominal aortic aneurysms were reviewed. Growth rates (instrumental variables approach), yearly complication rates, 5-year event-free survival (Kaplan–Meier), and risk of complications as a function of aortic height index (aortic diameter centimeters/height meters) (competing-risks regression) were calculated.
Estimated mean growth rate of descending thoracic and thoracoabdominal aortic aneurysms was 0.19 cm/year, increasing with increasing aortic size. Median size at acute type B dissection was 4.1 cm. Some 80% of dissections occurred below 5 cm, whereas 93% of ruptures occurred above 5 cm. Descending thoracic and thoracoabdominal aortic aneurysm diameter 6 cm or greater was associated with a 19% yearly rate of rupture, dissection, or death. Five-year complication-free survival progressively decreased with increasing aortic height index. Hazard of complications showed a 6-fold increase at an aortic height index of 4.2 or greater compared with an aortic height index of 3.0 to 3.5 (P < .05). The probability of fatal complications (aortic rupture or death) increased sharply at 2 hinge points: 6.0 and 6.5 cm.
Acute type B dissections occur frequently at small aortic sizes; thus, prophylactic size-based surgery may not afford a means for dissection protection. However, fatal complications increase dramatically at 6.0 cm, suggesting that preemptive intervention before that criterion can save lives.
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