Proliferative Vascular Smooth Muscle Cells Stimulate Extracellular Matrix Production via Osteopontin/p38 MAPK Signaling Pathway.

INTRODUCTION: Extracellular matrix disorder and cellular phenotype transformation are the major histopathological features associated with ascending aortic aneurysms. Rare studies have investigated the relationship between cellular phenotype transformation and the abnormalities of the matrix constituents. In this study, we investigated whether the cellular phenotype transformation resulted in the extracellular matrix disorder. METHODS: Aortic samples were obtained from 20 patients undergoing operations for ascending aortic aneurysms. Control aortic samples were obtained from 15 patients who underwent coronary artery bypass graft. The protein levels of osteopontin (OPN), collagen, and elastin were examined using Western blot, and quantitative reverse transcriptase-PCR was used to analyze the mRNA expression of collagen and elastin. In vitro experiment, vascular smooth muscle cells (VSMCs) were treated with recombinant human OPN (rh-OPN) or p38 MAPK inhibitor (SB203580) to investigate whether OPN and p38 MAPK regulated the expression of collagen and elastin. RESULTS: The protein level of OPN and collagen III increased in ascending aortic aneurysm samples, compared with controls (p < 0.05). There was no difference in the protein level of elastin between aneurysm tissues and the controls. VSMCs treated with rh-OPN increased the collagen III and elastin protein level and mRNA expression (p < 0.05). Cells treated with SB203580 decreased the collagen III and elastin protein level and mRNA expression (p < 0.05). Furthermore, VSMCs incubated with SB203580 reduced the rh-OPN-induced production of collagen III and elastin (p < 0.05). CONCLUSION: OPN, the proliferative VSMCs maker, increased the expression of extracellular matrix. OPN/p38 MAPK signaling pathways may protect against ascending aortic aneurysm progression.

Single Stage Hybrid Repair for DeBakey Type I Aortic Dissection in High Risk Patients.

OBJECTIVES: To evaluate the efficacy of the less invasive hybrid zone 0 (Z0) total aortic arch repair (HAR, ascending repair + complete debranching + thoracic endovascular aortic repair [TEVAR]) without deep hypothermic circulatory arrest in management of DeBakey type I aortic dissection (IAD). The adverse outcome was defined as a single composite endpoint comprising peri-operative mortality, permanent neurological deficit, and renal failure necessitating haemodialysis at discharge. METHODS: A retrospective review of prospectively collected data was conducted of 120 consecutive patients (mean EuroSCORE = 11.6%) with IAD undergoing HAR (urgent/emergency, n = 97, 80.8%) involving reconstruction of the ascending aorta (zone 0) and total arch exclusion with TEVAR during a 7.5 year period. Multivariable analysis of 27 potential pre-operative and intra-operative risk factors was performed to examine the early composite endpoint and short and long-term overall mortality. RESULTS: The total early (30 day or in hospital) mortality was 9.2% (n = 11). The incidence of the composite endpoint was 11.7% (n = 14). On multivariable analysis, malperfusion syndromes were predictors of the composite endpoint (odds ratio [OR], 4.789; 95% CI 1.362-16.896; p = .015), and previous cerebrovascular accident (OR, 13.74; 95% CI 2.330-81.039; p = .004) and myocardial ischaemia time (OR, 1.038; 95% CI 1.015-1.061; p = .001) predicted short and long-term overall mortality. The overall survival was 84.7% during a median follow up of 3.4 years. Freedom from late aortic adverse events was 93.1% at 5 years, including secondary aortic intervention and endoleak. The maximum diameters of the true lumen increased significantly in stented thoracic (14.4 ± 6.5 mm to 29.7 ± 5.3 mm, p < .001), lower thoracic (14.2 ± 6 mm to 21.6 ± 7.2 mm, p < .001) and abdominal (11.7 ± 4.8 mm to 17.4 ± 4.1 mm, p < .001) aorta. Complete thrombosis of the peri-stent false lumen was achieved in 88.2% of CT scans (82/93) performed a mean of 12 ± 17 months (median 5 months; 25-75% quartile, 2-12 months) post-operatively. CONCLUSIONS: IAD was treated safely and durably by Z0 HAR, and peri-operative mortality and morbidity were not substantially higher despite the older age and high risk of patients.

Angiotensin II Induces an Increase in Matrix Metalloproteinase 2 Expression in Aortic Smooth Muscle Cells of Ascending Thoracic Aortic Aneurysms Through JNK, ERK1/2, and p38 MAPK Activation.

In this study, we hypothesized that angiotensin II (Ang II) induces matrix metalloproteinase 2 (MMP-2) upregulation in aneurysmal smooth muscle cells (ASMCs) derived from ascending thoracic aortic aneurysms (ATAAs). We compared MMP-2 protein levels in ascending aortic specimens using Western blot and plasma concentrations by enzyme-linked immunosorbent assay between ATAA (n = 40) and coronary heart disease patients (n = 40). Additionally, the protein level of angiotensinogen (AGT) in the ascending aorta and the plasma concentration of Ang II were detected by Western blot and radioimmunoassay, respectively, in ATAA and coronary heart disease patients. In ATAA patients, Ang II and MMP-2 plasma levels were significantly increased (P < 0.05). Additionally, AGT and MMP-2 protein levels in the aorta of ATAA patients were higher (P < 0.01). Enhanced AGT suggested that the amount of Ang II in aneurysmal aorta specimens may be also increased, which was confirmed by immunofluorescent staining for Ang II. Moreover, we investigated the effect of Ang II on MMP-2 upregulation by ASMCs and determined the Ang II receptors and intracellular signaling pathways that are involved. Our results showed that treatment with Ang II significantly increased the expression of MMP-2 through the Ang II type 1 receptor (AT1R) and activated the 3 major mitogen-activated protein kinases (MAPKs), JNK, ERK1/2, and p38 MAPK. In conclusion, these results indicate that Ang II can induce MMP-2 expression elevation through AT1R and MAPK pathways in ASMCs and suggest that there is therapeutic potential for angiotensin receptor blocker drugs and MAPK inhibitors in the prevention and treatment of ATAAs.

Early and mid-term results after hybrid total arch repair of DeBakey type I dissection without deep hypothermic circulatory arrest.

OBJECTIVES: The purpose of this study was to assess the efficacy of the hybrid total arch procedure for the treatment of DeBakey type I dissection by analyzing mid-term results. METHODS: From November 2009 to September 2014, 56 patients with DeBakey type I dissection underwent hybrid total arch repair without deep hypothermic circulatory arrest. During the follow-up, computed tomographic imaging was performed to evaluate the aortic diameter, true lumen diameter, false lumen diameter and false patency at the following three levels: pulmonary bifurcation, diaphragm and superior mesenteric artery. RESULTS: The hospital mortality rate was 3.6% (2/56 patients). Three patients exhibited type Ia endoleak during the operation and 1 patient demonstrated type II endoleak 5 days after surgery. During the follow-up, false lumen complete thrombosis was observed at the level of the pulmonary bifurcation in 94% of patients (P < 0.001). At the level of the diaphragm and superior mesenteric artery, false lumen thrombosis was observed in 68% (P < 0.001) and 36% (P < 0.001) of patients, respectively. No patient had type I or III endoleak and no reoperation was related to residual dissected aorta. The actuarial 1-, 3- and 5-year survival rates were 96.4% [95% confidence interval (95% CI), 91.5-100], 92.3% (95% CI, 85-99.6) and 89.6% (95% CI, 80.8-98.4), respectively. CONCLUSIONS: For patients with DeBakey type I dissection, the hybrid total arch procedure can be safely adopted with good mid-term results and with low morbidity and mortality. Longer-term follow-up is required to confirm the viability of this technique.