Ou Liu

Clopidogrel, a Platelet P2Y12 Receptor Inhibitor, Reduces Vascular Inflammation and Angiotensin II Induced-Abdominal Aortic Aneurysm Progression

Medial degeneration and inflammation are features of abdominal aortic aneurysms (AAAs). However, the early inflammatory event initiating aneurysm formation remains to be identified. Activated platelets release abundant proinflammatory cytokines and are involved in initial inflammation in various vascular diseases. We investigated the role of platelets in progression of AAA in vivo and in vitro. Histological studies of tissues of patients with AAA revealed that the number of platelets was increased in aneurysm sites along with the increased infiltration of T lymphocytes and augmented angiogenesis. In a murine model of AAA, apolipoprotein E-knockout mice infused with 1,000 ng/kg/min angiotensin II, treatment with clopidogrel, an inhibitor of platelets, significantly suppressed aneurysm formation (47% decrease, P<0.05). The clopidogrel also suppressed changes in aortic expansion, elastic lamina degradation and inflammatory cytokine expression. Moreover, the infiltration of macrophages and production of matrix metalloproteinases (MMPs) were also significantly reduced by clopidogrel treatment. In vitro incubation of macrophages with isolated platelets stimulated MMP activity by 45%. These results demonstrate a critical role for platelets in vascular inflammation and AAA progression.

Genetic analysis of six SNPs in candidate genes associated with high cross-race risk of development of thoracic aortic aneurysms and dissections in Chinese Han population

Aim:Genetic susceptibility is an important risk factor for aortic aneurysm and dissection. Recent case-control association studies have identified six single nucleotide polymorphisms (SNPs) associated with abdominal aortic aneurysm (AAA) in a Caucasian population. We aimed to determine whether these loci confer susceptibility to thoracic aortic dissection (TAD) in a Chinese Han population and thus to establish cross-race susceptibility to TAD.Methods:This study analyzed blood DNA isolated from 206 TAD patients and 180 controls from the ethnic Chinese Han population. Six SNPs – rs819146, rs8003379, rs2853523, rs326118, rs3788205, and rs10757278 – were genotyped using high-throughput matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) mass spectrometry.Results:The A allele frequency for the SNP on 9p21, tagged as rs10757278, was higher in male TAD patients than in male controls (P=0.017). Moreover, with adjustment for traditional cardiovascular risk factors (sex, age, hypertension, dyslipidemia, diabetes, and smoking), the rs10757278 [odds ratio (OR) 0.63, 95% confidence interval (CI) 0.43 to 0.93] polymorphism was found to be an independent susceptibility factor for TAD in men.Conclusion:Our results suggest that a sequence variant on 9p21 is an important susceptibility locus that confers high cross-race risk for development of TAD in Chinese Han population.

Combined Cathepsin S and hs-CRP predicting inflammation of abdominal aortic aneurysm.

OBJECTIVES Cathepsin S (Cat S) protein expression is increased in human abdominal aortic aneurysm (AAA) lesions and Cat S has been suggested a direct role by promoting inflammatory response partly in experimental AAA. The purpose of this study is to observe the expression of serum Cat S and hs-CRP and its clinical significance in AAA patients. DESIGN AND METHODS We collected serum samples from 31 AAA patients and 32 controls. Cat S and hs-CRP levels were measured by a sandwich-type enzyme-linked immunosorbent assay (ELISA) and an enhanced immunoturbidimetric assay respectively. The maximum diameter of the AAA was identified by ultrasonography. RESULTS The patients with AAA had higher serum Cat S and hs-CRP levels than the controls (p<0.05). Furthermore, human serum Cat S levels were strongly correlated with hs-CRP by the nonparametric Spearman correlation tests (B=0.849, p<0.05). Based on Pearsons correlation test, human serum Cat S and hs-CRP levels were positively correlated with AAA diameter size (p<0.05). Cat S was correlated independently with the hs-CRP in all subjects (p<0.01). After adjustment for the maximum diameter of the abdominal aorta-associated variables, Cat S combined hs-CRP (R(2)=0.801) is better than Cat S (R(2)=0.740) in predicting the maximum diameter of AAA lesions. CONCLUSION Combined serum Cat S and hs-CRP levels are better in predicting the inflammatory activity of AAA lesions in the clinical setting.

Association of the polymorphisms of MMP-9 and TIMP-3 genes with thoracic aortic dissection in Chinese Han population.

Aim:Thoracic aortic dissection (TAD) is the most common life-threatening disorder, and a shifted balance of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) is involved in TAD pathogenesis. The aim of this study was to evaluate the association of 4 single-nucleotide polymorphisms (SNPs) in MMP-9 and TIMP-3 genes with TAD risk in Chinese Han population.Methods:A total of 206 Chinese patients with TAD and 180 controls were included in this study. Four SNPs (rs3918249, rs2274756, rs9609643 and rs8136803) were genotyped using high-throughput MALDI-TOF mass spectrometry. Allele and genotype association analyses were conducted using PLINK.Results:All the 4 SNPs resulted in Hardy-Weinberg equilibrium in patients and controls. The G allele frequency for the MMP-9 SNP rs2274756 was significantly higher in female TAD patients than in female controls (P=0.0099). Moreover, after adjusting for traditional cardiovascular risk factors (sex, age, hypertension, dyslipidemia, diabetes and smoking habit), the rs2274756 polymorphism (odds ratio: 0.30; 95% confidence interval: 0.11 to 0.79, P=0.015) resulted in an independent susceptibility factor for TAD in females. No associations were found between the other SNPs and TAD.Conclusion:The results provide strong evidence for an association between MMP-9 SNP rs2274756 and female TAD risk in Chinese Han population.

Sustained activation of ADP/P2ry12 signaling induces SMC senescence contributing to thoracic aortic aneurysm/dissection

Thoracic aortic aneurysm/dissection (TAAD) is characterized by excessive smooth muscle cell (SMC) loss, extracellular matrix (ECM) degradation and inflammation. However, the mechanism whereby signaling leads to SMC loss is unclear. We used senescence-associated (SA)-β-gal staining and analysis of expression of senescence-related proteins (p53, p21, p19) to show that excessive mechanical stretch (20% elongation, 3600cycles/h, 48h) induced SMC senescence. SMC senescence was also detected in TAAD specimens from both mice and humans. High-performance liquid chromatography and luciferin-luciferase-based assay revealed that excessive mechanical stretch increased adenosine diphosphate (ADP) release from SMCs both in vivo and in vitro. Elevated ADP induced SMC senescence while genetic knockout of the ADP receptor, P2Y G protein-coupled receptor 12 (P2ry12), in mice protected against SMC senescence and inflammation. Both TAAD formation and rupture were significantly reduced in P2ry12-/- mice. SMCs from P2ry12-/- mice were resistant to senescence induced by excessive mechanical stretch or ADP treatment. Mechanistically, ADP treatment sustained Ras activation, whereas pharmacological inhibition of Ras protected against SMC senescence and reduced TAAD formation. Taken together, excessive mechanical stress may induce a sustained release of ADP and promote SMC senescence via P2ry12-dependent sustained Ras activation, thereby contributing to excessive inflammation and degeneration, which provides insights into TAAD formation and progression.

Association of MMP-2 gene haplotypes with thoracic aortic dissection in chinese han population

BackgroundThoracic aortic dissection (TAD) is the most common life-threatening disorder, and MMP-2 is involved in TAD pathogenesis. Our purpose is to systematically evaluate the association of the MMP-2 gene with TAD risk in Chinese Han population.MethodsIn our case–control study, we recruited 755 unrelated participants: 315 case participants with TAD and 440 controls. Twenty-two tag SNPs were selected from MMP-2 gene and were genotyped. Genotype data were analyzed by logistic regression.ResultsAlthough we did not find any significant association for MMP-2 SNPs using single-marker analysis, we identified many windows with haplotype frequencies significantly different between case participants and control participants using a variable-sized sliding-window strategy. In particular, the most significant association was shown by a 2-SNP window consisting of rs2241145 and rs9928731 (omnibus test: asymptotic Pasym = 7.48 × 10 −5 and empirical Pemp = 0.001867). There were two protective haplotypes: CT (Pasym = 0.00303; odds ratio [OR], 0.403) and GC (Pasym = 0.000976; OR, 0.448).ConclusionsMMP-2 haplotypes are associated with genetic susceptibility to thoracic aortic dissection in Chinese Han population.

Changes in the Hemostatic System of Patients With Acute Aortic Dissection Undergoing Aortic Arch Surgery.

BACKGROUND Aortic arch surgery for patients with acute aortic dissection is frequently complicated by excessive bleeding and transfusion of allogeneic blood products. However, the physiopathology of acute aortic dissection and surgery-induced coagulopathy has never been precisely studied. The aim of the present study is to describe the changes of the perioperative hemostatic system in patients with acute aortic dissection undergoing aortic arch surgery. METHODS Sixty-two patients undergoing emergent aortic arch surgery for Stanford type A acute aortic dissection were enrolled in this study from January 2013 to September 2014. The hemostatic system was evaluated using standard laboratory tests, plasma fibrinogen levels, and thromboelastogragh at 5 time points: anesthesia induction (T0), lowest nasopharyngeal temperature (T1), protamine reversal (T2), 4 h after surgery (T3), and on the first postoperative day (T4). RESULTS The study results revealed that clotting factors had a tendency to be consumed in the preoperative period. Surgery and hypothermia resulted in a progressive reduction in clotting factors, platelet counts, and function, as well as fibrinogen concentration and function. After hemostatic therapy, although platelet counts were constantly low, clotting factors and platelet function returned to nearly preoperative levels. In contrast, fibrinogen concentration and function were still significantly lower than preoperative levels. CONCLUSIONS The results of this prospective analysis showed that acute aortic dissection itself activated the hemostatic system even before surgery. After hemostatic therapy, fibrin formation was more impaired than platelet function. In this setting, we proposed that hemostatic therapy should focus on rapid and sufficient supplementation of fibrinogen. Thus, we recommend further increases in fibrinogen concentration to improve coagulopathy in patients with acute aortic dissection.

MMP-2 gene polymorphisms are associated with type A aortic dissection and aortic diameters in patients.

AbstractMatrix metalloproteinases-2 (MMP-2) plays an important role in the pathogenesis of type A aortic dissection (AD). The aim of this study was to evaluate the association of 3 single nucleotide polymorphisms (SNPs) in the MMP-2 gene with type A AD risk and aortic diameters in patients. We performed a case–control study with 172 unrelated type A AD patients and 439 controls. Three SNPs rs11644561, rs11643630, and rs243865 were genotyped through the MassARRAY platform. Allelic associations of SNPs and SNP haplotypes with type A AD and aortic diameters in patients were evaluated. The frequency of the G allele of the rs11643630 polymorphism was significantly lower in type A AD patients than in control subjects (odds ratio 0.705, 95% confidence interval 0.545–0.912, P = 0.008). The association remained significant after adjusting for clinical covariates (P = 0.008). Carriers of the GG genotype of the rs11643630 polymorphism had significantly smaller aortic diameters than those with GT genotype or TT genotype (P = 0.02). Further haplotype analysis identified 1 protective haplotype (GC; P = 0.008) for development of type A AD. Again, a significant correlation was observed between haplotype GC and AD size (P = 0.020). Our results suggest that MMP-2 gene polymorphisms contribute to type A AD susceptibility. In addition, MMP-2 gene SNPs are associated with AD size, which could be used as a target for the development of new drug therapy.

Innominate artery aneurysm, how to solve it?

We herein describe our *These authors contributed equally to this work. experience with a congenital innominate artery aneurysm (IAA) that was managed with a simple surgical procedure. A 44-year-old woman was admitted for chest distress. Computed tomography angiography showed a 3.6-cm IAA arising from the aortic arch and compressing the trachea. A median sternotomy was performed with the patient under general anesthesia, and the IAA was found to involve the origin of the innominate artery and the bifurcation of the right subclavian artery and common carotid artery; however, the aorta was intact. An 8-mm Dacron graft was anastomosed to the ascending aorta and distal end of the IAA without cardiopulmonary bypass. The postoperative course was uneventful, and repeat computed tomography angiography revealed no evidence of recurrence 6 months postoperatively. We also herein present a literature review of this rare clinical condition.

Changes in coagulation factor XII and its function during aortic arch surgery for acute aortic dissection—a prospective observational study

Background Changes in the intrinsic coagulation pathway during aortic arch surgery in patients with acute aortic dissection (AAD) have not yet been reported. The aim of this study is to describe the changes in intrinsic coagulation factor XII, explore its function and find a new target for the treatment of coagulopathy during surgery. Methods Eighty-eight patients undergoing emergent surgery for AAD were enrolled. Changes in the intrinsic and extrinsic coagulation pathways were evaluated at 5 different timepoints during the perioperative period by measuring intrinsic coagulation factor XII, extrinsic coagulation factor VII and some intrinsic upstream stimulating factors. The 88 patients were also divided into two groups according to whether reoperation for coagulopathy was required after surgery. Results Both coagulation factors XII and VII demonstrated a significant and similar change during the perioperative period. These factors decreased significantly during hypothermia circulation arrest (P<0.001) and recovered to normal levels by 24 hours after surgery. Among the intrinsic upstream stimulating factors, bradykinin (BK) demonstrated a similar changing trend with coagulation factors XII and VII, while other stimulating factors did not. However, compared with factor VII, factor XII demonstrated a greater decline during surgery. The proportion of decline of factor XII from anesthesia induction to hypothermia circulation arrest was 42%, whereas the proportion of decline of factor VII during the same period was 20% (P<0.001). Moreover, factor VII recovered to preoperative levels 4 hours after surgery with a relatively faster speed (P<0.001) while factor XII had not recovered (P=0.010). The independent t-test and Wilcoxon test showed that coagulation factor XII levels during hypothermia circulation arrest (P=0.002), total dosage of fibrinogen (P=0.027), total dosage of packed red blood cells (PRBCs) (P=0.006) and total dosage of fresh frozen plasma (FFP) (P=0.022) during the perioperative period were significantly different between the patients who did or did not require reoperation for coagulopathy. Multivariable logistic regression analysis suggested that the factor XII level during hypothermia circulation arrest was an independent risk factor for reoperation for coagulopathy [odds ratio (OR): 1.342, 95% confidence interval (CI): 1.058-1.570; P=0.012]. Conclusions Factor XII levels are more influenced by surgery and require a longer period of time to recover to preoperative levels compared with factor VII, and the level of factor XII during hypothermia circulation arrest might be an independent risk factor for reoperation for coagulopathy. Therefore, supplementation of coagulation factor XII and its upstream stimulating factors might be a promising therapeutic modality in the future.