Connective tissue disease type mediates branch patency of grafts in open thoracoabdominal aortic reconstruction.

OBJECTIVE: Despite a shared degenerative vascular phenotype, Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), and other genetically distinct connective tissue diseases (CTDs) have unique extravascular pathologies that impact the outcomes of aortic replacement. The aim of our study was to investigate the association of CTD genotype with postoperative outcomes and branch patency following open thoracoabdominal aortic replacement in a large institutional cohort. METHODS: All patients undergoing open branched thoracoabdominal aortic replacement at a single academic center from 2006 to 2020 were included and classified as CTD or non-CTD based on the presence of genotypic documentation. Outcomes were compared using analysis of variance and χ2 testing for continuous and discrete variables, respectively. Kaplan-Meier curves were utilized to examine patency of graft branches over time. RESULTS: Overall, 172 patients were included, with a mean follow-up of 30.5 ± 34.9 months. CTD was present in 45 patients (26%); specifically, 32 had MFS, five had LDS, and eight had another CTD. Patients with CTDs had more extent II thoracoabdominal aneurysms (40% vs 15%), more reconstructed branches (3.5 vs 1.8), more frequently reconstructed visceral branches (86.7% vs 22.7%), and higher intraoperative blood loss (13.3 vs 6.8 L; all P < .05) compared with non-CTD patients. Patients with MFS were more frequently systemically anticoagulated preoperatively (50% vs 5%) and demonstrated higher rates of postoperative deep vein thrombosis/pulmonary embolism compared with non-CTD patients (9% vs 2%; both P < .05). Five-year renal branch patency was decreased among all patients compared with visceral branches (87.3% vs 95.6%; P = .05), but there were no individual branch patency differences between patients with and without CTDs (P = .086). Overall branch patency at 1 and 5 years was significantly higher in patients with MFS than in non-CTD patients (98.9% vs 89.1% at 5 years); there were no significant patency differences between non-CTD patients and any other CTD subgroup, mostly due to early patency loss. CONCLUSIONS: Open thoracoabdominal reconstruction in patients with CTD is technically challenging and associated with increased transfusion and postoperative thromboembolic events when compared with non-CTD patients. Technical outcomes of the procedure are excellent and are differentially associated with genotype, with patients with MFS experiencing significantly improved branch patency over both non-CTD patients and patients with other CTDs, a finding which has multifactorial drivers.

The association of genotype polymorphisms with vascular access patency in hemodialysis patients.

Some hemodialysis patients suffer from repeat dysfunction of dialysis vascular access and need procedures of angioplasty, thrombectomy, and even temporary catheter use. Why these patients are vulnerable to vascular access dysfunction and how to improve its patency are imperative to be discovered. Traditional risk factors for vascular access function had been widely investigated but could not fully explain this question. Several genotype polymorphisms were demonstrated to increase the incidence of cardiovascular disease and might also be linked to higher risk of vascular access dysfunction. As the major causes of arteriovenous access thrombosis are hypercoagulable status and arteriovenous access stenosis, the investigated genes mainly focus on the mediators of the coagulation cascade, inflammatory process, and endothelial dysfunction. The reported polymorphisms of genes significantly associated with arteriovenous access dysfunction included genes encoding methylene tetrahydrofolate reductase, coagulation factors, heme oxygenase-1, matrix metalloproteinase, transforming growth factor-ß1, tumor necrosis factor-α, vascular endothelial growth factor-A, renin-angiotensin-aldosterone system, and protein methyl transferase. However, further prospective study is indispensable to elucidate the association between the genotype polymorphisms and the outcome of vascular access. More and more therapeutic options that focus on genotype polymorphisms may generate a great benefit to the patency of vascular access of uremic patients.

Scavenger receptor class A member 5 (SCARA5) and suprabasin (SBSN) are hub genes of coexpression network modules associated with peripheral vein graft patency.

OBJECTIVE: Approximately 30% of autogenous vein grafts develop luminal narrowing and fail because of intimal hyperplasia or negative remodeling. We previously found that vein graft cells from patients who later develop stenosis proliferate more in vitro in response to growth factors than cells from patients who maintain patent grafts. To discover novel determinants of vein graft outcome, we have analyzed gene expression profiles of these cells using a systems biology approach to cluster the genes into modules by their coexpression patterns and to correlate the results with growth data from our prior study and with new studies of migration and matrix remodeling. METHODS: RNA from 4-hour serum- or platelet-derived growth factor (PDGF)-BB-stimulated human saphenous vein cells obtained from the outer vein wall (20 cell lines) was used for microarray analysis of gene expression, followed by weighted gene coexpression network analysis. Cell migration in microchemotaxis chambers in response to PDGF-BB and cell-mediated collagen gel contraction in response to serum were also determined. Gene function was determined using short-interfering RNA to inhibit gene expression before subjecting cells to growth or collagen gel contraction assays. These cells were derived from samples of the vein grafts obtained at surgery, and the long-term fate of these bypass grafts was known. RESULTS: Neither migration nor cell-mediated collagen gel contraction showed a correlation with graft outcome. Although 1188 and 1340 genes were differentially expressed in response to treatment with serum and PDGF, respectively, no single gene was differentially expressed in cells isolated from patients whose grafts stenosed compared with those that remained patent. Network analysis revealed four unique groups of genes, which we term modules, associated with PDGF responses, and 20 unique modules associated with serum responses. The "yellow" and "skyblue" modules, from PDGF and serum analyses, respectively, correlated with later graft stenosis (P = .005 and P = .02, respectively). In response to PDGF, yellow was also associated with increased cell growth. For serum, skyblue was also associated with inhibition of collagen gel contraction. The hub genes for yellow and skyblue (ie, the gene most connected to other genes in the module), scavenger receptor class A member 5 (SCARA5) and suprabasin (SBSN), respectively, were tested for effects on proliferation and collagen contraction. Knockdown of SCARA5 increased proliferation by 29.9% ± 7.8% (P < .01), whereas knockdown of SBSN had no effect. Knockdown of SBSN increased collagen gel contraction by 24.2% ± 8.6% (P < .05), whereas knockdown of SCARA5 had no effect. CONCLUSIONS: Using weighted gene coexpression network analysis of cultured vein graft cell gene expression, we have discovered two small gene modules, which comprise 42 genes, that are associated with vein graft failure. Further experiments are needed to delineate the venous cells that express these genes in vivo and the roles these genes play in vein graft healing, starting with the module hub genes SCARA5 and SBSN, which have been shown to have modest effects on cell proliferation or collagen gel contraction.

Transcriptional profiling reveals ductus arteriosus-specific genes that regulate vascular tone.

Failure of the ductus arteriosus (DA) to close at birth can lead to serious complications. Conversely, certain profound congenital cardiac malformations require the DA to be patent until corrective surgery can be performed. In each instance, clinicians have a very limited repertoire of therapeutic options at their disposal - indomethacin or ibuprofen to close a patent DA (PDA) and prostaglandin E1 to maintain patency of the DA. Neither treatment is specific to the DA and both may have deleterious off-target effects. Therefore, more therapeutic options specifically targeted to the DA should be considered. We hypothesized the DA possesses a unique genetic signature that would set it apart from other vessels. A microarray was used to compare the genetic profiles of the murine DA and ascending aorta (AO). Over 4,000 genes were differentially expressed between these vessels including a subset of ion channel-related genes. Specifically, the alpha and beta subunits of large-conductance calcium-activated potassium (BKCa) channels are enriched in the DA. Gain- and loss-of-function studies showed inhibition of BKCa channels caused the DA to constrict, while activation caused DA relaxation even in the presence of O2. This study identifies subsets of genes that are enriched in the DA that may be used to develop DA-specific drugs. Ion channels that regulate DA tone, including BKCa channels, are promising targets. Specifically, BKCa channel agonists like NS1619 maintain DA patency even in the presence of O2 and may be clinically useful.

Clinical, biochemical, and genetic predictors of coronary artery bypass graft failure.

OBJECTIVES: To identify novel predictors for coronary artery bypass grafting failure, we probed for associations with known clinical and biochemical risk factors for atherosclerosis. We also used microarray analysis to identify novel single nucleotide polymorphisms to better understand the genetics and pathogenesis of graft occlusion. METHODS: The present study was a nested case-control substudy of the Radial Artery Patency Study 5-year follow-up data. From 1996 to 2001, 87 patients underwent coronary artery bypass grafting. Of these, 26 patients (29.9%) had an occluded study graft (saphenous vein or radial artery) at 8.0 ± 1.1 years. The clinical parameters, late angiography, blood biomarker levels, and surgical outcomes data were included in a multivariate analysis to determine the independent predictors of graft failure. RESULTS: The risk factors of graft failure were fibrinogen (odds ratio [OR], 3.94; 95% confidence interval [CI], 1.33-11.63; P = .01), creatinine (OR, 1.06; 95% CI, 1.02-1.10; P = .006), and diabetes mellitus (OR, 5.15; 95% CI, 1.08-24.59; P = .04). High-density lipoprotein (OR, 0.74; 95% CI, 0.53-1.02; P = .06) was weakly protective; however, low-density lipoprotein and total cholesterol were not predictors. We then identified the association of several human single nucleotide polymorphisms with graft failure, including mutations in glutathione-S-transferase α3. Human coronary arteries and bypass grafts demonstrated increased protein expression of glutathione-S-transferase α3, a known cardioprotective factor, in the atherosclerotic regions and surrounding adventitial tissues. CONCLUSIONS: We identified diabetes as a potential clinical predictor and plasma fibrinogen, creatinine, and high-density lipoprotein as potential novel biomarkers. These might help risk stratify patients for the development of graft failure. We also demonstrated a novel association between glutathione-S-transferase α3 and graft failure.

PP2A regulatory subunit Bα controls endothelial contractility and vessel lumen integrity via regulation of HDAC7.

To supply tissues with nutrients and oxygen, the cardiovascular system forms a seamless, hierarchically branched, network of lumenized tubes. Here, we show that maintenance of patent vessel lumens requires the Bα regulatory subunit of protein phosphatase 2A (PP2A). Deficiency of Bα in zebrafish precludes vascular lumen stabilization resulting in perfusion defects. Similarly, inactivation of PP2A-Bα in cultured ECs induces tubulogenesis failure due to alteration of cytoskeleton dynamics, actomyosin contractility and maturation of cell-extracellular matrix (ECM) contacts. Mechanistically, we show that PP2A-Bα controls the activity of HDAC7, an essential transcriptional regulator of vascular stability. In the absence of PP2A-Bα, transcriptional repression by HDAC7 is abrogated leading to enhanced expression of the cytoskeleton adaptor protein ArgBP2. ArgBP2 hyperactivates RhoA causing inadequate rearrangements of the EC actomyosin cytoskeleton. This study unravels the first specific role for a PP2A holoenzyme in development: the PP2A-Bα/HDAC7/ArgBP2 axis maintains vascular lumens by balancing endothelial cytoskeletal dynamics and cell-matrix adhesion.

Plasminogen activator inhibitor-1 5G/5G genotype is associated with early spontaneous recanalization of the infarct-related artery in patients presenting with acute ST-elevation myocardial infarction.

BACKGROUND: We aimed to examine the association between plasminogen activator inhibitor-1 (PAI-1) genetic polymorphism and early spontaneous recanalization in patients presenting with acute ST-elevation myocardial infarction. METHODS: Patients admitted to our emergency department with ST-elevation myocardial infarction in the first 6 h of symptom onset were included. An immediate primary percutaneous coronary intervention was performed. Patients were grouped according to the initial patency of the infarct-related artery (IRA) as follows: total occlusion (TO) group [Thrombolysis in Myocardial Infarction (TIMI) 0-1 flow in the IRA], partial recanalization group (TIMI 2 flow in the IRA), and complete recanalization (CR) group (TIMI 3 flow in the IRA). PAI-1 4G/5G polymorphism was detected using the real-time PCR method. RESULTS: There were 107 patients in the TO group, 30 patients in the partial recanalization group, and 45 patients in the CR group. When we evaluated degrees of patency according to the PAI-1 genotype, TO of the IRA was the highest in patients with the PAI 4G/4G genotype (PAI-1 4G/4G: 66.7%, PAI-1 4G/5G: 65.9%, PAI-1 5G/5G: 40.4%) and CR of the IRA was the highest in patients with the PAI 5G/5G genotype (PAI-1 5G/5G: 38.5%, PAI-1 4G/5G: 19.8%, PAI-1 4G/4G: 17.9%). The distribution of genotypes in different degrees of patency of IRA was statistically significant (P=0.029). In logistic regression analysis, the PAI-1 5G/5G genotype was associated independently with the spontaneous CR of the IRA (odds ratio: 2.875, 95% confidence interval [1.059-7.086], P=0.038). CONCLUSION: Patients with the PAI-1 5G/5G genotype seem to be luckier than others in terms of early spontaneous recanalization of the IRA. Further prospective studies with large patient populations are required for more precise results.

A single nucleotide polymorphism in the p27(Kip1) gene is associated with primary patency of lower extremity vein bypass grafts.

OBJECTIVE: Factors responsible for the variability in outcomes after lower extremity vein bypass grafting (LEVBG) are poorly understood. Recent evidence has suggested that a single nucleotide polymorphism (SNP) in the promoter region of the p27(Kip1) gene, a cell-cycle regulator, is associated with coronary in-stent restenosis. We hypothesized an association with vein graft patency. METHODS: This was a retrospective genetic association study nested within a prospective cohort of 204 patients from three referral centers undergoing LEVBG for claudication or critical ischemia. The main outcome measure was primary vein graft patency. RESULTS: All patients were followed up for a minimum of 1 year with duplex graft surveillance (median follow-up, 893 days; interquartile range, 539-1315). Genomic DNA was isolated and SNP analysis for the p27(Kip1)-838C>A variants was performed. Allele frequencies were correlated with graft outcome using survival analysis and Cox proportional hazards modeling. The p27(Kip1)-838C>A allele frequencies observed were CA, 53%; CC, 30%; and AA, 17%, satisfying Hardy-Weinberg equilibrium. Race (P = .025) and history of coronary artery disease (P = .027) were different across the genotypes; all other baseline variables were similar. Primary graft patency was greater among patients with the -838AA genotype (75% AA vs 55% CA/CC at 3 years; P = .029). In a Cox proportional hazards model including age, sex, race, diabetes, critical limb ischemia, redo (vs primary) bypass, vein type, and baseline C-reactive protein level, the p27(Kip1)-838AA genotype was significantly associated with higher graft patency (hazard ratio for failure, 0.4; 95% confidence interval, 0.17-0.93). Genotype was also associated with early (0-1 month) changes in graft lumen diameter by ultrasound imaging. CONCLUSIONS: These data suggest that the p27(Kip1)-838C>A SNP is associated with LEVBG patency and, together with previous reports, underscore a central role for p27(Kip1) in the generic response to vascular injury.

Length polymorphisms of heme oxygenase-1 determine the effect of far-infrared therapy on the function of arteriovenous fistula in hemodialysis patients: a novel physicogenomic study.

BACKGROUND: The objective of this study was to evaluate the interaction between the length polymorphism of the guanosine thymidine repeat [(GT)n] in the heme oxygenase-1 (HO-1) gene and far-infrared (FIR) therapy on access flow (Qa) and arteriovenous fistula (AVF) patency in hemodialysis (HD) patients. METHODS: A total of 280 HD patients were randomized into a control group (n = 141) and the FIR group (n = 139) who received 40 min of FIR therapy three times weekly for a year during the study period from May 2005 to December 2007. Access flow was measured during HD. The [(GT)n] was determined with the definition of long (L) allele as [(GT)n] ≥ 30 and short (S) allele as [(GT)n] < 30. RESULTS: The Qa decreased from S/S to S/L and further to the L/L group but increased by FIR therapy with the highest Qa increase in the S/S group. The incidence of AVF malfunction decreased both from the L/L, S/L to S/S group (32.4 versus 17.2 versus 10.9%, P = 0.007) and from the control group to FIR group (27.5 versus 12.6%, P = 0.004). Significant associations were found between AVF malfunction and the following factors (hazard ratio, P-value): a past history of AVF malfunction (2.45, P = 0.044), FIR therapy (0.369, P = 0.03) and L/L genotypes of HO-1 (2.531 versus S/S + S/L genotypes). The 1-year unassisted patency decreased from 91.9 and 77.6% in S/S and S/L subgroups with and without FIR therapy to 75.8 and 60% for L/L subgroup with and without FIR therapy, respectively (P < 0.001). CONCLUSIONS: FIR therapy improves Qa and patency of AVF in HD patients, with the best protective effect in those with S/S genotype of HO-1.

Interleukin-6 -634 C/G and -174 G/C polymorphisms in Korean patients undergoing hemodialysis.

BACKGROUND/AIMS: Chronic inflammatory status is a possible risk factor for vascular access dysfunction in hemodialysis (HD) patients, but susceptibility differences appear among individuals. Interleukin (IL)-6 is a well-known inflammatory cytokine with various polymorphisms. We examined whether IL-6 polymorphisms are associated with vascular access dysfunction in HD patients. METHODS: A total of 80 HD patients (including 42 diabetic patients) were enrolled. Polymorphisms in the IL-6 gene promoter (-634 C/G and -174 G/C) were studied using restriction length polymorphism polymerase chain reaction analysis. Vascular access patency was compared between the patient groups with respect to IL-6 polymorphisms. An additional 89 healthy individuals were enrolled in the control group. Plasma IL-6 levels were determined by enzyme-linked immunosorbent assay. RESULTS: The GG genotype and G allele at position -634 in the IL-6 promoter were more frequently observed in HD patients than in controls. Furthermore, the distribution of the -634 polymorphism differed according to vascular access patency in non-diabetic HD patients. However, the G allele was not a significant risk factor for early access failure. No significant association appeared between the IL-6 -634 C/G polymorphism and plasma IL-6 levels. The C allele of the IL-6 -174 G/C polymorphism was not detected in our study population. CONCLUSIONS: The IL-6 -634 G allele appears with greater frequently in patients with end-stage renal disease and may be associated with vascular access dysfunction in non-diabetic HD patients.

Interleukin-6 -634 C/G and -174 G/C Polymorphisms in Korean Patients Undergoing Hemodialysis

BACKGROUND/AIMS: Chronic inflammatory status is a possible risk factor for vascular access dysfunction in hemodialysis (HD) patients, but susceptibility differences appear among individuals. Interleukin (IL)-6 is a well-known inflammatory cytokine with various polymorphisms. We examined whether IL-6 polymorphisms are associated with vascular access dysfunction in HD patients. METHODS: A total of 80 HD patients (including 42 diabetic patients) were enrolled. Polymorphisms in the IL-6 gene promoter (-634 C/G and -174 G/C) were studied using restriction length polymorphism polymerase chain reaction analysis. Vascular access patency was compared between the patient groups with respect to IL-6 polymorphisms. An additional 89 healthy individuals were enrolled in the control group. Plasma IL-6 levels were de termined by enzyme-linked immunosorbent assay. RESULTS: The GG genotype and G allele at position -634 in the IL-6 promoter were more frequently observed in HD patients than in controls. Furthermore, the distribution of the -634 polymorphism differed according to vascular access patency in non-diabetic HD patients. However, the G allele was not a significant risk factor for early access failure. No significant association appeared between the IL-6 -634 C/G polymorphism and plasma IL-6 levels. The C allele of the IL-6 -174 G/C polymorphism was not detected in our study population. CONCLUSIONS: The IL-6 -634 G allele appears with greater frequently in patients with end-stage renal disease and may be associated with vascular access dysfunction in non-diabetic HD patients.

Expression and function of endothelial nitric oxide synthase messenger RNA and protein are higher in internal mammary than in radial arteries.

BACKGROUND: The internal mammary artery (IMA) has a better long-term patency rate than the radial artery (RA), but the underlying molecular mechanisms are unclear. We compared endothelial nitric oxide synthase (eNOS) and related NO release in these two arteries. METHODS: Real-time polymerase chain reaction was used to quantify eNOS messenger RNA (mRNA) expression level in the endothelial cells of IMAs and RAs. eNOS protein localization was determined by immunohistochemistry. NO release from the endothelium of IMAs and RAs was directly measured by an electrochemical method using a membrane-type NO-sensitive electrode. RESULTS: Endothelial nitric oxide synthase mRNA expression level was significantly higher in the endothelial cells of IMAs than in RAs (1.03±0.19 vs 0.53±0.09, n=7, p<0.05), but was similar in the whole vascular tissue. eNOS protein immunoreactivity was higher in the endothelial cells of IMAs than in RAs. NO release at both levels in IMAs was significantly greater than in RAs (basal: 17.5±1.9 vs 10.2±0.7 nM, n=11 each, p=0.003; stimulated with bradykinin -7 log M: 31.5±3.6 vs 14.3±5.3 nM, n=6 each, p=0.02). CONCLUSIONS: Endothelial cells in the IMA express higher levels of eNOS mRNA and protein than those in the RA, which is linked with higher release of NO. These findings may be related to the superior long-term patency rate of the IMA vs the RA. This study also provides some basic genetic information for grafting arteries.

Functional polymorphisms in matrix metalloproteinases-1, -3, -9 are associated with arteriovenous fistula patency in hemodialysis patients.

BACKGROUND AND OBJECTIVES: Matrix metalloproteinases (MMPs) are risk factors for cardiovascular diseases. This study evaluated the association of genotype polymorphisms of MMPs and tissue inhibitors of metalloproteinases (TIMPs) in hemodialysis (HD) patients with arteriovenous fistula (AVF) failure. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Genotype polymorphism of MMP-1, MMP-2, MMP-3, and MMP-9 and TIMP-1 and TIMP-2 and clinical and laboratory parameters were compared between Chinese HD patients with (n = 170) and without (n = 426) AVF failure. RESULTS: Significant associations were found between AVF failure and the following factors (hazard ratio): longer HD duration (1.007 per month), lower pump flow (0.991 per ml/min), higher dynamic venous pressure (1.016 per mmHg), location of AVF on right side (1.630 versus left side) and upper arm (2.385 versus forearm), history of cardiovascular disease (1.656 versus absence of history), 1G/1G genotype of MMP-1 -1607 1G >2G SNP (2.315 versus 1G/2G + 2G/2G genotypes), 6A/6A genotype of MMP-3 -1612 5A >6A SNP (1.712 versus 5A/6A + 5A/5A), and C/C genotype of MMP-9 -1562 C>T SNP (1.650 versus C/T+T/T). The positive predictive rates for AVF failure were 63.0% and 6.7% for patients with the highest-risk (1G1G/6A6A/CC) and lowest-risk (2G2G or 2G1G/5A5A or 6A6A/TT or TC) composite MMP-1/MMP-3/MMP-9 genotype, respectively. The unassisted patency of AVF at 5 years decreased significantly from 93.3% to 38.4% for the composite MMP-1/MMP-3/MMP-9 genotypes (lowest versus highest risk, P < 0.001). CONCLUSIONS: Specific genotypes of MMP-1, MMP-3 and MMP-9 with lower transcriptional activity are associated with higher frequencies of AVF failure, which may result from more accumulation of extracellular matrix, leading to AVF stenosis.

Methylenetetrahydrofolate reductase (MTHFR) C677T genetic polymorphism and late infarct-related coronary artery patency after thrombolysis.

In patients with acute myocardial infarction (AMI), a persistently occluded infarct-related artery (IRA) is associated with unfavorable prognosis and genetic factors may be contributing factors to thrombolysis failure. One-hundred and one consecutive patients treated with intravenous thrombolysis during AMI were blind-tested for methylenetetrahydrofolate reductase (MTHFR) and circulating homocysteine levels and underwent protocol angiography 14 +/- 6 days after the event. IRA was patent in 61 patients and occluded in 40. Overall MTHFR 677TT frequency was 22%. Patients with MTHFR 677TT homozygosis had higher prevalence of occluded IRA (73%) versus those with MTHFR 677CT/CC genotype (30%, P < 0.001); MTHFR 677TT genotype predicted independently the risk of IRA occlusion with a specificity of 90% (odds ratio 3.8, 95% confidence interval 1.1-9.1; P = 0.03). Moreover, patients with occluded IRA and MTHFR 677TT genotype had the highest homocysteine levels (21 +/- 7.6 micromol/l vs. < or =14.9 +/- 3.8 micromol/l; P = 0.011). In patients with AMI, MTHFR 677TT homozygosis is independently associated with a persistently occluded IRA after thrombolysis. This finding may have pathophysiological and therapeutic implications for recanalization strategies in patients with AMI.

Genetic ablation of IRAK4 kinase activity inhibits vascular lesion formation.

Inflammation is critically involved in atherogenesis. Signaling from innate immunity receptors TLR2 and 4, IL-1 and IL-18 is mediated by MyD88 and further by interleukin-1 receptor activated kinases (IRAK) 4 and 1. We hypothesized that IRAK4 kinase activity is critical for development of atherosclerosis. IRAK4 kinase-inactive knock-in mouse was crossed with the ApoE-/- mouse. Lesion development was stimulated by carotid ligation. IRAK4 functional deficiency was associated with down-regulation of several pro-inflammatory genes, inhibition of macrophage infiltration, smooth muscle cell and lipid accumulation in vascular lesions. Reduction of plaque size and inhibition of outward remodeling were also observed. Similar effects were observed when ApoE-/- mice subjected to carotid ligation were treated with recombinant IL-1 receptor antagonist thereby validating the model in the relevant pathway context. Thus, IRAK4 functional deficiency inhibits vascular lesion formation in ApoE-/- mice, which further unravels mechanisms of vascular inflammation and identifies IRAK4 as a potential therapeutic target.

Polymorphism in the promoter region of the klotho gene (G-395A) is associated with early dysfunction in vascular access in hemodialysis patients.

BACKGROUND/AIMS: Vascular access dysfunction is an important cause of morbidity and mortality in hemodialysis (HD) patients. Recent studies have shown that a klotho gene mutation is related to endothelial dysfunction, thrombosis, and arteriosclerosis, which are regarded as causes of vascular access dysfunction. We investigated the relationship between the klotho G-395A polymorphism and early dysfunction in vascular access in HD patients. METHODS: Patients who underwent vascular access operations between 1999 and 2002 were enrolled (n=126). Genotyping was performed by allelic discrimination using a 5'-nuclease polymerase chain reaction assay. Clinical data that could be relevant to access dysfunction were obtained from medical records. Early dysfunction of vascular access was defined as the need for any angioplastic or surgical intervention to correct or replace a poorly or nonfunctioning vascular access within 1 year and at least 8 weeks after initial access placement. RESULTS: Of the 126 patients, the genotype frequency of G-395A was 72.2% for GG (n=91), 24.6% for GA (n=31), and 3.2% for AA (n=4), and the frequency of minor allele was 0.155. Clinical data were similar between the two groups, divided according to the status of the A allele. Early dysfunction occurred in 34 (27.0%) of patients, but it occurred at a significantly higher rate in A allele carriers (45.7%, 16/35) than in noncarriers (19.8%, 18/91; p=0.003). CONCLUSIONS: Our results suggest that the klotho G-395A polymorphism could be a risk factor for early dysfunction of vascular access in HD patients.

Polymorphism in the promoter region of the klotho gene (G-395A) is associated with early dysfunction in vascular access in hemodialysis patients

BACKGROUND/AIMS: Vascular access dysfunction is an important cause of morbidity and mortality in hemodialysis (HD) patients. Recent studies have shown that a klotho gene mutation is related to endothelial dysfunction, thrombosis, and arteriosclerosis, which are regarded as causes of vascular access dysfunction. We investigated the relationship between the klotho G-395A polymorphism and early dysfunction in vascular access in HD patients. METHODS: Patients who underwent vascular access operations between 1999 and 2002 were enrolled (n=126). Genotyping was performed by allelic discrimination using a 5'-nuclease polymerase chain reaction assay. Clinical data that could be relevant to access dysfunction were obtained from medical records. Early dysfunction of vascular access was defined as the need for any angioplastic or surgical intervention to correct or replace a poorly or nonfunctioning vascular access within 1 year and at least 8 weeks after initial access placement. RESULTS: Of the 126 patients, the genotype frequency of G-395A was 72.2% for GG (n=91), 24.6% for GA (n=31), and 3.2% for AA (n=4), and the frequency of minor allele was 0.155. Clinical data were similar between the two groups, divided according to the status of the A allele. Early dysfunction occurred in 34 (27.0%) of patients, but it occurred at a significantly higher rate in A allele carriers (45.7%, 16/35) than in noncarriers (19.8%, 18/91; p=0.003). CONCLUSIONS: Our results suggest that the klotho G-395A polymorphism could be a risk factor for early dysfunction of vascular access in HD patients.

Relation of polymorphisms in five genes to long-term aortocoronary saphenous vein graft patency.

Saphenous veins grafts (SVGs) continue to be used as conduits for coronary bypass surgery in nearly 350,000 patients annually in the United States. A possible genetic contribution to SVG longevity has not been well studied. We analyzed 168 single nucleotide polymorphisms from 150 candidate genes in 155 patients (2.1 SVGs/patient) followed for 10 +/- 4 years who underwent coronary angiography for clinical indications. Age at coronary bypass was 54 +/- 8 years, 61% were men, and 39% had diabetes mellitus. At the time of study entry, 76% were on statins. SVG patency (<70% diameter stenosis, no intervention), the primary study end point, was 60% at 5 years and 19% at 10 years. After adjustment for other factors associated with SVG patency (male gender, p = 0.007; low low-density lipoprotein, p = 0.016), 7 polymorphisms in 5 genes were associated with SVG patency (p <0.01). In conclusion, these data represent an initial step toward the use of a personalized genetic approach to coronary revascularization.

Shear stress contributes to t-PA mRNA expression in human endothelial progenitor cells and nonthrombogenic potential of small diameter artificial vessels.

Seeding endothelial progenitor cells (EPCs) onto the surface of vascular grafts has been proved to be a promising strategy to improve nonthrombogenic potentials of small diameter artificial vessels. Here, we investigated whether in vitro shear stress modulates the tissue-type plasminogen activator (t-PA) secretion and mRNA expression in human EPCs and improves patency of the EPC-seeded polyurethane small diameter vascular grafts implanted in the canine carotid artery in vivo. In vitro shear stress, in a dose-dependent manner, increased t-PA secretion and mRNA expression of human EPCs. The in vivo implantation of EPC-seeded vascular grafts remained highly patent in shear stress pretreatment compared with stationary condition. The present findings demonstrate for the first time that in vitro shear stress can enhance t-PA secretion and gene expression in human EPCs, which contributes to improvement in nonthrombogenic potentials of EPC-seeded small diameter artificial vessels with maintenance of in vivo highly patency rate.

Is AV fistula patency associated with angiotensin-converting enzyme (ACE) polymorphism and ACE inhibitor intake?

BACKGROUND/AIMS: Hemodialysis treatment requires a well-functioning vascular access. Access patency is limited by the development of venous intimal hyperplasia, which predisposes to fistula stenosis and subsequent thrombosis. In animal models, the renin-angiotensin system has a major role in the development of intimal hyperplasia. We investigated the association of the insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE) and arteriovenous fistula patency in hemodialysis patients. METHODS: In a longitudinal study, 137 hemodialysis patients who had undergone creation of a primary AV fistula were genotyped. The main study endpoint was unassisted access patency (time from fistula placement to the first episode of access failure). In addition, the intake of drugs blocking the renin-angiotensin system was assessed. RESULTS: Fistula patency 12 months after fistula creation was 72% (DD patients), 65% (ID patients), and 73% (II patients; p = 0.40). Long-term intake of ACE inhibitors or AT-1 antagonists failed to increase fistula patency (p = 0.33). CONCLUSIONS: We suggest that pharmacological inhibition of the renin-angiotensin system is of limited value for prevention of arteriovenous fistula stenosis. Alternative strategies to prolong fistula patency should be studied.