Cheng Hsin Lin

Serum Vascular Adhesion Protein-1 Predicts 10-Year Cardiovascular and Cancer Mortality in Individuals With Type 2 Diabetes

OBJECTIVE Vascular adhesion protein-1 (VAP-1) participates in inflammation and catalyzes the breakdown of amines to produce aldehyde, hydrogen peroxide, and ammonia. Serum VAP-1 correlates positively with both acute hyperglycemia and diabetes. We conducted a cohort study to evaluate whether serum VAP-1 predicts 10-year survival in type 2 diabetic patients. RESEARCH DESIGN AND METHODS Between July 1996 and June 2003, we enrolled 661 type 2 diabetic subjects at National Taiwan University Hospital. Serum VAP-1 in the samples obtained at enrollment was measured by time-resolved immunofluorometric assay. The vital status of all subjects was ascertained by linking their data with computerized death certificates in Taiwan. RESULTS The medium follow-up period was 10.4 years. Subjects with serum VAP-1 in the highest tertile had a hazard ratio (HR) of 2.19 (95% CI 1.17–4.11) for all-cause mortality adjusted for age, sex, smoking, history of cardiovascular disease, obesity, hypertension, hemoglobin A1c, diabetes duration, total cholesterol, use of statins, abnormal ankle-brachial index, estimated glomerular filtration rate (eGFR), and proteinuria. The adjusted HRs for logarithmically transformed serum VAP-1 were 5.83 (95% CI 1.17–28.97) for cardiovascular mortality, 6.32 (95% CI 1.25–32.00) for mortality from cardiovascular and diabetic causes, and 17.24 (95% CI 4.57–65.07) for cancer mortality. There were four variables, including age, serum VAP-1, proteinuria, and eGFR, which could enhance mortality prediction significantly. CONCLUSIONS Serum VAP-1 can predict 10-year all-cause mortality, cardiovascular mortality, and cancer mortality independently in type 2 diabetic subjects. Serum VAP-1 is a novel biomarker that improves risk prediction over and above established risk factors.

Serum vascular adhesion protein-1 is increased in acute and chronic hyperglycemia

BACKGROUND The relationship between serum vascular adhesion protein-1 (VAP-1) and plasma glucose in normal and drug-naïve type 2 diabetes subjects is unclear. We examined if serum VAP-1 changed acutely to oral glucose loading and analyzed the relationship between serum VAP-1, fasting plasma glucose (FPG), hemoglobin A1c, and type 2 diabetes. METHODS Adults without history of diabetes were included. Subjects taking anti-diabetic drugs were excluded. Serum VAP-1 was analyzed by time-resolved immunofluorometric assay. RESULTS We recruited 333 subjects (186 females and 147 males), aged 56.1 +/- 11.6 y. After glucose challenge, serum VAP-1 rose significantly at 30 min (p < 0.0001) and lasted until 2 h (p < 0.0001). The change of serum VAP-1 between fasting and 30-min postload correlated inversely to the change of plasma insulin (r = -0.21, p = 0.049). Fasting serum VAP-1 was associated with FPG in those with FPG > or = 5.55 mmol/l (p = 0.025) but not in those with FPG < 5.55 mmol/l (p = NS). Fasting serum VAP-1 were higher in diabetic subjects (p = 0.04) and correlated positively to hemoglobin A1c (r = 0.18, p = 0.002) after adjusting for age, gender, and waist circumference. CONCLUSIONS Serum VAP-1 is increased in both acute and chronic hyperglycemia. Whether serum VAP-1 is a good biomarker for hyperglycemia-associated complications merits further investigation.

Serum vascular adhesion protein-1 is higher in subjects with early stages of chronic kidney disease

OBJECTIVES An increased level of serum vascular adhesion protein-1 (VAP-1) has been found in patients with diabetes mellitus and vascular disorders. This study examined whether serum VAP-1 levels are associated with chronic kidney disease (CKD). DESIGN AND METHODS We included 262 subjects aged 30 and above with fasting plasma glucose level <7 mmol/L checked within 1 year. First morning urine specimens were collected. Microalbuminuria was defined if urinary albumin-to-creatinine ratio > or =30 microg/mg creatinine. The glomerular filtration rate (GFR) was estimated. CKD stages were defined according to the suggestions of the National Kidney Foundation. Serum VAP-1 levels were analyzed by immunofluorometric assay. RESULTS Serum VAP-1 levels were positively associated with the urinary albumin-to-creatinine ratio (r=0.29, p<0.0001) and negatively associated with estimated GFR (r=-0.24, p=0.0001). Subjects with CKD stage 2 (N=51) and stage 3 (N=91) had significantly higher levels of serum VAP-1 than those without CKD (p=0.0003 and p=0.035, adjusted for age and gender, respectively). A high serum VAP-1 level was associated with the presence of CKD (OR 1.63 for 1 SD increase of VAP-1, p=0.018), adjusting for age, sex, and smoking. Ordered logit models revealed that high serum VAP-1 levels correlated with advanced stages of CKD. CONCLUSIONS Serum levels of VAP-1 are associated with the severity of kidney damage or stages of kidney disease. The true mechanism which links the serum VAP-1 and CKD remains to be elucidated in further studies.

Prostaglandin E2 Potentiates Mesenchymal Stem Cell–Induced IL-10+IFN-γ+CD4+ Regulatory T Cells To Control Transplant Arteriosclerosis

Mesenchymal stem cells (MSCs) are known for their immunomodulatory functions. We previously demonstrated that bone marrow–derived MSCs effectively control transplant arteriosclerosis (TA) by enhancing IL-10+ and IFN-γ+ cells. The objective of this study is to elucidate the mechanism by which MSCs induce IL-10+IFN-γ+CD4+ regulatory T type 1 (TR1)–like cells. In an MLR system using porcine PBMCs, MSC-induced IL-10+IFN-γ+CD4+ cells, which confer resistance to allogeneic proliferation in an IL-10–dependent manner, resemble TR1-like cells. Both cyclooxygenase-derived PGE2 and IDO help to induce TR1-like cells by MSCs. MSCs constitutively secrete PGE2, which is augmented in allogeneic reactions. However, TR1-like cells were deficient in PGE2 and 4-fold less potent than were MSCs in suppressing MLR. PGE2 mimetic supplements can enhance the immunosuppressive potency of TR1-like cells. In a porcine model of allogeneic femoral arterial transplantation, MSC-induced TR1-like cells combined with PGE2, but not either alone, significantly reduced TA at the end of 6 wk (percentage of luminal area stenosis: TR1-like cells + PGE2: 11 ± 10%; PGE2 alone: 93 ± 8.7%; TR1-like cells alone: 88 ± 2.4% versus untreated 94 ± 0.9%, p < 0.001). These findings indicate that PGE2 helps MSC-induced IL-10+IFN-γ+CD4+ TR1-like cells inhibit TA. PGE2 combined with MSC-induced TR1-like cells represents a new approach for achieving immune tolerance.

Procedural Safety and Potential Vascular Complication of Endovascular Recanalization for Chronic Cervical Internal Carotid Artery Occlusion

Background—Patients with chronic cervical internal carotid artery occlusion (ICAO) and cerebral ischemia may benefit from revascularization. The feasibility of endovascular recanalization for chronic ICAO has been reported recently, but its safety is still unproven. We report the follow-up results of 54 chronic ICAO patients who underwent endovascular recanalization, focusing on potential vascular complications and corresponding management. Methods and Results—Endovascular recanalization for chronic ICAO was attempted in 54 consecutive patients (48 men; 69.2±9.8 years old) with either recurrent neurological deficit or objective ipsilateral hemisphere ischemia. Mean duration from occlusion documentation to the procedure was 237±327 days (range, 56 to 1424 days). Adverse events while in the hospital and during the 3-month follow-up were recorded. Successful recanalization was achieved in 35 of 54 patients (65%). Three-month cumulative stroke and death rate was 4% (2 of 54), including 1 in-hospital fatal nonipsilateral stroke and 1 in-hospital minor ipsilateral stroke secondary to systemic hypotension. Vascular complications developed in 3 of 54 patients (6%), including 1 late pseudoaneurysm formation 3 months after recanalization, 1 immediate carotid-cavernous fistula after recanalization, and 1 minor extravasation at carotid bifurcation after failed recanalization. However, no clinical sequela was noted with close follow-up and adequate management. Conclusion—Certain immediate or delayed vascular complications may develop during or after the endovascular recanalization for chronic ICAO. Although periprocedural death and stroke rate is limited in our study, further study combining neuroimaging tools and cognitive function evaluation is mandatory to assess its utility and appropriateness in patients with chronic ICAO.

Change of serum vascular adhesion protein-1 after glucose loading correlates to carotid intima-medial thickness in non-diabetic subjects.

BACKGROUND We investigated if serum vascular adhesion protein-1 (SSAO/VAP-1) changed acutely following oral glucose loading and whether such changes are correlated with surrogate markers of atherosclerosis. METHODS A total of 115 non-diabetics subjects were enrolled for an oral glucose tolerance test (OGTT). Carotid intima-medial thickness (IMT) was measured by ultrasonography. Serum SSAO/VAP-1 was analyzed by time-resolved immunofluorometric assay. Serum thiobarbituric acid reactive substances (TBARS) and advanced glycated end products (AGEs) were measured by fluorometric assays. RESULTS Serum SSAO/VAP-1 increased significantly at 30 min after oral glucose loading and lasted to 2 h (p=0.0005 and p<0.0001, for 30 min and 2 h respectively). The area under curve of serum SSAO/VAP-1 during OGTT (AUC-VAP-1) correlated significantly with carotid IMT, independent of age, gender, low-density lipoprotein cholesterol, systolic blood pressure, hemoglobin A1c, serum TBARS, AGEs, and high-sensitivity C-reactive protein. Subjects with a positive AUC-VAP-1 had significantly higher serum TBARS and AGEs than subjects with a negative AUC-VAP-1 adjusted for age and gender. CONCLUSIONS Serum SSAO/VAP-1 changed acutely following oral glucose loading in non-diabetic subjects. Change of serum SSAO/VAP-1 correlated independently to serum TBARS, AGEs, and carotid IMT. Our findings suggest that acute change of serum SSAO/VAP-1 is a novel marker for hyperglycemia-induced atherosclerosis.

Poststernotomy mediastinitis due to methicillin-resistant Staphylococcus aureus endemic in a hospital.

The objective of this study was to determine the incidence of and risk factors for poststernotomy mediastinitis (PSM) due to methicillin-resistant Staphylococcus aureus (MRSA) infection in a hospital in which MRSA was endemic. A retrospective case-control study of patients with PSM after cardiac surgery during January 1997 through July 2002 was conducted. The incidence of PSM was 1.01% (48 of 4746 patients), and 31 episodes (64.6%) were due to MRSA infection. We analyzed the findings for 48 case and 65 control patients. Univariate analysis revealed that the risk factors for PSM were previous hospitalization, resternotomy, chronic renal insufficiency, longer operation time, postoperative heart failure, postoperative renal failure, and reoperation for bleeding. Multivariate analysis revealed that the independent risk factors for PSM were previous hospitalization and reoperation for bleeding. Previous hospitalization was the only significant risk factor for PSM due to MRSA infection. The hospital mortality rate associated with PSM was 41.7%, and there was a higher mortality rate associated with PSM due to MRSA infection.

Autologous mesenchymal stem cells prevent transplant arteriosclerosis by enhancing local expression of interleukin-10, interferon-γ, and indoleamine 2,3-dioxygenase.

Transplant arteriosclerosis (TA) remains the major limitation of long-term graft survival in heart transplantation despite the advances in immunosuppressants. Mesenchymal stem cells (MSCs) have been demonstrated to suppress allogeneic immune responses by numerous in vitro studies. However, the immunomodulatory effects of MSCs in vivo are controversial and the underlying molecular mechanisms are not conclusive. In this study, we investigated the therapeutic potential of autologous bone marrow-derived MSCs on TA in a porcine model of femoral artery transplantation. MSCs or saline were injected into the soft tissue surrounding the arterial grafts immediately postanastomosis. Four weeks after transplantation, neointimal formation increased significantly in untreated allografts compared with the MSC-treated grafts as assessed by intravascular ultrasound (maximum luminal area stenosis: 40 ± 12% vs. 18 ± 6%, p < 0.001). Grafts harvested at 4 weeks showed dense perivascular lymphocyte infiltration accompanied by significant intimal hyperplasia in the untreated but not in the MSC-treated allografts. Serial angiographic examination showed that all of the untreated allografts became occluded at the 8th week whereas the majority of the MSC-treated grafts remained patent at the 12th week posttransplantation (n = 12 each group, p < 0.001). Quantitative PCR analysis revealed that Foxp3 expression was comparable between the untreated and the MSC-treated groups. However, expression of interleukin-10 (IL-10), interferon-γ (IFN-γ), and indoleamine 2,3-dioxygenase (IDO) was increased significantly in the MSC-treated allografts compared with that in the allograft controls (p = 0.021 for IL-10, p = 0.003 for IFN-γ, and p = 0.008 for IDO). In conclusion, local delivery of autologous MSCs alleviates TA by inducing allograft tolerance via enhanced expression of IL-10, IFN-γ, and IDO but not Foxp3-positive cells in the vessel wall. These results suggest that MSCs induce immune tolerance by activating the type 1 regulatory T-like cells.

Plasma apelin: A novel biomarker for predicting diabetes

BACKGROUND Apelin regulates insulin sensitivity and secretion in animals. However, whether plasma apelin predicts incident diabetes in humans remains unknown. METHODS We studied a cohort including 447 subjects (148 men, 299 women) without diabetes and followed for an average of 3y. Diabetes was diagnosed by an oral glucose tolerance test, plasma hemoglobin A1c, and if the subject was taking medications for diabetes. Plasma apelin-12 at baseline was measured with a commercial kit. RESULTS Plasma apelin concentrations were higher in women than in men at baseline (p=0.007). During follow-up, 43 subjects developed type 2 diabetes. Higher plasma apelin concentrations were associated with a higher risk of diabetes in men (p=0.049) but not in women. Plasma apelin predicted incident type 2 diabetes in men (hazard ratio, 2.13, 95% CI 1.29-3.51, p<0.05), but not in women, adjusted for age, family history of diabetes, hemoglobin A1c, body mass index, hypertension, and HOMA2-IR. Apelin could improve the prediction ability beyond traditional risk factors in men, and the sensitivity and specificity of plasma apelin at 0.9ng/ml for this prediction were 63.2% and 58.9%, respectively. In men at risk for diabetes (HbA1c 5.7-6.4%, FPG 100-125mg/dl, or OGTT-2h-PG 140-199mg/dl), the risk for developing diabetes was higher in those with higher plasma apelin concentration than in those with lower plasma apelin concentrations (10.6%/year vs. 5.1%/year, p<0.001). CONCLUSIONS Plasma apelin is a novel biomarker for predicting type 2 diabetes in men.

Metabolic syndrome defined by IDF and AHA/NHLBI correlates better to carotid intima-media thickness than that defined by NCEP ATP III and WHO.

AIMS We conducted this study to compare the relationships between subclinical atherosclerosis and metabolic syndrome (MS) defined by four definitions in Chinese subjects. METHODS In 2006-2007, we enrolled 140 Chinese subjects without reported diabetes in this study. Anthropometric, biochemical profile, and carotid intima-media thickness (IMT) were measured. MS was defined by International Diabetes Federation (IDF), American Heart Association and the National Heart, Lung, and Blood Institute (AHA/NHLBI), National Cholesterol Education Program Adult Treatment Panal III (NCEP-ATP III), and World Health Organization (WHO) criteria. RESULTS Subjects with MS defined by IDF and AHA/NHLBI criteria had significantly higher carotid IMT, controlling for age, gender, smoking, and serum LDL-C (MS by IDF, partial r=0.225, p=0.008; AHA/NHLBI, partial r=0.176, p=0.04). The association between carotid IMT and MS defined by NCEP-ATP III or WHO criteria was not significant. Subjects with more components of MS defined by IDF, AHA/NHLBI, or NCEP-ATP III criteria correlated to higher carotid IMT in adjusted models (p-values for trend, MS by IDF, 0.011; AHA/NHLBI, 0.011; NCEP-ATPIII, 0.01; WHO, 0.113). CONCLUSION MS definitions by IDF and AHA/NHLBI criteria are the best among four definitions in detecting subclinical atherosclerosis in non-diabetic Chinese subjects; whereas MS defined by WHO criteria is the worst.