Redefining left bundle branch block from high-density electroanatomical mapping.

BACKGROUND: The existing ECG criteria for diagnosing left bundle branch block (LBBB) are insufficient to distinguish between true and false blocks accurately. METHODS: We hypothesized that the notch width of the QRS complex in the lateral leads (I, avL, V5, V6) on the LBBB-like ECG could further confirm the diagnosis of true complete left bundle branch block (t-LBBB). We conducted high-density, three-dimensional electroanatomical mapping in the cardiac chambers of 37 patients scheduled to undergo CRT. These patients' preoperative electrocardiograms met the ACC/AHA/HRS guidelines for the diagnosis of complete LBBB. If the left bundle branch potential could be mapped from the base of the heart to the apex on the left ventricular septum, it was defined as a false complete left bundle branch block (f-LBBB). Otherwise, it was categorized as a t-LBBB. We conducted a comparative analysis between the two groups, considering the clinical characteristics, real-time correspondence between the spread of ventricular electrical excitation and the QRS wave, QRS notch width of the lateral leads (I, avL, V5, V6), and the notch width/left ventricular end-diastolic diameter (Nw/LVd) ratio. We performed the ROC correlation analysis of Nw/LVd and t-LBBB to determine the sensitivity and specificity for diagnostic authenticity. RESULTS: Twenty-five patients were included in the t-LBBB group, while 12 patients were assigned to the f-LBBB group. Within the t-LBBB group, the first peak of the QRS notch correlated with the depolarization of the right ventricle and septum, the trough corresponded to the depolarization of the left ventricle across the left ventricle, and the second peak aligned with the depolarization of the left ventricular free wall. In contrast, within the f-LBBB group, the first peak coincided with the depolarization of the right ventricle and a majority of the left ventricle, the second peak occurred due to the depolarization of the latest, locally-activated myocardium in the left ventricle, and the trough was a result of delayed activation of the left ventricle that did not align with the usual peak timing. The QRS notch width (45.2 ± 12.3 ms vs. 52.5 ± 9.2 ms, P < 0.05) and the Nw/LVd ratio (0.65 ± 0.19 ms/mm vs. 0.81 ± 0.17 ms/mm, P < 0.05) were compared between the two groups. After conducting the ROC correlation analysis, a sensitivity of 56% and a specificity of 91.7% for diagnosing t-LBBB using Nw/LVd were obtained. CONCLUSION: By utilizing the current diagnostic criteria for LBBB, an increased Nw/LVd value can enhance the effectiveness of diagnosing LBBB.

Three-dimensional electroanatomical mapping guidelines for the selection of pacing site to achieve cardiac resynchronization therapy.

Objectives: We aimed to evaluate the feasibility of left ventricular electroanatomical mapping to choose between left bundle branch area pacing (LBBAP) or coronary venous pacing (CVP). Background: There are several ways to achieve left ventricular activation in cardiac resynchronization therapy (CRT): LBBAP and CVP are two possible methods of delivering CRT. However, the criteria for choosing the best approach remains unknown. Methods: A total of 71 patients with heart failure, reduced ejection fraction, and left bundle branch block (LBBB) were recruited, of which 38 patients underwent the three-dimensional electroanatomical mapping of the left ventricle to accurately assess whether the left bundle branch was blocked and the block level, while the remaining 33 patients were not mapped. Patients with true LBBB achieved CRT by LBBAP, while patients with pseudo-LBBB achieved CRT by CVP. After a mean follow-up of 6 months and 1 year, the QRS duration and transthoracic echocardiography, including mechanical synchrony indices, were evaluated. Results: Twenty-five patients with true LBBB received LBBAP, while 13 without true LBBB received CVP. Seventeen patients received LBBAP, and 16 patients received CVP without mapping. Paced QRS duration after the implantation of LBBAP and CVP was significantly narrower in the mapping subgroup compared to the non-mapping subgroup. A significant increase in post-implantation left ventricular ejection fraction was observed in patients with LBBAP or CVP, and the mapping subgroup were better than the non-mapping subgroup. After a 12-month follow-up, atrioventricular, intraventricular, and biventricular synchronization were significantly improved in the mapping subgroup compared to non-mapping groups in both LBBAP and CVP. Conclusion: In our study, three-dimensional electroanatomical mapping was used to choose LBBAP or CVP for heart failure patients, which proved feasible, with better cardiac resynchronization in the long-term follow-up. Therefore, three-dimensional electroanatomical mapping before CRT appears to be a reliable method for heart failure patients with LBBB who are indicated for CRT.

Novel oral edaravone attenuates diastolic dysfunction of diabetic cardiomyopathy by activating the Nrf2 signaling pathway.

Oxidative stress plays a crucial role in the pathophysiology of diastolic dysfunction associated with diabetic cardiomyopathy. Novel oral edaravone (OED) alleviates oxidative stress by scavenging free radicals and may be suitable for the treatment of chronic diseases such as diabetic cardiomyopathy. Oral administration of OED to type 2 diabetic rats (induced by high-sugar/high-fat diet and intraperitoneal injection of streptozotocin) for 4 w decreased malondialdehyde and increased superoxide dismutase. Moreover, it significantly improved ratios of early to late diastolic peak velocity, myocardium hypertrophy accompanied by decreased cross-sectional areas of cardiomyocytes, the proportion of apoptotic cells, collagen volume fractions, and deposition of collagen I/III. In H9c2 cells, OED reduced reactive oxygen species, cell surface area, and numbers of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling-positive cells induced by glucolipotoxicity. OED remarkably upregulated expression of the nuclear factor E2-related factor (Nrf2) signaling pathway both in vivo and in vitro. In addition, OED promoted Nrf2 nuclear translocation and upregulated nicotinamide adenine dinucleotide phosphate quinone oxidoreductase and heme oxygenase. Silencing of Nrf2 abolished the protective effect of OED in H9c2 cells. Our findings demonstrate that OED has the therapeutic potential to ameliorate diastolic dysfunction associated with diabetic cardiomyopathy. Its effect was mainly achieved by attenuating hyperglycemia and hyperlipidemia-induced cardiomyocyte hypertrophy, apoptosis, and fibrosis by activating the Nrf2 signaling pathway.

Increased glycated albumin and decreased esRAGE levels in serum are related to negative coronary artery remodeling in patients with type 2 diabetes: an Intravascular ultrasound study.

BACKGROUND: Negative coronary artery remodeling is frequent in patients with diabetes, but its mechanism remains unclear. We here evaluated the association of serum levels of glycated albumin (GA) and endogenous secretory receptor for advanced glycation end products (esRAGE) with coronary artery remodeling in type 2 diabetic patients. METHODS: Serum levels of GA and esRAGE were measured and intravascular ultrasound was performed in 136 consecutive diabetic patients with 143 coronary intermediate lesions. The remodeling index (RI) was calculated as the ratio between external elastic membrane (EEM) area at the lesion site and EEM area at the reference segment. Negative remodeling (NR) was defined as an RI < 0.95 and intermediate or positive remodeling as an RI ≥ 0.95. RESULTS: Mean plaque burden at the lesion site was 70.96 ± 9.98%, and RI was 0.96 ± 0.18. Negative coronary arterial remodeling existed in 81 (56.6%) lesions. RI correlated closely with serum esRAGE level (r = 0.236, P = 0.005) and was inversely related to serum GA level (r = - 0.240, P = 0.004) and plasma low-density lipoprotein cholesterol (LDL-C) (r = - 0.206, P = 0.014) and total cholesterol levels (r = - 0.183, P = 0.028). Generalized estimating equations logistic regression analysis identified esRAGE (OR 0.037; 95% CI 0.012-0.564, P = 0.021), GA (OR 1.093; 95% CI 1.013-1.179, P = 0.018) and LDL-C (OR 1.479; 95% CI 1.072-2.835, P = 0.023) as independent predictors for negative remodeling. CONCLUSIONS: In diabetic patients, negative coronary artery remodeling is associated with increased GA and decreased esRAGE levels in serum.

Panax notoginsenoside saponins Rb1 regulates the expressions of Akt/ mTOR/PTEN signals in the hippocampus after focal cerebral ischemia in rats.

Panax notoginsenoside saponins Rb1 (PNS-Rb1) is an important active ingredient of panax notoginseng for effective treatment of cerebrovascular diseases. However, the mechanism underlying its actions in the state of cerebral ischemia is still unclear. We asked whether the potential neuroprotection of PNS-Rb1 on the brain is due to, at least partially, its modulation of AkT/mTOR/PTEN signalling pathway along with down-regulation of caspase-3 in rats subjected to phototrombic stroke. To test this hypothesis, rats with induced photothrombotic stroke were treated with PNS-Rb1 (applied in three different doses, 25 mg/kg, 50 mg/kg,100 mg/kg, respectively) or saline, while sham operated rats injected with saline were used as the control. Our results indicate that PNS-Rb1 significantly alleviated the morphological lesion concomitant with improvement of cognitive and sensorimotor deficits induced by ischemic stroke. Moreover, immunohistochemistry and Western blot analyses showed that PNS Rb1 in a dose dependent manner increased the expressions of P-Akt, P-mTOR and reduced P-PTEN and caspase-3. The present study suggests that the improvement of cognitive and sensorimotor deficits by PNS-Rb1 is made, at least partially, by the modulation of the Akt/mTOR/PTEN signalling pathway.

Left univentricular pacing for cardiac resynchronization therapy using rate-adaptive atrioventricular delay.

OBJECTIVE: To evaluate left univentricular (LUV) pacing for cardiac resynchronization therapy (CRT) using a rate-adaptive atrioventricular delay (RAAVD) algorithm to track physiological atrioventricular delay (AVD). METHODS: A total of 72 patients with congestive heart failure (CHF) were randomized to RAAVD LUV pacing versus standard biventricular (BiV) pacing in a 1: 1 ratio. Echocardiography was used to optimize AVD for both groups. The effects of sequential BiV pacing and LUV pacing with optimized A-V (right atrio-LV) delay using an RAAVD algorithm were compared. The standard deviation (SD) of the S/R ratio in lead V1 at five heart rate (HR) segments (RS/R-SD5), defined as the "tracking index," was used to evaluate the accuracy of the RAAVD algorithm for tracking physiological AVD. RESULTS: The QRS complex duration (132 ± 9.8 vs. 138 ± 10 ms, P < 0.05), the time required for optimization (21 ± 5 vs. 50 ± 8 min, P < 0.001), the mitral regurgitant area (1.9 ± 1.1 vs. 2.5 ± 1.3 cm2, P < 0.05), the interventricular mechanical delay time (60.7 ± 13.3 ms vs. 68.3 ± 14.2 ms, P < 0.05), and the average annual cost (13,200 ± 1000 vs. 21,600 ± 2000 RMB, P < 0.001) in the RAAVD LUV pacing group were significantly less than those in the standard BiV pacing group. The aortic valve velocity-time integral in the RAAVD LUV pacing group was greater than that in the standard BiV pacing group (22.7 ± 2.2 vs. 21.4 ± 2.1 cm, P < 0.05). The RS/R-SD5 was 4.08 ± 1.91 in the RAAVD LUV pacing group, and was significantly negatively correlated with improved left ventricular ejection fraction (LVEF) (ΔLVEF, Pearson's r = -0.427, P = 0.009), and positively correlated with New York Heart Association class (Spearman's r = 0.348, P = 0.037). CONCLUSIONS: RAAVD LUV pacing is as effective as standard BiV pacing, can be more physiological than standard BiV pacing, and can decrease the average annual cost of CRT.

C1q/TNF-related protein-1: an adipokine marking and promoting atherosclerosis.

AIMS: We investigated the association of the adipokine C1q/TNF-related protein (CTRP) 1 with coronary artery disease (CAD), and the biological vascular effects of CTRP1. METHODS AND RESULTS: We analysed CTRP1 levels in sera of CAD patients (n = 451) and non-CAD controls (n = 686), and in coronary endarterectomy specimens (n = 32), non-atherosclerotic internal mammary arteries (n = 26), aortic atherosclerotic plaques (n = 15), and non-atherosclerotic aortic samples (n = 10). C1q/TNF-related protein-levels were higher in sera, endarterectomy specimens, aortic atherosclerotic plaques, and peripheral blood mononuclear cells (PBMCs) from CAD patients compared with controls, and were related to CAD severity. The production of CTRP1 was profusely induced by inflammatory cytokines and itself caused a concentration-dependent expression of adhesion molecules and inflammatory markers in human endothelial cells, human peripheral blood monocytes, and THP-1 cells. C1q/TNF-related protein-1 induced p38-dependent monocyte-endothelium adhesion in vitro and the recruitment of leucocytes to mesenteric venules in C57BL/6 mice. Immunohistochemistry of atherosclerotic femoral arteries exhibited CD68 and VE-cadherin loci-associated increased CTRP1 expression in plaques. Compared with saline, intraperitoneal injection of recombinant CTRP1 protein (200 µg/kg) every other day promoted atherogenesis in apoE(-/-) mice at 24 weeks. However, pro-atherogenic effects were significantly attenuated in CTRP1(-/-)/apoE(-/-) double-knockout mice compared with apoE(-/-) mice, with a consistent decrease in vascular adhesion molecule, phospho-p38 and TNF-α expression and macrophage infiltration in plaque in CTRP1(-/-) and double-knockout mice. Tumour necrosis factor-α-induced expression of adhesion molecules and cytokines were lower in primary endothelial cells and macrophages from CTRP(-/-) mice than in those from C57BL/6 mice. CONCLUSION: C1q/TNF-related protein-1 is a marker of atherosclerosis in humans and promotes atherogenesis in mice.

Elevated glycated albumin and reduced endogenous secretory receptor for advanced glycation endproducts levels in serum predict major adverse cardio-cerebral events in patients with type 2 diabetes and stable coronary artery disease.

BACKGROUND AND AIM: Glycated albumin (GA) and the endogenous secretory receptor for advanced glycation endproducts (esRAGE) may modulate risk related to atherosclerosis. We tested the hypothesis that elevated GA and reduced esRAGE in serum are associated with adverse clinical outcomes in patients with type 2 diabetes and stable coronary artery disease (CAD). METHODS: We determined GA and esRAGE serum levels in 576 consecutive patients with type 2 diabetes and stable CAD undergoing sirolimus-eluting stent (SES)-PCI. The primary endpoint was the incidence of major adverse cardio-cerebral events (MACCE) including cardiac death, non-fatal myocardial infarction, and non-fatal stroke during a 2-year follow-up. The secondary endpoint was the occurrence of clinically driven repeat revascularization during a 2-year follow-up. The prognostic value of GA and esRAGE was determined with the Cox-proportional hazard model after adjustment for covariates. RESULTS: A total 40 patients (6.9%) experienced MACCE, and 108 (18.8%) patients underwent repeat coronary revascularization during the follow-up. Serum GA (HR=1.22, 95% CI 1.16-1.28; HR=1.15, 95% CI 1.11-1.19, respectively; for both p<0.001) and esRAGE (HR=0.60, 95% CI 0.40-0.87; HR=0.75, 95% CI 0.61-0.92, respectively; for both p<0.01) levels remained independent predictors of the primary and secondary endpoints after adjustment for possible confounders. CONCLUSIONS: Serum GA and esRAGE are novel predictors of long-term clinical outcomes in patients with type 2 diabetes and stable CAD. Increased serum GA and decreased esRAGE are associated with a poor prognosis in such patients.

Association of elevated apoA-I glycation and reduced HDL-associated paraoxonase1, 3 activity, and their interaction with angiographic severity of coronary artery disease in patients with type 2 diabetes mellitus.

OBJECTIVE: To investigate whether apolipoprotein A (apoA)-I glycation and paraoxonase (PON) activities are associated with the severity of coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM). METHODS: Relative intensity of apoA-I glycation and activities of high-density lipoprotein (HDL)-associated PON1 and PON3 were determined in 205 consecutive T2DM patients with stable angina with (n = 144) or without (n = 61) significant CAD (luminal diameter stenosis ≥ 70 %). The severity of CAD was expressed by number of diseased coronary arteries, extent index, and cumulative coronary stenosis score (CCSS). RESULTS: The relative intensity of apoA-I glycation was higher but the activities of HDL-associated PON1 and PON3 were lower in diabetic patients with significant CAD than in those without. The relative intensity of apoA-I glycation increased but the activities of HDL-associated PON1 and PON3 decreased stepwise from 1 - to 3 - vessel disease patients (P for trend < 0.001). After adjusting for possible confounding variables, the relative intensity of apoA-I glycation correlated positively, while the activities of HDL-associated PON1 and PON3 negatively, with extent index and CCSS, respectively. At high level of apoA-I glycation (8.70 ~ 12.50 %), low tertile of HDL-associated PON1 (7.03 ~ 38.97U/mL) and PON3 activities (7.11 ~ 22.30U/mL) was associated with a 1.97- and 2.49- fold increase of extent index and 1.73- and 2.68- fold increase of CCSS compared with high tertile of HDL-associated PON1 (57.85 ~ 154.82U/mL) and PON3 activities (39.63 ~ 124.10U/mL), respectively (all P < 0.01). CONCLUSIONS: Elevated apoA-I glycation and decreased activities of HDL-associated PON1 and PON3, and their interaction are associated with the presence and severity of CAD in patients with T2DM.

Cardiac resynchronization therapy (CRT) with right ventricular sense triggered left ventricular pacing benefits for the hemodynamics compared with standard CRT for chronic congestive heart failure: A cross-over study.

BACKGROUND: The aim of this study was to investigate the effect of cardiac resynchronization therapy (CRT) with right ventricular (RV) sense triggered left ventricular (LV) pacing for chronic heart failure (CHF). METHODS: Thirty patients who were eligible for the Class I indication of CRT were enrolled and the informed consents were signed. Left ventricular ejection fraction (LVEF), diastolic mitral flow velocity time integral (VTI), mitral regurgitation flow VTI, and aortic valve flow VTI were measured with GE Vivid 7 (GE Medical, Milwaukee, WI, USA) before and after CRT. The echocardiographic measurements and the average annual costs of the device use were compared. RESULTS: The duration of QRS complex, the length of time used for optimization, and the average annual cost of the device use under RV sense triggered LV pacing were significantly less than that under standard biventricular (BiV) pacing (p < 0.01), while the average battery lifetime was longer. Subgroup analysis showed that LVEF, diastolic mitral flow VTI, and aortic valve flow VTI under RV sense triggered LV pacing were greater than that under standard BiV pacing with right or LV pre-activation. The average battery lifetime was significantly longer and the average annual cost of the device use was less. The mitral regurgitation flow VTI under RV sense triggered LV pacing was less than that under standard BiV pacing with RV pre-activation. CONCLUSIONS: RV sense triggered LV provides benefits for CHF patients over standard CRT in terms of maintaining the physiological atrio-ventricular delay of atrio-ventricular node and improving the acute hemodynamic effects.

Increased serum level of soluble vascular endothelial growth factor receptor-1 is associated with poor coronary collateralization in patients with stable coronary artery disease.

BACKGROUND: The present study investigated whether serum levels of soluble vascular endothelial growth factor receptor (sVEGFR)-1, -2 and -3 are related to poor coronary collateralization in patients with stable coronary artery disease (CAD). METHODS AND RESULTS: Serum levels of sVEGFR-1, -2, -3, VEGF, and placental growth factor (PLGF) were determined in 403 consecutive patients with angiographic total or subtotal occlusion of at least 1 major coronary artery. The degree of collateralization was graded according to the Rentrop scoring system. Low (Rentrop score of 0 or 1) and high (Rentrop score of 2 or 3) coronary collateralization occurred in 161 and 242 patients, respectively. Serum levels of sVEGFR-1 and -2 were significantly elevated, in contrast, VEGF and PLGF levels were remarkably decreased in patients with low collateralization than in those with high collateralization (all P<0.05). Significant differences in sVEGFR-1, VEGF and PLGF levels was consistently detected between the low and high collateralization subgroups for patients with and without type 2 diabetes mellitus (DM) (for all comparisons, P<0.01). Multivariable regression analysis revealed that DM, dyslipidemia, elevated sVEGFR-1, and reduced VEGF and PLGF in serum were independently associated with a low degree of coronary collateralization. CONCLUSIONS: Increased serum sVEGFR-1 level is associated with poor coronary collateralization in patients with stable CAD. Type 2 DM is a predominant factor affecting collateral growth in these patients.

Clinical and angiographic features associated with coronary collateralization in stable angina patients with chronic total occlusion.

OBJECTIVE: Coronary collateral circulation is an alternative source of blood supply to myocardium in the presence of advanced coronary artery disease. We sought to determine which clinical and angiographic variables are associated with collateral development in patients with stable angina and chronic total coronary occlusion. METHODS: Demographic variables, biochemical measurements, and angiographic findings were collected from 478 patients with stable angina and chronic total coronary occlusion. The presence and extent of collaterals supplying the distal aspect of a total coronary occlusion from the contra-lateral vessel were graded from 0 to 3 according to the Rentrop scoring system. RESULTS: Low (Rentrop score of 0 or 1) and high (Rentrop score of 2 or 3) coronary collateralizations were detected in 186 and 292 patients, respectively. Despite similar age, cigarette smoking, and medical treatment, patients with low collateralization were female in a higher proportion and less hypertensive, and had higher rates of type 2 diabetes and dyslipidemia than those with high collateralization (for all comparisons, P<0.05). In addition, patients with low collateralization exhibited more single-vessel disease, less right coronary artery occlusion, more impaired renal function, and higher serum levels of high-sensitivity C-reactive protein (hsCRP) compared with those with high collateralization. Multivariate analysis revealed that age of ≥65 years, female gender, diabetes, no history of hypertension, dyslipidemia, moderate to severe renal dysfunction, single-vessel disease, and elevated hsCRP levels were independently associated with low coronary collateralization. CONCLUSIONS: Coronary collateralization was reduced in almost 40% of stable angina patients with chronic total occlusion, which was related to clinical and angiographic factors. The impact of coronary collateralization on outcomes after revascularization needs further investigation.

Two-dimensional fluorescence in-gel electrophoresis of coronary restenosis tissues in minipigs: increased adipocyte fatty acid binding protein induces reactive oxygen species-mediated growth and migration in smooth muscle cells.

OBJECTIVE: We aimed to uncover the protein changes of coronary artery in-stent restenosis (ISR) tissue in minipigs with and without streptozotocin-induced diabetes mellitus by quantitative 2-dimensional fluorescence in-gel electrophoresis (2D-DIGE), and to investigate the influences of crucial proteins identified, particularly adipocyte fatty acid binding protein (AFABP), in human arterial smooth muscle cells. METHODS AND RESULTS: Sirolimus-eluting stents were implanted in the coronary arteries of 15 diabetic and 26 nondiabetic minipigs, and angiography was repeated after 6 months. The intima tissue of significant ISR and non-ISR segments in both diabetic and nondiabetic minipigs was analyzed by 2D-DIGE and MALDI-TOF/TOF mass spectrometry. AFABP level was significantly increased in ISR tissue than in non-ISR tissue in both diabetic and nondiabetic minipigs, with level being higher in diabetic ISR than in nondiabetic ISR tissue. In human arterial smooth muscle cells, overexpression of AFABP significantly altered phenotype and promoted growth and migration, with effects more prominent in high-glucose than in low-glucose medium, whereas AFABP knockdown inhibited these effects. AFABP overexpression increased reactive oxygen species production by upregulating the expression of NADPH oxidase subunits Nox1, Nox4, and P22 through multiple pathways, with elevation of downstream gene cyclin D1, matrix metalloproteinase-2, and monocyte chemoattractant protein-1. However, AFABP-induced effects were inhibited by diphenyleneiodonium, pathway inhibitors, and small interfering RNA. In addition, the supernatant from AFABP-expressing human arterial smooth muscle cells and recombinant AFABP also promoted cellular growth and migration. CONCLUSIONS: This study has demonstrated that AFABP is significantly increased in coronary artery ISR segments of both diabetic and nondiabetic minipigs. Increased AFABP expression and secretory AFABP of human arterial smooth muscle cells promote growth and migration via reactive oxygen species-mediated activation.

Impact of elevated serum glycated albumin levels on contrast-induced acute kidney injury in diabetic patients with moderate to severe renal insufficiency undergoing coronary angiography.

BACKGROUND: Glycated albumin (GA) has been shown to be a better indicator than glycosylated hemoglobin A1c (HbA1c) in terms of severity of renal impairment in patients with type 2 diabetes mellitus (T2DM). This study aimed to determine whether elevated serum GA levels are associated with an increased risk for contrast-induced acute kidney injury (CI-AKI) and worse clinical outcome in patients with T2DM and at least moderate renal insufficiency (RI) undergoing coronary angiography. METHODS: Serum levels of fasting blood glucose (FBG), HbA1c and GA were measured in 1030 patients with T2DM and moderate to severe RI (eGFR 15-59 mL/min/1.73 m(2)). CI-AKI was defined as ≥ 25% increase in serum creatinine within 72 h after the procedure. Receiver-operating characteristic curve was constructed to assess the predictive value of GA, HbA1c and FBG for CI-AKI. Multivariable logistic regression model was developed to identify risk factors for CI-AKI, and Kaplan-Meier curve analysis was used to compare the rates of dialysis and major adverse cardiac events (MACE) during one-year follow-up. RESULTS: The overall rate of CI-AKI was 11.1%. GA was significantly higher in patients with CI-AKI than in those without, and correlated positively with changes of renal function after the procedure. After adjusting for age, sex, left ventricular ejection fraction, multi-vessel disease, type and volume of contrast media, FBG, and HbA1c, GA remained an independent risk factor for CI-AKI. GA ≥ 21% was associated with increased rates of dialysis and MACE during one-year follow-up in patients with or without CI-AKI. CONCLUSIONS: Increased GA level serves as a valuable risk factor for CI-AKI and indicates poor one-year clinical outcome in patients with T2DM and moderate to severe RI.

Glycation of apoprotein A-I is associated with coronary artery plaque progression in type 2 diabetic patients.

OBJECTIVE: To investigate whether glycation level of apoprotein (apo)A-I is associated with coronary artery disease (CAD) and plaque progression in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Among 375 consecutive type 2 diabetic patients undergoing quantitative coronary angiography (QCA) and intravascular ultrasound (IVUS), 82 patients with nonsignificant stenosis (luminal diameter narrowing <30% [group I]) and 190 patients with significant CAD (luminal diameter stenosis ≥70% [group II]) were included for analysis of apoA-I glycation level and serum activity of lecithin: cholesterol acyltransferase (LCAT). The control group had 136 healthy subjects. At the 1-year follow-up, angiography and IVUS were repeated mainly in group II patients for plaque progression assessment. RESULTS: Relative intensity of apoA-I glycation by densitometry was increased, and serum LCAT activity was decreased stepwise across groups control, I, and II. These two measurements were associated with the number of diseased coronary arteries and extent index in group II. During 1-year follow-up, QCA detected 45 patients with plaque progression in 159 subjects, and IVUS found 38 patients with plaque progression in 127 subjects. Baseline relative intensity of apoA-I glycation was significantly increased in patients with plaque progression compared with those without, with values associated with changes in QCA and IVUS measurements. Multivariable regression analysis revealed that baseline relative intensity of apoA-I glycation was an independent determinant of CAD and plaque progression in type 2 diabetic patients. CONCLUSIONS: ApoA-I glycation level is associated with the severity of CAD and coronary artery plaque progression in type 2 diabetic patients.

Increase of ADAM10 level in coronary artery in-stent restenosis segments in diabetic minipigs: high ADAM10 expression promoting growth and migration in human vascular smooth muscle cells via Notch 1 and 3.

BACKGROUND: This study aimed to identify major proteins in the pathogenesis of coronary artery in-stent restenosis (ISR) in diabetic minipigs with sirolimus-eluting stenting, and to investigate the roles of key candidate molecules, particularly ADAM10, in human arterial smooth muscle cells (HASMCs). METHODS AND RESULTS: The stents were implanted in the coronary arteries of 15 diabetic and 26 non-diabetic minipigs, and angiography was repeated at six months. The intima of one vascular segment with significant ISR and one with non-ISR in diabetic minipigs were isolated and cultured in conditioned medium (CM). The CM was analyzed by LC-MS/MS to uncover proteins whose levels were significantly increased (≥ 1.5-fold) in ISR than in non-ISR tissues. After literature searching, we focused on the identified proteins, whose biological functions were most potentially related to ISR pathophysiology. Among them, ADAM10 was significantly increased in diabetic and non-diabetic ISR tissues as compared with non-ISR controls. In cell experiments, retrovirus-mediated overexpression of ADAM10 promoted growth and migration of HASMCs. The effects of ADAM10 were more remarkable in high-glucose culture than in low-glucose culture. Using shRNA and an inhibitor of γ-secretase (GSI), we found that the influences of ADAM10 were in part mediated by Notch1 and notch 3 pathway, which up-regulated Notch downstream genes and enhanced nuclear translocation of the small intracellular component of Notch1 and Notch3. CONCLUSIONS: This study has identified significantly increased expression of ADAM10 in the ISR versus non-ISR segment in diabetic minipigs and implicates ADAM10 in the enhanced neointimal formation observed in diabetes after vascular injury.

Serum advanced glycation end-products and receptors as prognostic biomarkers in diabetics undergoing coronary artery stent implantation.

BACKGROUND: This study investigated the impact of elevated glycated albumin (GA) and reduced soluble receptor for advanced glycation end-products (sRAGE) and endogenous secretory receptor for advanced glycation end-products (esRAGE) levels in serum on the severity of albuminuria, occurrence of contrast-induced acute kidney injury (CI-AKI) and 1-year clinical outcome in type 2 diabetic patients undergoing sirolimus-eluting stent-based percutaneous coronary intervention. METHODS: We compared serum levels of GA, sRAGE, esRAGE, and glycosylated hemoglobin (HbA1c), occurrence of CI-AKI, and major adverse cardiac events at 1-year clinical follow-up in 3 groups of type 2 diabetes based on 24-hour urinary albumin excretion: I = normoalbuminuria (< 30 mg; n = 190); II = microalbuminuria (30-300 mg; n = 102); and III = macroalbuminuria (≥ 300 mg; n = 86). RESULTS: Serum levels of GA and HbA1c increased step-wise from group I to III, and serum levels of sRAGE and esRAGE were decreased in the groups with albuminuria, with the lowest values in those with microalbuminuria. GA (Pearson's r = 0.264; P < 0.001), sRAGE (Pearson's r = -0.210; P < 0.001), esRAGE (Pearson's r = -0.145; P = 0.04), and HbA1c (Pearson's r = 0.214; P < 0.001) correlated significantly with urinary albumin excretion. After adjusting for confounding factors, GA, sRAGE, esRAGE, and albuminuria status remained independently associated with both CI-AKI and 1-year major adverse cardiac events. CONCLUSIONS: Elevated GA and reduced sRAGE and esRAGE levels in serum are associated with severity of albuminuria and postprocedural CI-AKI, and exert a negative impact on 1-year clinical outcome in patients with type 2 diabetes undergoing percutaneous coronary intervention with sirolimus-eluting stent implantation.

Glycated albumin is superior to hemoglobin A1c for evaluating the presence and severity of coronary artery disease in type 2 diabetic patients.

OBJECTIVES: This study aimed to compare the value of serum glycated albumin (GA) level versus glycated hemoglobin A(1c) (HbA(1c)) for evaluating the presence and severity of coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM). METHODS: Serum GA and blood HbA(1c) levels were measured in 829 consecutive T2DM patients with or without angiographically documented significant CAD (≥70% diameter stenosis). RESULTS: Serum GA levels were higher in diabetic patients with significant CAD than in those without (20.57 ± 4.23 vs. 19.00 ± 4.48%; p < 0.001), but HbA(1c) was similar in the two groups (7.74 ± 1.34 vs. 7.51 ± 1.37% p > 0.05). Compared to HbA(1c), GA correlated more closely with the sum of significant stenotic lesions (r = 0.275, p < 0.001 and r = 0.092, p = 0.019) and the extent index (r = 0.375, p < 0.001 and r = 0.091, p = 0.019). The area under the curve of GA was larger than that of HbA(1c) for detecting the presence of significant CAD (0.637 vs. 0.568; p = 0.046) and 3-vessel disease (0.620 vs. 0.536; p = 0.039). GA, but not HbA(1c), was independently associated with significant CAD. CONCLUSIONS: Serum GA level is a better indicator than HbA(1c) for evaluating the presence and severity of CAD and predicting major adverse cardiac events in patients with T2DM.

Increased blood glycohemoglobin A1c levels lead to overestimation of arterial oxygen saturation by pulse oximetry in patients with type 2 diabetes.

BACKGROUND: Non-enzymatic glycation increases hemoglobin-oxygen affinity and reduces oxygen delivery to tissues by altering the structure and function of hemoglobin. OBJECTIVES: We investigated whether an elevated blood concentration of glycosylated hemoglobin (HbA1c) could induce falsely high pulse oximeter oxygen saturation (SpO2) in type 2 diabetic patients during mechanical ventilation or oxygen therapy. METHODS: Arterial oxygen saturation (SaO2) and partial pressure of oxygen (PO2) were determined with simultaneous monitoring of SpO2 in 261 type 2 diabetic patients during ventilation or oxygen inhalation. RESULTS: Blood concentration of HbA1c was >7% in 114 patients and ≤ 7% in 147 patients. Both SaO2 (96.2 ± 2.9%, 95% confidence interval [CI] 95.7-96.7% vs. 95.1 ± 2.8%, 95% CI 94.7-95.6%) and SpO2 (98.0 ± 2.6%, 95% CI 97.6-98.5% vs. 95.3 ± 2.8%, 95% CI 94.9-95.8%) were significantly higher in patients with HbA1c >7% than in those with HbA1c ≤ 7% (Data are mean ± SD, all p < 0.01), but PO2 did not significantly differ between the two groups. Bland-Altman analysis demonstrated a significant bias between SpO2 and SaO2 (1.83 ±0.55%, 95% CI 1.73% -1.94%) and limits of agreement (0.76% and 2.92%) in patients with HbA1c >7%. The differences between SpO2 and SaO2 correlated closely with blood HbA1c levels (Pearson's r = 0.307, p < 0.01). CONCLUSIONS: Elevated blood HbA1c levels lead to an overestimation of SaO2 by SpO2, suggesting that arterial blood gas analysis may be needed for type 2 diabetic patients with poor glycemic control during the treatment of hypoxemia.

Screening for significant atherosclerotic renal artery stenosis with a regression model in patients undergoing transradial coronary angiography/intervention.

OBJECTIVE: Early detection of atherosclerotic renal artery stenosis (ARAS) is clinically important with respect to blood pressure control, prevention of renal insufficiency, and even improving survival. We investigated whether the presence of significant ARAS (luminal diameter narrowing ≥70%) could be predicted using a logistic regression model before coronary angiography/intervention. METHODS: Initially, we developed a logistic regression model for detecting significant ARAS based upon clinical and angiographic features and biochemical measurements in a cohort of 1813 patients undergoing transfemoral coronary and renal angiography. This model was then prospectively applied to an additional 495 patients who received transradial renal angiography to ascertain its predictive accuracy for the presence of significant ARAS. RESULTS: Multivariate regression analysis revealed that older age (≥65 years), resistant hypertension, type 2 diabetes, creatinine clearance (Ccr) ≤60 ml/min, and multivessel coronary disease were independent predictors for significant ARAS. A logistic regression model for detecting ARAS by incorporating conventional risk factors and multivessel coronary disease was generated as: P/(1-P)=exp(-2.618+1.112[age≥65 years]+1.891[resistant hypertension]+0.453[type 2 diabetes]+0.587[Ccr≤60 ml/min]+2.254[multivessel coronary disease]). When this regression model was prospectively applied to the additional 495 patients undergoing transradial coronary and renal angiography, significant ARAS could be detected with a sensitivity of 81.2%, specificity of 88.9%, and positive and negative predictive accuracies of 53.8% and 96.7%, respectively. CONCLUSIONS: The logistic regression model generated in this study may be useful for screening for significant ARAS in patients undergoing transradial coronary angiography/intervention.