The prognosis of patients with variant angina with ASCD was worse than other patients with variant angina. In addition, our findings supported ICDs in these high-risk patients as a secondary prevention because current multiple vasodilator therapy appeared to be less optimal.

This study evaluated the relationship of insulin resistance (IR) and glycemic control status to the presence and severity of coronary artery disease (CAD) according to diabetes. The relationship of IR parameters including homeostatic model assessment of IR (HOMA-IR), triglyceride-glucose (TyG) index, and triglyceride-to-high density lipoprotein cholesterol ratio (TG/HDL), and hemoglobin A1C (HbA1C) level to CAD and obstructive CAD was evaluated in 5,764 asymptomatic subjects who underwent coronary computed tomographic angiography. Non-diabetics (n = 4768) and diabetics (n = 996) were stratified into four groups based on the quartiles of HOMA-IR and the TyG index and were grouped based on the TG/HDL cut-offs of 3.5, respectively. CAD and obstructive CAD were defined as the presence of any plaques and plaques with ≥50% stenosis, respectively. The prevalence of CAD (59.0% vs. 39.0%) and obstructive CAD (15.0% vs. 6.6%) was higher in diabetic than in non-diabetic patients (p < 0.001, respectively). In non-diabetic patients, the adjusted odds ratio for both CAD and obstructive CAD significantly increased, but only with higher TyG index quartiles. Unlike non-diabetics, the adjusted odds ratio for obstructive CAD significantly increased in diabetic patients with a TG/HDL level ≥ 3.5. The HbA1C, rather than IR parameters, was independently associated with both CAD and obstructive CAD in diabetics. In conclusion, among IR parameters, TyG index was independently associated with the presence of CAD and obstructive CAD in non-diabetic patients. In contrast, the glycemic control status, rather than IR, was importantly related to both CAD and obstructive CAD in established diabetic patients.

The prevalence of newly revealed abnormal, asymptomatic ABI among patients who have significant CAD on coronary angiography was 15.9%. The presence of abnormal ABI was associated with a higher incidence of adverse clinical outcomes over 3 years.

Background Atherosclerotic cardiovascular (CV) events commonly occur in individuals with a low CV risk burden. This study evaluated the ability of the triglyceride glucose (TyG) index to predict subclinical coronary artery disease (CAD) in asymptomatic subjects without traditional CV risk factors (CVRFs). Methods This retrospective, cross-sectional, and observational study evaluated the association of TyG index with CAD in 1250 (52.8 ± 6.5 years, 46.9% male) asymptomatic individuals without traditional CVRFs (defined as systolic/diastolic blood pressure ≥ 140/90 mmHg; fasting glucose ≥126 mg/dL; total cholesterol ≥240 mg/dL; low-density lipoprotein cholesterol ≥160 mg/dL; high-density lipoprotein cholesterol < 40 mg/dL; body mass index ≥25.0 kg/m2; current smoking; and previous medical history of hypertension, diabetes, or dyslipidemia). CAD was defined as the presence of any coronary plaque on coronary computed tomographic angiography. The participants were divided into three groups based on TyG index tertiles. Results The prevalence of CAD increased with elevating TyG index tertiles (group I: 14.8% vs. group II: 19.3% vs. group III: 27.6%; P < 0.001). Multivariate logistic regression models showed that TyG index was associated with an increased risk of CAD (odds ratio [OR] 1.473, 95% confidence interval [CI] 1.026–2.166); especially non-calcified (OR 1.581, 95% CI 1.002–2.493) and mixed plaques (OR 2.419, 95% CI 1.051–5.569) (all P < 0.05). The optimal TyG index cut-off for predicting CAD was 8.44 (sensitivity 47.9%; specificity 68.5%; area under the curve 0.600; P < 0.001). The predictive value of this cut-off improved after considering the non-modifiable factors of old age and male sex. Conclusions TyG index is an independent marker for predicting subclinical CAD in individuals conventionally considered healthy.

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We have previously reported that tissue inhibitor of metalloproteinases-2 (TIMP-2), an endogenous inhibitor of matrix metalloproteinase, modulates angiogenic responses through the MMP inhibitionindependent activity. In this study, we investigate the molecular mechanisms of TIMP-2-mediated growth inhibition in response to fibroblast growth factor-2 (FGF-2). Pretreatment with a protein tyrosine phosphatase inhibitor orthovanadate or expression of a dominant negative Shp-1 mutant fails to induce TIMP-2 inactivation of FGF-2 signaling pathways in human microvascular endothelial cells. We also show that TIMP-2 inhibition of FGF-2-induced p42/44 MAPK activation and cell proliferation is associated with TIMP-2 binding to integrin α3β1 on endothelial cell surfaces, as demonstrated by use of anti-integrin α3 or β1 blocking antibodies, or disruption of integrin α3 experssion by siRNA.Collectively, our results indicate that TIMP-2 inhibits FGF-2 signaling pathways through association with integrin α3β1 and Shp-1-dependent inhibition of p42/44 MAPK signaling, which in turn, results in suppression of FGF-2-stimulated endothelial cell mitogenesis.

In cancer, VEGF-induced increase in vascular permeability results in increased interstitial pressure, reducing perfusion and increasing hypoxia, which reduce delivery of chemotherapeutic agents and increase resistance to ionizing radiation. Here, we show that both TIMP-2 and Ala ؉ TIMP-2, a TIMP-2 mutant without matrix metalloproteinase inhibitory activity, antagonize the VEGF-A-induced increase in vascular permeability, both in vitro and in vivo. Like other agents known to preserve endothelial barrier function, TIMP-2 elevates cytosolic levels of cAMP and increases cytoskeletal-associated vascular endothelial cadherin in human microvascular endothelial cells. All of these effects are completely ablated by selective knockdown of integrin ␣3␤1 expression, expression of a dominant negative protein tyrosine phosphatase Shp-1 mutant, administration of the protein tyrosine phosphatase inhibitor orthovanadate, or the adenylate cyclase inhibitor SQ22536. This TIMP-2-mediated inhibition of vascular permeability involves an integrin ␣3␤1-Shp-1-cAMP/protein kinase A-dependent vascular endothelial cadherin cytoskeletal association, as evidenced by using siRNAs to integrin ␣3␤1 and Shp-1, or treatment with Shp-1 inhibitor NSC87877 and protein kinase A inhibitor H89. Our results demonstrate the potential utility for TIMP-2 in cancer therapy through "normalization" of vascular permeability in addition to previously described antiangiogenic effects. (Blood. 2012;120(24):4892-4902) IntroductionTumor-associated angiogenesis is critical for tumor progression and metastasis. The central role of vascular endothelial growth factor-A (VEGF-A) in this process is evidenced by the development and approval of bevacizumab, a VEGF-A neutralizing antibody, for therapy in several human cancers. VEGF-A-induced angiogenesis is often accompanied by increased vascular permeability, which can result in fibrin deposition and may facilitate tumor cell extravasation enhancing metastasis formation. 1 The resulting vascular leak has also been shown to increase interstitial pressure within the tumor, decrease tumor blood flow, and hinder drug delivery to the tumor. Indeed, it has been proposed that VEGF-axis targeted therapies may result in "normalization" of tumor vasculature improving chemotherapeutic delivery and decreasing hypoxia, resulting in enhanced radiosensitivity. 2,3 Vascular permeability can be modulated by the phosphorylation, cleavage, and internalization of vascular endothelial (VE)-cadherin. [4][5][6] Tyrosine phosphorylation of the cadherin-catenin complexes is regulated by the activities of protein tyrosine phosphatases and src-family kinases. 7-11 Inhibition of tyrosine phosphorylation of VE-cadherin increases the stability of adherens junctions and improves vascular barrier function. Matrix metalloproteinase (MMP)-mediated cleavage of VE-cadherin may promote vascular permeability and cell proliferation by dissociating cadherin-catenin complex and disrupting cell-cell adhesion. [12][13][14][15] In contrast, it is widely recognized t...

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