leptin and Coronary-Restenosis

Impaired insulin sensitivity and endothelial dysfunction are important markers in the development of restenosis after coronary stenting. In addition, new markers of inflammation and endothelium activation, such as increased leptin levels, also have to considered. Many studies have shown that hyperinsulinemia and insulin resistance increase neointimal index measured six months after coronary stenting, and that insulin-sensitizers have beneficial effects by decreasing the rate of restenosis. The role of endothelial dysfunction in the process of restenosis is a fascinating problem. The pathobiology of restenosis in stented arteries is largely related to neointimal hyperplasia, which is dependent upon several factors, such as a reduction in nitric oxide activity that determines endothelial dysfunction and oxidative stress. Abnormal endothelium-dependent vasodilation (related to decreased nitric oxide production in the insulin-resistant state) might be explained by alterations in intracellular signaling and increased endothelin-1 production. Leptin is a hormone related to both fat metabolism and insulin resistance that has been recognized as an independent predictor of coronary restenosis. Chronic hyperleptinemia can reduce the synthesis of nitric oxide owing to the increased oxidative stress in endothelial cells. As a result, the goal in prevention of in-stent restenosis is to develop drugs that are able to act both as insulin- and endothelium-sensitizers.

Topics: Animals; Coronary Restenosis; Endothelium, Vascular; Humans; Insulin Resistance; Leptin

Patients with type 2 diabetes (T2DM) have a high restenosis rate after percutaneous coronary intervention (PCI). This study investigated whether markers of inflammation and the adipo-insular axis associated with T2DM and poor metabolic control were able to predict restenosis after PCI in T2DM patients.. The predictive value of traditional and non-traditional risk markers, including IL-1β, IL-6, TNF-α, hsCRP, interferon gamma, leptin, IGF-I, insulin, proinsulin and NT-proBNP, was investigated in 82 patients with T2DM. A re-angiography 6 months after the index percutaneous coronary intervention (PCI) revealed that 43% of the patients had a restenosis. In a multiple regression analysis, the only independent predictors of restenosis were fasting glucose before the PCI and previous myocardial infarction (odds ratio [OR] 1.44, 95% confidence interval [CI] 1.07-1.92; p = 0.015 and OR 8.00, 95% CI 2.49-25.67; p ≤ 0.001, respectively). None of the other markers remained as significant predictors.. Fasting glucose prior to the PCI was an independent predictor of restenosis in patients with T2DM while analyses of a variety of markers related to inflammation and the adipo-insular axis did not add any further information.

Topics: Aged; Angioplasty, Balloon, Coronary; Biomarkers; Blood Glucose; Coronary Angiography; Coronary Restenosis; Coronary Stenosis; Cytokines; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Inflammation Mediators; Insulin; Insulin-Like Growth Factor I; Leptin; Logistic Models; Male; Middle Aged; Myocardial Infarction; Natriuretic Peptide, Brain; Odds Ratio; Peptide Fragments; Proinsulin; Prospective Studies; Risk Assessment; Risk Factors; Sweden; Time Factors; Treatment Outcome

Previously undiagnosed diabetes, impaired glucose tolerance, and insulin resistance are common in patients with acute myocardial infarction and coronary heart disease (CHD) and might be involved in early restenosis after stent implantation. To evaluate whether markers of insulin resistance syndrome, including leptin, and endothelial dysfunction are related to increased rate of early restenosis, we studied nondiabetic patients with CHD after successful coronary stenting.. Both patients with CHD undergoing coronary stenting (120 patients) and control subjects (58 patients) were submitted to an oral glucose tolerance test (OGTT). Fasting leptin levels and fasting and postglucose load insulin sensitivity were assessed. Endothelial function was measured by nitrite and nitrate release (NOx) during OGTT. More than 50% of patients treated with stent implantation presented impaired glucose tolerance or type 2 diabetes, which was previously undiagnosed. These patients also had higher glucose, insulin, and leptin levels than control subjects. Among the stented patients, insulin and leptin levels were higher in patients with restenosis than in patients without restenosis. A significant increase in NOx levels was found during OGTT both in patients without restenosis and in control subjects. On the contrary, NOx profiles were blunted in patients with restenosis. At multiple regression analysis, only DeltaAUC-NOx areas and insulin sensitivity index showed an independent correlation with the minimal lumen diameter at follow-up.. We demonstrated that insulin resistance and endothelial dysfunction are independent predictors of early restenosis after coronary stenting.

Topics: Area Under Curve; Blood Glucose; Blood Vessel Prosthesis Implantation; Coronary Angiography; Coronary Disease; Coronary Restenosis; Diabetes Mellitus, Type 2; Endothelium, Vascular; Follow-Up Studies; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Leptin; Middle Aged; Nitric Oxide; Predictive Value of Tests; Regression Analysis; Stents; Vascular Patency

The hypertrophy of vascular smooth muscle cells as well as neointimal proliferation is critical in vascular remodeling, whereas leptin has proved to play an important role recently. The aim of the study was to investigate possible associations of two common leptin gene polymorphisms with restenosis after percutaneous coronary intervention (PCI). To study the association of two promoter polymorphisms, LEP -2548 G/A and LEP -188 C/A (dbSNP ID rs7799039 and rs791620) with neointimal proliferation in humans, 98 consecutive patients undergoing stenting into small coronary arteries (<3 mm) were genotyped. After a 6-month follow-up, the restenosis rate was estimated. Restenosis >50% occurred in 33.3% of patients carrying both A alleles, 33.3% of carriers of A and C alleles, and 31.4% of carriers of two CC alleles of LEP -188 C/A polymorphism; and in 25.0% of patients with AA, 32.7% with AG, and 30.4% with GG genotype of LEP -2548 G/A polymorphism. Interestingly, the heterozygote AG genotype of LEP -2548 polymorphism represented a highly significant risk for multiple-vessel disease when compared to both homozygote genotypes AA/GG (odds ratio = 4.038, 95% confidence interval: 1.732-9.465, P(corr) = 0.001). Based on our findings, the AG genotype of LEP -2548 G/A polymorphism might be considered a genetic marker for multiple-vessel disease but not for restenosis after PCI. The role of the leptin gene polymorphisms as genetic markers of restenosis will require further investigation to elucidate the underlying pathophysiological consequences.

Topics: Adult; Aged; Alleles; Angiography; Cell Proliferation; Coronary Restenosis; Female; Genotype; Heterozygote; Humans; Leptin; Male; Middle Aged; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Risk; Stents

Topics: Cell Membrane; Coronary Restenosis; Erythrocytes; Humans; Hyperinsulinism; Leptin; Nitric Oxide; Viscosity

A diabetic mouse model of accelerated neointimal formation would be a useful tool to understand the increased incidence of restenosis in patients with diabetes.. Femoral artery endoluminal wire injury was performed in diabetic insulin 2 Akita (ins2Akita) and leptin receptor db/db (leprdb/db) mutant mice. Neointima size in ins2Akita mouse arteries was unchanged compared with nondiabetic wild-type littermates. Although Ki67 labeling demonstrated similar rates of replication in the neointima of leprdb/db mouse arteries, neointimal formation in leprdb/db mice was surprisingly reduced by approximately 90% compared with nondiabetic lepr+/+ mice. Four hours after arterial injury, medial smooth muscle cell death was diminished in leprdb/db arteries, suggesting that the initial response to arterial injury was altered in leprdb/db mice.. These studies highlight a differential response to arterial injury in leprdb/db mice and suggest a potential role for leptin in the regulation of neointimal formation in response to arterial injury.

Topics: Animals; Coronary Restenosis; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Disease Models, Animal; Female; Femoral Artery; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Muscle, Smooth, Vascular; Neovascularization, Pathologic; Sex Factors; Tunica Intima; Tunica Media