Central adiposity and left ventricular mass in obese children.

AIM: The impact of central adiposity on left ventricular (LV) mass in childhood obesity has been little explored. This study evaluates whether central obesity influences LV mass and function in obese children. METHODS AND RESULTS: Biochemical, anthropometric and echocardiographic measurements were taken in obese (n=111, mean age 10.6+/-2.5 years) and non-obese children (n=30, mean age 10.8+/-3.0 years). Left ventricular function was analyzed by conventional and tissue Doppler echocardiography. LV mass was calculated according to the Penn convention and indexed for height(2.7) (LVM(i)). The obese group showed increased levels of LVM(i) as compared to the non-obese group (35.7+/-8.5 vs 23.5+/-2.8 g/h(2.7), p<0.0001). Among obese children, we observed a significant increase of LVM(i) across tertile of waist-height ratio (WHtR). The subjects identified by the highest tertile of WHtR, as compared to subjects identified by the lowest tertile, showed higher levels of BMI (29.5+/-5.4 vs 31.0+/-5.0 kg/m(2), p<0.0001) and LVM(i) (32.1+/-6.5 vs 37.1+/-8.5 g/h(2.7), p<0.01). Among obese children a positive correlation (standardized for age and gender) was found between LVM(i) and BMI (r=0.282, p<0.01) and WHtR (r=0.334, p<0.0001). To analyze the independent predictors of LVM(i), a stepwise linear regression analysis was performed using age, gender, BMI, blood pressure, heart rate, HOMA-IR and WHtR as independent variables. LVM(i) was independently associated only with WHtR (beta=0.309, t=3.238, p=0.002). CONCLUSION: Obese children show an increased LVM(i) and a preserved LV function. Central adiposity is the major determinant of left ventricular mass.

Early detection of diabetic cardiomyopathy: usefulness of tissue Doppler imaging.

OBJECTIVE: The aim of the study was to evaluate whether tissue Doppler imaging (TDI) detects a pre-clinical impairment of diastolic function in subjects with Type 2 diabetes with short duration of disease and normal cardiac function with conventional echocardiography (CE), and whether echocardiographic parameters are related to metabolic abnormalities. PATIENTS AND METHODS: We studied 40 non-obese, normotensive, uncomplicated Type 2 diabetic subjects with short duration of disease and 20 control subjects. All participants underwent both CE and TDI echocardiography. With TDI, early velocity (Ea), atrial velocity (Aa), their ratio (Ea/Aa) and systolic velocity (Sa) were measured at the lateral corner of mitral annulus. Glycosylated haemoglobin, fasting plasma glucose and insulin were determined and homeostasis model assessment (HOMA-IR), as an index of insulin resistance, was calculated. RESULTS: Cardiac function with CE was similar in the two groups. Using TDI, diabetic subjects showed a lower Ea velocity (15.5+/-3.9 vs. 19.4+/-3.5 cm/s, P<0.0001), an increased Aa velocity (15.5+/-2.4 vs. 14.1+/-2.4 cm/s, P<0.05) and a reduced Ea/Aa ratio (1.00+/-0.2 vs. 1.39+/-0.3, P<0.0001), compared with control subjects. Linear regression analysis in the diabetic group showed that only HOMA-IR was negatively associated with Ea/Aa ratio (P=0.026). No significant association was observed with other metabolic variables. CONCLUSION: An early stage of diabetic cardiomyopathy can be evidenced by TDI in Type 2 diabetic subjects even in the presence of a normal cardiac function with CE. This abnormality is associated with insulin resistance.

Effects of balloon injury on neointimal hyperplasia in streptozotocin-induced diabetes and in hyperinsulinemic nondiabetic pancreatic islet-transplanted rats.

BACKGROUND: The mechanisms of increased neointimal hyperplasia after coronary interventions in diabetic patients are still unknown. METHODS AND RESULTS: Glucose and insulin effects on in vitro vascular smooth muscle cell (VSMC) proliferation and migration were assessed. The effect of balloon injury on neointimal hyperplasia was studied in streptozotocin-induced diabetic rats with or without adjunct insulin therapy. To study the effect of balloon injury in nondiabetic rats with hyperinsulinemia, pancreatic islets were transplanted under the kidney capsule in normal rats. Glucose did not increase VSMC proliferation and migration in vitro. In contrast, insulin induced a significant increase in VSMC proliferation and migration in cell cultures. Furthermore, in VSMC culture, insulin increased MAPK activation. A reduction in neointimal hyperplasia was consistently documented after vascular injury in hyperglycemic streptozotocin-induced diabetic rats. Insulin therapy significantly increased neointimal hyperplasia in these rats. This effect of hyperinsulinemia was totally abolished by transfection on the arterial wall of the N17H-ras-negative mutant gene. Finally, after experimental balloon angioplasty in hyperinsulinemic nondiabetic islet-transplanted rats, a significant increase in neointimal hyperplasia was observed. CONCLUSIONS: In rats with streptozotocin-induced diabetes, balloon injury was not associated with an increase in neointimal formation. Exogenous insulin administration in diabetic rats and islet transplantation in nondiabetic rats increased both blood insulin levels and neointimal hyperplasia after balloon injury. Hyperinsulinemia through activation of the ras/MAPK pathway, rather than hyperglycemia per se, seems to be of crucial importance in determining the exaggerated neointimal hyperplasia after balloon angioplasty in diabetic animals.

Membrane-bound protein kinase A inhibits smooth muscle cell proliferation in vitro and in vivo by amplifying cAMP-protein kinase A signals.

cAMP-dependent protein kinase is anchored to discrete cellular compartments by a family of proteins, the A-kinase anchor proteins (AKAPs). We have investigated in vivo and in vitro the biological effects of the expression of a prototypic member of the family, AKAP75, on smooth muscle cells. In vitro expression of AKAP75 in smooth muscle cells stimulated cAMP-induced transcription, increased the levels of the cyclin-dependent kinase-2 inhibitor p27(kip1), and reduced cell proliferation. In vivo expression of exogenous AKAP75 in common carotid arteries, subjected to balloon injury, significantly increased the levels of p27(kip1) and inhibited neointimal hyperplasia. Both the effects in smooth muscle cells in vitro and in carotid arteries in vivo were specifically dependent on the amplification of cAMP-dependent protein kinase (PKA) signals by membrane-bound PKA, as indicated by selective loss of the AKAP75 biological effects in mutants defective in the PKA anchor domain or by suppression of AKAP effects by the PKA-specific protein kinase inhibitor. These data indicate that AKAP proteins selectively amplify cAMP-PKA signaling in vitro and in vivo and suggest a possible target for the inhibition of the neointimal hyperplasia after vascular injury.

A new rat model of small vessel stenting.

OBJECTIVES: Restenosis is the major complication of coronary angioplasty and stenting. In addition, the small vessel diameter represents a major limitation to the wide use of the technology. The aim of this study was to assess the feasibility and the vascular response of stent deployment in rat small vessels. METHODS: In 40 Wistar rats (500-550 g) a Nir stent crimped on a 1.5 mm Comet angioplasty balloon catheter was deployed at high pressure in the common carotid artery. Neointimal area, neointima/media ratio and the arterial dimension were assessed immediately and at 7, 14, 21, and 28 days after stenting. RESULTS: After stent deployment, the neointimal area and the neointima/media ratio increased progressively and peaked at 14 days (p < 0.05 vs 0 and 7 days). Alpha-actin-positive cells were found circumferentially organized on the lumen surface. At 21 and 28 days after stenting, the neointima and the neointima/media ratio were not statistically different compared with the results obtained fourteen days after stent deployment. No significant differences in the area of external elastic lamina were observed during the study period. In contrast, the internal lumen area was reduced significantly at 14, 21, and 28 days after the stent deployment. Subacute thrombosis rate after stent implantation was 26.5 %. CONCLUSIONS: The results of this study demonstrated that the balloon expandable stents can be safely placed into rat arteries and the reduction of the internal arterial lumen observed after stent deployment was only due to the neointima formation whereas remodeling did not occur.

Effects of hydroxymethylglutaryl coenzyme A reductase inhibitor simvastatin on smooth muscle cell proliferation in vitro and neointimal formation in vivo after vascular injury.

OBJECTIVES: We sought to evaluate the effects of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors on vascular smooth muscle cell (VSMC) proliferation in vitro and neointimal formation in vivo after vascular injury. BACKGROUND: Neointimal hyperplasia after vascular injury is responsible for restenosis after arterial stenting, whereas arterial remodeling and neointimal formation are the causes of restenosis after percutaneous transluminal coronary angioplasty. METHODS: We assessed the effect of simvastatin on in vitro VSMC proliferation. To study the effects of simvastatin in vivo, balloon injury and stent deployment were performed in the common carotid artery of rats. Neointimal area was measured two weeks later in the balloon injury model and three weeks after stent deployment. RESULTS: Simvastatin markedly inhibits VSMC proliferation in vitro. In vivo, simvastatin reduced, in a dose-dependent manner, the neointimal area and the neointima-media ratio after balloon injury from 0.266 +/- 0.015 mm2 to 0.080 +/- 0.026 mm2 and from 1.271 +/- 0.074 to 0.436 +/- 0.158 (p < 0.001 vs. control rats) at the highest dose. Simvastatin also significantly reduced the neointimal formation and the neointima-media ratio after stenting from 0.508 +/- 0.035 mm2 to 0.362 +/- 0.047 mm2 (p < 0.05 vs. control rats) and from 2.000 +/- 0.136 to 1.374 +/- 0.180 (p < 0.05 vs. control rats). The vessel thrombosis rate after stent deployment was 30% in the control group and 11.1% in the treated group (p = NS). Moreover, the systemic administration of simvastatin did not affect hepatic and renal functions, blood pressure or heart rate. CONCLUSIONS: Simvastatin potently inhibits VSMC proliferation in vitro and reduces neointimal formation in a rat model of vascular injury.

Activation of cAMP-PKA signaling in vivo inhibits smooth muscle cell proliferation induced by vascular injury.

Injury of the arterial wall induces the formation of the neointima. This structure is generated by the growth of mitogenically activated smooth muscle cells of the arterial wall. The molecular mechanism underlying the formation of the neointima involves deregulated cell growth, primarily triggered by the injury of the arterial wall. The activated gene products transmitting the injury-induced mitogenic stimuli have been identified and inhibited by several means: transdominant negative expression vectors, antisense oligodeoxynucleotides, adenovirus-mediated gene transfer, antibodies and inactivating drugs. Results of our study show that local administration of 3',5'-cyclic AMP and phosphodiesterase-inhibitor drugs (aminophylline and amrinone) to rats markedly inhibits neointima formation after balloon injury in vivo and in smooth muscle cells in vitro. The growth inhibitory effect of aminophylline was completely reversed by the inhibition of cAMP-dependent protein kinase A (PKA). These findings indicate an alternative approach to the treatment of diseases associated with injury-induced cell growth of the arterial wall, as stimulation of cAMP signaling is pharmacologically feasible in the clinical setting.