Body mass index stratification in hospitalized Italian adults with congenital heart disease in relation to complexity, diagnosis, sex and age.

BACKGROUND AND AIMS: Adults with congenital heart disease (ACHD) are at risk of overweight and obesity, two major health problems, though underweight can be a negative prognostic factor too. Awareness of the body mass index (BMI) in ACHD is very limited. The present study describes the use and prevalence of BMI in Italian symptomatic hospitalized ACHD patients in relation to complexity by Bethesda system classification, diagnosis, sex and age. METHODS AND RESULTS: We classified 1388 ACHD patients, aged 18-69 years, on the basis of their BMI, and compared them to the Italian reference population. In our total ACHD population we found a significantly higher prevalence of underweight compared to the Italian reference population (6.34% vs 3.20%). ACHD women were more underweight than men. Underweight decreased with age. Overweight was significantly less frequent in the total ACHD population (26.73% compared to 31.70%) in the Italian reference population. Men were more likely to be overweight than women. In statistical terms obesity was similar in the Italian reference population (10.50%) and our ACHD population (9.58%). Both overweight and obesity increased with age. Results were comparable using a diagnostic anatomical-functional classification and the Bethesda system classification. CONCLUSIONS: In our cohort of ACHD the prevalence of underweight was double that of the Italian reference population. The prevalence of overweight was lower, while obesity was similar. Since BMI does not account for differences in body fat distribution, a future aim will be to quantify the visceral component of the adipose tissue in ACHD patients and examine their body composition in order to reflect their risk of acquired cardiovascular disease better, and either to maintain or achieve an adequate visceral component.

Epicardial adipose tissue volume in patients with coronary artery disease or non-ischaemic dilated cardiomyopathy: evaluation with cardiac magnetic resonance imaging.

AIM: To compare the amount of epicardial adipose tissue (EAT) in patients with coronary artery disease (CAD) or non-ischaemic dilated cardiomyopathy (NIDCM) with that in patients with negative cardiac magnetic resonance imaging (CMR). MATERIALS AND METHODS: One hundred and fifty patients (median age 57 years, interquartile range [IQR] 46-66 years) who underwent CMR were evaluated retrospectively: 50 with CAD, 50 with NIDCM, and 50 with negative CMR. For each patient, the EAT mass index (EATMI) to body surface area, end-diastolic volume index (EDVI), end-systolic volume index (ESVI), stroke volume (SV), ejection fraction (EF) for both ventricles, and left ventricle (LV) mass index were estimated. Intra and inter-reader reproducibility was tested in a random subset of 30 patients, 10 for each group. Mann-Whitney U test, Kruskal-Wallis test, Spearman's correlation, and Bland-Altman statistics were used. RESULTS: The EATMI in CAD patients (median 15.7 g/m2, IQR 8.3-25.7) or in NIDCM patients (15.9 g/m2, 11.5-18.1) was significantly higher than that in negative CMR patients (9.1 g/m2, 6-12; p<0.001 both). No significant difference was found between CAD and NIDCM patients (p=1.000). A correlation between EATMI and LV mass index was found in NIDCM patients (r=0.455, p=0.002). Intra- and inter-reader reproducibility were up to 80% and 72%, respectively. CONCLUSION: Patients with NIDCM or CAD exhibited an increased EATMI in comparison to negative CMR patients. CMR can be used to estimate EAT with good reproducibility.

Epicardial adipose tissue inflammation is related to vitamin D deficiency in patients affected by coronary artery disease.

BACKGROUND AND AIMS: Alterations in epicardial adipose tissue (EAT) biology (i.e. increased fat thickness and inflammation) have been described in coronary artery disease (CAD) patients. In addition to its classic role in the regulation of calcium-phosphate homeostasis, vitamin D may exert immune-regulatory and anti-inflammatory effects. Whether EAT inflammation may be linked to vitamin D deficiency is still unknown. In the present study we evaluated plasma 25-hydroxycholecalciferol (25OHD) level in CAD patients and its relationship with EAT ability to locally metabolize vitamin D, EAT expression of inflammation-related molecules and EAT thickness. METHODS AND RESULTS: Plasma 25OHD level was quantified by an immunoluminometric assay. EAT expression of inflammation-related molecules (MCP-1, PTX3, TNFα, IL-6, adiponectin), vitamin D receptor (VDR), CYP27B1 (25OHD-activating enzyme) and CYP24A1 (1,25-dihydroxycholecalciferol-metabolizing enzyme) was performed by microarray. EAT thickness was quantified by echocardiography. Median plasma 25OHD level was 10.85 ng/mL and 83% of CAD patients displayed 25OHD level below 20 ng/mL. At decreasing plasma 25OHD concentration, we observed a down-regulation in CYP27B1 and CYP24A1 level and an increased expression of VDR and pro-inflammatory cytokines (MCP-1, PTX3, TNFα, IL-6) at EAT level. No correlation was observed between plasma 25OHD level and EAT thickness. CONCLUSION: Our data suggest an increased activation of inflammatory pathways at EAT level possibly related to systemic and local vitamin D deficiency in CAD patients. Whether maintaining an optimal vitamin D status may be helpful to reduce EAT inflammation and to prevent CAD and its progression needs further investigation.

Epicardial fat thickness significantly decreases after short-term growth hormone (GH) replacement therapy in adults with GH deficiency.

BACKGROUND AND AIM: Growth Hormone Deficiency (GHD) is characterized by increased visceral fat accumulation. Echocardiographic epicardial fat thickness is a new marker of visceral adiposity. Aim of the present study was to evaluate whether epicardial fat thickness can significantly change and therefore serve as a marker of visceral fat reduction after short-term rhGH replacement therapy in patients with adult-onset GHD. METHODS AND RESULTS: Echocardiographic epicardial fat thickness was measured in 18 patients (10 M, 8 F, age 48 ± 11.8 yrs, BMI 29 ± 5.9 kg/m(2)) with adult-onset GHD, at baseline and after 6 and 12 months of rhGH therapy and in 18 healthy matched controls, at baseline. Echocardiographic epicardial fat thickness, conventional anthropometric and metabolic parameters, body fat percentage and quality of life were also evaluated. Epicardial fat thickness in adult GHD patients was higher than in controls (9.8 ± 2.8 vs 8 ± 3 mm, p < 0.05). Epicardial fat thickness significantly decreased after 6-months of rhGH replacement therapy (from 9.8 ± 2.8 to 7.0 ± 2.3 mm, P < 0.01, i.e. -29% from baseline). After 12 months of rhGH replacement therapy, epicardial fat thickness showed a further significant decrease (from 7.0 ± 2.3 to 5.9 ± 3.1 mm, P < 0.01, i.e. -40% from baseline). No significant changes in BMI or waist circumference after 6 or 12 months of rhGH therapy were observed. CONCLUSIONS: Echocardiographic epicardial fat thickness may represent a valuable and easy marker of visceral fat and visceral fat changes during rhGH replacement treatment in patients with adult-onset growth hormone deficiency.

IL-18 level in patients undergoing coronary artery bypass grafting surgery or valve replacement: which link with epicardial fat depot?

Interleukin-18 (IL-18) is a member of the interleukin-1 family of cytokines produced constitutively by different cell types and by adipose tissue. Due to the link between obesity, inflammation and cardiovascular diseases, we aimed to measure IL-18 circulating level in patients undergoing open-heart surgery both for elective coronary artery bypass grafting (CABG) or for valve replacement (VR), and we also evaluated whether epicardial adipose tissue (EAT) depot may be a potential source of IL-18. Circulating IL-18 protein was quantified by enzyme-linked immunosorbent assay. IL-18, IL-18 receptor 1 (IL-18 R1) and IL-18 receptor accessory protein (IL-18-RAP) gene expression in EAT depot were evaluated by one colour microarray platform. EAT thickness was measured by echocardiography. In this study we found that all cardiovascular patients (CABG and VR) have increased circulating IL-18 level compared to healthy control subjects (p < 0.0001), but no statistical significant difference was observed between CABG and VR groups (p = 0.35). A great increase in the gene expression of IL-18 (p < 0.05), IL-18 R1 (p < 0.01) and IL-18 RAP (p < 0.001) was observed in EAT samples obtained from CABG vs VR patients. In conclusion, CABG and VR patients had similar increased level of circulating IL-18 protein, but in EAT depots isolated from CABG gene expression of IL-18, IL-18 R1 and IL-18-RAP resulted higher than in VR patients. Future investigation on local IL-18 protein production, its autocrine-paracrine effect and its correlation with plasmatic IL-18 level could give more information on the relationship between IL-18 and coronary artery disease.

Effects of treatment strategy on endothelial function.

A large body of evidence indicates that endothelial dysfunction is a characteristic of patients with arterial hypertension. As functional abnormalities lead to impaired endothelium-dependent vasodilation, this early step of atherogenesis is potentially reversible. In addition to reducing blood pressure, the major families of anti-hypertensive drugs have a number of pleiotropic effects that could improve endothelial function. In particular, the renin-angiotensin system plays an important role in the pathogenesis of both arterial hypertension and endothelial dysfunction, and so drugs capable of limiting the dangerous effects of this hormonal axis, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers and renin inhibitors, could help prevent/delay/reverse the atherosclerotic process. New third-generation ß-blockers and 5-phosphodiesterase inhibitors may affect endothelial function. Furthermore, the HMGCoA-reductase inhibitors currently used to reduce cholesterol levels have major pleiotropic anti-inflammatory and anti-hypertensive effects. The preservation or recovery of endothelial function in hypertensive patients is crucial to inhibit the development of atherosclerosis and the onset of cardiovascular events. This review focuses on the ancillary effects of hypertensive drugs and HMGCoA-reductase inhibitors that go beyond lowering blood pressure and cholesterol levels.

Relationship of thyroid function with body mass index and insulin-resistance in euthyroid obese subjects.

BACKGROUND AND AIMS: It is recognized that overt thyroid dysfunction is associated with weight changes, but the influence of a minor alteration of thyroid function remains unclear. This study aimed to further investigate the relationship between obesity and thyroid function and to examine the possible role of insulin resistance on the hypothalamic-pituitary- thyroid axis. METHODS AND RESULTS: Serum TSH and free T4 (FT4) levels, anthropometric and metabolic parameters were evaluated in 581 obese patients. In all patients TSH values progressively increased according to the severity of obesity and were positively correlated with body mass index (p=0.001, r=0.13) and waist circumference (p=0.02, r=0.11). Patients with insulin resistance showed higher TSH (1.8±1.0 vs 1.6±0.9 µUI/l; p=0.03) and lower FT4 levels (13.8±2.3 vs 15.0±2.2 pmol/l; p<0.001), as compared with patients with normal insulin sensitivity. Moreover, TSH was positively correlated with fasting insulin (p<0.001, r=0.152) and homeostasis model assessment of insulin resistance (HOMA-IR; p<0.001, r=0.148), and negatively correlated with Quantitative Insulin Sensitivity Check Index (QUICKI; p<0.001, r=-0.148); FT4 was negatively associated with fasting insulin (p<0.001, r=-0.287) and HOMA-IR (p<0.001, r=-0.295), and positively associated with QUICKI (p<0.001, r=0.295). CONCLUSIONS: A relationship between thyroid function and overweight/ obesity condition seems to exist, mainly influenced by insulin resistance. Whether variations in TSH and/or thyroid hormones, within a normal range, can influence body weight or whether obesity per se can alter thyroid function cannot be stated so far. Further studies are needed to assess the link between thyroid function and body weight, by considering not only changes in thyroid hormones, but also body fat distribution, obesity duration and low-grade inflammation.

Peripheral insulin-like factor 3 concentrations are reduced in men with type 2 diabetes mellitus: effect of glycemic control and visceral adiposity on Leydig cell function.

BACKGROUND AND AIM: Hypogonadism frequently occurs in men with type 2 diabetes mellitus (T2DM), while the role of glycemic control and visceral obesity is still unclear. This study aimed to assess the Leydig cell function, including the new sensitive marker insulin-like factor 3 (INSL3), in T2DM patients without overt hypogonadism and the influence of either glycemic control or visceral adiposity. SUBJECTS AND METHODS: Thirty T2DM patients (age 57.1+/-6.2 years, body mass index (BMI) 28.0+/-4.3) without overt hypogonadism and 30 age- and BMI-matched controls were studied. Anthropometric, glycometabolic parameters and testosterone, SHBG, LH, INSL3 levels, bioavailable and free testosterone (BT and cFT) were evaluated. The human chorionic gonadotrophin (hCG) test was also performed. RESULTS: Patients had lower total testosterone (452.6+/-130.0 vs 512.6+/-117.3 ng/dl, P=0.06), BT (189.7+/-36.4 vs 237.1+/-94.1 ng/dl, P=0.002), cFT (8.1+/-1.6 vs 10.1+/-4.0 ng/dl, P=0.002), and higher LH levels (3.5+/-1.6 vs 2.6+/-1.2 mU/ml, P=0.01) versus controls. Serum INSL3 concentrations were also lower in patients (1.1+/-0.3 vs 1.5+/-0.7 ng/ml, P=0.01). These hormonal parameters, including INSL3, did not differ between T2DM patients with poor or good glycemic control (HbA1c>9 or <7% respectively). In patients, waist circumferences (97.9+/-12.4 cm) negatively correlated with INSL3 (P=0.03) and basal, as well as hCG-stimulated testosterone levels (P=0.04 and 0.004 respectively). Basal or stimulated hormonal levels and INSL3 concentrations were not different between patients with (40%) or without erectile dysfunction. CONCLUSIONS: An early impairment of the overall Leydig cell function is present in men with T2DM, mainly related to visceral adiposity rather than to glycemic control.

Echocardiographic alterations in patients with non-functioning adrenal incidentaloma.

OBJECTIVE: While left ventricular (LV) dysfunction has been described in patients with Cushing's syndrome (CS), data concerning morphologic and functional cardiac alterations in patients with incidentally discovered adrenal masses [adrenal "incidentaloma" (AI)], without overt hypercortisolism, are lacking. In this study the echocardiographic characteristics of patients with AI were evaluated and then compared with those of lean and obese normotensive subjects. SUBJECTS AND METHODS: Twenty-one patients with AI, without clinical or subclinical hypercortisolism, 18 normotensive obese subjects matched for gender and body mass index (BMI) and 20 normotensive lean subjects were studied. Echocardiography was performed in all subjects. In all patients plasma ACTH, serum cortisol, and DHEA-S levels were measured. RESULTS: Patients with AI showed greater impairment of several echocardiographic indices of LV hypertrophy and diastolic dysfunction compared to normotensive lean subjects (p<0.05), but did not differ from those in obese subjects. Hypertensive AI patients showed a greater alteration of echocardiographic parameters (p<0.05) and higher BMI (p<0.01) and cortisol values (p<0.05) than normotensive ones. Plasma ACTH and serum cortisol were similar in AI patients and in obese controls, while DHEA-S levels were lower in AI (p<0.05). No correlations between cortisol secretion and echocardiographic parameters were found. CONCLUSION: In patients with non-functioning AI there is an impairment of cardiac morphology and function. These data suggest that patients with AI should be carefully screened also by means of echocardiographic studies.

Soluble adhesion molecules levels in patients with Cushing's syndrome before and after cure.

OBJECTIVE: Patients with Cushing's syndrome (CS) show a high prevalence of cardiovascular risk factors and atherosclerosis, persisting even after cure. Soluble intercellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1) are surrogate markers of endothelial function involved in the initiation of atherosclerosis. This study aimed to evaluate sICAM-1 and sVCAM-1 levels in patients with CS before and after successful cure. SUBJECTS AND METHODS: sICAM-1 and sVCAM-1 levels were evaluated in 28 patients with active CS and in 12 patients with Cushing's disease (CD), 6-12 months after disease remission. Body mass index (BMI), blood pressure, glucose, serum lipids, ACTH, cortisol and urinary free cortisol (UFC) were measured in basal conditions in all patients. RESULTS: At baseline, sICAM-1 levels positively correlated with BMI (r=0.443, p<0.01), while no correlations between sICAM/sVCAM levels and ACTH, cortisol or UFC were found. Plasma ACTH, serum cortisol, and UFC levels significantly decreased in 12 cured patients, but ICAM-1 and VCAM-1 levels were unchanged (12.7+/-1.8 vs 10.1+/-0.9 ng/ml and 33.5+/-4.4 vs 35.8+/-4.0 ng/ml, respectively). Obesity, hypertension, and impaired glucose metabolism persisted 1 yr after the biochemical cure of hypercortisolism. A significant reduction in ICAM-1 levels was observed in 4 out of 12 cured patients as well as a remission from diabetes, hypertension or obesity. CONCLUSIONS: ICAM/VCAM-1 levels show a great variability in patients with active CS, not correlated with cortisol levels, and are slightly modified in some cured patients with CD. The persistence of obesity, hypertension, and impaired glucose metabolism may be responsible for the maintenance of a subclinical endothelial dysfunction, making these subjects still at high cardiovascular risk and needing a long-term follow-up.

Oxidated low-density lipoproteins (oxLDL) and peroxides in plasma of Down syndrome patients.

A low prevalence of coronary artery disease is usually observed in adult Down syndrome (DS) subjects, and these patients rarely die because of atherosclerotic complications. High levels of oxLDL were found in plasma from children and adults with DS. Plasma oxLDL were still increased in elderly with DS, however, difference with controls was not statistically significant. Concentrations of plasma peroxides were significantly higher in children and adults with DS than controls. No differences between elderly DS subjects and controls were present. We speculated that increased levels of protective antiathero-sclerosis factors might be produced in young and adult DS subjects and these may explain low incidence of cardiovascular diseases in the syndrome. Up-regulation of vascular andothelial growth factor (VEGF)-mediated signals and increased nerve growth factor (NGF) expression might be two of these important protective factors.