The effects of hypothyroidism on the mechanical properties and histomorphological structure of the thoracic aorta.

This experimental study investigates the effects of hypothyroidism on the descending thoracic aorta. Hypothyroidism was induced in 20 male Wistar rats by administering 0.05% of 6-n propyl 2-thiouracil (PTU) in their drinking water for 8 weeks. Euthyroid rats were used as controls. Animals were sacrificed and longitudinal strips of the descending aorta were subjected to various preselected levels of stress in a uniaxial tensile-testing device. Analysis of stress-strain, elastic modulus-strain curves disclosed significant differences between groups, indicative of stiffer aortas in hypothyroid animals at the upper physiologic and higher levels of pressure. Remodeling of the aortic wall of hypothyroid animals revealed significant histological changes. The thoracic aorta of hypothyroid rats compared with that of euthyroid ones became stiffer at high strains, including the upper physiologic range, loosing part of its distensibility. Hypothyroidism was also associated with diameter enlargement and substantial lengthening of the aorta.

Hypothyroidism and the aorta. evidence of increased oxidative DNA damage to the aorta of hypothyroid rats.

BACKGROUND: Although it has been suggested that the hypometabolic state is associated with a decrease in oxidative stress, literature data are controversial, revealing an individuality of oxidant status in relation to tissue properties and responsiveness. Hypothyroidism has profound direct and indirect actions on the vascular system, inducing characteristic hemodynamic changes while the aorta represents an important determinant of vascular performance. This study aims to examine the oxidant status on the aorta in chronic experimental hypothyroidism. MATERIALS AND METHODS: Chronic hypothyroidism was successfully induced in 20 male Wistar rats by administration of 0.05% 6-n-propyl 2-thiouracil in their drinking water for 8 weeks. Age-matched euthyroid rats were used as controls. Lipid peroxidation in the serum was determined by the end-product malondialdehyde (MDA). Oxidative damage to genomic DNA of aortic tissue and serum was investigated by measuring 8-oxo-dG, one of the base modifications produced in DNA by the reaction of reactive oxygen species. Serum lipids measurement was performed. RESULTS: A hypothyroid state was confirmed by levels of serum thyroid hormones, lipidemic profile, clinical examination, pathological findings and cardiovascular hemodynamics parameters. Hypothyroidism was associated with a significant increase in lipid peroxidation. (MDA 1.44 +/-0.93 vs 0.64 +/- 0.53 nmol/l, p < 0 .01). Levels of 8-oxo-dG on the aortic ring, expressing the oxidant damage on genomic DNA and in the serum, were observed to be significantly raised in the hypothyroid group compared to controls (8-oxodG(serum) 29.22 +/- 17.78 vs. 17.56 +/- 4.44 ng/ml, p < 0.01; 8-oxo-dG(aorta)11.58 +/- 2.70 vs. 4.09 +/- 1.27 ng/ml, p < 0. 001). A statistical correlation between measurements of 8-oxo-dG in the aorta and serum was found (correlation coefficient = 0.36, p < 0.05). A hyperlipidemic profile in hypothyroid animals was revealed. CONCLUSION: Vascular oxidative stress seems to play a pivotal role in the evolution of vascular pathology. Hypothyroidism was associated with increased DNA oxidative damage to the aorta. Hypercholesterolemia and an increase in mean arterial pressure associated with hypothyroidism may have a contributive role in the accumulation of damage in nuclear DNA of the vascular wall. 8-Oxo-dG is one of the mutagenic base modifications produced in DNA. Although clinical studies in other tissues have indicated a direct correlation between in vivo 8-oxo-dG formation and pathological processes, its role on the vascular wall needs further investigation.

Association between plasma levels and immunolocalization of cytokines in heart valve lesions: a possible target for treatment?

OBJECTIVE: To compare the distribution of pro-inflammatory cytokines in heart valve lesions with their plasma levels. METHODS: Plasma levels of TNF-alpha and IL-10 were determined in 70 patients with heart valve lesions. TNF-alpha and IL-6 levels were also quantified in tissue specimens obtained from these patients after valve replacement. RESULTS: Plasma concentrations of TNF-alpha and the extent of calcium deposits were significantly higher in patients with aortic valve stenosis compared with individuals with mitral valve stenosis. A direct relationship was demonstrated between TNF-alpha blood and tissue levels. There was an increase in TNF-alpha and IL-6 tissue immunoreactivity with the progression of heart valve disease from mild to advanced inflammation. The increased accumulation of calcium deposits in damaged heart valves correlated with plasma TNF-alpha and IL-10 levels. CONCLUSIONS: The association between plasma and tissue sample cytokine concentrations suggests that plasma cytokine levels reflect the extent and severity of valvular lesions. Statins may attenuate progressive calcific valve stenosis. Statins also affect TNF-alpha and IL-10 plasma levels. These associations may help not only predict the progression but also attenuate the deterioration of valvular lesions. Verification of these results in larger scale studies is required before definite conclusions can be drawn.

Apolipoprotein J and leptin levels in patients with coronary heart disease.

BACKGROUND: Preliminary data suggest that apolipoprotein J (ApoJ) may play a role in the development and progression of atherosclerosis. Leptin, an adipose tissue hormone, exerts important cardiovascular effects. The association between serum ApoJ and leptin concentrations was assessed in patients with established or suspected coronary heart disease (CHD). PATIENTS AND METHODS: Serum ApoJ and leptin concentrations were evaluated in 67 CHD patients undergoing coronary angiography [54 individuals with significant (> or =50%) coronary artery stenosis and 13 patients without significant coronary artery stenosis on angiography]. RESULTS: Serum ApoJ concentrations in patients with significant coronary artery stenosis were significantly higher than in those without (303.9+/-118.6 vs. 121.2+/-37.5 microg/mL, respectively; p<0.001). The reverse pattern was observed for serum leptin levels (8.6+/-5.5 vs. 20.6+/-17.1 ng/ml, respectively; p=0.016). There was a significant negative correlation between ApoJ and leptin levels (r=-0.353; p=0.003). CONCLUSION: ApoJ and leptin may be markers for CHD.

Effect of statins on serum apolipoprotein j and paraoxonase-1 levels in patients with ischemic heart disease undergoing coronary angiography.

It has been proposed that apolipoprotein J (apo J) and paraoxonase-1 (PON1) correlate with the extent and severity of ischemic heart disease (IHD). This article compares apo J and PON1 serum concentrations, PON1 activity, and the apo J/PON1 ratio in 138 IHD patients (64 statins users and 74 statin nonusers) referred for angiography and possible percutaneous coronary intervention. The effect of statin treatment on apo J and PON1 concentrations, PON1 activity, and the degree of coronary artery stenosis were evaluated. In both groups, apo J levels were increased, whereas PON1 concentration and activity decreased. IHD patients on statins had significantly lower apo J concentration and higher PON1 concentration and activity. Patients on statins had less coronary artery stenosis. High apo J levels, low PON1 levels, low PON1 activity, and a high apo J/PON1 ratio were associated with IHD. Statin treatment reverses these changes, probably by multiple beneficial actions.

The effect of sexual hormone abnormalities on proximal femur bone mineral density in hemodialysis patients and the possible role of RANKL.

Sexual hormone concentrations are commonly affected in chronic renal failure. The contribution of sex steroids to bone turnover regulation implies that sex steroid's dysfunction may be implicated in the emergence of renal osteodystrophy. This study was conducted to evaluate sex steroids and gonadotrophins in hemodialysis (HD) patients and to investigate their role in bone homeostasis in concert with other hormones and cytokines. Bone mineral density (BMD) at the proximal femur and intact parathyroid hormone (iPTH), osteoprotegerin, soluble receptor activator of NF-kappaB ligand (sRANKL), prolactin, total testosterone, estradiol, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were measured in serum samples in 42 patients, 21 men and 21 women, on maintenance HD therapy. Possible associations between clinical characteristics, biochemical parameters, and BMD values were investigated. In male HD patients, the testosterone concentration declined significantly with aging, whereas the estradiol level increased with longer duration of HD. Concurrently, testosterone correlated negatively with sRANKL concentrations (r=-0.520, p=0.016). Luteinizing hormone levels in male patients demonstrated statistically significant negative correlations with BMD values of the proximal femur. In the entire cohort of patients, FSH and LH were negatively associated with absolute values of proximal femur BMD. Gonadotrophin and sexual hormone concentrations in HD patients are associated with bone mineral status and consequently their derangements appear to contribute to the development of bone composition abnormalities in different types of renal osteodystrophy. Furthermore, testosterone's association with sRANKL levels in male HD patients suggests that RANKL may mediate the effect of testosterone on bone metabolism in these patients.

Correlation between lipid abnormalities and immunosuppressive therapy in renal transplant recipients with stable renal function.

BACKGROUND: Hyperlipidemia following successful renal transplantation is a frequent and persistent complication. Several immunosuppressive agents including cyclosporine A (CyA), corticosteroids, and tacrolimus appear to have a significant pathogenetic role. The aim of this study is to investigate the differential effects of different immunosuppressive agents on lipids in renal transplant patients. METHODS: Two groups of renal transplant recipients, each treated with a different combination of immunosuppressive agents, were studied: Group A (n = 13), cyclosporine A, mycophenolate mofetil (MMF), steroids, and basiliximab; Group B (n = 13), tacrolimus, MMF, steroids, and daclizumab). Plasma lipids [cholesterol (CHOL), low-density lipoprotein (LDL)-CHOL, high-density lipoprotein (HDL)-CHOL, and triglycerides (TG)] were examined before transplantation and 1 and 6 months posttransplantation. RESULTS: The patients treated with cyclosporine A-MMF showed a significant increase in mean cholesterol and mean LDL-cholesterol values at the 1-month posttransplantation follow-up compared with pretransplant levels (CHOL: 208.9 +/- 47.4 vs. 268.7 +/- 42.2 mg/dl, P = 0.004; LDL: 118.4 +/- 49.9 vs. 198.7 +/- 40.7 mg/dl, P = 0.002; pretransplant vs. 1 month, respectively). At 6 months, LDL-cholesterol levels were significantly elevated compared with pretransplant levels (LDL: 118.4 +/- 49.9 vs. 148.3 +/- 48.5 mg/dl, P = 0.034), whereas there was no significant change in the cholesterol level during the same period. In cyclosporine A-MMF-treated patients, plasma triglyceride levels were reduced at the 1- and 6-month follow-up (TG: 293.9 +/- 59.2 vs. 182.9 +/- 48.7 mg/dl, P = 0.03; 293.9 +/- 59.2 vs. 178.6 +/- 74.2 mg/dl, +/- = 0.023; pretransplant vs. 1 and 6 months, respectively). Patients receiving combined therapy with tacrolimus-MMF showed no significant changes in LDL-CHOL levels during the trial. Cholesterol levels at 6 months posttransplantation were significantly lower than the pretransplant measurements (CHOL: 182.9 +/- 44.4 vs. 162.3 +/- 37.2 mg/dl, P = 0.024; pretransplant vs. 6 months). A significant reduction in triglyceride level was documented at the 1-month follow-up followed by a subsequent decrease within 6 months (TG: 228.5 +/- 61.6 vs. 147.6 +/- 51.5 mg/dl, P = 0.005; TG: 228.5 +/- 61.6 vs. 130.4 +/- 54.7 mg/dl, P = 0.011; pretransplant vs. 1 and 6 months, respectively). CONCLUSIONS: In posttransplant patients with stable renal function cyclosporine therapy is associated with increased cholesterol and LDL-cholesterol levels. Hyperlipidemia is less pronounced in patients given tacrolimus. Tacrolimus appears to an immunosuppressant agent with fewer and less severe adverse effects on lipid metabolism.

The mechanical performance and histomorphological structure of the descending aorta in hyperthyroidism.

Thyroid hormones decrease systemic vascular resistance by directly affecting vascular smooth muscle relaxation. There is limited literature about their effect on the mechanical performance of the aortic wall. Therefore, the authors determined the influence of hyperthyroidism on the mechanical properties and histomorphological structure of the descending thoracic aorta in rats. Severe hyperthyroidism was induced in 20 male Wistar rats by administering L-thyroxine (T(4)) in their drinking water for 8 weeks; age-matched normal euthyroid rats acted as controls. Animals were sacrificed, and the mechanical and histomorphometrical characteristics of the descending thoracic aorta were studied. The aortic wall of hyperthyroid rats was stiffer than that of euthyroid animals at the upper physiologic levels of stress or strain (p < 0.05) but less stiff at the lower physiologic and lower levels (p < 0.05). The aorta of hyperthyroid animals compared with that of euthyroid ones showed an increase of the internal and external diameters (p < 0.05), the media area (p < 0.05), the number of smooth muscle cell nuclei (p < 0.05), and the collagen density (p < 0.05) and a decrease in the elastin laminae thickness (p < 0.001) and elastin density (p < 0.001). In hyperthyroid rats, the aortic wall was stiffer at the upper physiologic and higher levels of stress and strain. These changes correlated with microstructural changes of the aortic wall. The coexistence of hyperthyroidism with disease states or clinical conditions that predispose to increased arterial pressure may be associated with increased arterial stiffness and have undesirable consequences on the mechanical performance of the thoracic aorta and hemodynamic homeostasis. These changes could lead to an increased risk for developing vascular complications.

Hyperthyroidism is associated with increased aortic oxidative DNA damage in a rat model.

BACKGROUND: Hyperthyroidism is associated with increased oxidative stress and oxygen free radical production. Oxygen free radicals are implicated in several signalling pathways leading to vascular pathology. The present study evaluates the extent of aortic oxidative stress in experimental hyperthyroidism. MATERIALS AND METHODS: Chronic hyperthyroidism was induced in 20 male Wistar rats; another 20 animals served as controls. Oxidative damage to lipids and genomic DNA was assessed by measuring serum and aortic wall 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) levels (a mutagenic marker of oxidative DNA damage), as well as serum ceruloplasmin, malondialdehyde (MDA) and lipids. RESULTS: Hyperthyroid animals had significantly higher values of serum ceruloplasmin (11.27+/-1.16 vs. 9.58+/-1.17 mg/dl), MDA (5.34+/-1.32 vs. 0.64+/-0.53 nmol/ml) and 8-oxo-dG (33.91+/-9.63 vs. 17.56+/-4.44 ng/ml) compared with controls (p<0.001 for all associations). Aortic 8-oxo-dG levels were elevated in the thyrotoxic compared with the control group (13.01+/-2.38 vs. 4.09+/-1.27 ng/ml, respectively; p<0.001). 8-Oxo-dG measurements in aortic rings and in serum were positively correlated in the hyperthyroid rats (Pearson's correlation coefficient =0.66; p=0.007). CONCLUSION: Hyperthyroidism is associated with increased oxidative stress in the aortic wall. The animal model we describe has provided some preliminary data regarding the effect of hyperthyroidism on the vascular system. Verification of our results and further exploration of our animal model may help determine the association between oxidative DNA damage with functional changes of the vascular wall, such as endothelial function and vascular nitric oxide signalling.

Mechanical behavior of colonic anastomosis in experimental settings as a measure of wound repair and tissue integrity.

AIM: To determine the mechanical properties of anastomotic colonic tissue in experimental settings and therefore give a measure of wound healing. METHODS: Thirty-six male Wistar rats were used as experimental models of anastomotic tissue integrity. On the 5th post-operative day, the tensile strength was measured by application of an axial force, providing a quantitative measure of anastomotic dehiscence and leakage. RESULTS: Diagrams of the load as a function of the time [P = P (t)] and of the displacement also as a function of time [Delta s = Delta s (t)] were recorded for each test, permitting the design of the load versus the displacement diagram and thus providing significant data about the critical values of anastomotic failure. Quantitative data were obtained concerning the anastomotic strength of both control specimens (healthy rats), as well as specimens from non-healthy rats for comparison. CONCLUSION: This experimental model provides an excellent method of measuring anastomotic strength. Despite the relative small number of specimens used, this method provides an accurate way of measuring wound repair. More experimental measurements need to be performed to correlate emerging tensile strength values to anastomotic failure.

Correlation between oxidative stress and immunosuppressive therapy in renal transplant recipients with an uneventful postoperative course and stable renal function.

BACKGROUND: Reactive oxygen species (ROS) are important mediators of cellular damage and lipid peroxidation is the most important expression of ROS-induced oxidative stress. Recent studies have suggested that increased plasma malondialdehyde (MDA) levels are a consequence of specific immunosuppressive therapies. This study aims at investigating the relation between oxidative stress and immunosuppressive therapies in renal transplant patients with stable renal function and uneventful postoperative course. METHODS: The study group included 26 renal patients. Two groups of renal transplant recipients, treated with a different combination of immunosuppressive agents were studied (Group A: CyA, MMF, Steroids and Basiliximab, Group B: Tacrolimus, MMF, Steroids and Daclizumab). All patients had an uneventful postoperative course. Plasma MDA levels were measured before transplantation, 1 and 6 months after. Plasma concentration of endogenous creatinine (Cr) was used as a measure of stable renal function. RESULTS: Levels of MDA were increased before the transplantation in all renal patients (MDA: 7.81 +/- 4.81, normal levels: 2.23-4.08 nmol/ml, P < 0.05). Combined therapy with CyA was associated with high values of MDA at 6 months measurement after transplantation. However this tendency of increased MDA levels did not achieve a statistical significance (Group A: 6.97 vs. 9.06 nmol/ml, P>0.05). On the contrary, statistically significant diminution of MDA levels was observed in Group B patients (Tacrolimus-MMF-steroids) at 6 months measurement after transplantation. (Group B: 8.61 vs. 4.11 nmol/ml, P<0.02<0.05). CONCLUSIONS: Immunosuppressive combined therapy with CyA was associated with the high values of MDA that were measured posttransplantly. Our study provides strong evidence that Tacrolimus is significantly associated with improved free radical metabolism.