Serum Irisin May Predict Cardiovascular Events in Elderly Patients With Chronic Kidney Disease Stage 3-5.

OBJECTIVE: Irisin is a circulating myokine released from skeletal muscles after physical exercise. Irisin production decreases during the course of chronic kidney disease (CKD) as a potential consequence of sarcopenia and physical inactivity. METHODS: This observational study explored the relationship of serum irisin with cardiovascular outcome in 79 patients with stage 3-5 CKD. RESULTS: Serum irisin was significantly higher in healthy subjects (n = 20) than that in CKD patients (7 ± 2 vs. 3.1 ± 0.9 µg/mL; P = .0001) and was higher in patients with CKD stage 3 (3.2 ± 1 µg/mL) than in patients at stage 4 and 5 taken together (n = 36, 2.8 ± 0.7 µg/mL, P = .05). Patients in the lowest serum irisin tertile had lower serum 1,25(OH)2D levels (21 ± 11 pg/mL) than patients in the middle (30 ± 13 pg/mL; P = .005) and the highest tertile (27 ± 14 pg/mL; P = .047). Patients in the highest tertile had lower Kauppila score (10.6 ± 6.9) than patients in the middle (11.8 ± 5.5; P = .007) and the lowest tertile (6.9 ± 6.8; P = .043). Twenty patients suffered from cardiovascular events during a 3-year follow-up. A Cox regression model using age, body weight, presence of diabetes mellitus, gender, Kauppila calcification score, serum values of FGF23 (as logarithm), phosphate, sclerostin, albumin and cholesterol, estimated glomerular filtration rate, and serum irisin tertiles as covariates showed that patients in the highest tertile of serum irisin had a lower cardiovascular risk than patients in the middle tertile (B, 2.38; odds ratio, 10.8; 95% confidence interval, 1.65-58.13; P = .013) or in the lowest tertile (B, 1.61; odds ratio, 5; 95% confidence interval, 1.09-22.83; P = .038). CONCLUSIONS: These findings suggest that serum irisin may be a marker of cardiovascular outcome in patients with CKD.

Transcutaneous electrical stimulation therapy and genetic analysis in Dercum's disease: A pilot study.

ABSTRACT: Dercum's disease (DD), or adiposis dolorosa, is a rare condition of unknown etiology characterized by growth of painful subcutaneous adipose tissue. No specific treatment exists. Pain is often invalidating and resistant to analgesic drugs. We tested the efficacy of Frequency Rhythmic Electrical Modulation System (FREMS) therapy on pain relief. Subcutaneous biopsies were performed for genetic analysis.Nine DD patients were enrolled. Five cycles of FREMS at 3-month intervals during 1 year were administered. Visual analogue scale (VAS), Bartel Index Questionnaire and Short Form 36 questionnaire were used to measure pain and general health status at baseline, 6 and 12 months. Dual-energy X-ray absorptiometry (DEXA) quantified fat mass. Next-Generation Sequencing (NGS) was performed on adipose tissue biopsies and peripheral blood sample to search for somatic variants and specific protein pathway mutation.Seven patients were included in the final analysis. FREMS induced a reduction in VAS score (from 92 to 52.5, P = .0597) and a significant improvement in SF-36 domains (Physical functioning, Role limitation due to physical health, Body pain, Vitality, Social functioning, P < .05). No modification in anthropometrics and DEXA values was observed. The analysis of the mitochondrial Displacement loop (D-loop) region confirmed the clonality of all lipomatous lesions. The presence of the mitochondrially encoded tRNA-Lysine (MT-TK) m.8344A>G variant, occasionally identified in patients with multiple symmetric lipomatosis, was excluded in all subjects. On the other hand, we observed variants in genes belonging to signaling pathways involved in cell cycle and proliferation (Phosphoinositide 3-kinase/AKT/mTOR, MAPK/ERK, and Hippo).FREMS can be a useful tool to alleviate pain and improve overall quality of life in patients with DD. Genetic analysis highlighted the molecular heterogeneity of lipomas.

Bone and body composition analyses by DXA in adults with GH deficiency: effects of long-term replacement therapy.

PURPOSE: The effects of growth hormone (GH) replacement on bone mass and body composition in adult with GH deficiency (AGHD) are still debated with regard to their persistence in the long term. Moreover, the impact of the gender on the response to GH is controversial. Aim of this study was to evaluate the long-term effects of rhGH replacement on bone mass and body composition in a monocentric cohort of patients with AGHD. METHODS: Data from 118 patients with AGHD (34.8 ± 14.4 years, 43 women and 75 men) treated with rhGH for a period of at least 3 years up to a maximum of 10 were retrospectively collected. Bone mineral density (BMD) at the lumbar spine, femur, and 1/3 radius, and total and truncular body composition were evaluated by dual-energy X-ray absorption (DXA) before and during treatment. Clinical and laboratory evaluations were performed before and during the treatment period on an annual basis. RESULTS: Lumbar spine BMD consistently increased in males, while it decreased in females after a transient improvement observed during the first 4 years of therapy. There were no significant changes in femoral and 1/3 radial BMD in either sexes. Lean mass significantly increased in both sexes, while fat mass only decreased in males. CONCLUSIONS: In AGHD patients long-term rhGH replacement therapy induces a positive effect with regard to bone mass and body composition. A sexual dimorphism in the response to treatment is evident, with males displaying a more favorable outcome.

Glucagon-like peptide-1 receptor and sarcoglycan delta genetic variants can affect cardiovascular risk in chronic kidney disease patients under hemodialysis.

BACKGROUND: Chronic kidney disease (CKD) patients under hemodialysis show a higher risk of cardiovascular (CV) mortality and morbidity than the general population. This study aims to identify genetic markers that could explain the increased CV risk in hemodialysis. METHODS: A total of 245 CKD patients under hemodialysis were recruited and followed up for 5 years to record CV events. Genetic analysis was performed using single-nucleotide polymorphisms (SNPs) genotyping by Infinium Expanded Multi-Ethnic Genotyping Array (Illumina, San Diego, CA, USA) comparing patients with and without a history of CV events [161 cardiovascular diseases (CVDs) and 84 no CVDs]. The fixation index (Fst) measure was used to identify the most differentiated SNPs, and gene ontology analysis [Protein Analysis THrough Evolutionary Relationships (PANTHER) and Ingenuity Pathway Analysis (IPA)] was applied to define the biological/pathological roles of the associated SNPs. Partitioning tree analysis interrogated the genotype-phenotype relationship between discovered genetic variants and CV phenotypes. Cox regression analysis measured the effect of these SNPs on new CV events during the follow-up (FU). RESULTS: Fst analysis identified 3218 SNPs that were significantly different between CVD and no CVD. Gene ontology analysis identified two of these SNPs as involved in cardiovascular disease pathways (Ingenuity Pathway) and heart development (Panther) and belonging to 2 different genes: Glucagon-like peptide-1 receptor (GLP1R) and Sarcoglycan delta (SGCD). The phenotype-genotype analysis found a higher percentage of CVD patients carrying the GLP1R rs10305445 allele A (P = 0.03) and lower percentages of CVD patients carrying the SGCD rs145292439 allele A (P = 0.038). Moreover, SGCD rs145292439 was associated with higher levels of high-density lipoprotein (P = 0.015). Cox analysis confirmed the increased frequency of CV events during the 5-year FU in patients carrying GLP1R rs1035445 allele A but it did not show any significant association with SGCD rs145292439. CONCLUSIONS: This study identified GLP1R rs10305445 and SCGD rs145292439 as potential genetic markers that may explain the higher risk of CVD in hemodialysis patients.

Short-term evaluation of cardiac morphology, function, metabolism and structure following diagnosis of adult-onset growth hormone deficiency.

OBJECTIVE: The impact of growth hormone (GH) deficiency of the adult on cardiovascular function remains only partially elucidated. Purpose of this study was to test cardiac function in adult GH deficient patients using cardiac magnetic resonance (CMR). DESIGN: Cardiac magnetic resonance (CMR) techniques, including cardiac 31P MR spectroscopy and evaluation of gadolinium late-enhancement, were applied to assess simultaneously, in a cross-sectional fashion, morphological, functional, metabolic, and structural parameters of the left (LV) and right ventricle (RV) in 15 patients with adult onset GH deficiency. Fifteen healthy individuals served as controls. RESULTS: In GH deficient patients LV systolic function (EF%: 61 ±â€¯1.7 vs 62.1 ±â€¯0.8; p = .44) was not different in spite of a lower LV mass (83.2 ±â€¯5.3 vs 145.3 ±â€¯11.9 g; p = .001), a subclinical impairment of diastolic function (E/A peak ratio: 1.6 ±â€¯0.2 vs 2.1 ±â€¯0.2 p = .05), and a trend for lower PCr/ATP ratio (2.1 ±â€¯0.8 vs 2.3 ±â€¯0.1 p = .07). The RV showed reduced chamber size (end diastolic volume 123.8 ±â€¯9 vs 147.9 ±â€¯7.6 mL; p = .021) with preserved mass. No structural alterations of the LV and RV at late-enhancement were detected in these patients. CONCLUSIONS: GH deficient patients represent a unique model of reduced LV myocardial mass in which major structural and metabolic alterations are lacking. Mal-adaptive mechanisms developing in the long term in response to GH deficiency and more severely affecting the LV remain to be elucidated.

Role of plaque calcification regulators osteoprotegerin and matrix Gla-proteins in stable angina and acute myocardial infarction.

AIM: To assess serum levels of the plaque calcification regulators osteoprotegerin (OPG) and Matrix Gla-proteins (MGP) in individuals with stable angina and acute myocardial infarction submitted to coronary angiography and their relation to coronary artery disease burden. METHODS: The study included 40 individuals affected by ST-elevation myocardial infarction (STEMI) and 40 individuals with stable angina who all underwent coronary angiography, with evaluation of the extent of coronary artery disease by Syntax Score calculation and measurement of serum OPG and MGP levels. Osteoporosis was excluded by femoral and vertebral computerized bone mineralometry. RESULTS: Serum OPG and MGP levels were respectively 3.87 ±â€Š1.07 pmol/l and 6.80 ±â€Š2.43 nmol/l in the stable angina group, 7.57 ±â€Š1.5 pmol/l and 7.18 ±â€Š1.93 nmol/l in the STEMI group (P < 0.01 and P = 0.33, respectively). Pearson correlation coefficient for OPG and Syntax Score, MGP and Syntax score was respectively 0.79 (P < 0.01) and 0.18 (P = 0.22) in the stable angina group, -0.03 (P = 0.43) and 0.10 (P = 0.5) in the STEMI group.Serum OPG and MGP levels were respectively 5.52 ±â€Š1.02 pmol/l and 7.56 ±â€Š1.42 nmol/l in diabetics, 4.3 ±â€Š0.8 pmol/l and 6.52 ±â€Š1.14 nmol/l in nondiabetics (P < 0.05; P < 0.05). CONCLUSION: OPG, in a relatively small group of patients with stable angina, correlates proportionally with the extent of coronary artery disease (CAD), as evaluated by the Syntax Score. Higher serum OPG levels can be observed in individuals with STEMI regardless of CAD burden. As for MGP, a potential role as marker of plaque calcification remains unproven.

Serum dioxin concentrations and bone density and structure in the Seveso Women's Health Study.

BACKGROUND: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a widespread environmental contaminant, is a known endocrine disruptor. In animal studies, TCDD exposure impairs bone metabolism and increases fragility. To our knowledge, no epidemiologic studies have examined this association. OBJECTIVES: On 10 July 1976, a chemical explosion in Seveso, Italy, resulted in the highest known residential exposure to TCDD. In 1996, we initiated the Seveso Women's Health Study, a retrospective cohort study of the health of the women. In 2008, we followed up the cohort. Here, we evaluated the association between TCDD exposure and bone structure and geometry in adulthood, and considered whether timing of TCDD exposure before achievement of peak bone mass (assumed to occur 2 years after onset of menarche) modified the association. METHODS: Individual TCDD concentration was measured in archived serum collected soon after the explosion. In 2008, 350 women who were <20 years old in 1976 underwent a dual-energy X-ray absorptiometry (DXA) bone scan. Bone mineral density was measured at the lumbar spine and hip, and hip geometry was extracted from hip DXA scans using the hip structural analysis method. RESULTS: Among premenopausal women, TCDD serum levels were associated with some indexes indicating better bone structure in women exposed before peak bone mass (n=219), with stronger associations in those exposed before 5 years of age (n=46). In contrast, among postmenopausal women, TCDD levels were associated with evidence of better bone structure in women exposed after peak bone mass (n=48) than in other women (n=18). CONCLUSIONS: Our current results do not support the hypothesis that postnatal TCDD exposure adversely affects adult bone health. Continued follow-up of women who were youngest at exposure is warranted. Future studies should also focus on those exposed in utero.

Optimal dietary calcium intake in HIV treated patients: no femoral osteoporosis but higher cardiovascular risk.

BACKGROUND & AIMS: We performed a cross-sectional study on adult HIV-infected patients, on HAART, without calcium or vitamin D supplementation to evaluate if the cardiovascular risk or the presence of osteoporosis may be predictive factors of an optimal daily calcium intake (DCI>1000 mg/day). METHODS: Patients underwent a dual-energy X-ray absorptiometry, measured biochemical parameters and compiled a validated questionnaire for the assessment of DCI. Osteoporosis (OP) was defined according to the WHO classification at either the vertebral spine or femoral neck. Cardiovascular risk was assessed by the 10-year Framingham cardiovascular risk score. RESULTS: 200 HIV-infected patients evaluated: 171 (86%) males with a median age of 48.1 (42.3-53.8) years and 10.6 (4.3-13.6) years of HAART exposure. DCI was 889 (589-1308) mg/day and 79 (40%) patients had an optimal DCI. Framingham risk>20% was found in 13 (6.7%) patients and femoral OP was diagnosed in 12 (6%) pts. By multivariate analysis, optimal DCI was more likely in patients with a Framingham risk>20% [OR = 5.547, 95% CI:1.337, p = 0.025] and less likely in patients with femoral osteoporosis [OR = 0.159, 95% CI: 0.018-0.790, p = 0.047]. CONCLUSIONS: We found that an optimal dietary calcium intake was more likely in patients with high cardiovascular risk and no femoral osteoporosis.

Predictors of bone responsiveness to growth hormone (GH) replacement in adult GH-deficient patients.

Growth hormone (GH) replacement in adulthood results in variable bone responses as a function of the gonadic hormonal milieu. We performed a retrospective analysis of a large cohort of adult males and females with confirmed GH deficiency (GHD) prior to treatment and during 3 years of replacement therapy. Potential confounders and effect modifiers were taken into account. Sixty-four adult patients with GHD (20 females and 44 males; mean age 34 years, range 18-64) were included in the analysis. GH replacement induced a different effect on bone in males compared to females. Bone mineral content increased in males and decreased in females at the lumbar spine, total femur, and femoral neck; bone mineral density showed a similar trend at the lumbar spine and femoral neck. There was no significant gender difference in bone area at any measured bone site. In both sexes we observed a similar trend for serum markers of bone remodeling. Sex predicted bone outcome on multivariate analysis, as did age, onset of GHD (childhood/adulthood), pretreatment bone mass, baseline body mass index (BMI), and BMI change during GH replacement. Serum IGF-I levels during treatment did not show any relationship with bone outcome at any measured site. This study confirms that bone responsiveness to GH replacement in adult GHD varies as a function of sex even after controlling for potential confounders and highlights the importance of other cofactors that may affect the interaction between GH replacement therapy and bone remodeling.

Heritability and demographic analyses in the large isolated population of Val Borbera suggest advantages in mapping complex traits genes.

BACKGROUND: Isolated populations are a useful resource for mapping complex traits due to shared stable environment, reduced genetic complexity and extended Linkage Disequilibrium (LD) compared to the general population. Here we describe a large genetic isolate from the North West Apennines, the mountain range that runs through Italy from the North West Alps to the South. METHODOLOGY/PRINCIPAL FINDINGS: The study involved 1,803 people living in 7 villages of the upper Borbera Valley. For this large population cohort, data from genealogy reconstruction, medical questionnaires, blood, anthropometric and bone status QUS parameters were evaluated. Demographic and epidemiological analyses indicated a substantial genetic component contributing to each trait variation as well as overlapping genetic determinants and family clustering for some traits. CONCLUSIONS/SIGNIFICANCE: The data provide evidence for significant heritability of medical relevant traits that will be important in mapping quantitative traits. We suggest that this population isolate is suitable to identify rare variants associated with complex phenotypes that may be difficult to study in larger but more heterogeneous populations.

GH replacement therapy increases plasma osteoprotegerin levels in GH-deficient adults.

OBJECTIVE: Osteoprotegerin (OPG), a glycoprotein belonging to the tumor necrosis factor receptor family, is an endogenous inhibitor of osteoclastogenesis produced by cells of the osteoblast lineage. OPG is a key cytokine involved in the regulation of osteoblast/osteoclast cross-talk. Since GH replacement therapy in GH deficiency (GHD) activates bone remodeling and increases bone mass, we investigated if short-term GH replacement therapy affects plasma OPG levels. DESIGN AND METHODS: Eighteen adults with GHD, ranging from 17 to 51 Years (nine childhood-onset and nine adult-onset) were enrolled in the study. All subjects were on stable replacement therapy, especially sex hormones. The starting dose of GH replacement therapy was 4 microg/kg per day x 7 days/week, and was progressively increased according to the serum IGF-I values. Biochemical parameters of bone and mineral metabolism were measured before and after 6 Months of GH replacement therapy. Bone mass density (BMD) was monitored at three skeletal sites (lumbar vertebrae, femur, radius) by dual-energy X-ray absorptiometry. RESULTS: After 6 Months of therapy, ionized calcium, parathyroid hormone and 25-OH vitamin D did not change, whereas total serum calcium and urinary calcium excretion increased significantly (P<0.01). Also osteocalcin and urinary deoxypyridinoline/24 h increased significantly (P<0.02, P<0.05 respectively). Mean basal T-scores of BMD values showed an osteopenic state, which remained unchanged after GH therapy. Plasma OPG increased significantly after 6 Months of therapy (P<0.02) and this increase was significantly correlated with the increase of osteocalcin (r=-0.52; P=0.04) and deoxypyridinoline values (r=-0.64; P=0.011). CONCLUSIONS: Our results suggest that the bone anabolic effect of GH replacement therapy could in part be mediated by a positive bone balance at each remodeling unit due to the inhibitory action of OPG on osteoclastogenesis.