Clinical and Biological Predictors of Cancer Incidence and Mortality in Patients with Stable Coronary Artery Disease.

Clinical and epidemiological evidence has recently revealed a link between coronary artery disease (CAD) and cancer. Shared risk factors and common biological pathways are probably involved in both pathological conditions. The aim of this paper was to evaluate whether and which conventional risk factors and novel circulating biomarkers could predict cancer incidence and death in patients with CAD. The study included 750 CAD patients, who underwent blood sampling for the evaluation of systemic inflammatory indexes (NLR and SII) and specific biomarkers of oxidative damage (leukocyte telomere length (LTL), mitochondrial DNA copy number (mtDNAcn)). Study participants were followed up for a mean of 5.4 ± 1.2 years. Sixty-seven patients (8.9%) developed cancer during the follow-up time, and nineteen (2.5%) died of cancer. Cox multivariable analysis revealed that age (HR = 1.071; 95% CI: 1.034-1.109; p < 0.001), smoking habit (HR = 1.994; 95% CI: 1.140-3.488; p = 0.016), obesity (HR = 1.708; 95% CI: 1.022-2.854; p = 0.041) and SII (HR = 1.002; 95% CI: 1.001-1.003; p = 0.045) were associated with cancer incidence, while only age (HR = 1.132; 95% CI: 1.052-1.219; p = 0.001) was a predictor of cancer death. Patients with lung and gastrointestinal cancers had significantly higher median mtDNAcn levels than those without cancer. Our study suggests that aggressive risk factor modification and suppression of chronic inflammation may be essential to preventing cancer in CAD patients.

Biochemical but not imaging parameters are predictive of outcome in septic shock: a pilot study.

BACKGROUND: Septic shock is a severe form of sepsis marked by hypotension with an ominous outcome despite the introduction of modern intensive care. The aim of the present study is to obtain a panel with biomarkers, echocardiographic and vascular parameters to better risk stratify patients and identify those at higher risk of ominous outcome. METHODS: Between May 2013 and April 2016, 35 consecutive patients admitted at the Intensive Care Unit (ICU) of ASST Great Metropolitan Hospital Niguarda with the diagnosis of severe sepsis or septic shock were enrolled. All patients underwent rest echocardiography and several circulating biomarkers of myocardial damage or oxidative stress. RESULTS: The multivariate Cox's proportional hazard model showed that the only independent prognostic predictor for 30-day mortality was the angiopoietin-2, (HR 1.017, 95% CI 1.000-1.034; P = 0.049). An angiopoietin-2 concentrations ≥ of 33,418 pg/mL was identified as the optimal threshold for the discrimination between survivors and non survivors at the time of admission in ICU, with a sensitivity of 80% and a specificity of 68%. CONCLUSIONS: Septic shock has a poor in-hospital outcome even when the best of care is implemented. Among the biochemical parameters angiopoietin was able to identify patients at risk of death. The lowest the value at admission, the highest the risk of in-hospital death. No echocardiographic nor vascular parameter was able to predict outcome in this setting.

Correlates of olfactory impairment in middle-aged non-diabetic Caucasian subjects with stage I-II obesity.

PURPOSE: This study evaluates among middle-aged subjects with obesity the prevalence of olfactory impairment (OI) with respect to normative values and its correlation with body composition, cognition, sleep quality, and inflammation. METHODS: In 60 (31 women, 29 men) volunteers with a body mass index ≥ 30 to ≤ 40 kg/m2, aged ≥ 50 to ≤ 70 years, we assessed olfaction by the Sniffin' Stick test. We measured anthropometrics, body composition and metabolic profiles and evaluated cognition by the MiniMental State Examination (MMSE) and sleep disturbances by the Insomnia Severity Index (ISI). Patients were classified into two groups according to a total olfactory score (odor Threshold, Discrimination, Identification, TDI) below or above the 25th percentile from age and gender-adjusted normative data. RESULTS: Overall, 25 subjects (42%) had OI (TDI < 25th percentile). The largest differences between subjects with and without OI were observed in discrimination and identification scores, with a large overlap in olfactory threshold. Subjects with an abnormal TDI showed significantly higher fat mass index, ISI scores and urinary neopterin and lower MMSE scores than those without OI. By multivariable logistic regression, MMSE, ISI score and urinary neopterin were significantly associated to OI. CONCLUSIONS: Among middle-aged subjects with stage I and II obesity, OI is highly prevalent and is independently associated with poor self-reported sleep quality, lower cognition scores and higher levels of the inflammatory marker neopterin.

Intra- and interday repeatability of peripheral arterial function: suitability and potential limitations.

OBJECTIVE: This study aimed to investigate the inter-and intraday repeatability of RHI measured by Endo-PAT in healthy volunteers. METHODS: Interday RHI repeatability was tested in two consecutive days in a group of 31 male subjects. Intraday repeatability was investigated at baseline and after 2 and 4 hour in a group of 16 volunteers. Data were evaluated by analysis of variance. Bland-Altman plot, CV, CR, and ICC were measured. RESULTS: While interday RHI repeatability was found to be reliable (CV: 6.0%; CR: 0.51; ICC: 0.77), multiple evaluations within the same day significantly (P<.001) affected RHI (repeatability of the measurement -CV: 18.8%; CR: 1.26; ICC: 0.48). In particular, a significant increase in RHI occurred at 4 hour compared to 2 hour (+16.8%; P<.05) and to baseline (+30.1%; P<.05). CONCLUSIONS: RHI showed good interday but poor intraday repeatability. Multiple evaluations increased RHI especially in subjects with endothelial dysfunction who improved or reversed their impairment. These results show the potential limitations of multiple Endo-PAT measurements within the same day and the importance of standardizing the protocols before RHI evaluations.

A single blueberry (Vaccinium corymbosum) portion does not affect markers of antioxidant defence and oxidative stress in healthy volunteers following cigarette smoking.

We previously reported that a portion of blueberries reversed endothelial dysfunction induced by acute cigarette smoking. Since smoking-induced endothelial dysfunction is associated with a condition of oxidative stress, we evaluated whether the observed effect was mediated by modulation of markers of oxidative stress and antioxidant defence. Fourteen out of 16 male healthy smokers previously enrolled, participated in a three-armed randomized controlled study with the following experimental conditions: smoking treatment (one cigarette); blueberry treatment (300g of blueberries) + smoking (one cigarette); control treatment (300ml of water with sugar) + smoking (one cigarette). The cigarette was smoked 100min after blueberry/control/water consumption. Each treatment was separated by 1 week of washout period. Plasma vitamin (C, B12 and folate) and aminothiol concentrations, endogenous [formamidopyrimidine-DNA glycosylase (FPG)-sensitive sites] and oxidatively induced DNA damage (resistance to H2O2-induced DNA damage) in peripheral blood mononuclear cells (PBMCs) were measured at baseline and 20, 60, 90, 120min and 24h after smoking. On the whole, analysis of variance did not show a significant effect of treatment on the modulation of markers of oxidative stress and antioxidant defence but revealed an effect of time for plasma concentrations of vitamin C (P = 0.003), B12 (P < 0.001), folate (P < 0.001), total cysteine (P = 0.007) and cysteine-glycine (P = 0.010) that increased following the three treatments after smoking. No significant effect of treatment was observed for the levels of FPG-sensitive sites (P > 0.05) and H2O2-induced DNA damage (P > 0.05) in PBMCs. In conclusion, the consumption of a single blueberry portion failed to modulate markers of oxidative stress and antioxidant defence investigated in our experimental conditions. Further studies are necessary to elucidate this finding and help clarifying the mechanisms of protection of blueberries against smoking-induced endothelial dysfunction.

Myocardial interleukin-6 in the setting of left ventricular mechanical assistance: relation with outcome and C-reactive protein.

BACKGROUND: In left ventricular assist device (LVAD) recipients, plasma levels of interleukin (IL)-6 are associated with Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profiles, reflecting post-operative risk. However, it is not clear how the cardiac level of IL-6, detectable on the tissue samples at the time of implantation, can contribute to predict the post-operative outcome. METHODS: In 40 LVAD recipients, blood and myocardial samples from LV-apex were collected at the time of implantation to assess plasma and cardiac IL-6 levels. Serum C-reactive protein (CRP) levels were considered as inflammatory variable routinely used in LVAD-based therapy. RESULTS: Cardiac IL-6 levels did not correlate with either plasma IL-6 levels (R=0.296, p=0.063) and tissue IL-6 mRNA expression (R=-0.013, p=0.954). Contrary to what happened for the plasma IL-6 and CRP, no differences were observed in cardiac IL-6 levels with respect to INTERMACS profiles (p=0.090). Furthermore, cardiac IL-6 concentrations, unlike IL-6 and CRP circulating levels, were not correlated with the length of intensive care unit stay and hospitalization. CONCLUSIONS: Cardiac IL-6 levels do not contribute to improve risk profile of LVAD recipients in relation to clinical inpatient post-implantation. Instead, plasma IL-6 and serum CRP concentrations are more effective in predicting the severity of the clinical course in the early phase of LVAD therapy.

Inflammatory and antioxidant pattern unbalance in "clopidogrel-resistant" patients during acute coronary syndrome.

BACKGROUND: In acute coronary syndrome (ACS), inflammation and redox response are associated with increased residual platelet reactivity (RPR) on clopidogrel therapy. We investigated whether clopidogrel interaction affects platelet function and modulates factors related to inflammation and oxidation in ACS patients differently responding to clopidogrel. MATERIAL AND METHODS: Platelet aggregation was measured in 29 ACS patients on dual (aspirin/clopidogrel) antiplatelet therapy. Nonresponders (NR) were defined as RPR ≥70% by ADP. Several inflammatory and redox parameters were assayed and platelet proteome was determined. RESULTS: Eight (28%) out of 29 ACS patients resulted NR to clopidogrel. At 24 hours, the levels of Th2-type cytokines IL-4, IFNγ, and MCP-1 were higher in NR, while blood GSH (r-GSHbl) levels were lower in NR than responders (R). Proteomic analysis evidenced an upregulated level of platelet adhesion molecule, CD226, and a downregulation of the antioxidant peroxiredoxin-4. In R patients the proinflammatory cytokine IL-6 decreased, while the anti-inflammatory cytokine IL-1Ra increased. CONCLUSIONS: In patients with high RPR on clopidogrel therapy, an unbalance of inflammatory factors, platelet adhesion molecules, and circulatory and platelet antioxidant molecules was observed during the acute phase. Proinflammatory milieu persists in nonresponders for a long time after the acute event while antioxidant blood factors tend to conform to normal responsiveness.

Effects of sapropterin on endothelium-dependent vasodilation in patients with CADASIL: a randomized controlled trial.

BACKGROUND AND PURPOSE: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a rare autosomal dominant disorder caused by NOTCH3 mutations, is characterized by vascular smooth muscle and endothelial cells abnormalities, altered vasoreactivity, and recurrent lacunar infarcts. Vasomotor function may represent a key factor for disease progression. Tetrahydrobiopterin, essential cofactor for nitric oxide synthesis in endothelial cells, ameliorates endothelial function. We assessed whether supplementation with sapropterin, a synthetic tetrahydrobiopterin analog, improves endothelium-dependent vasodilation in CADASIL patients. METHODS: In a 24-month, multicenter randomized, double-blind, placebo-controlled trial, CADASIL patients aged 30 to 65 years were randomly assigned to receive placebo or sapropterin 200 to 400 mg BID. The primary end point was change in the reactive hyperemia index by peripheral arterial tonometry at 24 months. We also assessed the safety and tolerability of sapropterin. Analysis was done by intention-to-treat. RESULTS: The intention-to-treat population included 61 patients. We found no significant difference between sapropterin (n=32) and placebo (n=29) in the primary end point (mean difference in reactive hyperemia index by peripheral arterial tonometry changes 0.19 [95% confidence interval, -0.18, 0.56]). Reactive hyperemia index by peripheral arterial tonometry increased after 24 months in 37% of patients on sapropterin and in 28% on placebo; however, after adjustment for age, sex, and clinical characteristics, improvement was not associated with treatment arm. The proportion of patients with adverse events was similar on sapropterin and on placebo (50% versus 48.3%); serious adverse events occurred in 6.3% versus 13.8%, respectively. CONCLUSIONS: Sapropterin was safe and well-tolerated at the average dose of 5 mg/kg/day, but did not affect endothelium-dependent vasodilation in CADASIL patients. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrialsregister.eu. Unique identifier: 2007-004370-55.

Relationship between early inflammatory response and clinical evolution of the severe multiorgan failure in mechanical circulatory support-treated patients.

BACKGROUND: The mechanical circulatory support (MCS) is an effective treatment in critically ill patients with end-stage heart failure (ESHF) that, however, may cause a severe multiorgan failure syndrome (MOFS) in these subjects. The impact of altered inflammatory response, associated to MOFS, on clinical evolution of MCS postimplantation patients has not been yet clarified. METHODS: Circulating cytokines, adhesion molecules, and a marker of monocyte activation (neopterin) were determined in 53 MCS-treated patients, at preimplant and until 2 weeks. MOFS was evaluated by total sequential organ failure assessment score (tSOFA). RESULTS: During MCS treatment, 32 patients experienced moderate MOFS (tSOFA < 11; A group), while 21 patients experienced severe MOFS (tSOFA ≥ 11) with favorable (B group) or adverse (n = 13, C group) outcomes. At preimplant, higher values of left ventricular ejection fraction (LVEF) and estimated glomerular filtration rate (eGFR) were the only parameter independently associated with A group. In C group, during the first postoperative week, high levels of interleukin-8 (IL-8) and tumor necrosis factor (TNF)-α, and an increase of neopterin and adhesion molecules, precede tSOFA worsening and exitus. CONCLUSIONS: The MCS patients of C group show an excessive release to IL-8 and TNF-α, and monocyte-endothelial activation after surgery, that might contribute to the unfavourable evolution of severe MOFS.

Effect of 10-day broccoli consumption on inflammatory status of young healthy smokers.

This study evaluated the effects of 10-day broccoli (250 g/day) intake on dietary markers and markers of inflammations in young male smokers. A dietary intervention study with a repeated measures crossover design was conducted. Circulating levels of carotenoids, folate, C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 6 receptor (IL-6sR) and adiponectin were measured. Broccoli intake significantly increased plasma levels of folate (+17%) and lutein (+39%), while no significant effect was observed for TNF-α, IL-6, IL-6sR or adiponectin. Plasma CRP decreased by 48% (post-hoc analysis, p < 0.05) following broccoli diet; this resulted to be independent from the plasma variations in lutein and folate. An inverse correlation between lycopene, TNF-α and IL-6sR was observed at baseline. In conclusion, broccoli consumption may reduce CRP levels in smokers, consistent with epidemiologic observations that fruit and vegetable intake is associated with lower circulating CRP concentrations.

The burden of radiation exposure in congenital heart disease: the Italian cohort profile and bioresource collection in HARMONIC project.

BACKGROUND: The European-funded Health Effects of Cardiac Fluoroscopy and Modern Radiotherapy in Pediatrics (HARMONIC) project aims to improve knowledge on the effects of medical exposure to ionizing radiation (IR) received during childhood. One of its objectives is to build a consolidated European cohort of pediatric patients who have undergone cardiac catheterization (Cath) procedures, with the goal of enhancing the assessment of long-term radiation-associated cancer risk. The purpose of our study is to provide a detailed description of the Italian cohort contributing to the HARMONIC project, including an analysis of cumulative IR exposure, reduction trend over the years and an overview of the prospective collection of biological samples for research in this vulnerable population. METHODS: In a single-center retrospective cohort study, a total of 584 patients (323 males) with a median age of 6 (2-13) years, referred at the Pediatric Cardiology in Niguarda Hospital from January 2015 to October 2023, were included. Biological specimens from a subset of 60 patients were prospectively collected for biobanking at baseline, immediately post-procedure and after 12 months. RESULTS: Two hundred fifty-nine (44%) patients were under 1 year old at their first procedure. The median KAP/weight was 0.09 Gy·cm2/kg (IQR: 0.03-0.20), and the median fluoroscopy time was 8.10 min (IQR: 4.00-16.25). KAP/weight ratio showed a positive correlation with the fluoroscopy time (Spearman's rho = 0.679, p < 0.001). Significant dose reduction was observed either after implementation of an upgraded technology system and a radiation training among staff. The Italian cohort includes 1858 different types of specimens for Harmonic biobank, including blood, plasma, serum, clot, cell pellet/lymphocytes, saliva. CONCLUSIONS: In the Italian Harmonic cohort, radiation dose in cardiac catheterization varies by age and procedure type. An institution's radiological protection strategy has contributed to a reduction in radiation dose over time. Biological samples provide a valuable resource for future research, offering an opportunity to identify potential early biomarkers for health surveillance and personalized risk assessment.

Influence of Chromosome 9p21.3 rs1333049 Variant on Telomere Length and Their Interactive Impact on the Prognosis of Coronary Artery Disease.

BACKGROUND: Both telomere shortening and the chromosome 9p21.3 (Chr9p21) rs1333049 (G/C) variant are involved in coronary artery disease (CAD) risk, likely affecting mechanisms related to cell cycle arrest and vascular senescence. The aim of the study was to examine the link between Chr9p21 rs1333049 variant and leucocyte telomere length (LTL), as well as their interactive effect on the risk of major adverse cardiovascular events (MACEs). METHODS: A cohort of 472 patients with angiographically proven and clinically stable CAD were included in the study. At baseline, the LTL, biochemical parameters, and genotype analysis of Chr9p21 rs1333049 variant were measured in all patients. The primary endpoint of this study was the occurrence of MACE defined as a composite of coronary-related death, nonfatal MI, and coronary revascularization. RESULTS: On multivariable linear regression analysis, age (p = 0.02) and Chr9p21 rs1333049 variant (p = 0.002) were the only independent predictors of LTL levels. Carriers of the CC genotype of this SNP had shorter telomeres than GC carriers (p = 0.02) and GG carriers (p = 0.0005). After a follow-up with a mean period of 62 ± 19 months, 90 patients (19.1%) had MACE. Short LTL was an independent prognostic factor of MACE incidence (HR:2.2; 95% CI: 1.3-3.7; p = 0.005) after adjustment for potential confounders. There was a significant interaction (p = 0.01) between the LTL and rs1333049 variant, with patients with risk-allele C and short LTL having a higher risk (HR:5.8; 95% CI: 1.8-19.2; p = 0.004). CONCLUSION: A strong relationship between LTL and Chr9p21 rs1333049 variant was identified, and they interactively affect the risk of poor prognosis in CAD patients.

Genetic variants of the renin-angiotensin-aldosterone system and reverse remodeling after cardiac resynchronization therapy.

BACKGROUND: Reverse remodeling (RR) after cardiac resynchronization therapy (CRT) is associated with favorable clinical outcomes in heart failure (HF). The renin-angiotensin-aldosterone system (RAAS) is involved in the remodeling process. METHODS AND RESULTS: We assessed the association between RR and 8 common RAAS gene variants, which were determined by TaqMan assays, in 156 outpatients with chronic HF. RR was defined as a >15% decrease in left ventricular end systolic volume (LVESV) at 9 (interquartile range 7-12) months after CRT. We matched 76 patients who did not show RR (RR-) to 80 RR+ control subjects by age, sex, HF etiology, New York Heart Association (NYHA) functional class and left ventricular ejection fraction (LVEF). The frequency of the minor allele of the NR3C2 gene (rs5522 C/T), encoding the mineralocorticoid receptor, was higher in RR- than in RR (24/126 vs 10/150; P value after false discovery rate correction: <.0193). Conversely, LVESV decreased significantly less after CRT in carriers of the NR3C2 minor C allele (P = .02). After adjustment for age, sex, NYHA functional class, previous myocardial infarction, atrial fibrillation, and LVEF, RR- remained independently associated with NR3C2 C allele carriage (odds ratio 3.093, 95% confidence interval 1.253-7.632). CONCLUSIONS: The association of RR- after CRT with a common polymorphism in the mineralocorticoid receptor gene involved in aldosterone signaling suggests a possible role for variants in RAAS genes in progressive LV function decline, despite apparently effective CRT.

Severity of oxidative stress and inflammatory activation in end-stage heart failure patients are unaltered after 1 month of left ventricular mechanical assistance.

This study investigates the impact of early left ventricular (LV)-mechanical unloading on systemic oxidative stress and inflammation in terminal heart failure patients and their impact both on multi organ failure and on intensive care unit (ICU) stay. Circulating levels of urinary 15-isoprostane-F(2t) (8-epi-PGF2(α)) and pro-inflammatory markers [plasma interleukin (IL)-6, IL-8, and urinary neopterin, a monocyte activation index] were analyzed in 20 healthy subjects, 22 stable end-stage heart failure (ESHF) patients and in 23 LV assist device (LVAD) recipients at pre-implant and during first post-LVAD (PL) month. Multi-organ function was evaluated by total Sequential Organ Failure Assessment (tSOFA) score. In LVAD recipients the levels of oxidative-inflammatory markers and tSOFA score were higher compared to other groups. After device implantation 8-epi-PGF2(α) levels were unchanged, while IL-6, and IL-8 levels increased during first week, and at 1month returned to pre-implant values, while neopterin levels increased progressively during LVAD support. The tSOFA score worsened at 1 PL-week with respect to pre-implant value, but improved at 1 PL-month. The tSOFA score related with IL-6 and IL-8 levels, while length of ICU stay related with pre-implant IL-6 levels. These data suggest that hemodynamic instability in terminal HF is associated to worsening of systemic inflammatory and oxidative milieu that do not improve in the early phase of hemodynamic recovery and LV-unloading by LVAD, affecting multi-organ function and length of ICU stay. This data stimulate to evaluate the impact of inflammatory signals on long-term outcome of mechanical circulatory support.

Plasma total cysteine and cardiovascular risk burden: action and interaction.

We hypothesized that redox analysis could provide sensitive markers of the oxidative pathway associated to the presence of an increasing number of cardiovascular risk factors (RFs), independently of type. We classified 304 subjects without cardiovascular disease into 4 groups according to the total number of RFs (smoking, hypertension, hypercholesterolaemia, hyperhomocysteinaemia, diabetes, obesity, and their combination). Oxidative stress was evaluated by measuring plasma total and reduced homocysteine, cysteine (Cys), glutathione, cysteinylglycine, blood reduced glutathione, and malondialdehyde. Twenty-seven percent of subjects were in group 0 RF, 26% in 1 RF, 31% in 2 RF, and 16% in ≥ 3 RF. By multivariable ordinal regression analysis, plasma total Cys was associated to a higher number of RF (OR = 1.068; 95% CI = 1.027-1.110, P = 0.002). Total RF burden is associated with increased total Cys levels. These findings support a prooxidant effect of Cys in conjunction with RF burden, and shed light on the pathophysiologic role of redox state unbalance in preclinical atherosclerosis.

Relationship between myocardial redox state and matrix metalloproteinase activity in patients on left ventricular assist device support.

BACKGROUND: Redox aminothiols have been reported to modulate the activity of recombinant metalloproteinases (MMP). The aim of the present study was to investigate the effects of myocardial redox state on the activities of MMP-2 and -9 implicated in cardiac remodeling in end-stage heart failure patients supported by left ventricular assist device (LVAD). METHODS AND RESULTS: During heart transplant (HT) surgery, myocardial specimens (MS) from right ventricular walls and LV walls were obtained from 7 LVAD recipients (LVAD group, MS n=35) and from 7 stable HT candidates on medical therapy (MT group, MS n=35). Myocardial MMP-2 and -9 activities and expression, tissue inhibitor of MMP (TIMP)-1 and -4, transforming growth factor (TGF)-ß1 and aminothiol concentrations were measured. MMP-2 and -9 activities were evaluated also by incubating MS with different amounts of reduced and oxidized glutathione (GSH). MMP-2 and -9 activities and expression were lower in the LVAD group, whereas myocardial TIMP-1 and -4 concentrations were comparable to those of MT patients. Higher GSH and TGF-ß1 concentrations were found in LVAD-recipients. Only GSH concentrations were inversely related to MMP-2 and -9 activities. In vitro, GSH had an inhibitory effect on MMP-2 and -9 activities. CONCLUSIONS: LVAD recipients show reduced myocardial MMP-2 and -9 activities and expression when compared to medically treated patients. Changes of myocardial redox state, predominantly GSH-dependent, appear to modulate MMP-2 and -9 activities by an inhibitory effect dependent on thiol content. These data support a role of GSH cycle in modulating the extracellular matrix in end-stage heart failure patients supported by LVAD.

Gender-Specific Behaviour in Obesity Stages I-II: Imbalance of Aminothiol Status and Adipomyokine Profile in Subjects with Different Insulin Resistance Severity.

The hyperproduction of oxidative stress and inflammatory biomarkers, which is paralleled by decreased levels of antioxidant and anti-inflammatory mediators, is part of cellular mechanisms that contribute to the disruption of metabolic homeostasis in obesity. Whether gender-specific alterations and gender-restricted associations in these biomarkers underlie the increased cardiometabolic risk in men compared to women is unclear. We enrolled 31 women and 29 men, aged ≥50 and ≤70 years and with body mass index ≥ 30 and <40 kg/m2. We assessed the concentrations of aminothiols (cysteine, homocysteine, and glutathione), expression of oxidant/antioxidant balance, adipomyokines (leptin, adiponectin, myostatin, and interleukin-6), markers of chronic inflammation, and vitamin D, an index of nutritional state, in plasma and serum samples by using HPLC, ELISA, and chemiluminescent immunoassay methods. We measured insulin resistance (IR) by the homeostasis model assessment (HOMA) index. Despite comparable levels of visceral adiposity, IR, and a similar dietary regimen, men showed, with respect to women, higher oxidant concentrations and lower antioxidant levels, which paralleled IR severity. Myostatin levels correlated with prooxidant aminothiols among men only. Gender-specific alterations in aminothiol status and adipomyokine profile and the gender-restricted association between these biomarkers and metabolic derangement are consistent with an increased cardiometabolic risk in men compared to age-matched women with stage I-II obesity. Strict control of redox and inflammatory status, even addressing gender-specific nutritional targets, may be useful to prevent obesity-related metabolic alterations and comorbidities.

Irisin and markers of metabolic derangement in non-diabetic Caucasian subjects with stage I-II obesity during early aging.

Irisin concentrations are decreased in subjects with overt diabetes and upregulated in those with obesity or impaired fasting glucose. However, gender-balanced data in older populations, in whom risk factors commonly culminate in overt cardiovascular disease, are scarce. We assessed in non-diabetic Caucasian subjects with stage I-II obesity in the early aging range (50 to 70 years), the relationship between irisin, body composition and markers of metabolic derangement by gender. In 60 (31 women, 29 men) non-diabetics with a body mass index ≥30 - ≤40 kg/m2, we measured anthropometrics and body composition (Air Displacement Plethysmography). We assayed lipid and glucose profile by routine methods, plasma irisin by ELISA and measured insulin resistance by the HOMA index. Irisin levels were higher in women than in men (161 [105-198]) vs 83 [33-115] ng/ml, P<0.001), and correlated directly with HOMA index in both (rho 0.735, P<0.001 M, rho 0.452, P = 0.011 F). Sex differences were maintained across insulin resistance severity stages. In men, irisin concentrations correlated directly with body mass index (rho 0.755, P<0.001), waist circumference (rho 0.623, P<0.001), fat mass index (rho 0.762, P<0.001), glucose (rho 0.408, P = 0.028), the fatty liver index (rho 0.705, P<0.001) and FINDRISC score (rho 0.536, P = 0.003). Among non-diabetic Caucasian subjects with obesity in the early stages of aging, irisin levels reflect the amount of body fat and insulin resistance severity, independently of between-gender differences in the adipomyokine concentrations and are associated with markers of visceral adiposity in men but not in women.