Previous cardiovascular injury is a prerequisite for immune checkpoint inhibitor-associated lethal myocarditis in mice.

AIMS: Immune checkpoint inhibitors (ICIs) are antineoplastic drugs designed to activate the immune system's response against cancer cells. Evidence suggests that they may lead to immune-related adverse events, particularly when combined (e.g., anti-CTLA-4 plus anti-PD-1), sometimes resulting in severe conditions such as myocarditis. We aimed to investigate whether a previously sustained cardiac injury, such as pathological remodelling due to hypertension, is a prerequisite for ICI therapy-induced myocarditis. METHODS: We evaluated the cardiotoxicity of ICIs in a hypertension (HTN) mouse model (C57BL/6). Weekly doses were administered up to day 21 after the first administration. Our analysis encompassed the following parameters: (i) survival and cardiac pathological remodelling, (ii) cardiac function assessed using pressure-volume (PV)-loops, with brain natriuretic peptide (BNP) serving as a marker of haemodynamic dysfunction and (iii) cardiac inflammation (cytokine levels, infiltration, and cardiac antigen autoantibodies). RESULTS: After the first administration of ICI combined therapy, the treated HTN group showed a 30% increased mortality (P = 0.0002) and earlier signs of hypertrophy and pathological remodelling compared with the untreated HTN group. BNP (P = 0.01) and TNF-α (<0.0001) increased 2.5- and 1.7-fold, respectively, in the treated group, while IL-6 (P = 0.8336) remained unchanged. Myocarditis only developed in the HTN group treated with ICIs on day 21 (score >3), characterised by T cell infiltration and increased cardiac antigen antibodies (86% showed a titre of 1:160). The control group treated with ICI was unaffected in any evaluated feature. CONCLUSIONS: Our findings indicate that pre-existing sustained cardiac damage is a necessary condition for ICI-induced myocarditis.

Association of irisin levels with cardiac magnetic resonance, inflammatory, and biochemical parameters in patients with chronic heart failure versus controls.

BACKGROUND AND AIMS: Chronic heart failure (CHF) represents a significant cause of morbidity and mortality globally. Metabolic maladaptation has proven to be critical in the progression of this condition. Preclinical studies have shown that irisin, an adipomyokine involved in metabolic regulations, can induce positive cardioprotective effects by improving cardiac remodeling, cardiomyocyte viability, calcium delivery, and reducing inflammatory mediators. However, data on clinical studies identifying the associations between irisin levels and functional imaging parameters are scarce in CHF patients. The objective of this study was to determine the association of irisin levels with cardiac imaging measurements through cardiac magnetic resonance, inflammatory markers, and biochemical parameters in patients with CHF compared with control subjects. METHODS AND RESULTS: Thirty-two subjects diagnosed with CHF and thirty-two healthy controls were evaluated in a cross-sectional study. Serum irisin levels were significantly lower in patients with CHF than in controls. This is the first study to report a significant positive correlation between irisin levels and cardiac magnetic resonance parameters such as left ventricular ejection fraction, fraction shortening, and global radial strain. A negative correlation was demonstrated between irisin levels and brain natriuretic peptide, insulin levels, and Homeostatic model assessment for insulin resistance index. We did not observe significant correlations between irisin levels and inflammatory cytokines. CONCLUSIONS: Given the importance of fraction shortening and global radial strain as accurate markers of ventricular wall motion, these results support the hypothesis that irisin may play an essential role in maintaining an adequate myocardial wall architecture, deformation, and thickness.

A Systematic Review of the Mechanisms Involved in Immune Checkpoint Inhibitors Cardiotoxicity and Challenges to Improve Clinical Safety.

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block CTLA-4, PD-1, or PD-L1 and induce the activation of the immune system against cancer. Despite the efficacy of ICIs, which has improved the oncotherapy for patients with a variety of malignancies, several immune-related adverse events (irAEs) have been described, including those affecting the heart. Cardiac irAEs after ICI therapies, including myocarditis, can become life-threatening, and their pathogenic mechanisms remain unclear. Here, a systematic analysis was performed regarding the potential immune mechanisms underlying cardiac irAEs based on the immune adverse events induced by the ICIs: 1) recruitment of CD4+ and CD8+ T cells, 2) autoantibody-mediated cardiotoxicity, and 3) inflammatory cytokines. Furthermore, the impact of dual therapies in ICI-induced cardiac irAEs and the potential risk factors are reviewed. We propose that self-antigens released from cardiac tissues or cancer cells and the severity/advancement of cancer disease have an important role in ICI cardiotoxicity.

Prediction of Insulin Resistance Based on Anthropometric and Clinical Variables in Children with Overweight or Obesity at a Tertiary Center in Northeast Mexico.

Background: This study provides a clinical model to identify children with insulin resistance (IR) in health care units where laboratory tests are not readily available. Methods: A retrospective study of Mexican children aged 2-16 years at an obesity (OB) clinic. A receiver operating characteristic (ROC) curve was used to assess the accuracy of the proposed model consisting of clinical parameters and to establish the cutoff value for the variables (439 children). A second cohort of children with similar characteristics served as the cohort for the validation of the model (577 children). Results: To determine the best model for predicting IR, we performed a multivariate logistic regression analysis, which showed that waist circumference, acanthosis nigricans, and pubertal status are independent predictors of IR, and when integrated, their predictive power increases. Based on this model, we constructed a simplified equation. The predictive tool was constructed using an ROC curve, with an area under the curve of 0.849. A cutoff value of 7.68 was selected based on the Youden Index, with sensitivity and specificity of 78.3% and 83.3%, respectively. Incorporating metabolic laboratory determinations with a cutoff value of 20.64 improved the sensitivity to 94.9%. Conclusions: We developed a simple and affordable method of identifying IR in children with overweight or OB based on anthropometric variables and routine blood tests for metabolic indicators, such as glucose and triglycerides, which can be implemented in underserved sites.

Cardiotoxicity associated with immune checkpoint inhibitor therapy: a meta-analysis.

AIMS: This study aimed to estimate the incidence of cardiac immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitors (ICIs). METHODS AND RESULTS: First, we performed an ICI pharmacovigilance analysis, finding 4.2% of cardiac disorders, including myocarditis, for anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapies. Patients treated with anti-PD-1 antibodies presented a greater number of cardiac adverse events (AEs) than those treated with anti-CTLA-4 (69.4% vs. 20%). Then, we analysed the incidence and characteristics of cardiac irAEs in 1265 papers published prior to 31 August 2020. Of the 4751 patients studied, 1.3% presented cardiac irAEs, with myocarditis being the most frequent (50.8%); 15 patients died (24.6%) due to cardiac irAEs. Finally, we conducted a meta-analysis to determine cardiac irAEs in randomized clinical trials, identified through a systematic search from the ClinicalTrials.gov database, finding an incidence of 3.1% for ICI monotherapies, 5.8% for dual ICI therapies, 3.7% (irAEs/AEs) for ICIs plus chemotherapy, and cardiac AEs were reported in 2.5% of patients treated solely with chemotherapy. CONCLUSIONS: Our study provides precise data for the incidence of cardiac irAEs among patients using ICIs, where despite its low incidence, the high rate of mortality is an important issue to consider. ICIs induce mainly myocarditis at the first doses, and dual therapies seem to provoke higher rates of cardiac irAEs than monotherapies or ICIs plus chemotherapy.

Metabolic shift precedes the resolution of inflammation in a cohort of patients undergoing bariatric and metabolic surgery.

Bariatric and metabolic surgery has shown to promote weight loss and reduce systemic inflammation. However, the sequence and timing of events regarding metabolic improvement and inflammation resolution has been rarely explored. Furthermore, data on inflammatory markers of Th17 and Th1 cell responses after bariatric surgery is scarce. We conducted a prospective study in subjects with obesity that underwent bariatric and metabolic surgery, with follow-ups at 3 and 6 months. Anthropometric and metabolic markers such as insulin levels, HOMA-IR, and lipid parameters declined significantly 3 months after surgery; while hs-CRP, TNF-α, IL-1ß, IL-6, and IL-8 serum concentrations decreased 6 months after the procedure. Concentrations of Th1 signature and driver cytokines, particularly IFN-γ, IL-12, and IL-18, and of Th17 driver IL-23 also decreased significantly after 6 months. Significant positive correlations between triglyceride levels and hs-CRP, IL-1ß, and IFN-γ concentrations, and between Apo B and IFN-γ levels were observed 6 months after bariatric and metabolic surgery. In addition, BMI was associated with hs-CRP and TNF-α concentrations. Fat mass correlated with hs-CRP, TNF-α, and IL-12. Analysis of the temporality of metabolic and inflammatory events suggests that improvement in the metabolic status occurs before resolution of systemic inflammation and may be a requisite for the later event.

Bariatric surgery-induced weight loss reduces B cell activating cytokines and IgG immunoglobulins related to autoimmunity.

BACKGROUND: Obesity is associated with a chronic inflammatory state and autoimmune diseases, but little is known about the role of B cells in this context and the changes in B cell activation factors during obesity and after weight loss. To test whether bariatric-surgery-induced weight loss ameliorates the systemic inflammatory state associated with B cell activation molecules. METHODS: We conducted a prospective observational study in patients treated with bariatric surgery. Anthropometric and body composition measurements were performed preoperatively and at 6 months of follow-up post surgery. The patients were tested for a biochemical profile, plasmatic immunoglobulin G (IgG), cytokines (including specific B cell activating cytokines), and adipokines serum levels RESULTS: The patients' weight loss was accounted for mostly by fat mass (52.9%). We observed a significant reduction in total plasmatic IgG levels (p = 0.001), which could be associated with decreased B cell activity. Accordingly, there was a significant decrease in the B cell activating factors such as APRIL, BAFF, and soluble CD40L and a general improvement in the inflammatory markers hs-CRP, IL-1ß, IL-12, IL-18, and IFN-γ. CONCLUSIONS: These findings point toward reduced B cell activity after weight loss due to bariatric surgery. Moreover, they could be the initial link among the systemic inflammatory factors, and B cell activation in this inflammatory context that leads to IgG production and, potentially, to autoimmunity in patients with severe obesity.

Integrative Analysis of Lipid Profiles in Plasma Allows Cardiometabolic Risk Factor Clustering in Children with Metabolically Unhealthy Obesity.

Hypertension, central obesity, hyperglycemia, and dyslipidemia are key risk factors for cardiovascular disease. However, the specific factors contributing to the development of unfavorable cardiometabolic characteristics in children with obesity are unknown. In this study, we investigated the cross-sectional relationships between cytokines, irisin, and fatty acid (FA) composition in plasma in school-age children with metabolically healthy and unhealthy obesity (MHO and MUO, respectively) of the same age and body mass index and waist circumference percentiles. We compared the data with that of children with normal weight (NW). We found that inflammatory cytokines and low irisin plasma concentrations are associated with obesity but not with cardiometabolic risk (CMR). Lipid profiles showed that children with MUO have a distinctive FA profile compared with children with MHO and NW, whereas children with MHO shared 88% of the FA profile with the NW group. Among all FAs, concentration of myristic acid (14 : 0), arachidic acid (20 : 0), and n-3 polyunsaturated FAs (PUFAs) was higher in children with MHO, whereas n-6 PUFAs such as arachidonic acid (20 : 4n6) had a significant contribution in defining MUO. These data suggest that the plasma FA profile is not only a central link to obesity but also may act as an indicator of CMR presence.

What Is the Role of the Inflammation in the Pathogenesis of Heart Failure?

PURPOSE OF REVIEW: In heart failure, whether it is associated with reduced or preserved ejection fraction, the immune system is activated and contributes to heart remodeling and impaired function. RECENT FINDINGS: Studies indicate that cells of the immune system not only play a role in the pathology but are also critical regulators of heart function. Knowledge about the role of the immune system driving heart failure will lead to the development of new targets to this system, particularly in those patients that, despite the apparent wellness, relapse and worsen. In this review, we will address the diverse mechanisms that trigger inflammation and their impact on heart failure progression.

Serum Irisin Levels, Endothelial Dysfunction, and Inflammation in Pediatric Patients with Type 2 Diabetes Mellitus and Metabolic Syndrome.

The prevalence of type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) has increased in the pediatric population. Irisin, an adipomyokine, is involved in white adipose tissue browning, energy expenditure, insulin sensitivity, and anti-inflammatory pathways. Data on the associations among circulating irisin levels, soluble cell adhesion molecules (sCAMs), and inflammatory cytokines is scarce in children and adolescents with MetS and T2DM. Subjects aged 6-16 years were grouped into T2DM, MetS, and healthy controls. Serum irisin levels were significantly lower in the MetS (6.6 [2.8-18.0] ng/mL) and T2DM (6.8 [2.2-23.2] ng/mL) groups compared with controls (30.3 [24.6-57.1] ng/mL). Negative correlations between irisin and the BMI percentile (R = -0.358), WC percentile (R = -0.308), and triglycerides (R = -0.284) were identified, while positive associations with TC (R = 0.287), HDL-c (R = 0.488), and LDL-c (R = 0.414) were observed. Significant negative correlations were found between irisin and sNCAM (R = -0.382), sICAM-2 (R = -0.300), sVCAM-1 (R = -0.292), MCP-1 (R = -0.308), and IFN-α2 (R = -0.406). Of note, lower concentrations of most sCAMs (sICAM-1, sPSGL-1, sP-selectin, sEpCAM, sICAM-2, sALCAM, sPECAM-1, sCD44, sVCAM-1, sICAM-3, sL-selectin, and sNCAM) were shown in T2DM subjects compared with MetS patients. Lower irisin levels induce a lack of inhibition of oxidative stress and inflammation. In T2DM, higher ROS, AGEs, glucotoxicity, and inflammation trigger endothelial cell apoptosis, which downregulates the sCAM expression as a compensatory mechanism to prevent further vascular damage. In opposition, in subjects with MetS that have not yet developed T2DM and its accompanying stressors, the upregulation of the sCAM expression is ensued.

Association of the Triglyceride/High-Density Lipoprotein Cholesterol Index with Insulin Resistance in a Pediatric Population in Northeast Mexico.

Background: The present study aimed to determine the association of the triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) index with IR in pediatric patients with overweight (OW) and OB, to assess the ability of the TG/HDL-C index to predict IR, and to estimate the prevalence of IR and metabolic syndrome (MetS). Methods: A cross-sectional study comprised 628 Mexican children (2-16 years old) from the OB clinic. IR was estimated using the HOMA-IR index (‡2.5). The modified Adult Treatment Panel III criteria were used to define MetS. Correlation analyses and a receiver operating characteristic (ROC) curve were used to assess the association of the TG/HDL-C index with IR and to establish the best cutoff for the TG/HDL-C index. Results: About 79.3% of the children presented IR and 55.4% MetS. Common findings in patients with IR were acanthosis nigricans (94.8%) and a TG/HDL-C index ‡2.27 (70.5%). Considering all the patients with a high TG/HDL-C index, 78.4% presented MetS, and 88.0% IR. The area under the curve-ROC for the ability of the TG/HDL-C index to predict IR was 0.72 (P < 0.001), with a sensitivity of 70.5% and specificity of 63.1%. Conclusions: TG/HDL-C index is a feasible alternative to the HOMA-IR index to predict IR in Mexican children with OW or OB. It might be used to identify children with the greatest need for treatment interventions.

The role of B cells in heart failure and implications for future immunomodulatory treatment strategies.

Despite numerous demonstrations that the immune system is activated in heart failure, negatively affecting patients' outcomes, no definitive treatment strategy exists directed to modulate the immune system. In this review, we present the evidence that B cells contribute to the development of hypertrophy, inflammation, and maladaptive tissue remodelling. B cells produce antibodies that interfere with cardiomyocyte function, which culminates as the result of recruitment and activation of a variety of innate and structural cell populations, including neutrophils, macrophages, fibroblasts, and T cells. As B cells appear as active players in heart failure, we propose here novel immunomodulatory therapeutic strategies that target B cells and their products.

Amorphous SiO2 nanoparticles promote cardiac dysfunction via the opening of the mitochondrial permeability transition pore in rat heart and human cardiomyocytes.

BACKGROUND: Silica nanoparticles (nanoSiO2) are promising systems that can deliver biologically active compounds to tissues such as the heart in a controllable manner. However, cardiac toxicity induced by nanoSiO2 has been recently related to abnormal calcium handling and energetic failure in cardiomyocytes. Moreover, the precise mechanisms underlying this energetic debacle remain unclear. In order to elucidate these mechanisms, this article explores the ex vivo heart function and mitochondria after exposure to nanoSiO2. RESULTS: The cumulative administration of nanoSiO2 reduced the mechanical performance index of the rat heart with a half-maximal inhibitory concentration (IC50) of 93 µg/mL, affecting the relaxation rate. In isolated mitochondria nanoSiO2 was found to be internalized, inhibiting oxidative phosphorylation and significantly reducing the mitochondrial membrane potential (ΔΨm). The mitochondrial permeability transition pore (mPTP) was also induced with an increasing dose of nanoSiO2 and partially recovered with, a potent blocker of the mPTP, Cyclosporine A (CsA). The activity of aconitase and thiol oxidation, in the adenine nucleotide translocase, were found to be reduced due to nanoSiO2 exposure, suggesting that nanoSiO2 induces the mPTP via thiol modification and ROS generation. In cardiac cells exposed to nanoSiO2, enhanced viability and reduction of H2O2 were observed after application of a specific mitochondrial antioxidant, MitoTEMPO. Concomitantly, CsA treatment in adult rat cardiac cells reduced the nanoSiO2-triggered cell death and recovered ATP production (from 32.4 to 65.4%). Additionally, we performed evaluation of the mitochondrial effect of nanoSiO2 in human cardiomyocytes. We observed a 40% inhibition of maximal oxygen consumption rate in mitochondria at 500 µg/mL. Under this condition we identified a remarkable diminution in the spare respiratory capacity. This data indicates that a reduction in the amount of extra ATP that can be produced by mitochondria during a sudden increase in energy demand. In human cardiomyocytes, increased LDH release and necrosis were found at increased doses of nanoSiO2, reaching 85 and 48%, respectively. Such deleterious effects were partially prevented by the application of CsA. Therefore, exposure to nanoSiO2 affects cardiac function via mitochondrial dysfunction through the opening of the mPTP. CONCLUSION: The aforementioned effects can be partially avoided reducing ROS or retarding the opening of the mPTP. These novel strategies which resulted in cardioprotection could be considered as potential therapies to decrease the side effects of nanoSiO2 exposure.

Understanding the disrupting mechanism of the Tau aggregation motif "306 VQIVYK311 " by phenylthiazolyl-hydrazides inhibitors.

Alzheimer's disease is a progressive neurodegenerative disorder characterized by the abnormal processing of the Tau and the amyloid precursor proteins. The unusual aggregation of Tau is based on the formation of intermolecular ß-sheets through two motifs: 275 VQIINK280 and 306 VQIVYK311 . Phenylthiazolyl-hydrazides (PTHs) are capable of inhibiting/disassembling Tau aggregates. However, the disaggregation mechanism of Tau oligomers by PTHs is still unknown. In this work, we studied the disruption of the oligomeric form of the Tau motif 306 VQIVYK311 by PTHs through molecular docking, molecular dynamics, and free energy calculations. We predicted hydrophobic interactions as the major driving forces for the stabilization of Tau oligomer, with V306 and I308 being the major contributors. Nonpolar component of the binding free energy is essential to stabilize Tau-PTH complexes. PTHs disrupted mainly the van der Waals interactions between the monomers, leading to oligomer destabilization. Destabilization of full Tau filament by PTHs and emodin was not observed in the sampled 20 ns; however, in all cases, the nonpolar component of the binding free energy is essential for the formation of Tau filament-PTH and Tau filament-emodin. These results provide useful clues for the design of more effective Tau-aggregation inhibitors.

Interplay between the Adaptive Immune System and Insulin Resistance in Weight Loss Induced by Bariatric Surgery.

Low-grade chronic inflammation plays a pivotal role among other pathophysiological mechanisms involved in obesity. Innate and adaptive immune cells undergo systemic proinflammatory polarization that gives rise to an increased secretion of proinflammatory cytokines, which in turn leads to insulin resistance. Bariatric surgery is currently the most effective treatment for obesity, as it brings on significant weight loss, glucose metabolism improvement, and a decrease in systemic inflammation biomarkers. After bariatric surgery, several changes have been reported to occur in adaptive immunity, including reduction in CD4+ and CD8+ T cell counts, a decrease in the Th1/Th2 ratio, an increase in B regulatory cells, and reduction in proinflammatory cytokine secretion. Overall, there seems to be a major shift in several lymphocyte populations from a proinflammatory to an anti-inflammatory phenotype. Furthermore, increased antioxidant activity and reduced lipid and DNA oxidation products have been reported after bariatric surgery in circulating mononuclear cells. This paper highlights the shift in the adaptive immune system in response to weight loss and improved insulin sensitivity, as well as the interplay between immunological and metabolic adaptations as a result of bariatric surgery. Finally, based on data from research, we propose several mechanisms such as changes in adaptive immune cell phenotypes and their by-products, recruitment in adipose tissue, reduced oxidative stress, and modification in metabolic substrate availability as drivers to reduce low-grade chronic inflammation after bariatric surgery in severe obesity.

Design of a Helical-Stabilized, Cyclic, and Nontoxic Analogue of the Peptide Cm-p5 with Improved Antifungal Activity.

Following the information obtained by a rational design study, a cyclic and helical-stabilized analogue of the peptide Cm-p5 was synthetized. The cyclic monomer showed an increased activity in vitro against Candida albicans and Candida parapsilosis, compared to Cm-p5. Initially, 14 mutants of Cm-p5 were synthesized following a rational design to improve the antifungal activity and pharmacological properties. Antimicrobial testing showed that the activity was lost in each of these 14 analogues, suggesting, as a main conclusion, that a Glu-His salt bridge could stabilize Cm-p5 helical conformation during the interaction with the plasma membrane. A derivative, obtained by substitution of Glu and His for Cys, was synthesized and oxidized with the generation of a cyclic monomer with improved antifungal activity. In addition, two dimers were generated during the oxidation procedure, a parallel and antiparallel one. The dimers showed a helical secondary structure in water, whereas the cyclic monomer only showed this conformation in SDS. Molecular dynamic simulations confirmed the helical stabilizations for all of them, therefore indicating the possible essential role of the Glu-His salt bridge. In addition, the antiparallel dimer showed a moderate activity against Pseudomonas aeruginosa and a significant activity against Listeria monocytogenes. Neither the cyclic monomer nor the dimers were toxic against macrophages or THP-1 human cells. Due to its increased capacity for fungal control compared to fluconazole, its low cytotoxicity, together with a stabilized α-helix and disulfide bridges, that may advance its metabolic stability, and in vivo activity, the new cyclic Cm-p5 monomer represents a potential systemic antifungal therapeutic candidate.

Correlation of Vitamin D with Inflammatory Cytokines, Atherosclerotic Parameters, and Lifestyle Factors in the Setting of Heart Failure: A 12-Month Follow-Up Study.

Vitamin D deficiency is highly prevalent worldwide. It has been associated with heart failure (HF) given its immunoregulatory functions. In-vitro and animal models have shown protective roles through mechanisms involving procollagen-1, JNK2, calcineurin/NFAT, NF-κB, MAPK, Th1, Th2, Th17, cytokines, cholesterol-efflux, oxLDL, and GLUT4, among others. A 12-month follow-up in HF patients showed a high prevalence of vitamin D deficiency, with no seasonal variation (64.7-82.4%). A positive correlation between serum 25(OH)D concentration and dietary intake of vitamin D-rich foods was found. A significant inverse correlation with IL-1ß (R = -0.78), TNF-α (R = -0.53), IL-6 (R = -0.42), IL-8 (R = -0.41), IL-17A (R = -0.31), LDL-cholesterol (R = -0.51), Apo-B (R = -0.57), total-cholesterol (R = -0.48), and triglycerides (R = -0.32) was shown. Cluster analysis demonstrated that patients from cluster three, with the lowest 25(OH)D levels, presented the lowermost vitamin D intake, IL-10 (1.0 ± 0.9 pg/mL), and IL-12p70 (0.5 ± 0.4 pg/mL), but the highest TNF-α (9.1 ± 3.5 pg/mL), IL-8 (55.6 ± 117.1 pg/mL), IL-17A (3.5 ± 2.0 pg/mL), total-cholesterol (193.9 ± 61.4 mg/dL), LDL-cholesterol (127.7 ± 58.2 mg/dL), and Apo-B (101.4 ± 33.4 mg/dL) levels, compared with patients from cluster one. Although the role of vitamin D in the pathogenesis of HF in humans is still uncertain, we applied the molecular mechanisms of in-vitro and animal models to explain our findings. Vitamin D deficiency might contribute to inflammation, remodeling, fibrosis, and atherosclerosis in patients with HF.

Mitochondrial Hyperacetylation in the Failing Hearts of Obese Patients Mediated Partly by a Reduction in SIRT3: The Involvement of the Mitochondrial Permeability Transition Pore.

BACKGROUND/AIMS: Cyclophilin D (CypD) mediates the mitochondrial permeability transition pore (mPTP) opening that contributes to mitochondrial dysfunction. CypD is regulated by its acetylation/deacetylation state that depends on Sirtuin-3 (SIRT3) mitochondrial deacetylase. Since obesity and metabolic syndrome decrease SIRT3 activity and expression, we tested the hypothesis that CypD hyperacetylation promotes mitochondrial dysfunction under this pathophysiological state, which is associated with ventricular dysfunction and heart failure. METHODS: Myocardial tissue samples from patients with left ventricular heart failure, with either obesity or normal weight, were processed for the expression of SIRT3 and acetylation profile by Western Blot (WB). In addition, a rat model of obesity and metabolic syndrome induced by 30% (w/v) of sucrose was conducted. The WB analysis was used to determine the levels of mitochondrial expression of SIRT3, Adenine Nucleotide Translocator (ANT), CypD and the acetylation profile, as well as immunoprecipitation to establish the acetylation levels of CypD. Mitochondrial function was assessed by oxygen consumption analysis and maximum Ca2+ retention capacity. Oxidative stress was assessed by aconitase activity, protein carbonyl and thiol groups content. RESULTS: SIRT3 expression in the biopsies of the failing human hearts showed a 46% decrease in the expression levels of obese patients in comparison to the non-obese patients (p=0.0219). Remarkably, body mass index was associated with protein acetylation (0.627; p = 0.035), suggesting that the acetylation profiles of the failing hearts of obese patients are partly mediated by a reduction in SIRT3, which is also associated with higher BNP levels, indicating a more severe ventricular dysfunction (-0.636; p = 0.043). Accordingly, obese rats demonstrated a SIRT3 mitochondrial expression decrease of 22% concomitantly with a hyperacetylated mitochondrial profile, including CypD. Cardiac mitochondria from obese animals were 2.5-fold more prone to mPTP opening than the controls. CONCLUSION: Our results indicate that obesity reduces SIRT3 expression and that CypD hyperacetylation increases mPTP opening, suggesting that the activation of SIRT3 might be a potential target to decrease ventricular dysfunction and slow the progression of heart failure.

Myokine-adipokine cross-talk: potential mechanisms for the association between plasma irisin and adipokines and cardiometabolic risk factors in Mexican children with obesity and the metabolic syndrome.

BACKGROUND: Adipokines and the myokine irisin, involved in mechanisms associated with obesity and metabolic syndrome (MS), are understudied in the pediatric population. OBJECTIVE: To investigate the relationship between irisin, and leptin, resistin, adiponectin, adipsin, anthropometric and cardiovascular risk factors in Mexican children. METHODS: A cross-sample of 126 Mexican children aged 6-12 years old were classified as normal weight (n = 46), obese (n = 40), and MS (n = 40) according to CDC's and Cook's age-modified criteria for obesity and MS. Anthropometric parameters and blood pressure were determined and percentiles calculated for age and gender. Irisin, leptin, adiponectin, adipsin, resistin, triglycerides, glucose, high-density lipoprotein cholesterol (HDL-c) levels, and physical activity were determined. Statistical tests for differences between groups, correlation, and multiple regression analyses were performed. RESULTS: Irisin plasma levels were significantly lower in the obese (6.08 [4.68-6.65]) and MS groups (6.46 [5.74-7.02]) compared with the normal-weight group (8.05 [7.24-8.94]) (p < 0.001). Irisin levels were not influenced by age or gender, but significant dispersion was observed in obese girls (95% CI median [2.29-6.30]). Leptin, resistin, and adipsin levels were significantly increased in the obese and MS groups. Lean-fat ratio was significantly higher in the NW group. Irisin correlated negatively with leptin (- 0.310), resistin (- 0.389), adipsin (- 0.362), BMI% (-0.472), WC% (- 0.453), BMI z-score (- 0.496), fat free mass (- 0.257), fat percentage (- 0.532), fat mass (- 0.515), triglycerides (- 0.291), the number of cardiometabolic risk factors (- 0.443) (p < 0.001); positively with lean-fat ratio (0.489) and HDL-c (0.328) (p < 0.001) and none with physical activity (p < 0.001). Following stepwise multiple linear regression analysis, the lean-fat ratio was the only determinant of irisin levels (B = 1.168, p < 0.001). CONCLUSIONS: Lean-fat ratio, more than the absolute amount of muscle or fat mass, as well as potential myokine-adipokine cross-talk mechanisms may explain the lower irisin levels in children with obesity and MS, through blunted compensatory responses interfering with tissue-dependent irisin secretion, contributing to a continuous deleterious effect cycle.