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Background. Pulmonary vein isolation (PVI) represents the cornerstone of paroxysmal (PAF) and persistent atrial fibrillation (PsAF) ablation. Impedance values provide insights on tissue conductive properties. Methods. Consecutive patients undergoing PAF and PsAF ablation were prospectively enrolled. All the patients underwent a preprocedural multidetector computed tomography (MDCT) to evaluate left atrial wall thickness (LAWT). Electroanatomic maps were acquired with the ablation catheter, and impedance values (Ω) and voltage amplitude (mV) of bipolar electrograms were collected. Results. A total of 60 patients (40 with PAF and 20 with PsAF) were included in the study. In all PAF cases, no voltage value lower than 0.5 mV was found at LA mapping; the corresponding mean impedance value was 151.5 ± 5.4 Ω. In PsAF cases, voltage values inferior to 0.05 mV have been reported in 19/20 patients. PsAF patients showed a mean impedance value of 129.1 ± 3.8 Ω. The correlation analysis between bipolar voltage and impedance reported an r s value of 0.4166 ( p < 0.001), showing a positive correlation between the two variables. On the contrary, no direct correlation was found between voltage and LAWT and between impedance and LAWT (rsv-t = 0.1838; rsi-t = 0.1133, respectively). Conclusions. This research study suggests a correlation between voltage amplitude and impedance values, so that impedance might be used for arrhythmogenic substrate characterization.

Background and Aims: The increasing use of assisted reproductive technology (ART) has raised concerns regarding its long-term cardiovascular safety due to potential hormonal imbalances and pro-thrombotic states. This study aimed to assess the long-term cardiovascular risk associated with fertility treatments in women., Methods: Following PRISMA guidelines, a systematic review and meta-analysis was conducted in MEDLINE (via PubMed) from inception to January 2024. Randomized, cohort, or case-control studies were included if fulfilling the following criteria: the association between ART and the subsequent cardiovascular outcome was reported and adjusted for confounding factors (at least age); the presence of a control group; and minimum 1-year follow-up. Effect size (ES) estimates of the association between fertility therapy and subsequent cardiovascular disease were pooled using the DerSimonian and Laird random-effects model. Heterogeneity was assessed with the I2 index. This study is registered on PROSPERO (CRD42024505605)., Results: Of the 7298 articles screened, 10 studies were included, encompassing 500 664 women undergoing ART and 36 395 240 controls. The analysis found no significant increase in the long-term risk of major adverse cardiovascular events [ES 1.04, 95% confidence interval (CI) 0.88-1.23, I2 87.61%, P = .63], coronary heart disease (ES 0.88, 95% CI 0.71-1.10, I2 24.36%, P = .26), stroke (ES 1.21, 95% CI 0.92-1.59, I2 70.40%, P = .17), venous thromboembolism (ES 0.95, 95% CI 0.70-1.28, I2 49.13%, P = .73), hypertension (ES 1.08, 95% CI 0.88-1.32, I2 94.63%, P = .46), or diabetes (ES 1.03, 95% CI 0.86-1.22, I2 78.44%, P = .77). Assisted reproductive technology was associated with a lower risk of heart failure (ES 0.75, 95% CI 0.60-0.94, I2 0.00%, P = .01)., Conclusions: Assisted reproductive technology use does not appear to be significantly associated with an increased long-term risk of cardiovascular diseases in women. While these findings suggest the cardiovascular safety of fertility treatments, further research is warranted., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Aims: We conducted a prespecified subanalysis of the POEM trial to assess the association between sex and clinical outcomes following a short 1-month dual-antiplatelet-therapy (DAPT) period after percutaneous coronary intervention (PCI) with bioresorbable polymer everolimus-eluting stent (BP-EES) among patients at high bleeding risk (HBR)., Background: Shortening the DAPT period after PCI is an effective bleeding avoidance strategy with contemporary drug-eluting stents. Whether sex affects the risk of adverse events following PCI is still debated., Methods: Patients at HBR undergoing PCI with BP-EES were enrolled and treated with 1-month DAPT. If anticoagulation was needed, study participants received an oral anticoagulant (OAC) in addition to a P2Y 12 inhibitor for 1 month, followed by OAC only thereafter. The primary endpoint was a composite of cardiac death, myocardial infarction, or definite/probable stent thrombosis at 12 months. We report sex-based outcomes of patients included in the POEM study., Results: We enrolled 129 (29.1%) women and 314 (70.9%) men. Women were older, with lower hemoglobin levels, and worse renal function. Accordingly, they had a trend for a greater number of HBR criteria fulfilled and a higher PARIS bleeding score. However, they were not at a significantly higher risk for the primary endpoint (men vs. women: 5.17% vs. 3.94%; HR 1.30; 95% CI: 0.48-3.54, p = 0.61), or any of the hemorrhagic and ischemic secondary endpoints., Conclusions: This prespecified subanalysis of the POEM trial suggests that 1-month DAPT following PCI with BP-EES may be a safe and effective therapeutic strategy for women at HBR., (© 2024 The Author(s). Catheterization and Cardiovascular Interventions published by Wiley Periodicals LLC.)

Background: Previous studies have investigated a 1 to 6-month short dual antiplatelet therapy (S-DAPT) after percutaneous coronary intervention (PCI) with modern drug eluting-stents to reduce bleeding events., Objectives: To investigate cardiovascular outcomes in patients at high bleeding risk (HBR) according to the Academic Research Consortium for High Bleeding Risk (ARC-HBR) criteria after PCI with the Synergy bioresorbable-polymer everolimus-eluting stents (EES)., Methods: We applied ARC-HBR criteria in the population of the prospective, single-arm, multicenter POEM (Performance of Bioresorbable Polymer-Coated Everolimus-Eluting Synergy Stent in Patients at HBR Undergoing Percutaneous Coronary Revascularization Followed by 1-Month Dual Antiplatelet Therapy) trial. The primary endpoint was a composite of cardiac death, myocardial infarction, or definite or probable stent thrombosis at 12 months., Results: The original POEM cohort included 356 patients (80.4 %) fulfilling ARC-HBR criteria. Oral anticoagulant (OAC) usage and age ≥75 years were the most frequent major and minor ARC-HBR criteria, respectively. The ARC-HBR group was mainly represented by men (71.1 %), with 74.4 ± 9.3 years and a high burden of cardiovascular risk factors. DAPT was prescribed in 79.3 %, and single antiplatelet (SAPT) with OAC in 18.7 %. 12-month follow-up was completed in 96.2 %. The primary endpoint occurred in 5.2 % (95 % CI 3.29-8.10) of patients, whereas bleeding Academic Research Consortium type 3-5 occurred in 2.7 % (95 % CI, 1.39 %-5.05 %)., Conclusion: Previous results of the POEM trial showed positive outcomes regarding ischemic and bleeding events with an S-DAPT regimen after Synergy EES. These results are also confirmed in sub-group analysis when ARC-HBR criteria are applied., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Low-voltage area (LVA) ablation, in addition to pulmonary vein isolation (PVI), has been proposed as a new strategy in patients with atrial fibrillation (AF), but clinical trials have shown conflicting results. We performed a systematic review and meta-analysis to assess the impact of LVA ablation in patient undergoing AF ablation (PROSPERO-registered CRD42024537696). Methods: Randomized clinical trials investigating the role of LVA ablation in addition to PVI in patients with AF were searched on PubMed, Embase, and the Cochrane Library from inception to 22 April 2024. Primary outcome was atrial arrhythmia recurrence after the first AF ablation procedure. Secondary endpoints included procedure time, fluoroscopy time, and procedure-related complication rate. Sensitivity analysis including only patients with LVA demonstration at mapping and multiple subgroups analyses were also performed. Results: 1547 patients from 7 studies were included. LVA ablation in addition to PVI reduced atrial arrhythmia recurrence (odds ratio [OR] 0.65, 95% confidence interval [CI] 0.52-0.81, p < 0.001) with a number needed to treat to prevent recurrence of 10. No difference in procedure time (mean difference [MD] -5.32 min, 95% CI -19.01-8.46 min, p = 0.45), fluoroscopy time (MD -1.10 min, 95% CI -2.48-0.28 min, p = 0.12) and complication rate (OR 0.81, 95% CI 0.40-1.61, p = 0.54) was observed. Consistent results were demonstrated when considering only patients with LVA during mapping and in prespecified subgroups for AF type (paroxysmal vs. persistent), multicentric vs. monocentric trial, and ablation strategy in control group. Conclusions : In patients with AF, ablation of LVAs in addition to PVI reduces atrial arrhythmia recurrence without a significant increase in procedure time, fluoroscopy time, or complication rate.

Introduction: Atrial fibrillation (AF) represents the most common arrhythmia in the postoperative setting. We aimed to investigate the incidence of postoperative AF (POAF) and determine its predictors, with a specific focus on inflammation markers., Methods: We performed a retrospective single tertiary center cohort study including consecutive adult patients who underwent a major surgical procedure between January 2016 and January 2020. Patients were divided into four subgroups according to the type of surgery., Results: Among 53,387 included patients (79.4% male, age 64.5 ± 9.5 years), POAF occurred in 570 (1.1%) with a mean latency after surgery of 3.4 ± 2.6 days. Ninety patients died (0.17%) after a mean of 13.7 ± 8.4 days. The 28-day arrhythmia-free survival was lower in patients undergoing lung and cardiovascular surgery ( p  < .001). Patients who developed POAF had higher levels of C-reactive protein (CRP) (0.70 ± 0.03 vs. 0.40 ± 0.01 log10 mg/dl; p  < .001). In the multivariable Cox regression analysis, adjusting for confounding factors, CRP was an independent predictor of POAF [HR per 1 mg/dL increase in log-scale = 1.81 (95% CI 1.18-2.79); p  = .007]. Moreover, independent predictors of POAF were also age (HR/1 year increase = 1.06 (95% CI 1.04-1.08); I < .001), lung and cardiovascular surgery (HR 23.62; (95% CI 5.65-98.73); p  < .001), and abdominal and esophageal surgery (HR 6.26; 95% CI 1.48-26.49; p  = .013)., Conclusions: Lung and cardiovascular surgery had the highest risk of POAF in the presented cohort. CRP was an independent predictor of POAF and postsurgery inflammation may represent a major driver in the pathophysiology of the arrhythmia., Competing Interests: None., (© 2024 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of Japanese Heart Rhythm Society.)

Background/introduction: There is a need for further studies on the cardiovascular risk of women experiencing pre-eclampsia (PE)., Purpose: To update the literature regarding the association between a history of PE and subsequent cardiovascular diseases, including cardiovascular death, coronary heart diseases, heart failure, and stroke, focusing on the trend in the effect size (ES) estimates over time., Methods and Results: Following PRISMA guidelines, from inception to May 2023, we performed a systematic review of PubMed, MEDLINE, Scopus, and EMBASE. Randomized, cohort, or case-control studies in English were included if fulfiling the following criteria:(i) The association between PE and subsequent cardiovascular disease was adjusted for clinically relevant variables, (ii) the presence of a control group, and (iii) at least 1 year of follow-up. Pooled adjusted ESs and 95% confidence intervals (CIs) were used as effect estimates and calculated with a random-effect model. Twenty-two studies met the inclusion criteria. PE was associated with a higher risk of cardiovascular death (ES 2.08, 95% CI 1.70-2.54, I2 56%, P < 0.00001), coronary artery diseases (ES 2.04, 95% CI 1.76-2.38, I2 87%, P < 0.00001), heart failure (ES 2.47, 95% CI 1.89-3.22, I2 83%, P < 0.00001), and stroke (ES 1.75, 95% CI 1.52-2.02, I2 72%, P < 0.00001) after adjusting for potential confounders. This risk is evident in the first 1-to-3 years of follow-up and remains significant until 39 years of follow-up., Conclusions: Compared to women who experienced a normal pregnancy, those suffering from PE have about double the risk of lifetime cardiovascular disease., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

There is a paucity of data regarding the safety of a 1-month dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) in patients at high bleeding risk (HBR) presenting with acute coronary syndromes (ACS). We aimed to compare the clinical outcomes of patients at HBR with chronic coronary syndrome (CCS) or ACS treated with PCI using bioresorbable polymer everolimus-eluting stent (BP-EES) followed by 1-month DAPT. Patients at HBR who underwent PCI with BP-EES were prospectively enrolled in 10 Italian centers. All patients were treated with 1-month DAPT. In case of need for anticoagulation, patients received an oral anticoagulant in addition to a P2Y12 inhibitor for 1 month, followed by oral anticoagulation only after that. The primary end point was a composite of cardiac death, myocardial infarction, or definite/probable stent thrombosis at 12 months. Overall, 263 patients (59.4%) with CCS and 180 patients (40.6%) with ACS were enrolled. No significant difference was evident between patients with CCS and ACS for the primary end point (4.3% vs 5.6%, respectively, p = 0.497) and for each isolated component. The risk for Bleeding Academic Research Consortium (BARC) type 1 to 5 or type 3 to 5 bleedings was also similar between patients with CCS and ACS (4.3% vs 5.2%, p = 0.677, and 1.6% vs 2.9%, p = 0.351, respectively). In conclusion, among HBR patients with ACS who underwent PCI with BP-EES, a 1-month DAPT strategy is associated with a similar risk of ischemic and bleeding events compared with those with CCS., Competing Interests: Declaration of Competing Interest Dr. Testa has received consulting fees, personal and institutional honoraria, and has served on the advisory board participation from Abbott, Medtronic, Biotronik, Boston Scientific Corporation, Terumo Lifesciences, Meril, Cardionovum, Concept Medical. Dr. Piccolo has received speaker fees from Abbott Vascular and Biotronik and has served on the advisory board for Daiichi-Sankyo. Dr. De Luca has received speaker fees from AstraZeneca, Daiichi-Sankyo and Sanofi. Dr. Stefanini has received speaker fees from Abbott Vascular, Boston Scientific, and Pfizer (New York, NY, United States)/BMS. The remaining authors have no competing interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The confirmation of a hypothesis that desmoplakin-related (DSP) cardiomyopathy could represent a distinct clinical entity from the classical, RV-dominant, form of arrhythmogenic cardiomyopathy (ACM), most frequently caused by PKP2 mutations, would without any shadow of doubt signify a turning point in the history of this disease. The concept of gene-specific diseases underneath the umbrella diagnosis of ACM would bring fundamental changes not only in the clinical, diagnostic and therapeutic approach, but also in terms of risk stratification, pushing the scientific community towards a more patient-centered view of the disease, similarly to what has already been done in other inherited arrhythmogenic disease (e.g., long QT syndrome [LQTS]). We provide a state-of-the-art review, starting with a brief historical framework to give the necessary context and better focus the question. Then, we proceed with a novel, genotype-to-phenotype-based comparison of the most important aspects of DSP-related cardiomyopathy with the classical, RV-dominant ACM: this allows us to ascertain not only that the differences between the forms exist, but are also clinically relevant and actionable, leading to the underrecognition of the atypical, DSP-related, LV-dominant forms when applying the current diagnostic criteria. These findings will usher an exciting era, in which the scientific community will try to answer a range of questions, starting from the reasons why different desmosomal mutations cause such different phenotypes.

Leprosy is a disease with a clinical spectrum of presentations that is also manifested in diverse histological features. At one pole, lepromatous lesions (L-pole) have phagocytic foamy macrophages heavily parasitized with freely multiplying intracellular Mycobacterium leprae . At the other pole, the presence of epithelioid giant cells and granulomatous formation in tuberculoid lesions (T-pole) lead to the control of M. leprae replication and the containment of its spread. The mechanism that triggers this polarization is unknown, but macrophages are central in this process. Over the past few years, leprosy has been studied using large scale techniques to shed light on the basic pathways that, upon infection, rewire the host cellular metabolism and gene expression. M. leprae is particularly peculiar as it invades Schwann cells in the nerves, reprogramming their gene expression leading to a stem-like cell phenotype. This modulatory behavior exerted by M. leprae is also observed in skin macrophages. Here, we used live M. leprae to infect (10:1 multiplicity of infection) monocyte-derived macrophages (MDMs) for 48 h and analyzed the whole gene expression profile using microarrays. In this model, we observe an intense upregulation of genes consistent with a cellular immune response, with enriched pathways including peptide and protein secretion, leukocyte activation, inflammation, and cellular divalent inorganic cation homeostasis. Among the most differentially expressed genes (DEGs) are CCL5/RANTES and CYP27B1 , and several members of the metallothionein and metalloproteinase families. This is consistent with a proinflammatory state that would resemble macrophage rewiring toward granulomatous formation observed at the T-pole. Furthermore, a comparison with a dataset retrieved from the Gene Expression Omnibus of M. leprae -infected Schwann cells (MOI 100:1) showed that the patterns among the DEGs are highly distinct, as the Schwann cells under these conditions had a scavenging and phagocytic gene profile similar to M2-like macrophages, with enriched pathways rearrangements in the cytoskeleton, lipid and cholesterol metabolism and upregulated genes including MVK , MSMO1 , and LACC1 / FAMIN . In summary, macrophages may have a central role in defining the paradigmatic cellular (T-pole) vs. humoral (L-pole) responses and it is likely that the multiplicity of infection and genetic polymorphisms in key genes are gearing this polarization., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Leal-Calvo, Martins, Bertoluci, Rosa, Camargo, Germano, Brito de Souza, Pereira Latini and Moraes.)

Despite intense efforts, the number of new cases of leprosy has remained significantly high over the past 20 years. Host genetic background is strongly linked to the pathogenesis of this disease, which is caused by Mycobacterium leprae (M. leprae), and there is a consensus that the most significant genetic association with leprosy is attributed to the major histocompatibility complex (MHC). Here, we investigated the association of human leukocyte antigen (HLA) class I and II genes with leprosy in a Brazilian population encompassing 826 individuals from a hyperendemic area of Brazil; HLA typing of class I (-A, -B, -C) and class II (-DRB1, -DQA1, -DQB1, -DPA1, and -DPB1) loci was conducted. Initially, the associations were tested using the chi-square test, with p-values adjusted using the false discovery rate (FDR) method. Next, statistically significant signals of the associations were submitted to logistic regression analyses to adjust for sex and molecular ancestry data. The results showed that HLA-C*08, -DPB1*04, and -DPB1*18 were associated with protective effects, while HLA-C*12 and -DPB1*105 were associated with susceptibility to leprosy. Thus, our findings reveal new associations between leprosy and the HLA-DPB1 locus and confirm previous associations between the HLA-C locus and leprosy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Paracoccidioidomycosis (PCM) is a systemic mycosis caused by thermally dimorphic fungi of the genus Paracoccidioides that affects predominantly 30-60-year-old male rural workers. The main clinical forms of the disease are acute/subacute, chronic (CF); almost all CF patients develop pulmonary fibrosis, and they also exhibit emphysema due to smoke. An important cytokine in this context, IL-1β, different from the others, is produced by an intracellular multimolecular complex called inflammasome that is activated by pathogens and/or host signs of damage. Inflammasome has been recognized for its contribution to chronic inflammatory diseases, from that, we hypothesized that this activation could be involved in paracoccidioidomycosis, contributing to chronic inflammation. While inflammasome activation has been demonstrated in experimental models of Paracoccidioides brasiliensis infection, no information is available in patients, leading us to investigate the participation of NLRP3-inflammasome machinery in CF/PCM patients from a Brazilian endemic area. Our findings showed increased priming in mRNA levels of NLRP3 inflammasome genes by monocytes of PCM patients in vitro than healthy controls. Similar intracellular protein expression of NLRP3, CASP-1, ASC, and IL-1β were also observed in freshly isolated monocytes of PCM patients and smoker controls. Increased expression of NLRP3 and ASC was observed in monocytes from PCM patients under hypoxia in comparison with smoker controls. For the first time, we showed that primed monocytes of CF-PCM patients were associated with enhanced expression of components of NLRP3-inflammasome due to smoke. Also, hypoxemia boosted this machinery. These findings reinforce the systemic low-grade inflammation activation observed in PCM during and after treatment., Competing Interests: Declaration of Competing Interest We declare that the manuscript does not present any potential conflicts of interest., (Copyright © 2019 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.)

Leprosy Type-1 Reactions (T1Rs) are pathological inflammatory responses that afflict a sub-group of leprosy patients and result in peripheral nerve damage. Here, we employed a family-based GWAS in 221 families with 229 T1R-affect offspring with stepwise replication to identify risk factors for T1R. We discovered, replicated and validated T1R-specific associations with SNPs located in chromosome region 10p21.2. Combined analysis across the three independent samples resulted in strong evidence of association of rs1875147 with T1R (p = 4.5x10-8; OR = 1.54, 95% CI = 1.32-1.80). The T1R-risk locus was restricted to a lncRNA-encoding genomic interval with rs1875147 being an eQTL for the lncRNA. Since a genetic overlap between leprosy and inflammatory bowel disease (IBD) has been detected, we evaluated if the shared genetic control could be traced to the T1R endophenotype. Employing the results of a recent IBD GWAS meta-analysis we found that 10.6% of IBD SNPs available in our dataset shared a common risk-allele with T1R (p = 2.4x10-4). This finding points to a substantial overlap in the genetic control of clinically diverse inflammatory disorders.

Leprosy is a chronic infectious disease that requires better understanding since it continues to be a significant health problem in many parts of the world. Leprosy reactions are acute inflammatory episodes regarded as the central etiology of nerve damage in the disease. The activation of endothelium is a relevant phenomenon to be investigated in leprosy reactions. The present study evaluated the expression of endothelial factors in skin lesions and serum samples of leprosy patients. Immunohistochemical analysis of skin samples and serum measurements of VCAM-1, VEGF, tissue factor and thrombomodulin were performed in 77 leprosy patients and 12 controls. We observed significant increase of VCAM-1 circulating levels in non-reactional leprosy (p = 0.0009). The immunostaining of VEGF and tissue factor was higher in endothelium of non-reactional leprosy (p = 0.02 for both) than healthy controls. Patients with type 1 reaction presented increased thrombomodulin serum levels, compared with non-reactional leprosy (p = 0.02). In type 2 reaction, no significant modifications were observed for the endothelial factors investigated. The anti-inflammatory and antimicrobial activities of the endotfhelial factors may play key-roles in the pathogenesis of leprosy and should be enrolled in studies focusing on alternative targets to improve the management of leprosy and its reactions.

Dendritic cells (DCs) play a pivotal role in the connection of innate and adaptive immunity of hosts to mycobacterial infection. Studies on the interaction of monocyte-derived DCs (MO-DCs) using Mycobacterium leprae in leprosy patients are rare. The present study demonstrated that the differentiation of MOs to DCs was similar in all forms of leprosy compared to normal healthy individuals. In vitro stimulation of immature MO-DCs with sonicated M. leprae induced variable degrees of DC maturation as determined by the increased expression of HLA-DR, CD40, CD80 and CD86, but not CD83, in all studied groups. The production of different cytokines by the MO-DCs appeared similar in all of the studied groups under similar conditions. However, the production of interleukin (IL)-12p70 by MO-DCs from lepromatous (LL) leprosy patients after in vitro stimulation with M. leprae was lower than tuberculoid leprosy patients and healthy individuals, even after CD40 ligation with CD40 ligand-transfected cells. The present cumulative findings suggest that the MO-DCs of LL patients are generally a weak producer of IL-12p70 despite the moderate activating properties ofM. leprae. These results may explain the poor M. leprae-specific cell-mediated immunity in the LL type of leprosy.

Background: Type 1 reactions (T1R) affect a considerable proportion of patients with leprosy. In those with T1R, the host immune response pathologically overcompensates for the actual infectious threat, resulting in nerve damage and permanent disability. Based on the results of a genome-wide association study of leprosy per se, we investigated the TNFSF15 chromosomal region for a possible contribution to susceptibility to T1R., Methods: We performed a high-resolution association scan of the TNFSF15 locus to evaluate the association with T1R in 2 geographically and ethnically distinct populations: a family-based sample from Vietnam and a case-control sample from Brazil, comprising a total of 1768 subjects., Results: In the Vietnamese sample, 47 single-nucleotide polymorphisms (SNPs) overlapping TNFSF15 and the adjacent TNFSF8 gene were associated with T1R but not with leprosy. Of the 47 SNPs, 39 were cis-expression quantitative trait loci (cis-eQTL) for TNFSF8 including SNPs located within the TNFSF15 gene. In the Brazilian sample, 18 of these cis-eQTL SNPs overlapping the TNFSF8 gene were validated for association with T1R., Conclusions: Taken together, these results indicate TNFSF8 and not TNFSF15 as an important T1R susceptibility gene. Our data support the need for infection genetics to go beyond genes for pathogen control to explore genes involved in a commensurate host response., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Leprosy is a complex disease with phenotypes strongly influenced by genetic variation. A Chinese genome-wide association study (GWAS) depicted novel genes and pathways associated with leprosy susceptibility, only partially replicated by independent studies in different ethnicities. Here, we describe the results of a validation and replication study of the Chinese GWAS in Brazilians, using a stepwise strategy that involved two family-based and three independent case-control samples, resulting in 3,614 individuals enrolled. First, we genotyped a family-based sample for 36 tag single-nucleotide polymorphisms (SNPs) of five genes located in four different candidate loci: CCDC122-LACC1, NOD2, TNFSF15 and RIPK2. Association between leprosy and tag SNPs at NOD2 (rs8057431) and CCDC122-LACC1 (rs4942254) was then replicated in three additional, independent samples (combined OR(AA) = 0.49, P = 1.39e-06; OR(CC) = 0.72, P = 0.003, respectively). These results clearly implicate the NOD2 pathway in the regulation of leprosy susceptibility across diverse populations.

Iron is essential for all organisms and its availability can control the growth of microorganisms; therefore, we examined the role of iron metabolism in multibacillary (MB) leprosy, focusing on the involvement of hepcidin. Erythrograms, iron metabolism parameters, pro-inflammatory cytokines and urinary hepcidin levels were evaluated in patients with MB and matched control subjects. Hepcidin expression in MB lesions was evaluated by quantitative polymerase chain reaction. The expression of ferroportin and hepcidin was evaluated by immunofluorescence in paucibacillary and MB lesions. Analysis of hepcidin protein levels in urine and of hepcidin mRNA and protein levels in leprosy lesions and skin biopsies from healthy control subjects showed elevated hepcidin levels in MB patients. Decreases in haematologic parameters and total iron binding capacity were observed in patients with MB leprosy. Moreover, interleukin-1 beta, ferritin, soluble transferrin receptor and soluble transferrin receptor/log ferritin index values were increased in leprosy patients. Hepcidin was elevated in lepromatous lesions, whereas ferroportin was more abundant in tuberculoid lesions. In addition, hepcidin and ferroportin were not colocalised in the biopsies from leprosy lesions. Anaemia was not commonly observed in patients with MB; however, the observed changes in haematologic parameters indicating altered iron metabolism appeared to result from a mixture of anaemia of inflammation and iron deficiency. Thus, iron sequestration inside host cells might play a role in leprosy by providing an optimal environment for the bacillus.