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The hallmark of chronic Chagas' disease cardiomyopathy (CCC) is the finding of a T cell-rich inflammatory mononuclear cell infiltrate in the presence of extremely few parasites in the heart lesions. The scarcity of parasites in affected heart tissue casts doubt on the direct participation of Trypanosoma cruzi in CCC heart tissue lesions, and suggests the possible involvement of autoimmunity. The cells in the infiltrate are presumably the ultimate effectors of tissue damage, and there is evidence that such cells recognize cardiac myosin in molecular mimicry with T. cruzi proteins rather than primary reactivity to T. cruzi antigens (Cunha-Neto et al. (1996) Journal of Clinical Investigation, 98: 1709-1712). Recently, we have studied heart-infiltrating T cells at the functional level. In this short review we summarize the studies about the role of cytokines in human and experimental T. cruzi infection, along with our data on heart-infiltrating T cells in human Chagas' cardiomyopathy. The bulk of evidence points to a significant production of IFN-g and TNF-a which may be linked to T. cruzi-induced IL-12 production

PURPOSE:To determine the indication for and incidence and evolution of temporary and permanent pacemaker implantation in cardiac transplant recipients. METHODS: A retrospective review of 114 patients who underwent orthotopic heart transplantation InCor (Heart Institute USP BR) between March 1985 and May 1993. We studied the incidence of and indication for temporary pacing, the relationship between pacing and rejection, the need for pemanent pacing and the clinical follow-up. RESULTS: Fourteen of 114 (12%)heart transplant recipients required temporary pacing and 4 of 114 (3.5%) patients required permanent pacing. The indication for temporary pacing was sinus node dysfunction in 11 patients (78.5%) and atrioventricular (AV) block in 3 patients (21.4%). The indication for permanent pacemaker implantation was sinus node dysfunction in 3 patients (75%) and atrioventricular (AV) block in 1 patient (25%). We observed rejection in 3 patients (21.4%) who required temporary pacing and in 2 patients (50%) who required permanent pacing. The previous use of amiodarone was observed in 10 patients (71.4%) with temporary pacing. Seven of the 14 patients (50%) died during follow-up. CONCLUSION: Sinus node dysfunction was the principal indication for temporary and permanent pacemaker implantation in cardiac transplant recipients. The need for pacing was related to worse prognosis after cardiac transplantation.

Background: In pulmonary hypertension (PH), the identification of easily obtainable prognostic markers associated with right ventricular (RV) dysfunction and survival is needed., Objective: To evaluate the association of red cell distribution width (RDW) with clinical, echocardiographic parameters and survival in patients with pre-capillary PH, with the development of a mortality prediction model., Methods: Observational, longitudinal, and prospective study conducted from May 2019 to December 2022. Thirty-four patients with pre-capillary PH underwent two-dimensional echocardiography and complete blood count. A cutoff point of 14.5% was considered to define RDW as altered (≥14.5%) or normal (<14.5%). P values <0.05 were considered significant., Results: The median RDW was 14.4%. There was a significant difference in peripheral arterial oxygen saturation (SpO2) (p=0.028), RV strain (p=0.047), and pericardial effusion (p=0.002) between the normal and elevated RDW groups. During a median follow-up of 15 months, 20.6% died. Patients with increased RDW had a shorter overall survival (44.7%, log-rank p=0.019), which was a predictor of mortality in univariate Cox regression (HR 8.55, p=0.048). The addition of RV strain <16% and SpO2 ≤93% to the model including RDW alone showed incremental value in predicting mortality (χ2=8.2, p=0.049; χ2=12.4, p=0.041), with increased area under the receiver operating characteristic curve (0.729 vs. 0.837 vs. 0.909) and decreased probability of survival (44.7% vs. 35.6% vs. 25%, log-rank p=0.019)., Conclusions: RDW provides information on the severity of pre-capillary PH by correlating with echocardiographic parameters of RV dysfunction and mortality, which is best predicted by a model including RDW, RV strain and SpO2.

Background: Central Illustration : Percutaneous Strategies in Structural Heart Diseases: Focus on Chronic Heart Failure Transcatheter devices for monitoring and treating advanced chronic heart failure patients. PA: pulmonary artery; LA: left atrium; AFR: atrial flow regulator; TASS: Transcatheter Atrial Shunt System; VNS: vagus nerve stimulation; BAT: baroreceptor activation therapy; RDN: renal sympathetic denervation; F: approval by the American regulatory agency (FDA); E: approval by the European regulatory agency (CE Mark)., Background: Innovations in devices during the last decade contributed to enhanced diagnosis and treatment of patients with cardiac insufficiency. These tools progressively adapted to minimally invasive strategies with rapid, widespread use. The present article focuses on actual and future directions of device-related diagnosis and treatment of chronic heart failure.

Objectives: To measure Quality of Life (QoL) and costs of Heart Failure (HF) outpatients in Brazil as an introduction to the Value-Based Health Care (VBHC) concept., Materials and Methods: Cross-sectional study, patients with HF, with ejection fraction <50%, were recruited from three hospitals in Brazil. Two QoL (36-Item Short Form Survey [SF-36] and Minnesota Living with Heart Failure Questionnaire [MLHFQ]) and two anxiety/depression questionnaires were applied. SF-36 scores were stratified by domains. Treatment costs were calculated using the Time-Driven Activity-Based Costing (TDABC) method. Results were stratified by NYHA functional class and sex., Results: From October 2018 to January 2021, 198 patients were recruited, and the median MLHFQ (49.5 [IQR 21.0, 69.0]) and SF-36 scores demonstrated poor QoL, worse at higher NYHA classes. A third of patients had moderate/severe depression and anxiety symptoms, and women had higher anxiety scores. Mean costs of outpatient follow-up were US$ 215 ± 238 for NYHA I patients, US$ 296 ± 399 for NYHA II and US$ 667 ± 1012 for NYHA III/IV. Lab/exam costs represented 30% of the costs in NYHA I, and 74% in NYHA III/IV (US$ 63.26 vs. US$ 491.05)., Conclusion: Patients with HF in Brazil have poor QoL and high treatment costs; both worsen as the NYHA classification increases. It seems that HF has a greater impact on the mental health of women. Costs increase mostly related to lab/exams. Accurate and crossed information about QoL and costs is essential to drive care and reimbursement strategies based on value., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 HCFMUSP. Published by Elsevier España, S.L.U. All rights reserved.)

Chagas' disease (CD) is an important cause of heart transplantation (HT). The main obstacle is Chagas' disease reactivation (CDR), usually associated to high doses of immunosuppressants. Previous studies have suggested an association of mycophenolate mofetil with increased CDR. However, mortality predictors are unknown. To identify mortality risk factors in heart transplant patients with CD and the impact of antiproliferative regimen on survival. Retrospective study with CD patients who underwent HT between January 2004 and September 2020, under immunosuppression protocol that prioritized azathioprine and change to mycophenolate mofetil in case of rejection. We performed univariate regression to identify mortality predictors; and compared survival, rejection and evidence of CDR between who received azathioprine, mycophenolate mofetil and those who changed from azathioprine to mycophenolate mofetil after discharge ("Change" group). A p-value < 0.05 was considered statistically significant. Eighty-five patients were included, 54.1% men, median age 49 (39-57) years, and 91.8% were given priority in waiting list. Nineteen (22.4%) used azathioprine, 37 (43.5%) mycophenolate mofetil and 29 (34.1%) switched therapy; survival was not different between groups, 2.9 (1.6-5.0) x 2.9 (1.8-4.8) x 4.2 (2.0-5.0) years, respectively; p=0.4. There was no difference in rejection (42%, 73% and 59% respectively; p=0.08) or in CDR (T. cruzi positive by endomyocardial biopsy 5% x 11% x 7%; p=0.7; benznidazole use 58% x 65% x 69%; p=0.8; positive PCR for T. cruzi 20% x 68% x 42% respectively; p=0.1) rates. This retrospective study did not show difference in survival in heart transplant patients with CD receiving different antiproliferative regimens. Mycophenolate mofetil was not associated with statistically higher rates of CDR or graft rejection in this cohort. New randomized clinical trials are necessary to address this issue.

Dual antiplatelet therapy (DAPT) is currently the standard of care after percutaneous coronary intervention (PCI). Recent studies suggest that reducing DAPT to 1-3 months followed by an aspirin-free single antiplatelet therapy (SAPT) strategy with a potent P2Y 12 inhibitor is safe and associated with less bleeding. However, to date, no randomised trial has tested the impact of initiating SAPT immediately after PCI, particularly in patients with acute coronary syndromes (ACS). NEOMINDSET is a multicentre, randomised, open-label trial with a blinded outcome assessment designed to compare SAPT versus DAPT in 3,400 ACS patients undergoing PCI with the latest-generation drug-eluting stents (DES). After successful PCI and up to 4 days following hospital admission, patients are randomised to receive SAPT with a potent P2Y 12 inhibitor (ticagrelor or prasugrel) or DAPT (aspirin plus a potent P2Y 12 inhibitor) for 12 months. Aspirin is discontinued immediately after randomisation in the SAPT group. The choice between ticagrelor and prasugrel is at the investigator's discretion. The primary hypothesis is that SAPT will be non-inferior to DAPT with respect to the composite endpoint of all-cause mortality, stroke, myocardial infarction or urgent target vessel revascularisation, but superior to DAPT on rates of bleeding defined by Bleeding Academic Research Consortium 2, 3 or 5 criteria. NEOMINDSET is the first study that is specifically designed to test SAPT versus DAPT immediately following PCI with DES in ACS patients. This trial will provide important insights on the efficacy and safety of withdrawing aspirin in the early phase of ACS. (ClinicalTrials.gov: NCT04360720).

Introduction: Heart transplantation represents main therapy for end-stage heart failure. However, survival after transplantation is limited by development of graft rejection. Endomyocardial biopsy, an invasive and expensive procedure, is gold standard technique for diagnosis of rejection. Most of biopsy complications are observed using echocardiography. Novel echocardiographic techniques, such as myocardial strain and three-dimensional reconstruction, can be useful in heart transplant patients., Purpose: To evaluate ventricular strain in heart transplant patients and association with rejection, cellular or humoral, as well as two- and three-dimensional echocardiographic parameters., Methods: Cohort of patients from heart transplant program taken to echocardiography after endomyocardial biopsy, from December 2017 to January 2020. Ventricular strain and three-dimensional left ventricle parameters were studied. Rejection results were retrieved from medical record. Qualitative variables were expressed by absolute frequency and percentages, while continuous variables by means and standard deviations. Association between rejection and variables of interest was measured by odds ratio and confidence interval of 95%, with p -value < 0.05., Results: 123 post-endomyocardial biopsy echocardiographic exams were performed in 54 patients. Eighteen exams were excluded, lasting 105 exams to be evaluated for conventional and advanced echocardiographic parameters. Male patients were 60.4%. Prevalence of cellular rejection was 8.6%, humoral rejection 12.4%, and rejection of any type 20%. There was no association between right ventricular strain and rejection, whether cellular ( p = 0.118 and p = 0.227 for septum and free wall, respectively), humoral ( p = 0.845 and p = 0.283, respectively), or of any type (0.504 and 0.446). There was no correlation between rejection and left ventricle global longitudinal strain, three-dimensional ejection fraction or desynchrony index. Conventional parameters associated to rejection were left ventricle posterior wall thickness [OR 1.660 (1.163; 2.370), p = 0.005] and left ventricle mass index [OR 1.027 (1.011; 1.139), p = 0.001]. Left ventricle posterior wall thickness remained significant after analysis of cellular and humoral rejection separately [OR 1.825 (1.097; 3.036), p = 0.021 and OR 1.650 (1.028; 2.648), p = 0.038, respectively]., Conclusions: There was no association between ventricular strain, three-dimensional left ventricular ejection fraction and the desynchrony index and rejection, cellular or humoral. Evidence of association of graft rejection with left ventricle posterior wall thickness and left ventricle mass index was observed., 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 © 2022 Costa, Rodrigues, Vieira, Fischer, Monaco, Filho, Bacal, Caixeta and Morhy.)

Chagas disease, caused by the protozoan Trypanosoma cruzi , is an endemic parasitic disease of Latin America, affecting 7 million people. Although most patients are asymptomatic, 30% develop complications, including the often-fatal Chronic Chagasic Cardiomyopathy (CCC). Although previous studies have demonstrated some genetic deregulations associated with CCCs, the causes of their deregulations remain poorly described. Based on bulk RNA-seq and whole genome DNA methylation data, we investigated the genetic and epigenetic deregulations present in the moderate and severe stages of CCC. Analysis of heart tissue gene expression profile allowed us to identify 1407 differentially expressed transcripts (DEGs) specific from CCC patients. A tissue DNA methylation analysis done on the same tissue has permitted the identification of 92 regulatory Differentially Methylated Regions (DMR) localized in the promoter of DEGs. An in-depth study of the transcription factors binding sites (TFBS) in the DMRs corroborated the importance of TFBS's DNA methylation for gene expression in CCC myocardium. TBX21, RUNX3 and EBF1 are the transcription factors whose binding motif appears to be affected by DNA methylation in the largest number of genes. By combining both transcriptomic and methylomic analysis on heart tissue, and methylomic analysis on blood, 4 biological processes affected by severe CCC have been identified, including immune response, ion transport, cardiac muscle processes and nervous system. An additional study on blood methylation of moderate CCC samples put forward the importance of ion transport and nervous system in the development of the disease., 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 © 2022 Brochet, Ianni, Laugier, Frade, Silva Nunes, Teixeira, Mady, Ferreira, Ferré, Santos, Kuramoto, Cabantous, Steffen, Stolf, Pomerantzeff, Fiorelli, Bocchi, Pissetti, Saba, Cândido, Dias, Sampaio, Gaiotto, Marin-Neto, Fragata, Zaniratto, Siqueira, Peixoto, Rigaud, Bacal, Buck, Almeida, Lin-Wang, Schmidt, Martinelli, Hirata, Donadi, Costa Pereira, Rodrigues Junior, Puthier, Kalil, Spinelli, Cunha-Neto and Chevillard.)

Chronic Chagas disease (CCC) is an inflammatory dilated cardiomyopathy with a worse prognosis compared to other cardiomyopathies. We show the expression and activity of Matrix Metalloproteinases (MMP) and of their inhibitors TIMP (tissue inhibitor of metalloproteinases) in myocardial samples of end stage CCC, idiopathic dilated cardiomyopathy (DCM) patients, and from organ donors. Our results showed significantly increased mRNA expression of several MMPs, several TIMPs and EMMPRIN in CCC and DCM samples. MMP-2 and TIMP-2 protein levels were significantly elevated in both sample groups, while MMP-9 protein level was exclusively increased in CCC. MMPs 2 and 9 activities were also exclusively increased in CCC. Results suggest that the balance between proteins that inhibit the MMP-2 and 9 is shifted toward their activation. Inflammation-induced increases in MMP-2 and 9 activity and expression associated with imbalanced TIMP regulation could be related to a more extensive heart remodeling and poorer prognosis in CCC patients., 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 © 2022 Baron, Ferreira, Teixeira, Moretti, Santos, Frade, Kuramoto, Debbas, Benvenuti, Gaiotto, Bacal, Pomerantzeff, Chevillard, Kalil and Cunha-Neto.)

Objectives: Acute cellular rejection (ACR) remains a major complication of heart transplant (HT). The gold standard for its diagnosis is endomyocardial biopsy (EMB), whereas the role of non-invasive biomarkers for detecting ACR is unclear. This study aimed to identify non-invasive biomarkers for the diagnosis of ACR in patients undergoing HT and presenting with normal left ventricular function., Methods: We evaluated patients who underwent HT at a single center between January 2010 and June 2019. Patients were enrolled after HT, and those with left ventricular (LV) systolic dysfunction before EMB were excluded. We included only the results of the first EMB performed at least 30 days after HT (median, 90 days). Troponin, B-type natriuretic peptide (BNP), and C-reactive protein (CRP) levels were measured and echocardiography was performed up to 7 days before EMB. ACR was defined as International Society for Heart and Lung Transplantation grade 2R or 3R on EMB. We performed logistic regression analysis to identify the non-invasive predictors of ACR (2R or 3R) and evaluated the accuracy of each using area under the receiver operator characteristic curve analysis., Results: We analyzed 72 patients after HT (51.31±13.63 years; 25 [34.7%] women); of them, 9 (12.5%) developed ACR. Based on multivariate logistic regression analysis, we performed forward stepwise selection (entry criteria, p<0.05). The only independent predictors that remained in the model were CRP level and LV mass index. The optimal cut-off point for CRP level was ≥15.9 mg/L (odds ratio [OR], 11.7; p=0.007) and that for LV mass index was ≥111 g/m2 (OR, 13.6; p=0.003). The area under the receiver operating characteristic curve derived from this model was 0.87 (95% confidence interval [CI], 0.75-0.99), with sensitivity of 85.7% (95% CI, 42.1%-99.6%), specificity of 78.4% (95% CI, 64.7%-88.7%), positive predictive value of 35.3% (95% CI, 14.3%-61.7%), and negative predictive value of 97.6% (95% CI, 87.1%-99.9%)., Conclusions: Among patients undergoing HT, CRP level and LV mass were directly associated with ACR, but troponin and BNP levels were not.

Infection by the protozoan Trypanosoma cruzi causes Chagas disease cardiomyopathy (CCC) and can lead to arrhythmia, heart failure and death. Chagas disease affects 8 million people worldwide, and chronic production of the cytokines IFN-γ and TNF-α by T cells together with mitochondrial dysfunction are important players for the poor prognosis of the disease. Mitochondria occupy 40% of the cardiomyocytes volume and produce 95% of cellular ATP that sustain the life-long cycles of heart contraction. As IFN-γ and TNF-α have been described to affect mitochondrial function, we hypothesized that IFN-γ and TNF-α are involved in the myocardial mitochondrial dysfunction observed in CCC patients. In this study, we quantified markers of mitochondrial dysfunction and nitro-oxidative stress in CCC heart tissue and in IFN-γ/TNF-α-stimulated AC-16 human cardiomyocytes. We found that CCC myocardium displayed increased levels of nitro-oxidative stress and reduced mitochondrial DNA as compared with myocardial tissue from patients with dilated cardiomyopathy (DCM). IFN-γ/TNF-α treatment of AC-16 cardiomyocytes induced increased nitro-oxidative stress and decreased the mitochondrial membrane potential (ΔΨm). We found that the STAT1/NF-κB/NOS2 axis is involved in the IFN-γ/TNF-α-induced decrease of ΔΨm in AC-16 cardiomyocytes. Furthermore, treatment with mitochondria-sparing agonists of AMPK, NRF2 and SIRT1 rescues ΔΨm in IFN-γ/TNF-α-stimulated cells. Proteomic and gene expression analyses revealed that IFN-γ/TNF-α-treated cells corroborate mitochondrial dysfunction, transmembrane potential of mitochondria, altered fatty acid metabolism and cardiac necrosis/cell death. Functional assays conducted on Seahorse respirometer showed that cytokine-stimulated cells display decreased glycolytic and mitochondrial ATP production, dependency of fatty acid oxidation as well as increased proton leak and non-mitochondrial oxygen consumption. Together, our results suggest that IFN-γ and TNF-α cause direct damage to cardiomyocytes' mitochondria by promoting oxidative and nitrosative stress and impairing energy production pathways. We hypothesize that treatment with agonists of AMPK, NRF2 and SIRT1 might be an approach to ameliorate the progression of Chagas disease cardiomyopathy., 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 Nunes, Andrieux, Brochet, Almeida, Kitano, Honda, Iwai, Andrade-Silva, Goudenège, Alcântara Silva, Vieira, Levy, Bydlowski, Gallardo, Torres, Bocchi, Mano, Santos, Bacal, Pomerantzeff, Laurindo, Teixeira, Nakaya, Kalil, Procaccio, Chevillard and Cunha-Neto.)