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PURPOSE This study was aimed to determine the magnitude and predictors of self-reported short/long sleep duration (SDUR) reclassifications using objective measurements. METHODS Adult participants from the ELSA-Brasil study performed self-reported SDUR, 7-day wrist actigraphy, and a portable sleep study. We explored two strategies of defining self-reported SDUR reclassification: (1) short and long SDUR defined by 9 h). RESULTS Data from 2036 participants were used in the final analysis (43% males; age: 49±8 years). Self-reported SDUR were poorly correlated (r=0.263) and presented a low agreement with actigraphy-based total sleep time. 58% of participants who self-reported short SDUR were reclassified into the reference (6-7.99 h) or long SDUR groups using actigraphy data. 88% of participants that self-reported long SDUR were reclassified into the reference and short SDUR. The variables independently associated with higher likelihood of self-reported short SDUR reclassification included insomnia (3.5-fold), female (2.5-fold), higher sleep efficiency (1.35-fold), lowest O2 saturation (1.07-fold), higher wake after sleep onset (1.08-fold), and the higher number of awakening (1.05-fold). The presence of hypertension was associated with a 3.4-fold higher chance of self-reported long SDUR reclassification. Analysis of five self-reported SDUR categories revealed that the more extreme is the SDUR, the greater the self-reported SDUR reclassification. CONCLUSION In adults, we observed a significant rate of short/long SDUR reclassifications when comparing self-reported with objective data. These results underscore the need to reappraise subjective data use for future investigations addressing SDUR.

Background Limited evidence is available addressing the potential role of sleep disorders on renal function. Here, we aimed to explore the associations of obstructive sleep apnea (OSA) and sleep duration (SD) with renal function in subjects with high cardiovascular risk. Methods Consecutive subjects with coronary artery disease (CAD) underwent clinical evaluation, sleep study to define OSA and one-week wrist actigraphy to objectively measure SD. OSA was defined by an apnea-hypopnea index (AHI) of ≥15 events/hour. The estimated glomerular filtration rate (eGFR) was calculated using the CKD-EPI equation. We analyzed the associations of OSA and SD with continuous eGFR values and according to the presence of CKD (eGFR Results We studied 242 subjects (62.8% men). The frequency of OSA was 55.4% and the median SD was 412.8 (363.4–457.25) min. There was no difference in the eGFRs between participants with and without OSA (69.3 ± 19.1 vs. 74.6 ± 19.3 mL/min/1.73 m2, p = 0.72) and the rate of eGFR Conclusion OSA severity and SD were not independently associated with CKD in subjects with CAD.

Objective Adiposity is a well-established risk factor for obstructive sleep apnea (OSA) but the existence of a preferable anthropometric measurement is not established or whether the combination of measurements may improve the accuracy to detect OSA. This study aimed to compare the accuracies of body mass index (BMI), several surrogate markers of body fat (in isolation or combined) and validated questionnaires for screening OSA. Methods A total of 2059 participants from the ELSA-Brasil study given anthropometric measurements using standard procedures and a home sleep study. OSA was defined by an apnea-hypopnea index ≥15 events/hour. Results The frequency of OSA was 32.3%. Compared with the non-OSA group, all anthropometric measurements were higher in the OSA group. Age and gender-adjusted BMI afforded the highest accuracy to detect OSA [AUC = 0.760 (0.739–0.781)], followed by waist [AUC = 0.753 (0.732–0.775)] and neck [AUC = 0.733 (0.711–0.755)] circumferences, waist-to-hip ratio [AUC = 0.722 (0.699–0.745)] and body shape index [AUC = 0.680 (0.656–0.704)]. The combination of two or more anthropometric measurements did not improve the accuracy of BMI in predicting OSA. The adjusted BMI had similar predictive performance to the NoSAS score [AUC = 0.748 (0.727–0.770)] but a better accuracy than the Berlin Questionnaire [AUC = 0.676 (0.653–0.699)]. Conclusions Despite one's intuition, surrogate markers of regional adiposity are not better than BMI in screening OSA. Combining measurements of global and/or regional adiposity did not have additional value in detecting OSA. The merely fair accuracy range of BMI and sleep questionnaires underscore the need for additional tools to improve OSA underdiagnosis.

Chagas disease, caused by Trypanosoma cruzi, is an endemic parasitical disease of Latin America, affecting 7 million people. Although most patients are asymptomatic, 30% develop complications, including Chronic Chagasic Cardiomyopathy (CCC), which ranges from moderate to severe stages depending on the cardiac ejection fraction. The pathogenic process remains poorly understood, although genetic and epigenetic factors have already been proposed.Based on bulk RNA-seq and EPIC methylation data, we investigated the genetic and epigenetic deregulations present in the moderate and severe stages of CCC. We identified 4 main biological processes associated with the pathology development, including immune response, ion transport, cardiac muscle processes and nervous system. An in-depth study of the transcription factors binding sites in the differentially methylated regions corroborated the importance of these processes. We also conducted a methylation study on blood to identify potential biomarkers for CCC. Our data revealed 198 differentially methylated positions (DMPs) that could serve as biomarkers of the disease, of which 61 are associated with disease severity.

Background OSA and short sleep duration (SSD) are frequently associated with daytime symptoms and cardiometabolic deregulation. However, the vast majority of studies addressing OSA have not evaluated SSD, and vice versa. Our aim was to evaluate the association of OSA, SSD, and their interactions with sleepiness and cardiometabolic risk factors in a large cohort of adults. Methods Consecutive subjects from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) participated in clinical evaluations, sleep questionnaires, home sleep monitoring, and actigraphy. OSA was defined as an apnea-hypopnea index ≥ 15 events/hour. SSD was defined by a mean sleep duration Results Data from 2,064 participants were used in the final analysis (42.8% male; mean age, 49 ± 8 years). The overall frequency of OSA and SSD were 32.9% and 27.2%, respectively. Following an adjustment for multiple confounding factors, excessive daytime sleepiness was independently associated with SSD (OR, 1.448; 95% CI, 1.172-1.790) but not with OSA (OR, 1.107; 95% CI, 0.888-1.380). The SSD interaction with OSA was not significant. Prevalent obesity (OR, 3.894; 95% CI, 3.077-4.928), hypertension (OR, 1.314; 95% CI, 1.035-1.667), and dyslipidemia (OR, 1.251; 95% CI, 1.006-1.555) were independently associated with OSA but not with SSD. Similarly, the interactions of OSA with SSD were not significant. An additional analysis using Conclusions Objective SSD but not OSA was independently associated with daytime sleepiness. By contrast, OSA, but not SSD, was independently associated with obesity, hypertension, and dyslipidemia.

Objective: Polygraphy (PG) is an attractive alternative for diagnosing obstructive sleep apnea (OSA) in patients with high pre-test probability. However, several patients may not present typical symptoms. In this scenario, it is unclear the performance of PG for diagnosing OSA in nonreferred populations to sleep laboratories. Methods: Data from participants of the ELSA-Brasil cohort were used for this analysis. We performed an overnight home PG (Embletta GoldTM) synchronized with a wrist actigraphy (Actiwatch model 2TM). The validation strategy comprised three scorings from each participant: 1) Original scoring (PG): Routine scoring using data from the exclamation button mark to define “analysis start” and “analysis stop”; 2) Scoring using actigraphy data (PG+actigraphy): total sleep time defined by the actigraphy data; 3) Scoring using diaries (PG+diary): “analysis start” and “analysis stop” based on the diaries. Bland-Altman plots were generated to assess the agreements (Kappa) between each scoring strategy. Results: A total of 300 participants were included in the final analysis (45% males, mean age: 48±8 years). The frequency of OSA using the PG score was 27.3%. Despite small differences in the OSA severity index, we obtained a high concordance of AHI comparing the PG vs. PG+actigraphy (Kappa: 0.95) as well as PG+diary vs. PG+actigraphy (Kappa: 0.96). No significant changes in the OSA classification (mild, moderate and severe) were observed in the 3 protocols. Conclusion: Using a pragmatic approach to address OSA at home, our results suggest that PG is a useful tool for OSA diagnosis even in subjects not referred to sleep studies.

Objective: To elucidate the independent associations of obstructive sleep apnea (OSA) and sleep duration (SD) as well as the potential inflammatory and metabolic mediators on carotid intima-media thickness (CIMT) in a large cohort of adults. Approach and Results: Consecutive participants from the ELSA-Brasil performed a clinical evaluation, sleep study, 1-week actigraphy for defining SD and CIMT using standard techniques. Gamma regression models were used to explore the association between OSA and SD with CIMT. Mediation analysis was performed using the mediation R package. A total of 2009 participants were included in the main analysis. As compared with no OSA (apnea-hypopnea index [AHI] P 8 hours (0.740 [0.670–0.900]). All forms of OSA were independently associated with CIMT (mild: β: 0.019, SE 0.008; P =0.022; moderate: β: 0.025, SE 0.011; P =0.022; severe OSA: β: 0.040, SE 0.013; P =0.002). Moreover, the association of AHI with CIMT was mediated by increased C-reactive protein and triglycerides ( P Conclusions: OSA is independently associated with increased CIMT in a dose-response relationship. This association is partially mediated by inflammation and dyslipidemia. In contrast, SD is not associated nor interacted with OSA to increase CIMT.

Objective Every one-hour change in sleep duration (SDUR) has a dose-response impact on cardiovascular disease and mortality. However, self-reported SDUR may not represent the real sleep time in a significant proportion of the adult population. This study was designed to determine the frequency of potential SDUR under/overestimation when comparing subjective versus objective SDUR data. Methods Consecutive adults from the ELSA-Brasil study collected subjective SDUR and underwent wrist actigraphy for seven days. We defined SDUR underestimation (underSDUR) and overestimation (overSDUR) when the differences between subjective and objective SDUR reached at least -1/+1-hour, respectively. We performed multinomial logistic regression analyses to identify independent factors of under- and overSDUR. Results Data from 2,036 participants were used in the final analysis (42.7% males; age: 49±8 years). The frequency of underSDUR and overSDUR were 19.4% and 19.7%, respectively. The predictors of underSDUR included black race (OR: 1.65; 95% CI: 1.79–3.93), mixed-race (OR: 1.69; 95% CI: 1.20–2.38); daytime sleepiness (OR: 1.37; 95% CI: 1.05–1.80); longer objective SDUR (OR: 3.00; 95% CI: 2.54–3.56); longer wake time after sleep onset time, WASO (OR: 2.19; 95% CI: 1.22–3.95), and moderate/severe insomnia (OR: 2.54; 95% CI: 1.78–3.63). Longer WASO (OR: 2.26; 95% CI: 1.33–3.82), and a higher number of awakenings (OR: 1.02; 95% CI: 1.00–1.03) were independently associated with overSDUR. Conclusions We found a significant rate of SDUR under/overestimation when comparing subjective versus objective data. While underSDUR was independently associated with black/mixed race, daytime sleepiness, longer SDUR and WASO, overSDUR was specifically associated with markers of sleep fragmentation.

Chronic Chagas disease cardiomyopathy (CCC), an especially aggressive inflammatory dilated cardiomyopathy caused by lifelong infection with the protozoan Trypanosoma cruzi, is a major cause of cardiomyopathy in Latin America. Although chronic myocarditis may play a major pathogenetic role, little is known about the molecular mechanisms responsible for its severity. The aim of this study is to study the genes and microRNAs expression in tissues and their connections in regards to the pathobiological processes. To do so, we integrated for the first time global microRNA and mRNA expression profiling from myocardial tissue of CCC patients employing pathways and network analyses. We observed an enrichment in biological processes and pathways associated with the immune response and metabolism. IFNγ, TNF and NFkB were the top upstream regulators. The intersections between differentially expressed microRNAs and differentially expressed target mRNAs showed an enrichment in biological processes such as Inflammation, inflammation, Th1/IFN-γ-inducible genes, fibrosis, hypertrophy, and mitochondrial/oxidative stress/antioxidant response. MicroRNAs also played a role in the regulation of gene expression involved in the key cardiomyopathy-related processes fibrosis, hypertrophy, myocarditis and arrhythmia. Significantly, a discrete number of differentially expressed microRNAs targeted a high number of differentially expressed mRNAs (>20) in multiple processes. Our results suggest that miRNAs orchestrate expression of multiple genes in the major pathophysiological processes in CCC heart tissue. This may have a bearing on pathogenesis, biomarkers and therapy., Author summary Chronic Chagas disease cardiomyopathy (CCC), an aggressive dilated cardiomyopathy caused by Trypanosoma cruzi, is a major cause of cardiomyopathy in Latin America. Little is known about the molecular mechanisms responsible for its severity. Authors study the possible role of microRNAs in the regulation of gene expression in relevant pathways and pathobiological processes. Differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) -small RNAs that can regulate gene expression—associated to severe cardiomyopathy development. The inflammatory mediator Interferon-γ was the most likely inducer of gene expression in CCC, and most genes belonged to the immune response, fibrosis, hypertrophy and mitochondrial metabolism. A discrete number of differentially expressed mRNAs targeted a high number of differentially expressed mRNAs in multiple processes. Moreover, several pathways had multiple targets regulated by microRNAs, suggesting synergic effect. Results suggest that microRNAs orchestrate expression of multiple genes in the major pathophysiological processes in CCC heart tissue.

Obstructive sleep apnea (OSA) may contribute to metabolic and inflammatory deregulation but previous studies failed to consider sleep duration, sleep fragmentation, insomnia, and daytime sleepiness as potential confounders. Consecutive non-diabetic middle-aged participants from the ELSA-Brasil cohort were invited to perform a clinical evaluation, home sleep study for 1 night, and wrist actigraphy for 7 days. OSA was defined by an apnea-hypopnea index ≥ 15 events/h. Participants were stratified according to the presence of OSA measuring the following markers: fasting glucose, glucose tolerance test, homeostatic model assessment of insulin resistance (HOMA-IR) index, fasting insulin, insulin after 2 h of glucose load, glycated hemoglobin, total cholesterol and their fractions, triglycerides, C-reactive protein, TNF-alpha, interleukin-6, interleukin-10, leptin, adiponectin, E-selectin, ADMA, MCP-1, TGF, apolipoprotein B, fibrinogen, and lipoprotein(a). Differences between groups were identified by chi-square test and ANOVA. We studied 708 participants (mean age: 46 ± 5 years, men: 44%, BMI 26.1 ± 4.1 kg/m2). Compared to no OSA, participants with OSA presented higher levels while fasting and after 2 h glucose load of insulin, HOMA-IR, cholesterol, triglycerides, and C-reactive protein (all p < 0.001). After linear regression analysis adjusting for traditional risk factors plus sleep duration, fragmentation, insomnia, and daytime sleepiness, OSA was negatively associated with adiponectin (β = − 0.271 CI 95% − 0.456 − 0.085) and positively associated with cholesterol (β = 9.707 CI 95% 2.737 16.678). Sex-stratification revealed that these associations were significant for men but not women. In non-diabetic middle-age adults, men with OSA presented with lower adiponectin and higher cholesterol levels independently of sleep duration, sleep fragmentation, insomnia, and daytime sleepiness.

Summary DNA methylation analysis on global gene expression in myocardial samples from patients with end-stage chronic Chagas cardiomyopathy leads to the identification of novel potential disease pathways and therapeutic targets linked to electrical conduction or immune response modulation., Background Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America and affects 10 million people worldwide. Approximately 12000 deaths attributable to Chagas disease occur annually due to chronic Chagas disease cardiomyopathy (CCC), an inflammatory cardiomyopathy presenting with heart failure and arrythmia; 30% of infected subjects develop CCC years after infection. Genetic mechanisms play a role in differential progression to CCC, but little is known about the role of epigenetic modifications in pathological gene expression patterns in CCC patients’ myocardium. DNA methylation is the most common modification in the mammalian genome. Methods We investigated the impact of genome-wide cardiac DNA methylation on global gene expression in myocardial samples from end-stage CCC patients, compared to control samples from organ donors. Results In total, 4720 genes were differentially methylated between CCC patients and controls, of which 399 were also differentially expressed. Several of them were related to heart function or to the immune response and had methylation sites in their promoter region. Reporter gene and in silico transcription factor binding analyses indicated promoter methylation modified expression of key genes. Among those, we found potassium channel genes KCNA4 and KCNIP4, involved in electrical conduction and arrythmia, SMOC2, involved in matrix remodeling, as well as enkephalin and RUNX3, potentially involved in the increased T-helper 1 cytokine-mediated inflammatory damage in heart. Conclusions Results support that DNA methylation plays a role in the regulation of expression of pathogenically relevant genes in CCC myocardium, and identify novel potential disease pathways and therapeutic targets in CCC.

Background. Chronic Chagas disease cardiomyopathy (CCC), a late consequence ofTrypanosoma cruziinfection, is an inflammatory cardiomyopathy with prognosis worse than those of noninflammatory etiology (NIC). Although the T cell-rich myocarditis is known to play a pathogenetic role, the relative contribution of each of the functional T cell subsets has never been thoroughly investigated. We therefore assessed gene expression of cytokines and transcription factors involved in differentiation and effector function of each functional T cell subset (TH1/TH2/TH17/Treg) in CCC, NIC, and heart donor myocardial samples.Methods and Results. Quantitative PCR showed markedly upregulated expression ofIFN-γand transcription factorT-bet, and minor increases ofGATA-3;FoxP3andCTLA-4;IL-17andIL-18in CCC as compared with NIC samples. Conversely, cytokines expressed byTH2 cells (IL-4,IL-5, andIL-13) or associated with Treg (TGF-βandIL-10) were not upregulated in CCC myocardium. Expression ofTH1-related genes such asT-bet,IFN-γ, andIL-18correlated with ventricular dilation,FoxP3, andCTLA-4.Conclusions. Results are consistent with a strong localTH1-mediated response in most samples, possibly associated with pathological myocardial remodeling, and a proportionally smaller FoxP3+CTLA4+Treg cell population, which is unable to completely curb IFN-γproduction in CCC myocardium, therefore fueling inflammation.

Background: Discrepancies between pre and post-mortem diagnoses are reported in the literature, ranging from 4.1 to 49.8 % in cases referred for necropsy, with important impact on patient treatment. Objective: To analyze patients who died after cardiac transplantation and to compare the pre- and post-mortem diagnoses. Methods: Perform a review of medical records and analyze clinical data, comorbidities, immunosuppression regimen, laboratory tests, clinical cause of death and cause of death at the necropsy. Then, the clinical and necroscopic causes of death of each patient were compared. Results: 48 deaths undergoing necropsy were analyzed during 2000-2010; 29 (60.4 %) had concordant clinical and necroscopic diagnoses, 16 (33.3%) had discordant diagnoses and three (6.3%) had unclear diagnoses. Among the discordant ones, 15 (31.3%) had possible impact on survival and one (2.1%) had no impact on survival. The main clinical misdiagnosis was infection, with five cases (26.7 % of discordant), followed by hyperacute rejection, with four cases (20 % of the discordant ones), and pulmonary thromboembolism, with three cases (13.3% of discordant ones). Conclusion: Discrepancies between clinical diagnosis and necroscopic findings are commonly found in cardiac transplantation. New strategies to improve clinical diagnosis should be made, considering the results of the necropsy, to improve the treatment of heart failure by heart transplantation.

Long noncoding RNAs (lncRNAs) modulate gene expression at the epigenetic, transcriptional, and posttranscriptional levels. Dysregulation of the lncRNA known as myocardial infarction-associated transcript (MIAT) has been associated with myocardial infarction. Chagas disease causes a severe inflammatory dilated chronic cardiomyopathy (CCC). We investigated the role of MIAT in CCC. A whole-transcriptome analysis of heart biopsy specimens and formalin-fixed, paraffin-embedded samples revealed that MIAT was overexpressed in patients with CCC, compared with subjects with noninflammatory dilated cardiomyopathy and controls. These results were confirmed in a mouse model. Results suggest that MIAT is a specific biomarker of CCC.

BACKGROUND The aim of this study was to evaluate the degree of tricuspid valve insufficiency after orthotopic cardiac transplantation with bicaval anastomosis and prophylactic donor heart annuloplasty. METHODS At present, our cardiac transplantation experience includes 478 cases. After January 2002, we included 30 consecutive patients in this study who had undergone orthotopic cardiac transplantation and survived >6 months. The patients were divided into 2 groups: group I, 15 patients who underwent transplantation with prophylactic tricuspid annuloplasty on the donor heart with the De Vega technique; and group II, 15 patients who underwent transplantation without this procedure. Their preoperative clinical characteristics were the same. During the late postoperative follow-up, the degree of tricuspid insufficiency was evaluated by transthoracic Doppler echocardiography and assessed according to the Simpson scale: 0, absent; 1, mild; 2, moderate; and 3, severe. Hemodynamic parameters were evaluated invasively by means of a Swan-Ganz catheter during routine endomyocardial biopsies. RESULTS The mean follow-up time was 26.9 +/- 5.4 months (range, 12-36 months). In group I, 1 patient (6.6%) died from infection in the 18th month after the operation; the death was not related to the annuloplasty. In group II, 1 death (6.6%) occurred after 10 months because of rejection (P > .05). After the 24-month follow-up, the mean degree of tricuspid insufficiency was 0.4 +/- 0.5 in group I and 1.7 +/- 0.9 in group II (P < .05). Similarly, the 2 groups were significantly different with respect to the right atrium pressure, which was higher in group II. CONCLUSIONS Prophylactic tricuspid annuloplasty on the donor heart was able to reduce significantly the degree of valvular insufficiency, even in cardiac transplantation with bicaval anastomosis; however, it did not modify significantly the hemodynamic performance of the allograft during the investigation period. It is very important to extend the observation period and casuistics to verify other benefits that this technique may offer.

Background/methods Chagas disease is caused by an intracellular parasite, Trypanosoma cruzi , and it is a leading cause of heart failure in Latin America. The main clinical consequence of the infection is the development of a Chronic Chagas disease Cardiomyopathy (CCC), which is characterized by myocarditis, hypertrophy and fibrosis and affects about 30% of infected patients. CCC has a worse prognosis than other cardiomyopathies, like idiopathic dilated cardiomyopathy (DCM). It is well established that myocardial gene expression patterns are altered in CCC, but the molecular mechanisms underlying these differences are not clear. MicroRNAs are recently discovered regulators of gene expression, and are recognized as important factors in heart development and cardiovascular disorders (CD). We analyzed the expression of nine different miRNAs in myocardial tissue samples of CCC patients in comparison to DCM patients and samples from heart transplant donors. Using the results of a cDNA microarray database on CCC and DCM myocardium, signaling networks were built and nodal molecules were identified. Results We observed that five miRNAs were significantly altered in CCC and three in DCM; importantly, three miRNAs were significantly reduced in CCC as compared to DCM. We observed that multiple gene targets of the differentially expressed miRNAs showed a concordant inverse expression in CCC. Significantly, most gene targets and involved networks belong to crucial disease-related signaling pathways. Conclusion These results suggest that miRNAs may play a major role in the regulation of gene expression in CCC pathogenesis, with potential implication as diagnostic and prognostic tools.

Background Chronic Chagas cardiomyopathy (CCC), a life-threatening inflammatory dilated cardiomyopathy, affects 30% of the approximately 8 million patients infected by Trypanosoma cruzi. Even though the Th1 T cell-rich myocarditis plays a pivotal role in CCC pathogenesis, little is known about the factors controlling inflammatory cell migration to CCC myocardium. Methods and Results Using confocal immunofluorescence and quantitative PCR, we studied cell surface staining and gene expression of the CXCR3, CCR4, CCR5, CCR7, CCR8 receptors and their chemokine ligands in myocardial samples from end-stage CCC patients. CCR5+, CXCR3+, CCR4+, CCL5+ and CXCL9+ mononuclear cells were observed in CCC myocardium. mRNA expression of the chemokines CCL5, CXCL9, CXCL10, CCL17, CCL19 and their receptors was upregulated in CCC myocardium. CXCL9 mRNA expression directly correlated with the intensity of myocarditis, as well as with mRNA expression of CXCR3, CCR4, CCR5, CCR7, CCR8 and their ligands. We also analyzed single-nucleotide polymorphisms for genes encoding the most highly expressed chemokines and receptors in a cohort of Chagas disease patients. CCC patients with ventricular dysfunction displayed reduced genotypic frequencies of CXCL9 rs10336 CC, CXCL10 rs3921 GG, and increased CCR5 rs1799988CC as compared to those without dysfunction. Significantly, myocardial samples from CCC patients carrying the CXCL9/CXCL10 genotypes associated to a lower risk displayed a 2–6 fold reduction in mRNA expression of CXCL9, CXCL10, and other chemokines and receptors, along with reduced intensity of myocarditis, as compared to those with other CXCL9/CXCL10 genotypes. Conclusions Results may indicate that genotypes associated to reduced risk in closely linked CXCL9 and CXCL10 genes may modulate local expression of the chemokines themselves, and simultaneously affect myocardial expression of other key chemokines as well as intensity of myocarditis. Taken together our results may suggest that CXCL9 and CXCL10 are master regulators of myocardial inflammatory cell migration, perhaps affecting clinical progression to the life-threatening form of CCC., Author Summary Chronic Chagas cardiomyopathy (CCC) is an inflammatory heart disease that affects millions in Latin America, and in growing numbers in USA and Europe. Survival among CCC patients is shorter than among patients with cardiomyopathy of non-inflammatory etiology. This suggests that the inflammatory cell influx plays an important pathogenic role in CCC. However, little is known about the factors that maintain this myocardial inflammation. We hypothesized that Th1 T cell-attracting chemokines, involved in driving leukocyte migration, could play a role in myocardial inflammation. Herein, we have analyzed expression of several chemokines and receptors in heart tissue from patients with CCC and controls. We found inflammatory cells expressing chemokines and receptors consistent with Th1 T cell influx into CCC myocardium. mRNA expression levels of the chemokine CXCL9 correlated with inflammation. We also studied whether genetic variations in these genes could be associated to CCC development. Polymorphisms in CXCL9, CXCL10 and CCR5 were associated to differential risk of progression to the more severe form of CCC. Polymorphisms of CXCL9 and CXCL10 were also associated to the intensity of myocardial inflammation and chemokine expression. These results suggest that such chemokines may be master regulators of myocardial inflammatory cell migration, perhaps affecting clinical progression to severe CCC.

Background Chronic Chagas disease cardiomyopathy (CCC) is an inflammatory dilated cardiomyopathy with a worse prognosis than other cardiomyopathies. CCC occurs in 30 % of individuals infected with Trypanosoma cruzi, endemic in Latin America. Heart failure is associated with impaired energy metabolism, which may be correlated to contractile dysfunction. We thus analyzed the myocardial gene and protein expression, as well as activity, of key mitochondrial enzymes related to ATP production, in myocardial samples of end-stage CCC, idiopathic dilated (IDC) and ischemic (IC) cardiomyopathies. Methodology/Principal Findings Myocardium homogenates from CCC (N = 5), IC (N = 5) and IDC (N = 5) patients, as well as from heart donors (N = 5) were analyzed for protein and mRNA expression of mitochondrial creatine kinase (CKMit) and muscular creatine kinase (CKM) and ATP synthase subunits aplha and beta by immunoblotting and by real-time RT-PCR. Total myocardial CK activity was also assessed. Protein levels of CKM and CK activity were reduced in all three cardiomyopathy groups. However, total CK activity, as well as ATP synthase alpha chain protein levels, were significantly lower in CCC samples than IC and IDC samples. CCC myocardium displayed selective reduction of protein levels and activity of enzymes crucial for maintaining cytoplasmic ATP levels. Conclusions/Significance The selective impairment of the CK system may be associated to the loss of inotropic reserve observed in CCC. Reduction of ATP synthase alpha levels is consistent with a decrease in myocardial ATP generation through oxidative phosphorylation. Together, these results suggest that the energetic deficit is more intense in the myocardium of CCC patients than in the other tested dilated cardiomyopathies., Author Summary Chronic Chagas disease cardiomyopathy (CCC) affects millions in endemic areas and is presenting in growing numbers in the USA and European countries due to migration currents. Clinical progression, length of survival and overall prognosis are significantly worse in CCC patients when compared to patients with dilated cardiomyopathy of non-inflammatory etiology. Impairment of energy metabolism seems to play a role in heart failure due to cardiomyopathies. Herein, we have analyzed energy metabolism enzymes in myocardium samples of CCC patients comparing to other non-inflammatory cardiomyopathies. We found that myocardial tissue from CCC patients displays a significant reduction of both myocardial protein levels of ATP synthase alpha and creatine kinase enzyme activity, in comparison to control heart samples, as well as idiopathic dilated cardiomyopathy and ischemic cardiomyopathy. Our results suggest that CCC myocardium displays a selective energetic deficit, which may play a role in the reduced heart function observed in such patients.

OBJETIVOS: Com o aumento da expectativa de vida nas ultimas decadas, tem-se um aumento concomitante da prevalencia da estenose aortica degenerativa e da doenca aterosclerotica arterial coronaria. O presente estudo visa avaliar a influencia da doenca aterosclerotica arterial coronaria critica em pacientes portadores de estenose aortica submetidos ao implante isolado de protese valvar ou combinado a revascularizacao do miocardio. METODOS: No periodo de janeiro de 2001 a marco de 2006, foram analisados 448 pacientes submetidos ao implante isolado de protese valvar aortica (Grupo I) e 167 pacientes submetidos a substituicao valvar aortica combinada a revascularizacao do miocardio (Grupo II). As variaveis pre e intra-operatorias eleitas para analise foram: sexo, idade, indice de massa corporea, acidente vascular cerebral, diabete melito, doenca pulmonar obstrutiva cronica, febre reumatica, hipertensao arterial sistemica, endocardite, infarto agudo do miocardio e tabagismo, fracao de ejecao do ventriculo esquerdo, doenca aterosclerotica arterial coronaria critica, fibrilacao atrial cronica, operacao valvar aortica previa (conservadora), classe funcional de insuficiencia cardiaca congestiva, valor serico de creatinina, colesterol total, tamanho da protese utilizada, extensao e numero de anastomoses distais da revascularizacao do miocardio realizada, tempos de circulacao extracorporea de pincamento aortico. No estudo estatistico empregou-se analise univariada multivariada. RESULTADOS: A mortalidade hospitalar foi 14,3% (64 obitos) no Grupo I, sendo 14,5% (58 obitos) nos pacientes sem doenca aterosclerotica arterial coronaria critica associada (Grupo IB) e 12,8% (6 obitos) nos que apresentavam essa associacao (Grupo IA). A mortalidade hospitalar no Grupo II foi 17,6% (29 obitos), sendo 16,1% (20 obitos) nos pacientes submetidos a substituicao valvar aortica combinada a revascularizacao completa do miocardio (Grupo IIA) e 20,9% (nove obitos) nos com revascularizacao incompleta do miocardio (Grupo IIB). CONCLUSOES: Nos pacientes submetidos a substituicao valvar aortica isolada, a presenca de doenca aterosclerotica arterial coronaria critica associada, em pelo menos duas arterias, influenciou a mortalidade hospitalar. Nos pacientes submetidos ao tratamento cirurgico combinado, o numero de arterias coronarias com doenca aterosclerotica critica e a extensao da revascularizacao do miocardio (RM completa ou incompleta), nao influenciaram a mortalidade hospitalar, mas a realizacao de mais de tres anastomoses distais interferiu.

With the increase in life expectancy occurred in recent decades, it has been noted the concomitant increase in the prevalence of aortic stenosis and degenerative disease of atherosclerotic coronary artery. This study aims to evaluate the influence of atherosclerotic coronary artery disease in patients with critical aortic stenosis undergoing isolated or combined implant valve prosthesis and coronary artery by pass grafting.In the period of January 2001 to March 2006, there were analyzed 448 patients undergoing isolated implant aortic valve prosthesis (Group I) and 167 patients undergoing aortic valve prosthesis implant combined with coronary artery bypass grafting (Group II). Pre- and intra-operative variables elected for analysis were: age, gender, body mass index, stroke, diabetes mellitus, chronic obstructive pulmonary disease, rheumatic fever, hypertension, endocarditis, acute myocardial infarction, smoking, Fraction of the left ventricular ejection, critical atherosclerotic coronary artery disease, chronic atrial fibrillation, aortic valve operation prior (conservative), functional class of congestive heart failure, value serum creatinine, total cholesterol, size of the prosthesis used, length and number of distal anastomoses held in myocardial revascularization, duration of cardiopulmonary bypass and aortic clamping time. The statistical study employed invariant and multivariate analysis.Hospital mortality was 14.3% (64 deaths) in Group I, and 14.5% (58 deaths) in patients with atherosclerotic coronary artery disease associated criticism (Group IB) and 12.8% (six deaths) in which had this association (Group IA). Hospital mortality in Group II was 17.6% (29 deaths), and 16.1% (20 deaths) in patients undergoing implantation of prosthetic aortic valve combined to complete myocardial revascularization (Group II) and 20.9% (nine deaths) in the myocardial revascularization with incomplete (Group IIB).In patients undergoing implant isolated from aortic valve prosthesis, the presence of atherosclerotic coronary artery disease associated critical in at least two arteries, influenced the hospital mortality. In patients undergoing surgical treatment combined the number of coronary arteries with critical atherosclerotic disease and extent of coronary artery bypass grafting (complete or incomplete), did not affect the hospital mortality, but the realization of more than three anastomoses in the distal myocardial revascularization interfered.

FUNDAMENTO: La hipertension pulmonar (HP) se muestra factor de mal pronostico en el postoperatorio de transplante cardiaco (TC) y, de esta forma, el estudio del grado de reversibilidad a vasodilatadores se vuelve obligatorio durante evaluacion preoperatoria. OBJETIVO: Evaluar los efectos hemodinamicos pulmonares y sistemicos del Sildenafil como droga vasodilatadora durante la prueba de reversibilidad de la HP en candidatos a transplante cardiaco. METODOS: Pacientes en fila para TC fueron sometidos a la medicion de variables hemodinamicas sistemicas y pulmonares, antes y luego de la administracion de 100mg en dosificacion unica y sublingual de Sildenafil, durante cateterizacion cardiaca derecha. RESULTADOS: Se evaluaron en este estudio a 14 pacientes (edad: 47±12 anos, el 71,4% varones) con insuficiencia cardiaca avanzada, fraccion de eyeccion (FE) 25 ± 7%, clase funcional (CF-NYHA) CF III - 6 y CF IV - 8. La administracion aguda de Sildenafil se mostro eficaz en la reduccion de las presiones sistolica (62,4 ± 12,1 vs 51,5 ± 9,6 mmHg, IC=95%, p

Pulmonary hypertension (PH) is a factor of poor prognosis in the postoperative period of heart transplant (HT) and thus, the study of the degree of reversibility to vasodilators is mandatory during the preoperative assessment.To evaluate the pulmonary and systemic hemodynamic effects of sildenafil as a vasodilator during the PH reversibility test in patients that are candidates to HT.Patients awaiting HT were submitted to the measurement of systemic and pulmonary hemodynamic variables before and after the administration of a single sublingual dose of 100 mg of sildenafil during right heart catheterization.Fourteen patients (age: 47+/-12 years, 71.4% men) with advanced heart failure Ejection Fraction (EF) 25 +/- 7%, Functional Class (FC - NYHA) FC III - 6 and FC IV - 8, were evaluated in this study. The acute administration of sildenafil showed to be effective in decreasing the systolic (62.4 +/- 12.1 vs 51.5 +/- 9.6 mmHg, CI=95%, p0.05) and mean (40.7 +/- 7.3 vs 33.8 +/- 7.6 mmHg, CI=95%, p0.05) pressures of the pulmonary artery. There was also a significant decrease in the pulmonary (4.2 +/- 3 vs 2.0 +/- 0.9 uWood, CI=95%, p0.05) and systemic vascular resistance (22.9 +/- 6.8 vs 18.6 +/- 4.1 Wood, CI=95%, p0.05), associated to an increase in the cardiac output (3.28 +/- 0.79 vs 4.12 +/-1.12 uWood, CI=95%, p0.05) without, however, significantly interfering in the systemic arterial pressure (87.8 +/- 8.2 vs 83.6 +/- 9.1 mmHg, CI=95%, p=0.3).The sublingual administration of sildenafil is an effective and safe alternative as a vasodilator during the PH reversibility test in patients with heart failure and awaiting a HT.

This study aims to evaluate the effects of prophylactic heart donor tricuspid annuloplasty in patients after heart transplantation with bicaval anastomosis.From 2002 to 2005, 20 patients undergoing heart transplantation with bicaval anastomosis and with a survival rate over 6 months were deliberately selected. Patients were divided into two groups: Group I - 10 patients who underwent prophylactic heart donor tricuspid annuloplasty by the De Vega technique; and Group II - 10 patients did not undergo annuloplasty. In both groups, presurgical clinical characteristics were the same. The tricuspid regurgitation degree was evaluated by transthoracic Doppler echocardiography and it was qualified from 0 to 3 (0=absent, 1=mild, 2=moderated, 3=severe). Myocardial performance was evaluated by ventricular ejection fraction and invasive hemodynamic study performed during routine endomyocardial biopsies.Mean clinical follow-up was 14.6+/-4.3 (6 and 16) months. There was only one death in group II. It was not related to annuloplasty. Mean degree of tricuspid regurgitation in Group I was 0.4+/-0.6 and in Group II was 1.6+/-0.8 (p0.05). There was a statistically significant difference between both groups in right atrium pressure, which was higher in Group II.In view of the limitations of the study, the prophylactic tricuspid annuloplasty in heart donor reduced the degree of valvar regurgitation in the medium term after heart transplantation with bicaval anastomosis, in spite of not interfering with the allograft hemodynamic performance in the period under consideration.