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Objective: The use of ventricular assist devices (VAD) is increasing; however, diagnosis and management of device complications, such as the driveline exit site (DES) being the portal of entry for fungal infection, is not well known., Method: A systematic review involving searching PubMed (2005 to July 2020) was conducted. The case of a 43-year-old female patient who had a left VAD (LVAD) (HeartMate 3, Abbott, US) is also reported., Results: The patient was successfully treated with ketoconazole cream and oral fluconazole for likely superficial DES fungal infections. We included 36 studies that met our inclusion criteria; however, only one was included in our review. In the literature, five cases of DES fungal infection were reported, with Candida being the only fungal pathogen., Conclusion: LVAD fungal infections are uncommon but can be responsible for high mortality rates, require a prolonged period of treatment, and can present a huge problem when surgical alternatives are not available. However, Candida species are most common. Fungal infections can only produce clear discharge, and so the classic definition of driveline infection based on purulent secretion can vary. Negative skin culture does not exclude the diagnosis of infection of the DES, and so empirical diagnosis may only be clinically based., Competing Interests: Declaration of interest: The authors have no conflicts of interest.

Background: The evidence supporting the use of renin-angiotensin-aldosterone system (RAAS) inhibitors and beta-blockers for the prevention of anthracycline-induced cardiomyopathy is controversial., Objective: We performed a meta-analysis to assess the effectiveness of these drugs in preventing cardiotoxicity., Methods: The meta-analysis included prospective, randomized studies in adults receiving anthracycline chemotherapy and compared the use of RAAS inhibitors or beta-blockers versus placebo with a follow-up of 6 to 18 months. The primary outcome was change in left ventricular ejection fraction (LVEF) during chemotherapy. Secondary outcomes were the incidence of heart failure, all-cause mortality, and changes in end-diastolic measurement. Heterogeneity was assessed by stratification and meta-regression. A significance level of p < 0.05 was adopted., Results: The search resulted in 17 studies, totaling 1,530 patients. The variation (delta) in LVEF was evaluated in 14 studies. Neurohormonal therapy was associated with a lower delta in pre- versus post-therapy LVEF (weighted mean difference 4.42 [95% confidence interval 2.3 to 6.6]) and higher final LVEF (p < 0.001). Treatment resulted in a lower incidence of heart failure (risk ratio 0.45 [95% confidence interval 0.3 to 0.7]). There was no effect on mortality (p = 0.3). For analysis of LVEF, substantial heterogeneity was documented, which was not explained by the variables explored in the study., Conclusion: The use of RAAS inhibitors and beta-blockers to prevent anthracycline-induced cardiotoxicity was associated with less pronounced reduction in LVEF, higher final LVEF, and lower incidence of heart failure. No changes in mortality were observed. (CRD PROSPERO 42019133615).

Background: Anthracycline (ANT) is often used for breast cancer treatment but its clinical use is limited by cardiotoxicity (CTX). CECCY trial demonstrated that the β-blocker carvedilol (CVD) could attenuate myocardial injury secondary to ANT. Mieloperoxydase (MPO) is a biomarker of oxidative stress and galectin-3 (Gal-3) is a biomarker of fibrosis and cardiac remodeling. We evaluated the correlation between MPO and Gal-3 behavior with CTX., Materials and Methods: A post hoc analysis was performed in the patients who were included in the CECCY trial. A total of 192 women had her blood samples stored during the study at -80°C until the time of assay in a single batch. Stored blood samples were obtained at baseline, 3 and 6 months after randomization. We excluded samples from 18 patients because of hemolysis. MPO and Gal-3 were measured using Luminex xMAP technology through MILLIPLEX MAP KIT (Merck Laboratories)., Results: 26 patients (14.9%) had a decrease of at least 10% in LVEF at 6 months after the initiation of chemotherapy. Among these, there was no significant difference in the MPO and Gal-3 when compared to the group without drop in LVEF ( p = 0.85 for both MPO and Gal-3). Blood levels of MPO [baseline: 13.2 (7.9, 24.8), 3 months: 17.7 (11.1, 31.1), 6 months: 19.2 (11.1, 37.8) ng/mL] and Gal-3 [baseline: 6.3 (5.2, 9.6), 3 months: 12.3 (9.8, 16.0), 6 months: 10.3 (8.2, 13.1) ng/mL] increased after ANT chemotherapy, and the longitudinal changes were similar between the placebo and CVD groups (p for interaction: 0.28 and 0.32, respectively). In an exploratory analysis, as there is no normal cutoff value established for Gal-3 and MPO in the literature, the MPO and Gal-3 results were splited in two groups: above and below median. In the placebo group, women with high (above median) baseline MPO blood levels demonstrated a greater increase in TnI blood levels than those with low baseline MPO blood levels ( p = 0.041). Compared with placebo, CVD significantly reduced TnI blood levels in women with high MPO blood levels ( p < 0.001), but did not reduce the TnI levels in women with low baseline MPO blood levels ( p = 0.97; p for interaction = 0.009). There was no significant interaction between CVD treatment and baseline Gal-3 blood levels (p for interaction = 0.99)., Conclusions: In this subanalysis of the CECCY trial, MPO and Gal-3 biomarkers did not predict the development of CTX. However, MPO blood levels above median was associated with more severe myocardial injury and identified women who were most likely to benefit from carvedilol for primary prevention (NCT01724450)., Competing Interests: CONFLICTS OF INTEREST Authors have no conflicts of interest to declare., (Copyright: © 2022 Wanderley Jr. et al.)

Aims: This study aimed to analyse the clinical presentation and prognosis of patients with Chagas cardiomyopathy and decompensated heart failure (HF), as compared with other aetiologies., Methods and Results: A prospective cohort of patients admitted with decompensated HF. We included 767 patients (63.9% male), with median age of 58 years [interquartile range 48.2-66.7 years]. Main aetiologies were non-Chagas/non-ischaemic cardiomyopathies in 389 (50.7%) patients, ischaemic disease in 209 (27.2%), and Chagas disease in 169 (22%). Median left ventricular ejection fraction was 26% (interquartile range 22-35%). Patients with Chagas differed from both patients with non-Chagas/non-ischaemic and ischaemic cardiomyopathies for a higher proportion of cardiogenic shock at admission (17.8%, 11.6%, and 11%, respectively, P < 0.001) and had lower blood pressure at admission (systolic blood pressure 90 [80-102.5], 100 [85-110], and 100 [88.2-120] mmHg, P < 0.001) and lower heart rate (heart rate 71 [60-80], 87 [70-102], and 79 [64-96.5] b.p.m., P < 0.001). Further, patients with Chagas had higher serum BNP level (1544 [734-3148], 1061 [465-239], and 927 [369-1455] pg/mL, P < 0.001), higher serum bilirubin (1.4 [0.922.44], 1.2 [0.77-2.19], and 0.84 [0.49-1.45] mg/dL, P < 0.001), larger left ventricular diameter (68 [63-73], 67 [58-74], and 62 [56.8-68.3] mm, respectively, P < 0.001), lower left ventricular ejection fraction (25 [21-30]%, 26 [22-35]%, and 30 [25-38]%, P < 0.001), and a higher proportion of patients with right ventricular function (48.8%, 40.7%, and 25.9%, P < 0.001). Patients with Chagas disease were more likely to receive inotropes than patients with non-Chagas/non-ischaemic and ischaemic cardiomyopathies (77.5%, 67.5%, and 62.5%, respectively, P = 0.007) and also to receive intra-aortic balloon pumping (30.8%, 16.2%, and 10.5%, P < 0.001). Overall, the rates of death or urgent transplant were higher among patients with Chagas than in other aetiologies, a difference that was driven mostly due to increased rate of heart transplant during hospital admission (20.2%, 10.3%, and 8.1%). The prognosis of patients at 180 days after hospital admission was worse for patients with Chagas disease as compared with other aetiologies. In patients with Chagas, age [odds ratio (OR) = 0.934, confidence interval (CI) 95% 0.901-0.982, P = 0.005], right ventricular dysfunction by echocardiography (OR = 2.68, CI 95% 1.055-6.81, P = 0.016), and urea (OR = 1.009, CI 95% 1.001-1.018, P = 0.038) were significantly associated with prognosis., Conclusions: Patients with Chagas cardiomyopathy and decompensated HF have a distinct clinical presentation and worse prognosis compared with other aetiologies., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Exhaled breath acetone (EBA) has been described as a new biomarker of heart failure (HF) diagnosis. EBA concentration increases according to severity of HF and is associated with poor prognosis, especially in acute decompensated HF. However, there are no data on chronic HF patients. The aim is to evaluate the role of EBA for predicting cardiac and overall mortality in chronic HF patients., Methods and Results: In GENIUS-HF cohort, chronic patients were enrolled between August 2012 and December 2014. All patients had left ventricular ejection fraction ≤ 50%, and the diagnosis was established according to Framingham criteria. After consent, patients were submitted to clinical evaluation and exhaled breath collection. EBA identification and quantitative determination were done by spectrophotometry. The clinical characteristics associated with acetone were identified. All participants were followed for 18 months to assess cardiac and overall mortality. Around 700 participants were enrolled in the current analysis. Patients were 55.4 ± 12.2 years old, 67.6% male patients, and 81% New York Heart Association I/II with left ventricular ejection fraction of 32 ± 8.6%. EBA median concentration was 0.6 (0.3-1.2) ug/L. Acetone levels increased with the number of symptoms of HF and were associated with right HF signs/symptoms and liver biochemical changes. EBA at highest quartile (EBA > 1.2ug/L) was associated with a significantly worse prognosis (log rank test, P < 0.001). Cox proportional multivariable regression model revealed that EBA > 1.20ug/L was an independent predictor of cardiac (P = 0.011) and overall (P = 0.010) mortality in our population., Conclusions: This study shows that EBA levels reflect clinical HF features, especially right HF signs/symptoms. EBA is an independent predictor of cardiac and overall mortality in chronic HF patients., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Objectives: The prognostic significance of transient use of inotropes has been sufficiently studied in recent heart failure (HF) populations. We hypothesised that risk stratification in these patients could contribute to patient selection for advanced therapies., Methods: We analysed a prospective cohort of adult patients admitted with decompensated HF and ejection fraction (left ventricular ejection fraction (LVEF)) less than 50%. We explored the outcomes of patients requiring inotropic therapy during hospital admission and after discharge., Results: The study included 737 patients, (64.0% male), with a median age of 58 years (IQR 48-66 years). Main aetiologies were dilated cardiomyopathy in 273 (37.0%) patients, ischaemic heart disease in 195 (26.5%) patients and Chagas disease in 163 (22.1%) patients. Median LVEF was 26 % (IQR 22%-35%). Inotropes were used in 518 (70.3%) patients. In 431 (83.2%) patients, a single inotrope was administered. Inotropic therapy was associated with higher risk of in-hospital death/urgent heart transplant (OR=10.628, 95% CI 5.055 to 22.344, p<0.001). At 180-day follow-up, of the 431 patients discharged home, 39 (9.0%) died, 21 (4.9%) underwent transplantation and 183 (42.4%) were readmitted. Inotropes were not associated with outcome (death, transplant and rehospitalisation) after discharge., Conclusions: Inotropic drugs are still widely used in patients with advanced decompensated HF and are associated with a worse in-hospital prognosis. In contrast with previous results, intermittent use of inotropes during hospitalisation did not determine a worse prognosis at 180-day follow-up. These data may add to prognostic evaluation in patients with advanced HF in centres where mechanical circulatory support is not broadly available., Competing Interests: Competing interests: None declared.

Background: Published studies have generated mixed, controversial results regarding the cost-effectiveness of heart failure disease management programs (HF-DMPs). This study assessed the cost-effectiveness of an HF-DMP in ambulatory patients compared with usual care (UC)., Methods: In the prospective randomized REMADHE trial, we evaluated incremental costs per quality-adjusted life-year (QALY) and life-year (LY) gained as effectiveness ratios (ICERs) over a study period of 2.47 ± 1.75 years., Results: The REMADHE HF-DMP was more effective and less costly than UC in terms of both QALYs and LYs (95% and 55% chance of dominance, respectively). Average saving was US$7345 (2.5%-97.5% bootstrapped confidence interval -16,573 to +921). The chance of DMP being cost-effective at a willingness to pay US$10,000 per QALY or LY was 99% and 96%, respectively. Cost-effectiveness of HF-DMP was highest in subgroups with left ventricular ejection fraction <35%, age >50 years, male sex, New York Heart Association (NYHA) functional class ≥III, and ischemic etiology. The chance of DMP being cost-effective at a willingness to pay US$10,000 per QALY was ≥90% in all subgroups apart from NYHA functional class I-II, where it was 70%. Even when the intervention costs increased by 500% or when excluding outliers in costs, DMP had a high chance of being cost-effective (87%-99%)., Conclusions: The HF-DMP of the REMADHE trial, which encompasses long-term repeated education alongside telephone monitoring, has a high probability of being cost-effective in ambulatory patients with HF., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to evaluate the efficacy of perioperative intra-aortic balloon pump use in high-risk cardiac surgery patients., Design: A single-center randomized controlled trial and a meta-analysis of randomized controlled trials., Setting: Heart Institute of São Paulo University., Patients: High-risk patients undergoing elective coronary artery bypass surgery., Intervention: Patients were randomized to receive preskin incision intra-aortic balloon pump insertion after anesthesia induction versus no intra-aortic balloon pump use., Measurements and Main Results: The primary outcome was a composite endpoint of 30-day mortality and major morbidity (cardiogenic shock, stroke, acute renal failure, mediastinitis, prolonged mechanical ventilation, and a need for reoperation). A total of 181 patients (mean [SD] age 65.4 [9.4] yr; 32% female) were randomized. The primary outcome was observed in 43 patients (47.8%) in the intra-aortic balloon pump group and 42 patients (46.2%) in the control group (p = 0.46). The median duration of inotrope use (51 hr [interquartile range, 32-94 hr] vs 39 hr [interquartile range, 25-66 hr]; p = 0.007) and the ICU length of stay (5 d [interquartile range, 3-8 d] vs 4 d [interquartile range, 3-6 d]; p = 0.035) were longer in the intra-aortic balloon pump group than in the control group. A meta-analysis of 11 randomized controlled trials confirmed a lack of survival improvement in high-risk cardiac surgery patients with perioperative intra-aortic balloon pump use., Conclusions: In high-risk patients undergoing cardiac surgery, the perioperative use of an intra-aortic balloon pump did not reduce the occurrence of a composite outcome of 30-day mortality and major complications compared with usual care alone.

Background: The risk of thromboembolic events is increased in patients with heart failure (HF); however, few studies have reported thromboembolic findings in HF patients who have undergone autopsy., Methods and Results: We reviewed 1457 autopsies (January 2000/July 2006) and selected 595 patients with HF. We studied the occurrence of thromboembolic events in patients' autopsy reports. Mean age was 61.8±15.9 years; 376 (63.2%) were men and 219 (36.8%) women; left ventricular ejection fraction was 42.1±18.7%. HF etiologies were coronary artery disease in 235 (39.5%) patients, valvular disease in 121 (20.3%), and Chagas' disease in 81 (13.6%). The main cause of death was progressive HF in 253 (42.5%) patients, infections in 112 (18.8%), myocardial infarction in 86 (14.5%), and pulmonary embolism in 81 (13.6%). Altogether, 233 patients (39.2%) suffered 374 thromboembolic events. A thromboembolic event was considered the direct cause of death in 93 (24.9%) patients and related to death in 158 (42.2%). The most frequent thromboembolism was pulmonary embolism in 135 (36.1%) patients; in 81 events (60%), it was considered the cause of death. When we compared clinical characteristics of patients, sex (OR=1.511, CI 95% 1.066-2.143, P=.021) and Chagas disease (OR=2.362, CI 95% 1.424-3.918, P=.001) were independently associated with the occurrence of thromboembolisms., Conclusions: Thromboembolic events are frequent in patients with heart failure revealed at autopsy, and are frequently associated with the death process. Our findings warrant a high degree of suspicion for these occurrences, especially during the care of more susceptible populations, such as women and Chagas patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Anthracycline (ANT) chemotherapy is associated with cardiotoxicity. Prevention with β-blockers remains controversial., Objectives: This prospective, randomized, double-blind, placebo-controlled study sought to evaluate the role of carvedilol in preventing ANT cardiotoxicity., Methods: The authors randomized 200 patients with HER2-negative breast cancer tumor status and normal left ventricular ejection fraction (LVEF) referred for ANT (240 mg/m 2 ) to receive carvedilol or placebo until chemotherapy completion. The primary endpoint was prevention of a ≥10% reduction in LVEF at 6 months. Secondary outcomes were effects of carvedilol on troponin I, B-type natriuretic peptide, and diastolic dysfunction., Results: Primary endpoint occurred in 14 patients (14.5%) in the carvedilol group and 13 patients (13.5%) in the placebo group (p = 1.0). No differences in changes of LVEF or B-type natriuretic peptide were noted between groups. A significant difference existed between groups in troponin I levels over time, with lower levels in the carvedilol group (p = 0.003). Additionally, a lower incidence of diastolic dysfunction was noted in the carvedilol group (p = 0.039). A nonsignificant trend toward a less-pronounced increase in LV end-diastolic diameter during the follow-up was noted in the carvedilol group (44.1 ± 3.64 mm to 45.2 ± 3.2 mm vs. 44.9 ± 3.6 mm to 46.4 ± 4.0 mm; p = 0.057)., Conclusions: In this largest clinical trial of β-blockers for prevention of cardiotoxicity under contemporary ANT dosage, the authors noted a 13.5% to 14.5% incidence of cardiotoxicity. In this scenario, carvedilol had no impact on the incidence of early onset of LVEF reduction. However, the use of carvedilol resulted in a significant reduction in troponin levels and diastolic dysfunction. (Carvedilol Effect in Preventing Chemotherapy-Induced Cardiotoxicity [CECCY]; NCT01724450)., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: Explore the association between clinical findings and prognosis in patients with acute decompensated heart failure (ADHF) and analyze the influence of etiology on clinical presentation and prognosis., Methods and Results: Prospective cohort of 500 patients admitted with ADHF from Aug/2013-Feb/2016; patients were predominantly male (61.8%), median age was 58 (IQ25-75% 47-66 years); etiology was dilated cardiomyopathy in 141 (28.2%), ischemic heart disease in 137 (27.4%), and Chagas heart disease in 113 (22.6%). Patients who died (154 [30.8%]) or underwent heart transplantation (53[10.6%]) were younger (56 years [IQ25-75% 45-64 vs 60 years, IQ25-75% 49-67], P = 0.032), more frequently admitted for cardiogenic shock (20.3% vs 6.8%, P<0.001), had longer duration of symptoms (14 days [IQ25-75% 4-32.8 vs 7.5 days, IQ25-75% 2-31], P = 0.004), had signs of congestion (90.8% vs 76.5%, P<0.001) and inadequate perfusion more frequently (45.9% vs 28%, P<0.001), and had lower blood pressure (90 [IQ25-75% 80-100 vs 100, IQ25-75% 90-120], P<0.001). In a logistic regression model analysis, systolic blood pressure (P<0.001, OR 0.97 [95%CI 0.96-0.98] per mmHg) and jugular distention (P = 0.004, OR 1.923 [95%CI 1.232-3.001]) were significant. Chagas patients were more frequently admitted for cardiogenic shock (15%) and syncope/arrhythmia (20.4%). Pulmonary congestion was rare among Chagas patients and blood pressure was lower. The rate of in-hospital death or heart transplant was higher among patients with Chagas (50.5%)., Conclusions: A physical exam may identify patients at higher risk in a contemporaneous population. Our findings support specific therapies targeted at Chagas patients in the setting of ADHF.

The World Health Organization considers the Zika virus (ZIKV) outbreak in the Americas a global public health emergency. The neurologic complications due to ZIKV infection comprise microcephaly, meningoencephalitis, and Guillain-Barré syndrome. We describe a fatal case of an adult patient receiving an immunosuppressive regimen following heart transplant. The patient was admitted with acute neurologic impairment and experienced progressive hemodynamic instability and mental deterioration that finally culminated in death. At autopsy, a pseudotumoral form of ZIKV meningoencephalitis was confirmed. Zika virus infection was documented by reverse trancriptase-polymerase chain reaction, immunohistochemistry, and immunofluorescence and electron microscopy of the brain parenchyma and cerebral spinal fluid. The sequencing of the viral genome in this patient confirmed a Brazilian ZIKV strain. In this case, central nervous system involvement and ZIKV propagation to other organs in a disseminated pattern is quite similar to that observed in other fatal Flaviviridae viral infections., (Copyright © 2017 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Cardiotoxicity is associated with the chronic use of doxorubicin leading to cardiomyopathy and heart failure. Identification of cardiotoxicity-specific miRNA biomarkers could provide clinicians with a valuable prognostic tool. The aim of the study was to evaluate circulating levels of miRNAs in breast cancer patients receiving doxorubicin treatment and to correlate with cardiac function. This is an ancillary study from "Carvedilol Effect on Chemotherapy-induced Cardiotoxicity" (CECCY trial), which included 56 female patients (49.9±3.3 years of age) from the placebo arm. Enrolled patients were treated with doxorubicin followed by taxanes. cTnI, LVEF, and miRNAs were measured periodically. Circulating levels of miR-1, -133b, -146a, and -423-5p increased during the treatment whereas miR-208a and -208b were undetectable. cTnI increased from 6.6±0.3 to 46.7±5.5 pg/mL (p<0.001), while overall LVEF tended to decrease from 65.3±0.5 to 63.8±0.9 (p=0.053) over 12 months. Ten patients (17.9%) developed cardiotoxicity showing a decrease in LVEF from 67.2±1.0 to 58.8±2.7 (p=0.005). miR-1 was associated with changes in LVEF (r=-0.531, p<0.001). In a ROC curve analysis miR-1 showed an AUC greater than cTnI to discriminate between patients who did and did not develop cardiotoxicity (AUC = 0.851 and 0.544, p= 0.0016). Our data suggest that circulating miR-1 might be a potential new biomarker of doxorubicin-induced cardiotoxicity in breast cancer patients.

Autopsies are the gold standard for diagnostic accuracy; however, no recent study has analyzed autopsies in heart failure (HF).We reviewed 1241 autopsies (January 2000-May 2005) and selected 232 patients with HF. Clinical and autopsy diagnoses were analyzed and discrepancies categorized according to their importance regarding therapy and prognosis.Mean age was 63.3 ± 15.9 years; 154 (66.4%) patients were male. The causes of death at autopsy were end-stage HF (40.9%), acute myocardial infarction (17.2%), infection (15.9), and pulmonary embolism 36 (15.5). Diagnostic discrepancies occurred in 191 (82.3%) cases; in 56 (24.1%), discrepancies were related to major diagnoses with potential influence on survival or treatment; pulmonary embolism was the cause of death for 24 (42.9%) of these patients. In 35 (15.1%), discrepancies were related to a major diagnosis with equivocal influence on survival or treatment; in 100 (43.1%), discrepancies did not influence survival or treatment. In multivariate analysis, age (OR: 1.03, 95% CI: 1.008-1.052, P = 0.007) and presence of diabetes mellitus (OR: 0.359, 95% CI: 0.168-0.767, P = 0.008) influenced the occurrence discrepancies.Diagnostic discrepancies with a potential impact on prognosis are frequent in HF. These findings warrant reconsideration in diagnostic and therapeutic practices with HF patients., Competing Interests: The authors have no conflicts of interest to disclose.

Background: The identification of new biomarkers of heart failure (HF) could help in its treatment. Previously, our group studied 89 patients with HF and showed that exhaled breath acetone (EBA) is a new noninvasive biomarker of HF diagnosis. However, there is no data about the relevance of EBA as a biomarker of prognosis., Objectives: To evaluate whether EBA could give prognostic information in patients with heart failure with reduced ejection fraction (HFrEF)., Methods: After breath collection and analysis by gas chromatography-mass spectrometry and by spectrophotometry, the 89 patients referred before were followed by one year. Study physicians, blind to the results of cardiac biomarker testing, ascertained vital status of each study participant at 12 months., Results: The composite endpoint death and heart transplantation (HT) were observed in 35 patients (39.3%): 29 patients (32.6%) died and 6 (6.7%) were submitted to HT within 12 months after study enrollment. High levels of EBA (≥3.7μg/L, 50th percentile) were associated with a progressively worse prognosis in 12-month follow-up (log-rank = 11.06, p = 0.001). Concentrations of EBA above 3.7μg/L increased the risk of death or HT in 3.26 times (HR = 3.26, 95%CI = 1.56-6.80, p = 0.002) within 12 months. In a multivariable cox regression model, the independent predictors of all-cause mortality were systolic blood pressure, respiratory rate and EBA levels., Conclusions: High EBA levels could be associated to poor prognosis in HFrEF patients., Competing Interests: The authors have declared that no competing interests exist.

Background: Polypharmacy is a significant economic burden., Objective: We tested whether using reverse auction (RA) as compared with commercial pharmacy (CP) to purchase medicine results in lower pharmaceutical costs for heart failure (HF) and heart transplantation (HT) outpatients., Methods: We compared the costs via RA versus CP in 808 HF and 147 HT patients followed from 2009 through 2011, and evaluated the influence of clinical and demographic variables on cost., Results: The monthly cost per patient for HF drugs acquired via RA was $10.15 (IQ 3.51-40.22) versus $161.76 (IQ 86.05‑340.15) via CP; for HT, those costs were $393.08 (IQ 124.74-774.76) and $1,207.70 (IQ 604.48-2,499.97), respectively., Conclusion: RA may reduce the cost of prescription drugs for HF and HT, potentially making HF treatment more accessible. Clinical characteristics can influence the cost and benefits of RA. RA may be a new health policy strategy to reduce costs of prescribed medications for HF and HT patients, reducing the economic burden of treatment.

Background: Hypertension is the most prevalent comorbidity after heart transplantation (HT). Exercise training (ET) is widely recommended as a key non-pharmacologic intervention for the prevention and management of hypertension, but its effects on ambulatory blood pressure (ABP) and some mechanisms involved in the pathophysiology of hypertension have not been studied in this population. The primary purpose of this study was to investigate the effects of ET on ABP and arterial stiffness of HT recipients., Methods: 40 HT patients, randomized to ET (n = 31) or a control group (n = 9) underwent a maximal graded exercise test, 24-hour ABP monitoring, and carotid-femoral pulse wave velocity (PWV) assessment before the intervention and at a 12-week follow-up assessment. The ET program was performed thrice-weekly and consisted primarily of endurance exercise (40 minutes) at ~70% of maximum oxygen uptake (Vo2MAX)., Results: The ET group had reduced 24-hour (4.0 ± 1.4 mm Hg, p < 0.01) and daytime (4.8 ± 1.6 mm Hg, p < 0.01) systolic ABP, and 24-hour (7.0 ± 1.4 mm Hg, p < 0.001) daytime (7.5 ± 1.6 mm Hg, p < 0.001) and nighttime (5.9 ± 1.5 mm Hg, p < 0.001) diastolic ABP after the intervention. The ET group also had improved Vo2MAX (9.7% ± 2.6%, p < 0.001) after the intervention. However, PWV did not change after ET. No variable was changed in the control group after the intervention., Conclusions: The 12-week ET program was effective for reducing ABP but not PWV in heart transplant recipients. This result suggests that endurance ET may be a tool to counteract hypertension in this high-risk population., (Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Objective: To establish the determinants of the peak VO2 in heart transplant recipients., Methods: Patient's assessment was performed in two consecutive days. In the first day, patients performed the heart rate variability assessment followed by a cardiopulmonary exercise test. In the second day, patients performed a resting echocardiography. Heart transplant recipients were eligible if they were in a stable condition and without any evidence of tissue rejection diagnosed by endomyocardial biopsy. Patients with pacemaker, noncardiovascular functional limitations such as osteoarthritis and chronic obstructive pulmonary disease were excluded from this study., Results: Sixty patients (68% male, 48 years and 64 months following heart transplantation) were assessed. Multivariate analysis selected the following variables: receptor's gender (P=0.001), receptor age (P=0.049), receptor Body Mass Index (P=0.005), heart rate reserve (P <0.0001), left atrium diameter (P=0.016). Multivariate analysis showed r=0.77 and r2=0.6 with P <0.001. Equation: peakVO2=32.851 - 3.708 (receptor gender) - 0.067 (receptor age) - 0.318 (receptor BMI) + 0.145 (heart rate reserve) - 0.111 (left atrium diameter)., Conclusion: The determinants of the peak VO2 in heart transplant recipients were: receptor sex, age, Body Mass Index, heart rate reserve and left atrium diameter. Heart rate reserve was the unique variable positively associated with peak VO2. This data suggest the importance of the sympathetic reinnervation in peak VO2 in heart transplant recipients.

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.

Background: Renal dysfunction is associated with increased mortality in patients with decompensated heart failure. However, interventions targeted to prevention in this setting have been disappointing. We investigated the effects of hypertonic saline solution (HSS) for prevention of renal dysfunction in decompensated heart failure., Methods: In a double-blind randomized trial, patients with decompensated heart failure were assigned to receive three-day course of 100mL HSS (NaCl 7.5%) twice daily or placebo. Primary end point was an increase in serum creatinine of 0.3mg/dL or more. Main secondary end point was change in biomarkers of renal function, including serum levels of creatinine, cystatin C, neutrophil gelatinase-associated lipocalin-NGAL and the urinary excretion of aquaporin 2 (AQP2), urea transporter (UT-A1), and sodium/hydrogen exchanger 3 (NHE3)., Results: Twenty-two patients were assigned to HSS and 12 to placebo. Primary end point occurred in two (10%) patients in HSS group and six (50%) in placebo group (relative risk 0.3; 95% CI 0.09-0.98; P=0.01). Relative to baseline, serum creatinine and cystatin C levels were lower in HSS as compared to placebo (P=0.004 and 0.03, respectively). NGAL level was not statistically different between groups, however the urinary expression of AQP2, UT-A1 and NHE3 was significantly higher in HSS than in placebo., Conclusions: HSS administration attenuated heart failure-induced kidney dysfunction as indicated by improvement in both glomerular and tubular defects, a finding with important clinical implications. HSS modulated the expression of tubular proteins involved in regulation of water and electrolyte homeostasis., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Sudden death has been considered the main cause of death in patients with Chagas heart disease. Nevertheless, this information comes from a period before the introduction of drugs that changed the natural history of heart failure. We sought to study the mode of death of patients with heart failure caused by Chagas heart disease, comparing with non-Chagas cardiomyopathy., Methods and Results: We examined the REMADHE trial and grouped patients according to etiology (Chagas vs non-Chagas) and mode of death. The primary end-point was all-cause, heart failure and sudden death mortality; 342 patients were analyzed and 185 (54.1%) died. Death occurred in 56.4% Chagas patients and 53.7% non-Chagas patients. The cumulative incidence of all-cause mortality and heart failure mortality was significantly higher in Chagas patients compared to non-Chagas. There was no difference in the cumulative incidence of sudden death mortality between the two groups. In the Cox regression model, Chagas etiology (HR 2.76; CI 1.34-5.69; p = 0.006), LVEDD (left ventricular end diastolic diameter) (HR 1.07; CI 1.04-1.10; p<0.001), creatinine clearance (HR 0.98; CI 0.97-0.99; p = 0.006) and use of amiodarone (HR 3.05; CI 1.47-6.34; p = 0.003) were independently associated with heart failure mortality. LVEDD (HR 1.04; CI 1.01-1.07; p = 0.005) and use of beta-blocker (HR 0.52; CI 0.34-0.94; p = 0.014) were independently associated with sudden death mortality., Conclusions: In severe Chagas heart disease, progressive heart failure is the most important mode of death. These data challenge the current understanding of Chagas heart disease and may have implications in the selection of treatment choices, considering the mode of death., Trial Registration: ClinicalTrials.gov NCT00505050 (REMADHE).

Background: Heart failure (HF) is associated with poor prognosis, and the identification of biomarkers of its severity could help in its treatment. In a pilot study, we observed high levels of acetone in the exhaled breath of patients with HF. The present study was designed to evaluate exhaled acetone as a biomarker of HF diagnosis and HF severity., Methods: Of 235 patients with systolic dysfunction evaluated between May 2009 and September 2010, 89 patients (HF group) fulfilled inclusion criteria and were compared with sex- and age-matched healthy subjects (control group, n = 20). Patients with HF were grouped according to clinical stability (acute decompensated HF [ADHF], n = 59; chronic HF, n = 30) and submitted to exhaled breath collection. Identification of chemical species was done by gas chromatography-mass spectrometry and quantification by spectrophotometry. Patients with diabetes were excluded., Results: The concentration of exhaled breath acetone (EBA) was higher in the HF group (median, 3.7 μg/L; interquartile range [IQR], 1.69-10.45 μg/L) than in the control group (median, 0.39 μg/L; IQR, 0.30-0.79 μg/L; P < .001) and higher in the ADHF group (median, 7.8 μg/L; IQR, 3.6-15.2 μg/L) than in the chronic HF group (median, 1.22 μg/L; IQR, 0.68-2.19 μg/L; P < .001). The accuracy and sensitivity of this method in the diagnosis of HF and ADHF were about 85%, a value similar to that obtained with B-type natriuretic peptide (BNP). EBA levels differed significantly as a function of severity of HF (New York Heart Association classification, P < .001). There was a positive correlation between EBA and BNP (r = 0.772, P < .001)., Conclusions: EBA not only is a promising noninvasive diagnostic method of HF with an accuracy equivalent to BNP but also a new biomarker of HF severity.

Aims: Trials of disease management programmes (DMP) in heart failure (HF) have shown controversial results regarding quality of life. We hypothesized that a DMP applied over the long-term could produce different effects on each of the quality-of-life components., Methods and Results: We extended the prospective, randomized REMADHE Trial, which studied a DMP in HF patients. We analysed changes in Minnesota Living with Heart Failure Questionnaire components in 412 patients, 60.5% male, age 50.2 +/- 11.4 years, left ventricular ejection fraction 34.7 +/- 10.5%. During a mean follow-up of 3.6 +/- 2.2 years, 6.3% of patients underwent heart transplantation and 31.8% died. Global quality-of-life scores improved in the DMP intervention group, compared with controls, respectively: 57.5 +/- 3.1 vs. 52.6 +/- 4.3 at baseline, 32.7 +/- 3.9 vs. 40.2 +/- 6.3 at 6 months, 31.9 +/- 4.3 vs. 41.5 +/- 7.4 at 12 months, 26.8 +/- 3.1 vs. 47.0 +/- 5.3 at the final assessment; P < 0.01. Similarly, the physical component (23.7 +/- 1.4 vs. 21.1 +/- 2.2 at baseline, 16.2 +/- 2.9 vs. 18.0 +/- 3.3 at 6 months, 17.3 +/- 2.9 vs. 23.1 +/- 5.7 at 12 months, 11.4 +/- 1.6 vs. 19.9 +/- 2.4 final; P < 0.01), the emotional component (13.2 +/- 1.0 vs. 12.1 +/- 1.4 at baseline, 11.7 +/- 2.7 vs. 12.3 +/- 3.1 at 6 months, 12.4 +/- 2.9 vs. 16.8 +/- 5.9 at 12 months, 6.7 +/- 1.0 vs. 10.6 +/- 1.4 final; P < 0.01) and the additional questions (20.8 +/- 1.2 vs. 19.3 +/- 1.8 at baseline, 14.3 +/- 2.7 vs. 17.3 +/- 3.1 at 6 months, 12.4 +/- 2.9 vs. 21.0 +/- 5.5 at 12 months, 6.7 +/- 1.4 vs. 17.3 +/- 2.2 final; P < 0.01) were better (lower) in the intervention group. The emotional component improved earlier than the others. Post-randomization quality of life was not associated with events., Conclusion: Components of the quality-of-life assessment responded differently to DMP. These results indicate the need for individualized DMP strategies in patients with HF. Trial registration information www.clincaltrials.gov NCT00505050-REMADHE.

Background: Renal failure is the most important comorbidity in patients with heart transplantation, it is associated with increased mortality. The major cause of renal dysfunction is the toxic effects of calcineurin inhibitors (CNI). Sirolimus, a proliferation signal inhibitor, is an imunossupressant recently introduced in cardiac transplantation. Its nonnephrotoxic properties make it an attractive immunosuppressive agent for patients with renal dysfunction. In this study, we evaluated the improvement in renal function after switching the CNI to sirolimus among patients with new-onset kidney dysfunction after heart transplantation., Methods: The study included orthotopic cardiac transplant (OHT) patients who required discontinuation of CNI due to worsening renal function (creatinine clearance < 50 mL/min). We excluded subjects who had another indication for initiation of sirolimus, that is, rejection, malignancy, or allograft vasculopathy. The patients were followed for 6 months. The creatinine clearance (CrCl) was estimated according to the Cockcroft-Gault equation using the baseline weight and the serum creatinine at the time of introduction of sirolimus and 6 months there after. Nine patients were included, 7 (78%) were males and the overall mean age was 60.1 +/- 12.3 years and time since transplantation 8.7 +/- 6.1 years. The allograft was beyond 1 year in all patients. There was a significant improvement in the serum creatinine (2.98 +/- 0.9 to 1.69 +/- 0.5 mg/dL, P = .01) and CrCl (24.9 +/- 6.5 to 45.7 +/- 17.2 mL/min, P = .005) at 6 months follow-up., Conclusion: The replacement of CNI by sirolimus for imunosuppressive therapy for patients with renal failure after OHT was associated with a significant improvement in renal function after 6 months., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Background: Heart failure and diabetes often occur simultaneously in patients, but the prognostic value of glycemia in chronic heart failure is debatable. We evaluated the role of glycemia on prognosis of heart failure., Methods: Outpatients with chronic heart failure from the Long-term Prospective Randomized Controlled Study Using Repetitive Education at Six-Month Intervals and Monitoring for Adherence in Heart Failure Outpatients (REMADHE) trial were grouped according to the presence of diabetes and level of glycemia. All-cause mortality/heart transplantation and unplanned hospital admission were evaluated., Results: Four hundred fifty-six patients were included (135 [29.5%] female, 124 [27.2%] with diabetes mellitus, age of 50.2 +/- 11.4 years, and left-ventricle ejection fraction of 34.7% +/- 10.5%). During follow-up (3.6 +/- 2.2 years), 27 (5.9%) patients were submitted to heart transplantation and 202 (44.2%) died; survival was similar in patients with and without diabetes mellitus. When patients with and without diabetes were categorized according to glucose range (glycemia < or = 100 mg/dL [5.5 mmol/L]), as well as when distributed in quintiles of glucose, the survival was significantly worse among patients with lower levels of glycemia. This finding persisted in Cox proportional hazards regression model that included gender, etiology, left ventricle ejection fraction, left ventricle diastolic diameter, creatinine level and beta-blocker therapy, and functional status (hazard ratio 1.45, 95% CI 1.09-1.69, P = .039). No difference regarding unplanned hospital admission was found., Conclusion: We report on an inverse association between glycemia and mortality in outpatients with chronic heart failure. These results point to a new pathophysiologic understanding of the interactions between diabetes mellitus, hyperglycemia, and heart disease., (Copyright 2010 Mosby, Inc. All rights reserved.)

Background: The effectiveness of heart failure disease management programs in patients under cardiologists' care over long-term follow-up is not established., Methods and Results: We investigated the effects of a disease management program with repetitive education and telephone monitoring on primary (combined death or unplanned first hospitalization and quality-of-life changes) and secondary end points (hospitalization, death, and adherence). The REMADHE [Repetitive Education and Monitoring for ADherence for Heart Failure] trial is a long-term randomized, prospective, parallel trial designed to compare intervention with control. One hundred seventeen patients were randomized to usual care, and 233 to additional intervention. The mean follow-up was 2.47+/-1.75 years, with 54% adherence to the program. In the intervention group, the primary end point composite of death or unplanned hospitalization was reduced (hazard ratio, 0.64; confidence interval, 0.43 to 0.88; P=0.008), driven by reduction in hospitalization. The quality-of-life questionnaire score improved only in the intervention group (P<0.003). Mortality was similar in both groups. Number of hospitalizations (1.3+/-1.7 versus 0.8+/-1.3, P<0.0001), total hospital days during the follow-up (19.9+/-51 versus 11.1+/-24 days, P<0.0001), and the need for emergency visits (4.5+/-10.6 versus 1.6+/-2.4, P<0.0001) were lower in the intervention group. Beneficial effects were homogeneous for sex, race, diabetes and no diabetes, age, functional class, and etiology., Conclusions: For a longer follow-up period than in previous studies, this heart failure disease management program model of patients under the supervision of a cardiologist is associated with a reduction in unplanned hospitalization, a reduction of total hospital days, and a reduced need for emergency care, as well as improved quality of life, despite modest program adherence over time.