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Raul C Maranhão,1,2 Maria C Guido,1 Aline D de Lima,1 Elaine R Tavares,1 Alyne F Marques,1 Marcelo D Tavares de Melo,3 Jose C Nicolau,3 Vera MC Salemi,3 Roberto Kalil-Filho3 1Laboratory of Metabolism and Lipids, 2Faculty of Pharmaceutical Sciences, 3Heart Failure Unit, Clinical Cardiology Division, Heart Institute (InCor), Medical School Hospital, University of São Paulo, São Paulo, Brazil Purpose: Acute myocardial infarction (MI) is accompanied by myocardial inflammation, fibrosis, and ventricular remodeling that, when excessive or not properly regulated, may lead to heart failure. Previously, lipid core nanoparticles (LDE) used as carriers of the anti-inflammatory drug methotrexate (MTX) produced an 80-fold increase in the cell uptake of MTX. LDE-MTX treatment reduced vessel inflammation and atheromatous lesions induced in rabbits by cholesterol feeding. The aim of the study was to investigate the effects of LDE-MTX on rats with MI, compared with commercial MTX treatment.Materials and methods: Thirty-eight Wistar rats underwent left coronary artery ligation and were treated with LDE-MTX, or with MTX (1 mg/kg intraperitoneally, once/week, starting 24 hours after surgery) or with LDE without drug (MI-controls). A sham-surgery group (n=12) was also included. Echocardiography was performed 24 hours and 6 weeks after surgery. The animals were euthanized and their hearts were analyzed for morphometry, protein expression, and confocal microscopy.Results: LDE-MTX treatment achieved a 40% improvement in left ventricular (LV) systolic function and reduced cardiac dilation and LV mass, as shown by echocardiography. LDE-MTX reduced the infarction size, myocyte hypertrophy and necrosis, number of inflammatory cells, and myocardial fibrosis, as shown by morphometric analysis. LDE-MTX increased antioxidant enzymes; decreased apoptosis, macrophages, reactive oxygen species production; and tissue hypoxia in non-infarcted myocardium. LDE-MTX increased adenosine bioavailability in the LV by increasing adenosine receptors and modulating adenosine catabolic enzymes. LDE-MTX increased the expression of myocardial vascular endothelium growth factor (VEGF) associated with adenosine release; this correlated not only with an increase in angiogenesis, but also with other parameters improved by LDE-MTX, suggesting that VEGF increase played an important role in the beneficial effects of LDE-MTX. Overall effects of commercial MTX were minor, and did not improve LV function or infarction size. Both treatments did not induce any toxicity. Conclusion: The remarkable improvement in heart function and reduction in infarction size achieved by LDE-MTX supports future clinical trials. Keywords: lipid particle, drug delivery, adenosine, VEGF, myocardial infarction

Jacqueline Freire Machi,1,2 Danielle da Silva Dias,3 Sarah Cristina Freitas,3 Oscar Albuquerque de Moraes,1 Maikon Barbosa da Silva,1 Paula Lázara Cruz,1 Cristiano Mostarda,4 Vera M C Salemi,1 Mariana Morris,2 Kátia De Angelis,3 Maria-Cláudia Irigoyen1 1Hypertension Unit, Heart Institute (InCor), School of Medicine, University of Sao Paulo, São Paulo, Brazil; 2Institute of Neuro-Immune Medicine, Nova Southeastern University, Fort Lauderdale, FL, USA; 3Laboratory of Translational Physiology, Universidade Nove de Julho (UNINOVE), São Paulo, 4Health Adult and Child, Federal University of Maranhao (UFMA), São Luiz, Maranhão, Brazil Objective: The aim of this study was to evaluate the effects of aging on metabolic, cardiovascular, autonomic, inflammatory, and oxidative stress parameters after ovarian hormone deprivation (OVX). Methods: Female Wistar rats (3 or 22 months old) were divided into: young controls, young ovariectomized, old controls, and old ovariectomized (bilateral ovaries removal). After a 9-week follow-up, physical capacity, metabolic parameters, and morphometric and cardiac functions were assessed. Subsequently, arterial pressure was recorded and cardiac autonomic control was evaluated. Oxidative stress was measured on the cardiac tissue, while inflammatory profile was assessed in the plasma. Results: Aging or OVX caused an increase in body and fat weight and triglyceride concentration and a decrease in both insulin sensitivity and aerobic exercise capacity. Left ventricular diastolic dysfunction and increased cardiac overload (myocardial performance index) were reported in old groups when compared with young groups. Aging and OVX led to an increased sympathetic tonus, and vagal tonus was lower only for the old groups. Tumor necrosis factor-α and interleukin-6 were increased in old groups when compared with young groups. Glutathione redox balance (GSH/GSSG) was reduced in young ovariectomized, old controls, and old ovariectomized groups when compared with young controls, indicating an increased oxidative stress. A negative correlation was found between GSH/GSSG and tumor necrosis factor-α (r=-0.6, P

Background: The mitral annular plane systolic excursion (MAPSE) is used to analyze the left ventricle longitudinal function. However, the accuracy of MAPSE in diagnosing oncological populations is unclear. In this study, we aimed to assess the accuracy of MAPSE in diagnosing subclinical cardiotoxicity in women with breast cancer undergoing anthracycline treatment., Methods: This retrospective cohort study included echocardiographic assessments of patients with breast cancer who underwent anthracycline treatment as part of their therapeutic regimen. Assessments were performed before treatment, after administering the first dose of anthracycline, after completing anthracycline treatment, and 6 and 12 months after treatment. Left ventricular ejection fraction was calculated using the modified biplane Simpson method. The performances of MAPSE and global longitudinal strain (GLS) were analyzed using receiver operating characteristic (ROC) curves. Their accuracies were measured using the area under the ROC curves., Results: Sixty-one patients were included in this study. Of them, 8.2% presented cardiotoxicity 6 months after treatment completion. Patients with cardiotoxicity had lower LVEF (47% vs. 63%; p < 0.001), MAPSE (10.23 mm vs. 12.25 mm; p = 0.012), and LV GLS (16.13% vs. 19.05%; p = 0.005) values than those without. A 12% reduction in the GLS exhibited sensitivity, specificity, and overall accuracy of 80%, 70%, and 78%, respectively. A relative reduction of 15% in MAPSE exhibited a sensitivity, specificity, and accuracy of 80%, 77%, and 81.2%, respectively. An absolute MAPSE reduction of 2 mm exhibited a sensitivity, specificity, and accuracy of 80%, 73.21%, and 81.2%, respectively. No differences were observed between the ROC curves., Conclusion: MAPSE showed similar accuracy to GLS in diagnosing subclinical cardiotoxicity in women with breast cancer undergoing anthracycline treatment., (© 2024. The Author(s).)

Central Illustration : Position Statement on the Use of Myocardial Strain in Cardiology Routines by the Brazilian Society of Cardiology's Department Of Cardiovascular Imaging - 2023 Proposal for including strain in the integrated diastolic function assessment algorithm, adapted from Nagueh et al.67 Am: mitral A-wave duration; Ap: reverse pulmonary A-wave duration; DD: diastolic dysfunction; LA: left atrium; LASr: LA strain reserve; LVGLS: left ventricular global longitudinal strain; TI: tricuspid insufficiency. Confirm concentric remodeling with LVGLS. In LVEF, mitral E wave deceleration time < 160 ms and pulmonary S-wave < D-wave are also parameters of increased filling pressure. This algorithm does not apply to patients with atrial fibrillation (AF), mitral annulus calcification, > mild mitral valve disease, left bundle branch block, paced rhythm, prosthetic valves, or severe primary pulmonary hypertension.

Introduction: Zika virus infection during pregnancy causes fetal microcephaly and brain damage. Congenital Zika syndrome (CZS) is characterized by systemic involvement with diffuse muscle impairment, a high frequency of arthrogryposis, and microphthalmia. Cardiac impairment in CZS has rarely been evaluated. Our study assessed morphology and biventricular cardiac function in children with CZS and advanced neurological dysfunction., Methods: This cross-sectional study was conducted on 52 children with CZS (Zika group; ZG) and 25 healthy children (control group; CG) in Paraiba, Brazil. Clinical evaluation, electrocardiogram (EKG), and transthoracic echocardiogram (TTE) were performed on all children. Additionally, troponin I and natriuretic peptide type B (BNP) levels, the degree of cerebral palsy, and neuroimaging findings were assessed in the ZG group., Results: The median age of the study population was 5 years in both groups, and 40.4% (ZG) and 60% (CG) were female. The most prevalent electrocardiographic alteration was sinus arrhythmia in both the ZG (n = 9, 17.3%) and CG (n = 4, 16%). The morphological parameters adjusted for Z score were as follows: left ventricular (LV) end-diastolic diameter in ZG: -2.36 [-5.10, 2.63] vs. CG: -1.07 [-3.43, 0.61], p<0.001); ascending aorta (ZG: -0.09 [-2.08, 1.60] vs. CG: 0.43 [-1.47, 2.2], p = 0.021); basal diameter of the right ventricle (RV) (ZG: -2.34 [-4.90, 0.97] vs. CG: -0.96 [-2.21, 0.40], p<0.01); and pulmonary artery dimension (ZG: -2.13 [-5.99, 0.98] vs. CG: -0.24 [-2.53, 0.59], p<0.01). The ejection fractions (%) were 65.7 and 65.6 in the ZG and CG, respectively (p = 0.968). The left atrium volume indices (mL/m2) in the ZG and CG were 13.15 [6.80, 18.00] and 18.80 [5.90, 25.30] (p<0.01), respectively, and the right atrium volume indices (mL/m2) were 10.10 [4.90, 15.30] and 15.80 [4.10, 24.80] (p<0.01). The functional findings adjusted for Z score were as follows: lateral systolic excursion of the mitral annular plane (MAPSE) (ZG: 0.36 [-2.79, 4.71] vs. CG: 1.79 [-0.93, 4.5], p = 0.001); tricuspid annular plane systolic excursion (TAPSE) (ZG: -2.43 [-5.47, 5.09] vs. CG: 0.07 [-1.98, 3.64], p<0.001); and the S' of the RV (ZG: 1.20 [3.35, 2.90] vs. CG: -0.20 [-2.15, 1.50], p = 0.0121). No differences in biventricular strain measurements were observed between the groups. Troponin I and BNP levels were normal in in the ZG. Grade V cerebral palsy and subcortical calcification were found in 88.6% and 97.22% of children in the ZG group, respectively., Conclusion: A reduction in cardiac dimensions and functional changes were found in CZS patients, based on the TAPSE, S' of the RV, and MAPSE, suggesting the importance of cardiac evaluation and follow-up in this group of patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Barbosa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Previous studies show that COVID-19 survivors have elevated muscle sympathetic nerve activity (MSNA), endothelial dysfunction, and aortic stiffening. However, the neurovascular responses to mental stress and exercise are still unexplored. We hypothesized that COVID-19 survivors, compared with age- and body mass index (BMI)-matched control subjects, exhibit abnormal neurovascular responses to mental stress and physical exercise. Fifteen severe COVID-19 survivors (aged: 49 ± 2 yr, BMI: 30 ± 1 kg/m 2 ) and 15 well-matched control subjects (aged: 46 ± 3 yr, BMI: 29 ± 1 kg/m 2 ) were studied. MSNA (microneurography), forearm blood flow (FBF), and forearm vascular conductance (FVC, venous occlusion plethysmography), mean arterial pressure (MAP, Finometer), and heart rate (HR, ECG) were measured during a 3-min mental stress (Stroop Color-Word Test) and during a 3-min isometric handgrip exercise (30% of maximal voluntary contraction). During mental stress, MSNA (frequency and incidence) responses were higher in COVID-19 survivors than in controls ( P < 0.001), and FBF and FVC responses were attenuated ( P < 0.05). MAP was similar between the groups ( P > 0.05). In contrast, the MSNA (frequency and incidence) and FBF and FVC responses to handgrip exercise were similar between the groups ( P > 0.05). MAP was lower in COVID-19 survivors ( P < 0.05). COVID-19 survivors exhibit an exaggerated MSNA and blunted vasodilatory response to mental challenge compared with healthy adults. However, the neurovascular response to handgrip exercise is preserved in COVID-19 survivors. Overall, the abnormal neurovascular control in response to mental stress suggests that COVID-19 survivors may have an increased risk to cardiovascular events during mental challenge.

Background: COVID-19 has become a dramatic health problem during this century. In addition to high mortality rate, COVID-19 survivors are at increased risk for cardiovascular diseases 1-year after infection. Explanations for these manifestations are still unclear but can involve a constellation of biological alterations. We hypothesized that COVID-19 survivors compared with controls exhibit sympathetic overdrive, vascular dysfunction, cardiac morpho-functional changes, impaired exercise capacity, and increased oxidative stress., Methods: Nineteen severe COVID-19 survivors and 19 well-matched controls completed the study. Muscle sympathetic nerve activity (microneurography), brachial artery flow-mediated dilation and blood flow (Doppler-Ultrasound), carotid-femoral pulse wave velocity (Complior), cardiac morpho-functional parameters (echocardiography), peak oxygen uptake (cardiopulmonary exercise testing), and oxidative stress were measured ~3 months after hospital discharge. Complementary experiments were conducted on human umbilical vein endothelial cells cultured with plasma samples from subjects., Results: Muscle sympathetic nerve activity and carotid-femoral pulse wave velocity were greater and brachial artery flow-mediated dilation, brachial artery blood flow, E/e' ratio, and peak oxygen uptake were lower in COVID-19 survivors than in controls. COVID-19 survivors had lower circulating antioxidant markers compared with controls, but there were no differences in plasma-treated human umbilical vein endothelial cells nitric oxide production and reactive oxygen species bioactivity. Diminished peak oxygen uptake was associated with sympathetic overdrive, vascular dysfunction, and reduced diastolic function in COVID-19 survivors., Conclusions: Our study revealed that COVID-19 survivors have sympathetic overactivation, vascular dysfunction, cardiac morpho-functional changes, and reduced exercise capacity. These findings indicate the need for further investigation to determine whether these manifestations are persistent longer-term and their impact on the cardiovascular health of COVID-19 survivors.

Background: Heart failure (HF) associated with atrial fibrillation increases patients' physical inactivity, worsening their clinical condition and mortality. Exercise training is safe and has clear benefits in HF. However, little is known about the effects of exercise training on patients with HF with reduced ejection fraction and permanent atrial fibrillation (HFAF)., Objective: The purpose of this study was to test the hypothesis that exercise training improves functional capacity, cardiac function, and quality of life in patients with HFAF., Methods: This randomized clinical trial was conducted at the Heart Institute. Patients with HFAF, left ventricular ejection fraction ≤40%, and resting heart rate (HR) ≤80 beats/min were included in the study. Cardiopulmonary testing, echocardiography, nervous system, and quality of life assessment were performed before and after the 12-week protocol period., Results: Twenty-six patients (mean age 58 ± 1 years) were randomized to exercise training (HFAF-trained group; n = 13) or no training (HFAF-untrained group; n = 13). At baseline, no differences between the groups were found. Exercise improved peak oxygen consumption, slope of ventilation per minute/carbon dioxide production, and quality of life. The HFAF-trained group had significantly decreased resting HR (from 73 ± 2 to 69 ± 2 beats/min; P = .02) and recovery HR (from 148 ± 11 to 128 ± 9 beats/min; P = .001). Concomitantly, left ventricular ejection fraction increased (from 31% ± 1% to 36% ± 0.9%; P = .01), left atrial dimension decreased (from 52 ± 1.2 to 47 ± 1 mm; P = .03), and left ventricular end-systolic volume and left ventricular end-diastolic volume deceased (from 69 ± 2 to 64 ± 1.8 mL/m 2 and from 99 ± 2.1 to 91 ± 2 mL/m 2 , respectively; P < .05). No changes were observed in the HFAF-untrained group., Conclusion: Exercise training can improve exercise capacity, quality of life, and cardiac function in patients with HF with reduced ejection fraction and permanent atrial fibrillation., (Copyright © 2022 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Objectives: To determine whether the time for peak exercise heart rate to return to resting heart rate after the 6-minute walk test (6MWT) can predict cardiac events in patients with heart failure (HF) within 2 years., Design: Prospective cohort study., Setting: HF outpatient facility at a tertiary teaching hospital., Participants: Seventy-six patients with HF, New York Heart Association functional classification II and III, and left ventricular ejection fraction <50%., Main Outcome Measures: Patients used a heart rate monitor to measure the time for peak exercise heart rate to return to resting heart rate after the 6MWT. Data were analysed using Polar Pro-Trainer 5 software (Kempele, Finland). Patients were followed for >2 years for cardiac events (hospitalisations and death)., Results: Thirty-four patients had cardiac events during the 2-year follow-up period. However, there was a significant difference in the time to return to resting heart rate between the groups with and without cardiac events {with 3.6 (SD 1.1) vs without 2.8 (SD 1.1) minutes; mean difference of 0.79 (95% confidence interval (CI) of the difference 0.28 to 1.28; P=0.003}. No significant differences between patients with and without cardiac events were found for mean walking distance, mean heart rate recovery at 1minute and mean heart rate recovery at 2minutes. The receiver operating curve discriminated between patients with and without cardiac events (área under the curve 0.71, 95% CI 0.61 to 0.81; P<0.001). Using logistic regression analysis, prolonged time to return to resting heart rate (≥3minutes) independently increased the risk for cardiac events 6.9-fold (95% CI 2.34 to 20.12; P<0.001). The Kaplan-Meier curve showed more cardiac events in patients with prolonged time to return to resting heart rate (P=0.028)., Conclusions: Prolonged time to return to resting heart rate (≥3minutes) after the 6MWT was an independent predictor of cardiac events in patients with HF., (Copyright © 2021 Chartered Society of Physiotherapy. Published by Elsevier Ltd. All rights reserved.)

Aims: Noncompaction cardiomyopathy (NCC) is considered a genetic cardiomyopathy with unknown pathophysiological mechanisms. We propose to evaluate echocardiographic predictors for rigid body rotation (RBR) in NCC using a machine learning (ML) based model., Methods and Results: Forty-nine outpatients with NCC diagnosis by echocardiography and magnetic resonance imaging (21 men, 42.8±14.8 years) were included. A comprehensive echocardiogram was performed. The layer-specific strain was analyzed from the apical two-, three, four-chamber views, short axis, and focused right ventricle views using 2D echocardiography (2DE) software. RBR was present in 44.9% of patients, and this group presented increased LV mass indexed (118±43.4 vs. 94.1±27.1g/m2, P = 0.034), LV end-diastolic and end-systolic volumes (P< 0.001), E/e' (12.2±8.68 vs. 7.69±3.13, P = 0.034), and decreased LV ejection fraction (40.7±8.71 vs. 58.9±8.76%, P < 0.001) when compared to patients without RBR. Also, patients with RBR presented a significant decrease of global longitudinal, radial, and circumferential strain. When ML model based on a random forest algorithm and a neural network model was applied, it found that twist, NC/C, torsion, LV ejection fraction, and diastolic dysfunction are the strongest predictors to RBR with accuracy, sensitivity, specificity, area under the curve of 0.93, 0.99, 0.80, and 0.88, respectively., Conclusion: In this study, a random forest algorithm was capable of selecting the best echocardiographic predictors to RBR pattern in NCC patients, which was consistent with worse systolic, diastolic, and myocardium deformation indices. Prospective studies are warranted to evaluate the role of this tool for NCC risk stratification., Competing Interests: The authors received no specific funding for this work and the authors have declared that no competing interests exist.

Background: There are few contemporary cohorts of Trypanosoma cruzi -seropositive individuals, and the basic clinical epidemiology of Chagas disease is poorly understood. Herein, we report the incidence of cardiomyopathy and death associated with T. cruzi seropositivity., Methods: Participants were selected in blood banks at 2 Brazilian centers. Cases were defined as T. cruzi -seropositive blood donors. T. cruzi -seronegative controls were matched for age, sex, and period of donation. Patients with established Chagas cardiomyopathy were recruited from a tertiary outpatient service. Participants underwent medical examination, blood collection, ECG, and echocardiogram at enrollment (2008-2010) and at follow-up (2018-2019). The primary outcomes were all-cause mortality and development of cardiomyopathy, defined as the presence of a left ventricular ejection fraction <50% or QRS complex duration ≥120 ms, or both. To handle loss to follow-up, a sensitivity analysis was performed using inverse probability weights for selection., Results: We enrolled 499 T. cruzi -seropositive donors (age 48±10 years, 52% male), 488 T. cruzi -seronegative donors (age 49±10 years, 49% male), and 101 patients with established Chagas cardiomyopathy (age 48±8 years, 59% male). The mortality in patients with established cardiomyopathy was 80.9 deaths/1000 person-years (py) (54/101, 53%) and 15.1 deaths/1000 py (17/114, 15%) in T. cruzi -seropositive donors with cardiomyopathy at baseline. Among T. cruzi -seropositive donors without cardiomyopathy at baseline, mortality was 3.7 events/1000 py (15/385, 4%), which was no different from T. cruzi -seronegative donors with 3.6 deaths/1000 py (17/488, 3%). The incidence of cardiomyopathy in T. cruzi -seropositive donors was 13.8 (95% CI, 9.5-19.6) events/1000 py (32/262, 12%) compared with 4.6 (95% CI, 2.3-8.3) events/1000 py (11/277, 4%) in seronegative controls, with an absolute incidence difference associated with T. cruzi seropositivity of 9.2 (95% CI, 3.6-15.0) events/1000 py. T. cruzi antibody level at baseline was associated with development of cardiomyopathy (adjusted odds ratio, 1.4 [95% CI, 1.1-1.8])., Conclusions: We present a comprehensive description of the natural history of T. cruzi seropositivity in a contemporary patient population. The results highlight the central importance of anti- T. cruzi antibody titer as a marker of Chagas disease activity and risk of progression.

Objective: Cardiac allograft vasculopathy is one of the leading causes of late graft failure and subsequent death in orthotopic heart transplant. Although invasive coronary angiography is the gold standard modality for detection of cardiac allograft vasculopathy, dobutamine stress echocardiography has been recently frequently used as an alternative. Our aim was to evaluate the diagnostic performance of dobutamine stress echocardiography for detection of cardiac allograft vasculopathy in transplant patients., Methods: A retrospective analysis was conducted using a total of 150 dobutamine stress echocardiographic exams that were performed on 99 patients in our institution, with paired coronary angiogram and no acute rejection, within a median of 538 [interquartile range 371-816] days. Sensitivity and specificity of dobutamine echocardiography to detect allograft vasculopathy was evaluated. Allograft vasculopathy was defined as Grade 1 or higher based on ISHLT criteria. A positive dobutamine stress echo result was defined by new or worsening wall motion abnormality., Results: Median age of the population at transplant was 34 [interquartile range 22-46] years; 76 (77%) patients were male. Allograft vasculopathy was present in 31 (20.6%) out of 150 coronary angiograms. Only 7 (4.6%) of that number were positive on dobutamine stress echocardiography. Sensitivity and specificity for allograft vasculopathy detection was 3% and 94%, respectively. Out of 7 false positive dobutamine stress echocardiograms, two were in patients with myocardial bridging. Two patients with mild acute rejection had both negative dobutamine stress echo., Conclusions: Overall, positivity of dobutamine stress echocardiography in patients after heart transplant is low. It has high specificity, but very low sensitivity for detection of cardiac allograft vasculopathy. Dobutamine stress echocardiography should only be cautiously used as an alternative to coronary angiography., Competing Interests: Conflict of interest None., (© 2021 Saudi Heart Association.)

Obesity and insulin resistance (IR) are well-studied risk factors for systemic cardiovascular disease, but their impact on pulmonary hypertension (PH) is not well clarified. This study aims to investigate if diet-induced obesity induces PH and if peroxisome-proliferator-activated receptor (PPAR-γ) and/or endoplasmic reticulum (ER) stress are involved in this process. Mice were maintained on a high-fat diet (HFD) for 4 months, and IR and PH were confirmed. In a separate group, after 4 months of HFD, mice were treated with pioglitazone (PIO) or 4-phenylbutyric acid for the last month. The results demonstrated that HFD for at least 4 months is able to increase pulmonary artery pressure, which is maintained, and this animal model can be used to investigate the link between IR and PH, without changes in ER stress in the pulmonary artery. There was also a reduction in circulating adiponectin and in perivascular adiponectin expression in the pulmonary artery, associated with a reduction in PPAR-γ expression. Treatment with PIO improved IR and PH and reversed the lower expression of adiponectin and PPAR-γ in the pulmonary artery, highlighting this drug as potential benefit for this poorly recognized complication of obesity., 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 Gonçalves, Rocha, Marin, Camargo, Santos, Carmo, Guadagnini, Petrucci, Moysés, Salemi, Oliveira and Saad.)

Aims: Patients with advanced heart failure (HF) with reduced left ventricular ejection fraction (HFrEF) and concurrent coronavirus disease 2019 (COVID-19) might have a higher risk of severe events., Methods and Results: We retrospectively studied 16 patients with advanced HFrEF who developed COVID-19 between 1 March and 29 May 2020. Follow-up lasted until 30 September. Ten patients previously hospitalized with decompensated HFrEF were infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during hospitalization. Six patients undergoing ambulatory care at initiation of COVID-19 symptoms were hospitalized because of advanced HFrEF. All patients who experienced worsening of HFrEF due to COVID-19 required higher doses or introduction of additional inotropic drugs or intra-aortic balloon pump in the intensive care unit. The mean intravenous dobutamine dose before SARS-CoV-2 infection in previously hospitalized patients (n = 10) and the median (inter-quartile range) peak intravenous dobutamine dose during SARS-CoV-2 infection in all patients (n = 16) were 2 (0-7) μg/kg/min and 20 (14-20) (P < 0.001), respectively. During follow-up, 56% underwent heart transplantation (n = 2) or died (n = 7). Four patients died during hospitalization from mixed shock consequent to severe acute respiratory syndrome with inflammatory storm syndrome associated with septic and cardiogenic shock during COVID-19. After COVID-19 recovery, two patients died from mixed septic and cardiogenic shock and one from sustained ventricular tachycardia and cardiogenic shock. Five patients were discharged from hospital to ambulatory care. Four were awaiting heart transplantation., Conclusion: Worsening of advanced HF by COVID-19 is associated with high mortality. This report highlights the importance of preventing COVID-19 in patients with advanced HF., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: In the COVID-19 pandemic, the increase in the incidence of cardiovascular diseases (CVD) and mortality from them has been recognized worldwide. In Brazil, the impact of COVID-19 on CVD must be evaluated., Objectives: To assess the impact of the current pandemic on the numbers of hospital admissions (HA), in-hospital deaths (ID), and in-hospital fatality (IF) from CVD by use of national epidemiological data from the Brazilian Unified Public Health System., Methods: Time-series observational study using comparative analysis of the HA, ID, and IF due to CVD recorded from January to May 2020, having as reference the values registered in the same period from 2016 to 2019 and the values projected by linear regression methods for 2020. The statistical significance level applied was 0.05., Results: Compared to the same period in 2019, there was a 15% decrease in the HA rate and a 9% decrease in the total ID due to CVD between March and May 2020, followed by a 9% increase in the IF rate due to CVD, especially among patients aged 20-59 years. The HA and IF rates registered in 2020 differed significantly from the projected trend for 2020 (p = 0.0005 and 0.0318, respectively)., Conclusions: During the first months of the pandemic, there were a decline in HA and an increase in IF due to CVD in Brazil. These data might have resulted from the inadequate planning of the CVD management during the pandemic. Thus, immediate actions are required to change this scenario. (Arq Bras Cardiol. 2021; [online].ahead print, PP.0-0).

Background Patients treated for breast cancer have a high incidence of cardiovascular complications. In this study, we evaluated the impact of breast cancer on cardiac function and cardiomyocyte Ca 2+ -handling protein expression. We also investigated whether exercise training (ET) would prevent these potential alterations. Methods and Results Transgenic mice with spontaneous breast cancer (mouse mammary tumor virus-polyomavirus middle T antigen [MMTV-PyMT+], n=15) and littermate mice with no cancer (MMTV-PyMT-, n=14) were studied. For the ET analysis, MMTV-PyMT+ were divided into sedentary (n=10) and exercise-trained (n=12) groups. Cardiac function was evaluated by echocardiography with speckle-tracking imaging. Exercise tolerance test was conducted on a treadmill. Both studies were performed when the tumor became palpable and when it reached 1 cm 3 . After euthanasia, Ca 2+ -handling protein expression (Western blot) was evaluated. Exercise capacity was reduced in MMTV-PyMT+ compared with MMTV-PyMT- ( P interaction =0.031). Longitudinal strain ( P group <0.001) and strain rate ( P group =0.030) were impaired. Cardiomyocyte phospholamban was increased ( P =0.011), whereas phospho-phospholamban and sodium/calcium exchanger were decreased ( P =0.038 and P =0.017, respectively) in MMTV-PyMT+. No significant difference in sarcoplasmic or endoplasmic reticulum calcium 2 ATPase (SERCA2a) was found. SERCA2a/phospholamban ratio was reduced ( P =0.007). ET was not associated with increased exercise capacity. ET decreased left ventricular end-systolic diameter ( P group =0.038) and end-diastolic volume ( P group =0.026). Other morphological and functional cardiac parameters were not improved by ET in MMTV-PyMT+. ET did not improve cardiomyocyte Ca 2+ -handling protein expression. Conclusions Breast cancer is associated with decreased exercise capacity and subclinical left ventricular dysfunction in MMTV-PyMT+, which is at least partly associated with dysregulation of cardiomyocyte Ca 2+ handling. ET did not prevent or reverse these changes.

Objectives: To evaluate the effects of sympathectomy on the myocardium in an experimental model., Methods: The study evaluated three groups of male Wistar rats: control (CT; n=15), left unilateral sympathectomy (UNI; n=15), and bilateral sympathectomy (BIL; n=31). Sympathectomy was performed by injection of absolute alcohol into the space of the spinous process of the C7 vertebra. After 6 weeks, we assessed the chronotropic properties at rest and stress, cardiovascular autonomic modulation, myocardial and peripheral catecholamines, and beta-adrenergic receptors in the myocardium. The treadmill test consisted of an escalated protocol with a velocity increment until the maximal velocity tolerated by the animal was reached., Results: The bilateral group had higher levels of peripheral catecholamines, and consequently, a higher heart rate (HR) and blood pressure levels. This suggests that the activation of a compensatory pathway in this group may have deleterious effects. The BIL group had basal tachycardia immediately before the exercise test and increased tachycardia at peak exercise (p<0.01); the blood pressure had the same pattern (p=0.0365). The variables related to autonomic modulation were not significantly different between groups, with the exception of the high frequency (HF) variable, which showed significant differences in CT vs UNI. There was no significant difference in beta receptor expression between groups. There was a higher concentration of peripheral norepinephrine in the BIL group (p=0.0001), and no significant difference in myocardial norepinephrine (p=0.09)., Conclusion: These findings suggest that an extra cardiac compensatory pathway increases the sympathetic tonus and maintains a higher HR and higher levels of peripheral catecholamines in the procedure groups. The increase in HF activity can be interpreted as an attempt to increase the parasympathetic tonus to balance the greater sympathetic activity.

Aims: Left ventricular non-compaction cardiomyopathy (LVNC) is a genetic heart disease, with heart failure, arrhythmias, and embolic events as main clinical manifestations. The goal of this study was to analyse a large set of echocardiographic (echo) and cardiac magnetic resonance imaging (CMRI) parameters using machine learning (ML) techniques to find imaging predictors of clinical outcomes in a long-term follow-up of LVNC patients., Methods and Results: Patients with echo and/or CMRI criteria of LVNC, followed from January 2011 to December 2017 in the heart failure section of a tertiary referral cardiologic hospital, were enrolled in a retrospective study. Two-dimensional colour Doppler echocardiography and subsequent CMRI were carried out. Twenty-four hour Holter monitoring was also performed in all patients. Death, cardiac transplantation, heart failure hospitalization, aborted sudden cardiac death, complex ventricular arrhythmias (sustained and non-sustained ventricular tachycardia), and embolisms (i.e. stroke, pulmonary thromboembolism and/or peripheral arterial embolism) were registered and were referred to as major adverse cardiovascular events (MACEs) in this study. Recruited for the study were 108 LVNC patients, aged 38.3 ± 15.5 years, 48.1% men, diagnosed by echo and CMRI criteria. They were followed for 5.8 ± 3.9 years, and MACEs were registered. CMRI and echo parameters were analysed via a supervised ML methodology. Forty-seven (43.5%) patients had at least one MACE. The best performance of imaging variables was achieved by combining four parameters: left ventricular (LV) ejection fraction (by CMRI), right ventricular (RV) end-systolic volume (by CMRI), RV systolic dysfunction (by echo), and RV lower diameter (by CMRI) with accuracy, sensitivity, and specificity rates of 75.5%, 77%, 75%, respectively., Conclusions: Our findings show the importance of biventricular assessment to detect the severity of this cardiomyopathy and to plan for early clinical intervention. In addition, this study shows that even patients with normal LV function and negative late gadolinium enhancement had MACE. ML is a promising tool for analysing a large set of parameters to stratify and predict prognosis in LVNC patients., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Diabetes can elicit direct deleterious effects on the myocardium, independent of coronary artery disease or hypertension. These cardiac disturbances are termed diabetic cardiomyopathy showing increased risk of heart failure with or without reduced ejection fraction. Presently, there is no specific treatment for this type of cardiomyopathy and in the case of type I diabetes, it may start in early childhood independent of glycemic control. We hypothesized that alterations in isolated myocyte contractility and cardiac function are present in the early stages of experimental diabetes in rats before overt changes in myocardium structure occur. Diabetes was induced by single-dose injection of streptozotocin (STZ) in rats with data collected from control and diabetic animals 3 weeks after injection. Left ventricle myocyte contractility was measured by single-cell length variation under electrical stimulation. Cardiac function and morphology were studied by high-resolution echocardiography with pulsed-wave tissue Doppler imaging (TDI) measurements and three-lead surface electrocardiogram. Triglycerides, cholesterol and liver enzyme levels were measured from plasma samples obtained from both groups. Myocardial collagen content and perivascular fibrosis of atria and ventricle were studied by histological analysis after picrosirius red staining. Diabetes resulted in altered contractility of isolated cardiac myocytes with increased contraction and relaxation time intervals. Echocardiography showed left atrium dilation, increased end-diastolic LV and posterior wall thickness, with reduced longitudinal systolic peak velocity (S') of the septum mitral annulus at the apical four-chamber view obtained by TDI. Triglycerides, aspartate aminotransferase and alkaline phosphatase were elevated in diabetic animals. Intertitial collagen content was higher in atria of both groups and did not differ among control and diabetic animals. Perivascular intramyocardial arterioles collagen did not differ between groups. These results suggest that alterations in cardiac function are present in the early phase in this model of diabetes type 1 and occur before overt changes in myocardium structure appear as evaluated by intersticial collagen deposition and perivascular fibrosis of intramyocardial arterioles., Competing Interests: The authors have declared that no competing interests exist.

The use of sacubitril/valsartan significantly reduces death or hospitalization in patients with ejection fraction < 40%. There is no study evaluating this drug effects in non-compaction cardiomyopathy (NCCM) individuals. The aim of this article is to report a case of a patient with NCCM initially refractory to gold standard treatment and afterwards treated with sacubitril/valsartan and its improvements. This is a case report of a 48-year-old woman, presenting with NCCM heart failure, who had received standard guideline-directed medical therapy for 18 months without any improvement in clinical and echocardiographic parameters. After that period, sacubitril/valsartan was initiated. After 18 months of refractory usage of guideline-directed medical therapy, sacubitril/valsartan was started, and significant change in functional class (III to I) and important ventricular remodelling were achieved with an improvement of 29% in the ejection fraction, reduction of 7 mm in ventricular diastolic diameter, and mild to none mitral valve functional regurgitation. In this case report, sacubitril/valsartan use was associated with improvement of echocardiographic and clinical parameters in a patient with NCCM., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Purpose: Endomyocardial fibrosis (EMF) is a restrictive cardiomyopathy associated with low functional capacity and high mortality rates. Exercise training has been proved to be a nonpharmacological treatment of cardiovascular diseases. Therefore, the purpose of this study was to determine the effects of exercise rehabilitation in EMF patients., Methods: Twenty-two EMF patients, functional classes II and III (New York Heart Association [NYHA]), were randomized to the control (C-EMF) or exercise rehabilitation (Rehab-EMF) group. Patients in the Rehab-EMF group underwent 4 mo of exercise rehabilitation, whereas patients in the C-EMF group were instructed to maintain their usual daily routine. Peak oxygen uptake ((Equation is included in full-text article.)O2), cardiac function, and quality of life were evaluated. All assessments were performed at baseline and after 4 mo., Results: After 4 mo of rehabilitation, peak (Equation is included in full-text article.)O2 increased in the Rehab-EMF group (17.4 ± 3.0 to 19.7 ± 4.4 mL/kg/min, P < .001), whereas the C-EMF group showed no difference (15.3 ± 3.0 to 15.0 ± 2.0 mL/kg/min, P = .87). Also, post-intervention, peak (Equation is included in full-text article.)O2 in the Rehab-EMF group was greater than that in the C-EMF group (P < .001). Furthermore, the Rehab-EMF group, when compared to the C-EMF group, showed an increase in left ventricular end-diastolic volume (102.1 ± 64.6 to 136.2 ± 75.8 mL vs 114.4 ± 55.0 to 100.4 ± 49.9 mL, P < .001, respectively) and decrease in left atrial diastolic volume (69.0 ± 33.0 to 34.9 ± 15.0 mL vs 44.6 ± 21.0 to 45.6 ± 23.0 mL, P < .001, respectively). Quality-of-life scores also improved in the Rehab-EMF group, whereas the C-EMF group showed no change (45 ± 23 to 27 ± 15 vs 47 ± 15 to 45 ± 17, P < .001, respectively)., Conclusion: Exercise rehabilitation is a nonpharmacological intervention that improves functional capacity, cardiac volumes, and quality of life in EMF patients after endocardial resection surgery. In addition, exercise rehabilitation should be prescribed to EMF patients to improve their clinical condition.

Background: Heart failure is associated with exercise intolerance and sleep- disordered breathing; however, studies in patients with chronic constrictive pericarditis are scarce. The purpose of our study was to assess exercise capacity and sleep in patients with chronic constrictive pericarditis (CCP) undergoing a pericardiectomy., Methods: We studied consecutive patients scheduled for pericardiectomy due to symptomatic CCP. Were performed quality of life (Minnesota Living with Heart Failure Questionnaire-MLHFQ) and sleep questionnaires (Epworth, Pittsburgh Sleep Quality Index-PSQI), serum B-type natriuretic peptide (BNP), serum C-reactive protein, transthoracic echocardiography, cardiopulmonary exercise test and overnight polysomnography immediately before and six months after pericardiectomy., Results: Twenty-five patients (76% males, age: 45.5±13.8 years, body mass index: 24.9±3.7 kg/m2, left ventricular ejection fraction: 60±6%) with CCP (76% idiopathic, 12% tuberculosis) were studied. As compared to the preoperative period, pericardiectomy resulted in reduction in BNP (143 (83.5-209.5) vs 76 (40-117.5) pg/mL, p = 0.011), improvement in VO2 peak (18.7±5.6 vs. 25.2±6.3 mL/kg/min, p<0.001), quality of life (MLHFQ score 62 (43,5-77,5) vs. 18 (8,5-22), p<0,001) and sleep (PSQI score 7.8±4.1 vs. 4.7±3.7, p<0.001) and no significant change in sleep disordered breathing (apnea hypopnea index-AHI 15.6 (8.3-31.7) vs. 14.6 (5.75-29.9) events/h, p = 0.253)., Conclusion: Patients with symptomatic CCP showed reduced exercise capacity and sleep-disordered breathing. After pericardiectomy, there was improvement in exercise capacity and neutral effect on sleep-disordered breathing., Competing Interests: The authors have declared that no competing interests exist.

Cardiac involvement in systemic light chain (AL) amyloidosis carries a poor prognosis mainly through involvement of the left ventricular (LV) myocardium. Despite its limitations, two-dimensional transthoracic echocardiography (2D-TTE) remains the main tool used for the assessment of LV systolic function in AL patients. We hypothesize that 3D-TTE coupled with speckle tracking imaging allows earlier detection of LV systolic dysfunction than 2D-TTE in AL amyloidosis. We prospectively studied 71 subjects including 58 patients with confirmed AL amyloidosis (mean age 66 ± 10 years, 60% male) and 21 healthy control (mean age 64 ± 7 years, 48% male) from 2011 to 2014 at the University Hospital of Limoges. The AL patients were divided into three groups according to Mayo Clinic (MC) staging and all subjects underwent 2D-TTE and 3D-TTE at the same setting. Using 2D-TTE, there was no significant difference in LV ejection fraction (EF) between the groups [LVEF = 63 ± 7% (control), 59 ± 6% (MC stage I), 60 ± 8% (MC stage II) and 57 ± 14% (MC stage III) (p = 0.24)]. In contrast, 3D-TTE demonstrated significantly worse LV systolic function in stage II and III patients using 3D-LVEF [MC II and III 45 ± 8% and 39 ± 12% vs. control 53 ± 8% (p < 0.0001)], global longitudinal strain (GLS) [MC II and III - 11 ± 4% and - 8 ± 3% vs. control - 15 ± 3% (p < 0.0001)] and global radial strain (GRS) [MC II and III 14 ± 9% and 10 ± 8% vs. control 25 ± 10% (p < 0.0001)]. Furthermore, MC III patients had significantly worse global circumferential strain and area tracking [- 17 ± 6% and - 25 ± 8% vs. - 24 ± 7% and - 36 ± 7% for control (p < 0.0001)]. Additionally, MC I had significantly better 3D GLS, GRS and global strain (- 15 ± 3%, 25 ± 10% and 28 ± 12%) than MC II (- 11 ± 4%, 14 ± 9% and 16 ± 10%) and MC III patients (- 8 ± 3%, 10 ± 8% and 12 ± 8%), respectively. Despite an apparently preserved LVEF by 2D-TTE, AL patients in MC stage II and III demonstrate evidence of LV systolic dysfunction by 3D imaging using LVEF and strain analysis. Worse LV involvement by AL amyloidosis was associated with more impaired 3D-TTE LV systolic parameters.

Introduction: Heart failure with reduced ejection fraction (HFrEF) is associated with a worse outcome. Heart rate (HR) is related to outcome in HFrEF. Ivabradine selectively inhibits I f (funny) channels in a concentration-dependent manner reducing HR., Areas Covered: The effects of ivabradine in HF were reviewed. The SHIFT trial results indicated that ivabradine improves chronic HFrEF outcomes, whereas published data suggest that amiodarone, digoxin, or verapamil may not be safe or the safety is controversial in HFrEF patients. In the CONSTATHE-DHF study, ivabradine reduced HR and improved left ventricular (LV) ejection fraction, LV diastolic functions, and right ventricle function in acute decompensated HF (ADHF). In chagasic patients, ivabradine reduced HR and a trend toward reduction in all-cause death was observed with ivabradine ( p  = 0.07). In children with HFrEF, ivabradine increased NYHA functional class. The most common side effects with ivabradine are bradycardia, atrial fibrillation, and phosphenes. Ivabradine was approved for HFrEF treatment by the EMA and FDA and seems to be cost-effective in HFrEF treatment. Ivabradine is indicated for HFrEF by the ESC HF Guidelines (IIa) and by the 2016 ACC/AHA/HFSA Guidelines (IIa-B-R)., Expert Opinion: Published evidences demonstrate that ivabradine improves the outcome of chronic HFrEF and it seems to have a promising role in ADHF.

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.

The study aimed at evaluating the effects of combined aerobic and resistance exercise training on cardiac morphometry and function, oxidative stress and inflammatory parameters in diabetic ovariectomized rats. For this, female Wistar rats (10 weeks-old) were divided into 4 groups (n = 8): euglycemic (E), diabetic (streptozotocin, 50 mg/kg, iv) (D), diabetic ovariectomized (DO) and trained diabetic ovariectomized (TDO). The combined exercise training was performed on a treadmill and in a ladder adapted to rats (8 weeks, at 40-60% of maximal capacity). The left ventricle (LV) morphometry and function were evaluated by echocardiography. Oxidative stress and inflammatory markers were measured on ventricles tissue. The sedentary diabetic animals (D and DO) showed impaired systolic and diastolic functions, as well as increased cardiac overload, evaluated by myocardial performance index (MPI- D: 0.32 ± 0.05; DO: 0.39 ± 0.13 vs. E: 0.25 ± 0.07), in relation to E group. Systolic and MPI dysfunctions were exacerbated in DO when compared to D group. The DO group presented higher protein oxidation and TNF-α/IL-10 ratio than D groups. Glutathione redox ratio (GSH/GSSG) and IL-10 were decreased in both D and DO groups when compared to E group. Exercise training improved exercise capacity, systolic and diastolic functions and MPI (0.18±0.11). The TDO group showed reduced protein oxidation and TNF-α/IL-10 ratio and increased GSH/GSSG and IL-10 in relation to the DO group. These results showed that combined exercise training was able to attenuate the cardiac dysfunctions, probably by reducing inflammation and oxidative stress in an experimental model of diabetes and menopause., Competing Interests: The authors have declared that no competing interests exist.

Aims: From pathophysiological mechanisms to risk stratification and management, much debate and discussion persist regarding left ventricular non-compaction cardiomyopathy (LVNC). This study aimed to characterize myocardial T1 mapping and extracellular volume (ECV) fraction by cardiovascular magnetic resonance (CMR), and investigate how these biomarkers relate to left ventricular ejection fraction (LVEF) and ventricular arrhythmias (VA) in LVNC., Methods and Results: Patients with LVNC (n = 36) and healthy controls (n = 18) were enrolled to perform a CMR with T1 mapping. ECV was quantified in LV segments without late gadolinium enhancement (LGE) areas to investigate diffuse myocardial fibrosis. Patients with LVNC had slightly higher native T1 (1024 ± 43 ms vs. 995 ± 22 ms, P = 0.01) and substantially expanded ECV (28.0 ± 4.5% vs. 23.5 ± 2.2%, P < 0.001) compared to controls. The ECV was independently associated with LVEF (β = -1.3, P = 0.001). Among patients without LGE, VAs were associated with higher ECV (27.7% with VA vs. 25.8% without VA, P = 0.002)., Conclusion: In LVNC, tissue characterization by T1 mapping suggests an extracellular expansion by diffuse fibrosis in myocardium without LGE, which was associated with myocardial dysfunction and VA, but not with the amount of non-compacted myocardium.

Myocardial remodeling includes inappropriate collagen deposition in the interstitium. Erythropoietin (EPO) may have cardioprotective effects. We aimed to assess the role of EPO on myocardial remodeling during the chronic phase. We studied 60 Wistar rats divided into the following groups: control (CT), control + EPO (CT + EPO), myocardial infarction + EPO (MI + EPO), and myocardial infarction (MI). The interstitial collagen volume fraction (ICVF) was quantified and echocardiography was performed. We quantified asymmetric dimethylarginine and glutathione by ELISA, and used real-time PCR to assess apoptosis and inflammation. Western blotting was used to evaluate inflammatory proteins and tissue inhibitors of metalloproteinases (TIMPs), and TUNEL staining was used to detect apoptosis. For matrix metalloproteinases (MMPs), we performed zymography. Parametric and nonparametric analyses were performed according to normality testing. ICVF was greater in MI groups (p < 0.001) and was attenuated by EPO (p = 0.05). The MMP-2 did not show any difference between groups. The TIMP-1 and TIMP-2 did not have difference between groups. The MI groups had worse fraction shortening (p < 0.001), without EPO protection (p = 0.666). The MI groups had increased left ventricle diastolic dimension (p < 0.001) without EPO attenuation (p = 0.79). EPO did not act on oxidative stress. Apoptosis and inflammation were not modulated by EPO. We concluded that EPO attenuated interstitial collagen accumulation, but did not protect from heart dilation or dysfunction.

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.

Left ventricular (LV) remodeling after myocardial infarction constitutes the structural basis for ventricular dysfunction and heart failure. The characterization underlying the expression of lipoprotein receptors in cardiac dysfunction is scarcely explored. The aim of this study was to analyze the status of lipoprotein receptors on the infarcted and noninfarcted areas of LV and to verify whether nanoparticles that mimic the lipid structure of low-density lipoprotein (LDL) and have the ability to bind to LDL receptors (LDE) are taken up more avidly by the noninfarcted LV. 13 male Wistar rats with left coronary artery ligation (myocardial infarction [MI]) and 12 animals with SHAM operation (SHAM) were used in this study. 6 weeks after the procedure, the quantification of low-density lipoprotein receptor (LDLR), LDL receptor-related protein 1 (LRP1), scavenger receptor-class B type I (SR-BI) lipoprotein receptors, and PCNA proliferation marker, and tissue uptake of radioactively labeled LDE were performed. Immunohistochemistry and Western blot analysis showed that LDLR, LRP1, SR-BI, and PCNA, expression in infarcted area of MI was remarkably higher than SHAM and noninfarcted subendocardial (SEN) and interstitial (INT) areas. In addition, in SEN noninfarcted area of MI, the presence of LDLR was about threefold higher than in SHAM SEN and INT noninfarcted areas. The LDE uptake of noninfarcted LV of MI group was about 30% greater than that of SHAM group. In conclusion, these findings regarding the status of lipoprotein receptors after MI induction could help to establish mechanisms on myocardial repairing. In conclusion, infarcted rats with LV dysfunction showed increased expression of lipoprotein receptors mainly in the infarcted area., (© 2018 AOCS.)

Background: Endomyocardial fibrosis (EMF) is a rare disease, characterized by diastolic dysfunction which leads to reduced peak oxygen consumption (VO2). Cardiopulmonary exercise testing (CPET) has been proved to be a fundamental tool to identify central and peripheral alterations. However, most studies prioritize peak VO2 as the main variable, leaving aside other important CPET variables that can specify the severity of the disease and guide the clinical treatment., Objective: The aim of this study was to evaluate central and peripheral limitations in symptomatic patients with EMF by different CPET variables., Methods: Twenty-six EMF patients (functional class III, NYHA) were compared with 15 healthy subjects (HS). Functional capacity was evaluated using CPET and diastolic and systolic functions were evaluated by echocardiography., Results: Age and gender were similar between EMF patients and HS. Left ventricular ejection fraction was normal in EMF patients, but decreased compared to HS. Peak heart rate, peak workload, peak VO2, peak oxygen (O2) pulse and peak pulmonary ventilation (VE) were decreased in EMF compared to HS. Also, EMF patients showed increased Δ heart rate /Δ oxygen uptake and Δ oxygen uptake /Δ work rate compared to HS., Conclusion: Determination of the aerobic capacity by noninvasive respiratory gas exchange during incremental exercise provides additional information about the exercise tolerance in patients with EMF. The analysis of different CPET variables is necessary to help us understand more about the central and peripheral alterations cause by both diastolic dysfunction and restrictive pattern.

Increase in oxidative/nitrosative stress is one of the mechanisms associated with the development of cardiotoxicity due to doxorubicin (Dox), a potent chemotherapy drug. Previously, we reported mitigation of Dox-induced oxidative/nitrosative stress and apoptosis by vitamin C (Vit C) in isolated cardiomyocytes. In the present in vivo study in rats, we investigated the effect of prophylactic treatment with Vit C on Dox-induced apoptosis, inflammation, oxidative/nitrosative stress, cardiac dysfunction, and Vit C transporter proteins. Dox (cumulative dose: 15 mg/kg) in rats reduced systolic and diastolic cardiac function and caused structural damage. These changes were associated with a myocardial increase in reactive oxygen species, reduction in antioxidant enzyme activities, increased expression of apoptotic proteins, and inflammation. Dox also caused an increase in the expression of proapoptotic proteins Bax, Bnip-3, Bak, and caspase-3. An increase in oxidative/nitrosative stress attributable to Dox was indicated by an increase in superoxide, protein carbonyl formation, lipid peroxidation, nitric oxide (NO), NO synthase (NOS) activity, protein nitrosylation, and inducible NOS protein expression. Dox increased the levels of cardiac proinflammatory cytokines TNF-α, IL-1β, and IL-6, whereas the expression of Vit C transporter proteins (sodium-ascorbate cotransporter 2 and glucose transporter 4) was reduced. Prophylactic and concurrent treatment with Vit C prevented all these changes and improved survival in the Vit C + Dox group. Vit C also improved Dox-mediated systolic and diastolic dysfunctions and structural damage. These results suggest a cardioprotective role of Vit C in Dox-induced cardiomyopathy by reducing oxidative/nitrosative stress, inflammation, and apoptosis, as well as improving Vit C transporter proteins. NEW & NOTEWORTHY This in vivo study provides novel data that vitamin C improves cardiac structure and function in doxorubicin-induced cardiomyopathy by reducing oxidative/nitrosative stress, apoptosis, and inflammation along with upregulation of cardiac vitamin C transporter proteins. The latter may have a crucial role in improving antioxidant status in this cardiomyopathy., (Copyright © 2017 the American Physiological Society.)

Aims: Autonomic dysfunction determines the advance of dilated cardiomyopathy (DCM) and is related to poor outcomes. However, this autonomic imbalance is unknown in patients with restrictive cardiomyopathy (RCM) even though they have similar symptoms and poor quality of life as DCM patients have. The aim of this study was to evaluate if autonomic and neurovascular controls were altered in RCM patients., Methods and Results: Fifteen RCM patients, 10 DCM patients, and 10 healthy subjects were evaluated. Heart rate and blood pressure (BP) were recorded. Peripheral sympathetic activity [muscle sympathetic nerve activity (MSNA)] by microneurography and cardiac sympathetic activity by power spectrum analysis of heart rate variability. Spontaneous baroreflex sensitivity (BRS) was evaluated by the sequence method and forearm blood flow by venous occlusion plethysmography. Both cardiomyopathy groups had higher MSNA frequency (P < 0.001) and MSNA incidence (P < 0.001), higher cardiac sympathovagal balance (P < 0.02), reduced BRS for increase (P = 0.002) and for decrease in BP (P = 0.002), and lower forearm blood flow (P < 0.001) compared with healthy subjects. We found an inverse correlation between BRS for increase and decrease in BP and peripheral sympathetic activity (r = -0.609, P = 0.001 and r = -0.648, P < 0.001, respectively) and between BRS for increase and decrease in BP and cardiac sympathetic activity (r = -0.503, P = 0.03 and r = -0.487, P = 0.04, respectively)., Conclusions: The RCM patients had cardiac and peripheral autonomic dysfunctions associated with peripheral vasoconstriction. Nonetheless, the presence of normal ejection fraction underestimates the evolution of the disease and makes clinical treatment difficult. These alterations could lead to a similar cardiovascular risk as that observed in DCM patients., (© 2017 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)